• Males or females age ≥ 18 years
• Patient has non-metastatic, histologically confirmed primary or locoregionally recurrent estrogen receptor (ER) ≤ 10%, progesterone receptor (PR) ≤ 10%, and HER2-negative breast cancer (triple negative breast cancer [TNBC]) either using the baseline biopsy specimen or the post-neoadjuvant chemotherapy (NAC) residual surgical specimen and residual cancer burden (RCB)2 or RCB3, as defined by Symmans et al., 2007, and received neoadjuvant anthracycline and/or taxane-based chemotherapy OR patient has non-metastatic, histologically confirmed primary ER > 10% and/or PR > 10%, HER2-negative breast cancer with RCB3 and received neoadjuvant anthracycline and/or taxane-based chemotherapy OR patient has locoregionally recurrent TNBC or ER > 10% and/or PR > 10%, HER2-negative breast cancer.
  • Note: The RCB can be calculated at http://www3.mdanderson.org/ap/medcalc/index.cfm?pagename=jsconvert2
  • Note: Results from any CLIA-certified lab are acceptable for the purpose of determining study eligibility.
  • Note: For patients with primary breast cancer, there is no minimum number of neoadjuvant cycles required provided the patient received an anthracycline or taxane preoperatively. Patients with locoregionally recurrent breast cancer are not required to have received preoperative chemotherapy.
• Patient has undergone total mastectomy or wide local excision with axillary staging, and the margins of the resected wide local excision or mastectomy specimens are free of invasive tumor and ductal carcinoma in situ (DCIS) or patient has undergone axillary surgery for regionally recurrent breast cancer. Unresected axillary level III, internal mammary, and supraclavicular nodal disease is permitted.
  • Note: For patients who have undergone mastectomy, immediate reconstruction is allowed.
• Patients must have completed their final breast surgery including re-excision of margins for invasive cancer and DCIS, or received their last adjuvant chemotherapy infusion,  within 90 but not fewer than 21 days prior to registration unless patient received postoperative chemotherapy in which case patients must have completed their adjuvant chemotherapy within 90 days but not fewer than 28 days prior to registration. but no sooner than 21 days prior to the initiation of RT for surgery or 28 days for chemotherapy. Post-radiotherapy adjuvant systemic therapy (e.g. adjuvant capecitabine) may not be completed less than 21 days prior to the first fraction of RT or begin less than 28 days from the last fraction of RT.
• Patient must have recovered from surgery with the incision completely healed and no signs of infection prior to registration.
• Patients must be proceeding with breast/chest wall and regional nodal irradiation including internal mammary node treatment. BFor patients with bilateral breast cancer is permitted provided that , RT ismust be indicated and administered only to one side.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
• Willing to provide tissue and blood samples for correlative research:
  • Leukocytes ≥ 3,000/mcL;
  • Absolute neutrophil count ≥ 1,500/mcL;
  • Platelets ≥ 100,000/mcL;
  • Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN);
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 3 x institutional ULN;
  • Creatinine ≤ institutional ULN; OR
  • Glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m^2 for patients with creatinine levels above ULN.
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
• Negative urine or serum pregnancy test for individuals of childbearing potential.
  • Note: The effects of berzosertib on the developing human fetus are unknown. For this reason and because DNA-damage repair inhibitors as well as radiation used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation, and for 6 months after completion of M6620 administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.  Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 6 months after completion of berzosertib administration.
• Ability to understand and the willingness to sign a written informed consent document.

• Patients who have had chemotherapy within 4 weeks prior to entering the study.
• Prior RT to the ipsilateral chest wall or ipsilateral breast or thorax. Individuals with prior RT to the contralateral breast or chest wall are eligible.
• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia and grade 1-2 taxane-induced neuropathy which will be permitted.
• Patients who are receiving any other investigational agents or concomitant anti-neoplastic treatment, except endocrine therapies and bisphosphonates which are permitted without restriction even during protocol treatment. Postoperative chemotherapy is allowed but must be discontinued >28 days prior to registration.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to berzosertib.
• Berzosertib is primarily metabolized by CYP3A4; therefore, concomitant administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir, indinavir, nelfinavir, and saquinavir) or inducers of CYP3A4 (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St. John's wort) should be avoided. Patients requiring any medications or substances that are strong inhibitors or inducers of CYP3A during the course of the study and for 14 days prior to enrollment are ineligible. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.
• Patients with uncontrolled intercurrent illness. This includes but is not limited to, ongoing uncontrolled serious infection requiring IV antibiotics at the time of registration, symptomatic congestive heart failure, unstable angina pectoris, symptomatic/uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Active systemic lupus, scleroderma, or dermatomyositis with a CPK level above normal.
• Pregnant women are excluded from this study because berzosertib as a DNA damage repair inhibitor may have the potential for teratogenic or abortifacient. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with berzosertib, breastfeeding should be discontinued if the mother is treated with berzosertib.
• Patients with known hereditary syndromes predisposing to radiosensitivity such as Li Fraumeni syndrome and ataxia telangiectasia are excluded from the study. Patients with mutations in breast cancer predisposition genes such as BRCA1, BRCA2, PALB2, CHEK2, and ATM are eligible.
• Patients with a prior or concurrent malignancy, excluding non-melanoma skin cancers and non-invasive cancers whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen.

• Age ≥ 18 years at the time of consent.
• Signed written informed consent.
• JCAR017 monotherapy and ibrutinib + JCAR017 combination cohorts must have diagnosis of:
  • CLL with an indication for treatment based on the Investigator’s opinion and measurable disease (any of the following: bone marrow involvement by ≥ 30% lymphocytes, peripheral blood lymphocytosis > 5 × 10^9 /L, and/or measurable lymph nodes ≥ 1.5 cm in the greatest transverse diameter and/or hepatomegaly or splenomegaly); or
  • SLL (lymphadenopathy and/or splenomegaly and < 5 × 10^9 CD19+ CD5+ clonal B lymphocytes/L [< 5000/µL] in the peripheral blood at diagnosis with measurable disease defined as at least one lesion ≥ 1.5 cm in the greatest transverse diameter) that is biopsy-proven SLL Venetoclax + JCAR017 combination cohorts must have diagnosis of:
  • CLL or SLL with an indication for treatment based on the Investigator’s opinion and measurable disease (any of the following: measurable lymph nodes ≥ 1.5 cm in the greatest transverse diameter and/or hepatomegaly or splenomegaly), and demonstration of CLL cells in the peripheral blood by flow cytometry.
• Subjects (other than those in the ibrutinib + JCAR017 combination therapy cohort) must have received and failed BTKi treatment or have been deemed ineligible for BTKi therapy due to requirement for full dose anticoagulation or history of arrhythmia. Failure to BTKi is defined as having stable disease or progressive disease (PD) as best response, or progression after previous response, or discontinuation due to intolerance. Intolerance is defined as failure to tolerate treatment due to unmanageable toxicity.
• Subjects in the JCAR017 monotherapy cohorts must have received previous treatment as follows:
  • Subjects with CLL or SLL and high-risk features, defined as having complex cytogenetic abnormalities (3 or more chromosomal abnormalities), 17p deletion, TP53 mutation, or unmutated immunoglobulin heavy chain variable region (IGHV), must have failed at least 2 lines of prior therapy;
  • Subjects with CLL or SLL and standard-risk features must have failed at least 3 lines of prior therapy.
• Subjects in the ibrutinib + JCAR017 combination cohorts must either:
  • be receiving ibrutinib, or other BTKi, and progressing at the time of study enrollment; or
  • be receiving ibrutinib, or other BTKi, for at least 6 months with a response less than CR and have high-risk features, as defined in inclusion criterion 5a; or
  • have BTK or phospholipase C gamma 2 (PLCγ2) mutations per local laboratory assessment, with or without progression on ibrutinib; or
  • have previously received ibrutinib, or other BTKi, and have no contraindications to initiate or reinitiate ibrutinib (i.e., ibrutinib was not discontinued due to intolerability and subject has no medical contraindications such as arrhythmia or need for anticoagulation) Subjects in the ibrutinib + JCAR017 combination therapy cohorts enrolled under at least amendment 5, must also meet the below criteria:
  • have progressed on a BTKi and f. have received prior therapy with venetoclax which is considered if they meet one of the following criteria:
    • the subject continued on venetoclax due to disease progression or intolerability and if the subject’s disease met indications for further therapy per iwCLL 2018 criteria; or
    • the subject failed to achieve an objective response within 3 months of initiating therapy. Subjects in the venetoclax + JCAR017 combination cohorts must:
  • Have failed at least 1 prior line of therapy, including having failed BTKi therapy or have been deemed ineligible to receive BTKi, as defined in Inclusion Criterion #4;
  • Be venetoclax naïve (required for dose expansion cohort); or
    • If prior venetoclax, (only for dose escalation cohort) (1) have no contraindications to reinitiation of venetoclax based on prior intolerance and (2) have had at least 6 months elapsed since the last dose of venetoclax, if either of the following criteria are met:
    • the best response was stable disease; or
    • the subject experienced disease progression on venetoclax within 6 months of venetoclax discontinuation.
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1.
• Assessed by the Investigator to have adequate bone marrow function to receive lymphodepleting chemotherapy.
• Adequate organ function, defined as:
  • Serum creatinine ≤ 1.5 × age-adjusted upper limit of normal (ULN) OR calculated creatinine clearance (Cockcroft and Gault) > 30 mL/min;
  • Alanine aminotransferase (ALT) ≤ 5 × ULN and total bilirubin < 2.0 mg/dL (or < 3.0 mg/dL for subjects with Gilbert’s syndrome or leukemic infiltration of the liver);
  • Adequate pulmonary function, defined as ≤ Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 dyspnea and saturated oxygen (SaO2) ≥ 92% on room air;
  • Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) ≥ 40% as assessed by echocardiogram (ECHO) or multiple uptake gated acquisition (MUGA) scan performed within 30 days prior to determination of eligibility Subjects in the venetoclax + JCAR017 combination dose escalation and expansion cohorts must have:
    • Hemoglobin ≥ 9 g/dL, absolute neutrophil count (ANC) ≥ 500/mm^3 , and platelets ≥ 75,000/mm^3 , unless cytopenias judged by the Investigator to be due to CLL infiltration of the bone marrow.
• Subject either currently has central vascular access or is a candidate to receive central vascular access or peripheral vascular access for leukapheresis procedure.
• If prior CD19-targeted therapy has been administered, subject must have CD19-positive disease confirmed by immunohistochemistry or flow cytometry since completing the prior CD19-targeted therapy.
• Females of childbearing potential must either commit to true abstinence from heterosexual contact or agree to use one highly effective method of contraception from screening until at least 1 year after receiving lymphodepleting chemotherapy.
• Females of childbearing potential must have a negative serum beta human chorionic gonadotropin (ß-hCG) pregnancy test result at screening and within 48 hours prior to the first dose of lymphodepleting therapy.
• Males who have partners of childbearing potential must practice true abstinence or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential for at least 1 year after receiving lymphodepleting chemotherapy even if he has undergone a successful vasectomy.

• Subjects with known active central nervous system (CNS) involvement by malignancy. Subjects with prior CNS disease that has been effectively treated will be eligible if treatment was completed at least 3 months prior to enrollment with no evidence of symptomatic disease and stable abnormalities on repeat imaging.
• History of another primary malignancy that has not been in remission for at least 2 years. (The following are exempt from the 2-year limit: nonmelanoma skin cancer, completely resected stage 1 solid tumor with low risk for recurrence, curatively treated localized prostate cancer, cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on Pap smear, and in situ breast cancer that has been completely resected.).
• Subjects with Richter’s transformation.
• Prior treatment with any gene therapy product.
• Active hepatitis B, or active hepatitis C (Subjects with a negative polymerase chain reaction (PCR) assay for viral load for hepatitis B or C are permitted; subjects positive for hepatitis B surface antigen and/or anti-hepatitis B core antibody with negative viral load are eligible and should be considered for prophylactic antiviral therapy), or history of or active human immunodeficiency virus (HIV) infection.
• Systemic fungal, bacterial, viral, or other infection that is not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment).
• Presence of acute or extensive chronic graft versus host disease (GVHD).
• History of any one of the following cardiovascular conditions within the past 6 months: Class III or IV heart failure as defined by the New York Heart Association (NYHA), cardiac angioplasty or stenting, myocardial infarction, unstable angina, or other clinically significant cardiac disease.
• History or presence of clinically relevant CNS pathology such as epilepsy, generalized seizure disorder, aphasia, stroke with current neurologic sequelae, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, cerebral edema, or psychosis.
• Pregnant or nursing (lactating) women.
• Use of any of the following medications or treatments within the noted time prior to leukapheresis:
  • Alemtuzumab within 6 months prior to leukapheresis;
  • Allogeneic hematopoietic stem cell transplant within 100 days prior to leukapheresis;
  • Cladribine within 3 months prior to leukapheresis;
  • Donor lymphocyte infusions (DLI) within 2 months prior to leukapheresis;
  • Radiation including large bone marrow fields such as sternum or pelvis within 6 weeks prior to leukapheresis;
  • Fludarabine within 4 weeks prior to leukapheresis;
  • GVHD therapies such as calcineurin inhibitors, methotrexate or other chemotherapeutics, mycophenolate mofetil, rapamycin, or immunosuppressive antibodies (such as anti-tumor necrosis factor-α [TNFα], anti-interleukin-6 [IL-6], or anti-interleukin-6 receptor [IL-6R]) within 4 weeks prior to leukapheresis;
  • Cyclophosphamide, ifosfamide, bendamustine, chlorambucil, or melphalan within 2 weeks prior to leukapheresis;
  • Therapeutic doses of corticosteroids (defined as > 20 mg/day prednisone or equivalent) within 7 days prior to leukapheresis;
  • Anti-CD20 monoclonal antibodies within 7 days prior to leukapheresis;
  • Venetoclax within 4 days prior to leukapheresis;
  • Idelalisib or duvelisib within 2 days prior to leukapheresis;
  • Lenalidomide or acalabrutinib within 1 day prior to leukapheresis;
  • Experimental agents, including off-label use of approved drugs, within 4 weeks prior to leukapheresis unless progression is documented on the experimental therapy and at least 3 halflives have elapsed prior to leukapheresis.
• Uncontrolled medical, psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol, as judged by the Investigator; or subject unwillingness or inability to follow the procedures required in the protocol.
• Progressive vascular tumor invasion, thrombosis, or embolism.
• Venous thrombosis or embolism requiring treatment but not managed on a stable regimen of anticoagulation.
• For subjects in the venetoclax + JCAR017 combination cohorts only, concomitant treatment with CYP3A moderate/strong inducers or moderate/strong inhibitors which cannot be discontinued.

Inclusion Criteria:

• Age ≥ 4 years to ≤ 18 years old.
• Receiving intracranial radiation for a primary CNS malignancy.
• Histological or radiologic confirmation of intracranial disease.
• Able to use the computer for CogState assessment battery.
• Serum creatinine and total bilirubin obtained ≤ 35 days prior to study entry, with adequate kidney and liver function defined as follows:
  • Normal serum creatinine per institutional normal limits;
  • Total bilirubin ≤ 1.5 x upper limit of normal (ULN) OR Direct bilirubin ≤ ULN for patients with total bilirubin levels > 1.5 x ULN, Aspartate transaminase (AST) AND alanine transaminase (ALT) ≤ 2.5 x ULN.
• Provide informed consent if over age 18, or provide assent with consent from parent or legal guardian if age 7-17.
• Negative pregnancy test done ≤ 7 days prior to registration, for women of childbearing potential only. Patients capable of childbearing must use adequate contraception.

• Patients with WHO Grade IV astrocytoma or glioblastoma tumors.
  • Note: A patient with Grade IV tumors of other histology can participate in the study if they meet all other criteria.
• Any prior intracranial radiation.
• Any contraindication or allergy to memantine.
• Use of short-acting benzodiazepines (may excite lethargy/dizziness with memantine).
  • Note: occasional use as a sleep aid or as needed  for anxiety or nausea is allowed.
• Intractable seizures while on adequate anticonvulsant therapy, defined as more than one seizure per month for the past 2 months.
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Eligibility last updated 3/28/23. Questions regarding updates should be directed to the study team contact.

Diagnosis of CLL according to the National Cancer Institute (NCI)/International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria or small lymphocytic lymphoma (SLL) according to the World Health Organization (WHO) criteria. This includes previous documentation of: 

• Biopsy-proven small lymphocytic lymphoma; OR 
• Diagnosis of CLL according to the NCI/IWCLL criteria as evidenced by all of the following: 
  • Peripheral blood lymphocyte count of greater than 5 x10^9/L;
  • Immunophenotype consistent with CLL defined as: 
    • The predominant population of lymphocytes share both B-cell antigens (CD19, CD20 [typically dim expression], or CD23) as well as CD5 in the absence of other pan-T-cell markers (CD3, CD2, etc.);
    • Clonality as evidenced by kappa or lambda light chain restriction (typically dim immunoglobulin expression).
  • Negative fluorescent in situ hybridization (FISH) analysis for t(11;14)(IgH/CCND1) on peripheral blood or tissue biopsy (e.g., marrow aspirate) or negative immunohistochemical stains for cyclin D1 staining on involved tissue biopsy (e.g., marrow aspirate or lymph node biopsy.
• No prior chemotherapy, BTK inhibitor therapy, venetoclax, small molecule signaling inhibitor, or monoclonal anti-body therapy for treatment of CLL or SLL. 
• Has met at least one of the following indications for treatment: 
  • Evidence of progressive marrow failure as manifested by the development of worsening anemia (hemoglobin [Hg] < 11 g/dl) and/or thrombocytopenia (platelets < 100 x 10^9/L);
  • Symptomatic or progressive lymphadenopathy, splenomegaly, or hepatomegaly; 
  • One or more of the following disease-related symptoms: 
    • Weight loss >= 10% within the previous 6 months;
    • Grade 2 or 3 fatigue attributed to CLL;
    • Fevers > 100.5 degree Fahrenheit (F) for 2 weeks without evidence of infection;
    • Clinically significant night sweats without evidence of infection.
  • Progressive lymphocytosis (not due to the effects of corticosteroids) with an increase of > 50% over a two-month period or an anticipated doubling time of less than six months.
• Eastern Cooperative Oncology Group (ECOG) performance status between 0-2
  •Life expectancy of >= 12 months. 
• No deletion of 17p13 on cytogenetic analysis by FISH. 
• Glomerular filtration rate (GFR) > 40 mL/minute as calculated by the Cockcroft-Gault Formula (obtained =< 14 days prior to registration).
• Total bilirubin =< 1.5 x upper limit of normal (ULN) unless due to Gilbert's disease. For those with a total bilirubin > 1.5 x ULN, a direct bilirubin should be performed and must be < 1.5 mg/dL for Gilbert's to be diagnosed (obtained =< 14 days prior to registration).
• Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST])/serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3.0 x the institutional ULN (obtained =< 14 days prior to registration).
• Prothrombin time (PT)/international normalized ratio (INR) < 1.5 ULN and partial thromboplastin time (PTT) (activated partial thromboplastin time [aPTT]) < 1.5 x ULN (obtained =< 14 days prior to registration). 
  • NOTE: If value is higher due to hepatic involvement by CLL, patient is eligible. 
• No active hemolytic anemia requiring immunosuppressive therapy or other pharmacologic treatment. Patients who have a positive Coombs test but no evidence of hemolysis are NOT excluded from participation.
• No current use of corticosteroids. EXCEPTION: Low doses of steroids (< 10 mg of prednisone or equivalent dose of other steroid) used for treatment of non-hematologic medical condition (e.g. chronic adrenal insufficiency) is permitted.
• No previous autoimmune complications (e.g. autoimmune hemolytic anemia or immune thrombocytopenia) that have developed since the initial diagnosis of CLL and have required treatment with high dose corticosteroids (e.g., equivalent of > 20 mg/day of prednisone), monoclonal antibody based therapy, or chemotherapy. Prior use of corticosteroids for reasons other than treatment of autoimmune complications is allowed.
• No other active primary malignancy (other than non-melanomatous skin cancer or carcinoma in situ of the cervix) requiring treatment or limiting expected survival to =< 2 years. 
  • NOTE: If there is a history of prior malignancy, the patient must not currently be receiving other specific treatment (other than hormonal therapy for their cancer). 
• Able to adhere to the study visit schedule and other protocol requirements.
• No major surgery within 4 weeks (28 days) of first dose of study drug or minor surgery within 3 days of first dose of study drug. 
• No radiation therapy =< 4 weeks prior to registration. 
• Patients who are human immunodeficiency virus positive (HIV+) with undetectable HIV viral load are eligible provided they meet all other protocol criteria for participation and are not being treated with protease inhibitors or any non-nucleoside reverse transcriptase inhibitors (NNRTI) that are CYP3A4 inducers; if being treated for HIV, patients should be receiving an alternative antiretroviral therapy (ART) that is not a CYP3A inhibitor. 
• Patients must not have any of the following conditions: 
  • Congestive heart failure or New York Heart Association Functional Classification III or IV congestive heart failure; 
  • History of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to registration;
  • Recent infections requiring systemic treatment; need to have completed anti-biotic therapy > 14 days before the first dose of study drug; 
  • Cerebral vascular accident or intracranial bleed within the last 6 months
    •Infection with known chronic, active hepatitis C; 
  • Serologic status reflecting active hepatitis B or C infection. Patients with hepatitis B or C infection may be eligible if viral loads are undetectable. Patients may be on suppressive therapy.
• Patients are not eligible if they require treatment with a strong cytochrome P450 (CYP) 3A inhibitor.
• Patients may not have received the following within 7 days prior to the first dose of study drug: 
  • Steroid therapy for anti-neoplastic intent;
  • Strong and Moderate CYP3A inhibitors; 
  • Strong and Moderate CYP3A inducers.
• Patients may not be on any other investigational agents.
• Patients may not have received warfarin or another vitamin K antagonist in the preceding 30 days. 
• Women must not be pregnant or breast-feeding since this study involves investigational agents whose genotoxic, mutagenic, and teratogenic effects on the developing fetus and newborn are unknown. All females of childbearing potential must have a blood test within 2 weeks prior to registration to rule out pregnancy. A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (e.g., has had menses at any time in the preceding 24 consecutive months. 
• Women of childbearing potential and sexually active males must be strongly advised to use accepted and highly effective method(s) of contraception or to abstain from sexual intercourse for the duration of their participation in the study and for: 
  • 18 months after the last dose of obinutuzumab; 
  • 90 days after the last dose of ibrutinib; and 
  • 30 days after the last dose of venetoclax Male subjects must also agree to refrain from sperm donation until 90 days after the last dose of protocol treatment.
• Patient must be able to swallow capsules and not have the following conditions: 
  • Disease significantly affecting gastrointestinal function;
  • Resection of the stomach or small bowel;
  • Symptomatic inflammatory bowel disease; 
  • Ulcerative colitis; 
  • Partial or complete bowel obstruction. 
• Patient must not be on any other systemic immunosuppressant therapy other than corticosteroids within 28 days of the first dose of study drug. 
• Patient must not be vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.
• Patient must not have any known bleeding disorders (e.g., von Willebrand's disease) or hemophilia. 
• Patient must not have currently active, clinically significant hepatic impairment (>= moderate hepatic impairment according to the NCI/Child Pugh classification. 
• Patient must undergo assessment with Timed Up and Go (TUG) test. 
• Patient must be able to receive xanthine oxidase inhibitor or rasburicase for tumor lysis syndrome (TLS) prophylaxis.

Diagnosis of CLL according to the National Cancer Institute (NCI)/International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria or small lymphocytic lymphoma (SLL) according to the World Health Organization (WHO) criteria. This includes previous documentation of: 

• Biopsy-proven small lymphocytic lymphoma; OR 
• Diagnosis of CLL according to the NCI/IWCLL criteria as evidenced by all of the following: 
  • Peripheral blood lymphocyte count of greater than 5 x10^9/L;
  • Immunophenotype consistent with CLL defined as: 
    • The predominant population of lymphocytes share both B-cell antigens (CD19, CD20 [typically dim expression], or CD23) as well as CD5 in the absence of other pan-T-cell markers (CD3, CD2, etc.);
    • Clonality as evidenced by kappa or lambda light chain restriction (typically dim immunoglobulin expression).
  • Negative fluorescent in situ hybridization (FISH) analysis for t(11;14)(IgH/CCND1) on peripheral blood or tissue biopsy (e.g., marrow aspirate) or negative immunohistochemical stains for cyclin D1 staining on involved tissue biopsy (e.g., marrow aspirate or lymph node biopsy.
• No prior chemotherapy, BTK inhibitor therapy, venetoclax, small molecule signaling inhibitor, or monoclonal anti-body therapy for treatment of CLL or SLL. 
• Has met at least one of the following indications for treatment: 
  • Evidence of progressive marrow failure as manifested by the development of worsening anemia (hemoglobin [Hg] < 11 g/dl) and/or thrombocytopenia (platelets < 100 x 10^9/L);
  • Symptomatic or progressive lymphadenopathy, splenomegaly, or hepatomegaly; 
  • One or more of the following disease-related symptoms: 
    • Weight loss >= 10% within the previous 6 months;
    • Grade 2 or 3 fatigue attributed to CLL;
    • Fevers > 100.5 degree Fahrenheit (F) for 2 weeks without evidence of infection;
    • Clinically significant night sweats without evidence of infection.
  • Progressive lymphocytosis (not due to the effects of corticosteroids) with an increase of > 50% over a two-month period or an anticipated doubling time of less than six months.
• Eastern Cooperative Oncology Group (ECOG) performance status between 0-2
  •Life expectancy of >= 12 months. 
• No deletion of 17p13 on cytogenetic analysis by FISH. 
• Glomerular filtration rate (GFR) > 40 mL/minute as calculated by the Cockcroft-Gault Formula (obtained =< 14 days prior to registration).
• Total bilirubin =< 1.5 x upper limit of normal (ULN) unless due to Gilbert's disease. For those with a total bilirubin > 1.5 x ULN, a direct bilirubin should be performed and must be < 1.5 mg/dL for Gilbert's to be diagnosed (obtained =< 14 days prior to registration).
• Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST])/serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3.0 x the institutional ULN (obtained =< 14 days prior to registration).
• Prothrombin time (PT)/international normalized ratio (INR) < 1.5 ULN and partial thromboplastin time (PTT) (activated partial thromboplastin time [aPTT]) < 1.5 x ULN (obtained =< 14 days prior to registration). 
  • NOTE: If value is higher due to hepatic involvement by CLL, patient is eligible. 
• No active hemolytic anemia requiring immunosuppressive therapy or other pharmacologic treatment. Patients who have a positive Coombs test but no evidence of hemolysis are NOT excluded from participation.
• No current use of corticosteroids. EXCEPTION: Low doses of steroids (< 10 mg of prednisone or equivalent dose of other steroid) used for treatment of non-hematologic medical condition (e.g. chronic adrenal insufficiency) is permitted.
• No previous autoimmune complications (e.g. autoimmune hemolytic anemia or immune thrombocytopenia) that have developed since the initial diagnosis of CLL and have required treatment with high dose corticosteroids (e.g., equivalent of > 20 mg/day of prednisone), monoclonal antibody based therapy, or chemotherapy. Prior use of corticosteroids for reasons other than treatment of autoimmune complications is allowed.
• No other active primary malignancy (other than non-melanomatous skin cancer or carcinoma in situ of the cervix) requiring treatment or limiting expected survival to =< 2 years. 
  • NOTE: If there is a history of prior malignancy, the patient must not currently be receiving other specific treatment (other than hormonal therapy for their cancer). 
• Able to adhere to the study visit schedule and other protocol requirements.
• No major surgery within 4 weeks (28 days) of first dose of study drug or minor surgery within 3 days of first dose of study drug. 
• No radiation therapy =< 4 weeks prior to registration. 
• Patients who are human immunodeficiency virus positive (HIV+) with undetectable HIV viral load are eligible provided they meet all other protocol criteria for participation and are not being treated with protease inhibitors or any non-nucleoside reverse transcriptase inhibitors (NNRTI) that are CYP3A4 inducers; if being treated for HIV, patients should be receiving an alternative antiretroviral therapy (ART) that is not a CYP3A inhibitor. 
• Patients must not have any of the following conditions: 
  • Congestive heart failure or New York Heart Association Functional Classification III or IV congestive heart failure; 
  • History of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to registration;
  • Recent infections requiring systemic treatment; need to have completed anti-biotic therapy > 14 days before the first dose of study drug; 
  • Cerebral vascular accident or intracranial bleed within the last 6 months
    •Infection with known chronic, active hepatitis C; 
  • Serologic status reflecting active hepatitis B or C infection. Patients with hepatitis B or C infection may be eligible if viral loads are undetectable. Patients may be on suppressive therapy.
• Patients are not eligible if they require treatment with a strong cytochrome P450 (CYP) 3A inhibitor.
• Patients may not have received the following within 7 days prior to the first dose of study drug: 
  • Steroid therapy for anti-neoplastic intent;
  • Strong and Moderate CYP3A inhibitors; 
  • Strong and Moderate CYP3A inducers.
• Patients may not be on any other investigational agents.
• Patients may not have received warfarin or another vitamin K antagonist in the preceding 30 days. 
• Women must not be pregnant or breast-feeding since this study involves investigational agents whose genotoxic, mutagenic, and teratogenic effects on the developing fetus and newborn are unknown. All females of childbearing potential must have a blood test within 2 weeks prior to registration to rule out pregnancy. A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (e.g., has had menses at any time in the preceding 24 consecutive months. 
• Women of childbearing potential and sexually active males must be strongly advised to use accepted and highly effective method(s) of contraception or to abstain from sexual intercourse for the duration of their participation in the study and for: 
  • 18 months after the last dose of obinutuzumab; 
  • 90 days after the last dose of ibrutinib; and 
  • 30 days after the last dose of venetoclax Male subjects must also agree to refrain from sperm donation until 90 days after the last dose of protocol treatment.
• Patient must be able to swallow capsules and not have the following conditions: 
  • Disease significantly affecting gastrointestinal function;
  • Resection of the stomach or small bowel;
  • Symptomatic inflammatory bowel disease; 
  • Ulcerative colitis; 
  • Partial or complete bowel obstruction. 
• Patient must not be on any other systemic immunosuppressant therapy other than corticosteroids within 28 days of the first dose of study drug. 
• Patient must not be vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.
• Patient must not have any known bleeding disorders (e.g., von Willebrand's disease) or hemophilia. 
• Patient must not have currently active, clinically significant hepatic impairment (>= moderate hepatic impairment according to the NCI/Child Pugh classification. 
• Patient must undergo assessment with Timed Up and Go (TUG) test. 
• Patient must be able to receive xanthine oxidase inhibitor or rasburicase for tumor lysis syndrome (TLS) prophylaxis.

Registration
•Inclusion Criteria

• Age ≥ 18 years.
• Diagnosed with cancer and receiving chemotherapy.
• Able to provide informed consent.
• Willingness to complete questionnaires.
• ECOG Performance Status (PS) 0, 1, 2.
• One or more of the following nasal symptoms for which the patient reports they would appreciate treatment. Symptoms must have started after the initiation of systemic, antineoplastic therapies, be attributed to the systemic, antineoplastic therapies, and symptoms must be reported  as being moderate (corresponding to a score of 2) or worse on a scale from mild (1) to very severe (4) on at least one of the items below.
• Dryness;
• Discomfort/Pain;
• Bleeding;
• Scabbing;
• Sores.

 Registration
•

• Predisposition to epistaxis prior to the initiation of cancer-directed therapy (more than once a month over the previous year).
• Planned initiation or continuation of any topical nasal treatment other than the studied nasal spray,( such as nasal steroids, Ayr nasal gel, Neosporin ointment or nasal administration of petroleum jelly).  Taking Imitrex for migraines is acceptable.
• Previous exposure to rose geranium in sesame oil nasal spray.
• Concurrent upper respiratory tract infection.
• History of allergic or other adverse reactions to sesame oil or essential rose geranium oil.
• Any other reason that the study clinician or investigator feels precludes safe or appropriate inclusion in this study.

Re-Registration:

• The patient will be un-blinded and determined to have been on the saline arm, when initially randomized.

PREREGISTRATION (STEP 0)

• Age ≥ 18 years.
• Patient has pathologically-confirmed chronic phase-CML one of the following the following criteria:
  • Patient has been in MMR (i.e. MR3) with detectable BCR/ABL transcript by a standard RQ-PCR assay for at least 12 months from the first documentation of the MMR;
  • Has been in MMR (i.e. MR3) but still has detectable BCR/ABL transcript by a standard RQ-PCR assay for at least 12 months from the first documentation of the MMR;
  • Up to two values above MMR (0.1%) are allowed in the last 12 months long as there was no change in the type or dose of TKI in last 6 months, none of the lab values were higher than CCR (1% or more) in the last 12 months, and all values in the last 6 months were at MMR or deeper;
  • Patient has not maintained MR4.5 (CMR) within the time of initiation of TKI therapy and pre-registration. Patient can have intermittent values of CMR (at or below MR4.5). However the patient has to have detectable disease (i.e. cannot be in CMR) in the last 2 assessments before pre-registration; AND 
  • Patient must have a diagnosis of chronic phase-CML has been confirmed by a bone marrow aspirate and/or biopsy with ≤ 10 % myeloid blasts (i.e., no accelerated or blast phase) within 21after consenting and pre -registration to step 0 and MMR status and BCR/ABL results meets the criteria outlined above.
    • NOTE: Please be aware of the required timeframe restrictions. Patients are required to enroll on Step 1 within 21 days from the date of consenting (step 0, pre-registration)
• Patients with diagnoses of accelerated or blast phase CML are not eligible.
• Patient has been on TKI therapy (first and/or second line) for at least 2 years (starting from when first TKI was initiated) prior to pre-registration:
  • Allowed TKIs include:
    • • Dasatinib: 50 – 180 mg per day;
    • • Imatinib: 200 – 800 mg per day;
    • • Nilotinib: 200 – 400 mg every 12-24 hours.
• Patients must have been on a stable dose of the current TKI for the last 3 months prior to pre-registration. For patients with two values of above MMR (0.1%) within the last 12 months, patient must have been on stable dose of the current TKI for the last 6 months prior to pre-registration.
• For patients who are on second line TKI, patient has been on second line TKI for at least a year from start date of second line TKI.
• Patient must not have received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
• Patients must not have received a prior allogeneic transplant.

REGISTRATION TO TREATMENT (STEP 1)

• Institution has received central BCR-ABL test results confirming MRD positive status and bone marrow aspirate and/or biopsy has confirmed chronic phase CML (i.e. no accelerated or blast phase CML) Bone marrow showing morphologic remission is acceptable.
• Patients have an ECOG Performance Status of 0-2.
• Diagnosis of chronic phase-CML must had been confirmed by a bone marrow aspirate and/or biopsy with ≤ 10 % myeloid blasts (i.e., no accelerated or blast phase) within 21 days prior to registration to step 1. Bone marrow aspirate and/or biopsy showing morphologic remission is acceptable. MMR and BCR/ABL status meets the criteria defined above.
• No active hemolytic anemia requiring immunosuppressive therapy or other pharmacologic treatment. Patients who have a positive Coombs test but no evidence of hemolysis are NOT excluded from participation
• No current use of corticosteroids from time of consent to registration.
  • EXCEPTION: Low doses of steroids (< 10 mg of prednisone or equivalent dose of other steroid) used for treatment of non-hematologic medical condition (e.g., chronic adrenal insufficiency) is permitted.
• No other active primary malignancy (other than non-melanomatous skin cancer or carcinoma in situ of the cervix) requiring treatment or limiting expected survival to ≤ 2 years.
  • NOTE: If there is a history of prior malignancy, they must not be receiving other specific treatment (other than hormonal therapy for their cancer).
• Women must not be pregnant or breastfeeding due to the potential for congenital abnormalities and of harm to nursing infants due to the treatment regimens used. Patients must also not expect to conceive or father children from the time of registration, while on study treatment, and continue for 120 days after the last dose of study treatment
  • All females of childbearing potential must have a negative urine or serum pregnancy test conducted within 14 days prior to registration to rule out pregnancy. A urine or serum pregnancy test must be repeated within 72 hours prior to receiving the first dose of pembrolizumab if the test done for eligibility/registration to step 1 is done outside of this 72 hour window. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required;
  • A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point; 2)has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential)for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
  • Female of child bearing potential? ______ (Yes or No)
    • Date of urine/serum study: ___________
• Women of childbearing potential and sexually active males must use accepted and effective method(s) of contraception or to abstain from sex from time of registration, while on study treatment, and continue for 120 days after the last dose of study treatment. 
• Patient may not be currently participating and receiving study therapy or have participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of registration.
• Patient must not have a diagnosis of immunodeficiency or be receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of treatment.
• Patient must not have a known history of active TB (Bacillus Tuberculosis).
• Patient must not have a history of hypersensitivity to pembrolizumab or any of its excipients.
• Patient must not have received a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to registration or have not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
• Patient must not have had prior chemotherapy, targeted small molecule therapy (aside from imatinib, dasatinib, or nilotinib), or radiation therapy within 2 weeks prior to registration to Step 1. Patients also must have recovered from all adverse events due to a previously administered agent.
  • NOTE: Patients with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
  • NOTE: Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤ 2 weeks of radiotherapy) to non-CNS disease).
• Patients who have received major surgery must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
• Patient must not have a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
• Patient must not have known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of protocol treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to protocol treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
• Patient must not have active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
• Patient must not have known history of, or any evidence of active, non-infectious pneumonitis.
• Patient must not have an active infection requiring systemic therapy.
• Patient must not have a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
• Patient must not have known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Patients who are Human Immunodeficiency Virus (HIV) positive are eligible if they have undetectable HIV viral load and CD4+ T-cell count ≥ 250/mm^3.
• Patients with a known positive test for Hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection may be be enrolled if the viral load by PCR is undetectable with/without active treatment.
• Patients must not have a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive).
• Patient must not have received a live vaccine within 30 days of registration.
  • NOTE: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
• Patients must meet the following criteria with all screening labs performed within 14 days prior to registration:
  • Absolute neutrophil count (ANC) ≥ 1,500 /mcL
    • ANC: _________ Date of Test: _________
  • Platelet count ≥ 100,000 /mcL
    • Platelet:_______ Date of Test: _________
  • Hgb ≥ 9.0 g/dL OR ≥ 5.6 mmol/L without transfusion of EPO dependency
    • Hgb:__________ Date of Test:__________
  • Serum creatinine ≤ 1.5 X upper limit of normal (ULN) OR Creatinine clearance (per institutional standards) ≥ 60 mL/min for patient with creatinine levels > 1.5 X ULN
    • Serum creatinine ______________Date of Test: ________
  • or
    • Creatinine clearance: __________ Date of Test: ________
  • Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 X ULN
    • Bilirubin: __________ Institutional ULN: _________ Date of Test: __________
  • AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases
    • ALT: _______ Institutional ULN: _________ Date of Test: _______
    • AST:_______  Institutional ULN:_________ Date of Test: _______
• Patients should not be receiving concomitant strong CYP3A4 inducers or inhibitors ≤ 7 days prior to registration due to their potential to effect the activity or pharmacokinetics of study agents and/or QT interval prolongation toxicity. Should treatment with any of these agents be required, consult with study chair and reference Section 5.5 for TKI dose modifications related to concomitant drugs.
• Patients who received prior allogeneic transplant are not eligible.

REGISTRATION TO TREATMENT (STEP 2)

• Institution has received central BCR-ABL test results confirming MRD positive status at Cycle 16 or 17 or 18 following Step 1 treatment (MMR or deeper but not in CMR in the last two central lab checks before Step 2).
• Patients have an ECOG Performance Status of 0-2.
• No active hemolytic anemia requiring immunosuppressive therapy or other pharmacologic treatment. Patients who have a positive Coombs test but no evidence of hemolysis are NOT excluded from participation.
• No current use of corticosteroids. EXCEPTION: Low doses of steroids (< 10 mg of prednisone or equivalent dose of other steroid) used for treatment of non-hematologic medical condition (e.g., chronic adrenal insufficiency) is permitted.
• No other active primary malignancy (other than non-melanomatous skin cancer or carcinoma in situ of the cervix) requiring treatment or limiting expected survival to ≤ 2 years.
  • NOTE: If there is a history of prior malignancy, they must not be receiving other specific treatment (other than hormonal therapy for their cancer).
• Patient must not have a diagnosis of immunodeficiency or be receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of treatment.
• Patient must not have a known history of active TB (Bacillus Tuberculosis).
• Patient must not have a history of hypersensitivity to pembrolizumab or any of its excipients.
• Women must not be pregnant or breastfeeding due to the potential for congenital abnormalities and of harm to nursing infants due to the treatment regimens used. Patients must also not expect to conceive or father children from the time of registration, while on study treatment, and continue for 120 days after the last dose of study treatment
• All females of childbearing potential must have a negative urine or serum pregnancy within 14 days prior to registration on step 2 to rule out a pregnancy. A urine or serum pregnancy test must be repeated within 72 hours prior to receiving the first dose of pembrolizumab on step 2 if the test done for eligibility/registration to step 2 is done outside of this 72 hour window. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2)has not undergone a hysterectomy or bilateral oophorectomy; or3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
• Female of child bearing potential? ______ (Yes or No)
  • Date of urine/serum study: ___________
• Women of childbearing potential and sexually active males must use accepted and effective method(s)of contraception or to abstain from sex from time of registration, while on study treatment, and continue for 120 days after the last dose of study treatment. (Refer to Section 5.6.2 for detailed information on contraception requirements while on this study).
• Patient must not have known history of, or any evidence of active, non-infectious pneumonitis.
• Patient must not have an active infection requiring systemic therapy.
• Patient must not have a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
• Patients who are Human Immunodeficiency Virus (HIV) positive are eligible if they have undetectable HIV viral load and CD4+ T-cell count ≥ 250/mm^3.
• Patient with a known positive test for Hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection might be enrolled if the viral load by PCR is undetectable with/without active treatment.
• Patients must not have a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive).
• Patient must not have received a live vaccine within 30 days of planned start of study therapy.
  • NOTE: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
• Patients must meet the following criteria with all screening labs performed within 14 days prior to registration:
• Absolute neutrophil count (ANC) ≥ 1,500 /mcL
  • ANC:__________ Date of Test:__________
• Platelet count ≥ 100,000 /mcL
  • Platelet:__________ Date of Test:__________
• Hgb ≥ 9.0 g/dL OR ≥ 5.6 mmol/L without transfusion of EPO dependency
  • Hgb:__________ Date of Test:__________
• Serum creatinine ≤ 1.5 X upper limit of normal (ULN) OR Creatinine clearance (per institutional standards) ≥ 60 mL/min for patient with creatinine levels > 1.5 X ULN
  • Serum creatinine ______________Date of Test:________
• or
  • Creatinine clearance:__________ Date of Test:_________
• Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 X ULN
  • Bilirubin:__________ Institutional ULN:_________ Date of Test:__________
• AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases
  • ALT: _______ Institutional ULN:_________ Date of Test: _______
  • AST: _______ Institutional ULN:_________ Date of Test: _______
• Patients should not be receiving concomitant strong CYP3A4 inducers or inhibitors ≤ 7 days prior to registration due to their potential to effect the activity or pharmacokinetics of study agents and/or QT interval prolongation toxicity. Should treatment with any of these agents be required, consult with study chair and reference Section 5.5 for TKI dose modifications related to concomitant drugs.

• Histologically confirmed metastatic and unresectable CRC.
• Documentation of a KRAS mutation in exon 2, 3, or 4 in primary tumor or metastasis, assessed by a CLIA-certified laboratory. Patients with concomitant KRAS and BRAF-V600 mutations are excluded from this study. Patients with Microsatellite Instability High/Deficient Mismatch Repair (MSI-H/dMMR) are also ineligible for enrollment in this study.
• FFPE tumor tissue must be available for submission to a central laboratory in order for a patient to be eligible. If no archival tissue biopsy is available the patient must have a biopsy obtained at screening. Refer to Section 6.2.4 for guidelines regarding provision of tumor tissue samples.
• Age ≥ 18 years.
• ECOG performance status of 0 or 1
• Signed informed consent for participation in the study.
• Subject is not receiving any other standard-of-care or experimental cancer therapy. Patients participating in non-interventional surveys or observational studies are allowed.
• Has failed treatment or is intolerant of fluoropyrimidine and oxaliplatin with or without bevacizumab.
  • Patients must have had systemic therapy within 180 days of the screening visit, but can have no anti-cancer therapy within 28 days of the planned first day of treatment on study;
  • Patients must have received oxaliplatin based chemotherapy with or without bevacizumab (≥ 6 weeks in duration). Patients who received maintenance therapy with fluoropyrimidines are eligible with or without rechallenge with oxaliplatin in combination with fluoropyrimidines;
  • Patients who received oxaliplatin/fluoropyrimidine-based neoadjuvant or adjuvant therapy and have disease recurrence or progression > 6 months from their last dose of neoadjuvant or adjuvant treatment (or > 6 months from surgery if no adjuvant therapy was administered) will be required to have received fluoropyrimidine/ oxaliplatin-based therapy with or without bevacizumab as first-line treatment for metastatic disease;
  • Patients must not have received prior irinotecan;
  • For patients with rectal cancer, sequential neoadjuvant and adjuvant therapy will count as a single systemic regimen for advanced disease;
  • Patients who discontinued first-line therapy because of toxicity are eligible as long as progression occurred < 6 months after the last dose of first-line therapy.
• FOLFIRI therapy is appropriate for the patient as determined by the Investigator.
• For a woman of child-bearing potential (WOCBP) or a male with a female partner who is a WOCBP: Must agree to use contraception or take measures to avoid pregnancy during the study and for 180 days of the final dose of any study drug.
  • Adequate contraception is defined as follows:
  • Complete true abstinence;
  • Consistent and correct use of 1 of the following methods of birth control:
  • Male partner who is sterile prior to the female patient’s entry into the study and is the sole sexual partner for that female patient;
  • Implants of levonorgesterol;
  • Injectable progestogen;
  • Intrauterine device (IUD) with a documented failure rate of less than 1% per year;
  • Oral contraceptive pill (either combined or progesterone only);
  • Barrier method, for example: diaphragm with spermicide or condom with spermicide in combination with either implants of levonorgesterol or injectable progestogen.
• WOCBP must have a negative serum or urine pregnancy test within 5 days prior to enrollment.
  • WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea > 12 consecutive months); or women on hormone replacement therapy (HRT) with documented serum follicle stimulating hormone (FSH) level > 35 mIU/mL. Even women who are using oral, implanted or injectable contraceptive hormones or mechanical products such as an IUD or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy or practicing abstinence or where partner is sterile (e.g., vasectomy), should be considered to be of child-bearing potential.
• Imaging computed tomography (CT)/magnetic resonance imaging (MRI) of chest/abdomen/pelvis or other scans as necessary to document all sites of disease performed within 28 days prior to the first dose of onvansertib. Only patients with measurable disease as defined per RECIST v1.1 are eligible for enrollment. CT is the preferred imaging modality, but MRI is also accepted.
• Signed informed consent to provide blood sample(s) for specific correlative assays.

• Concomitant KRAS and BRAF-V600 mutation or MSI-H/dMMR.
• Anti-cancer chemotherapy or biologic therapy administered within 28 days prior to the first dose of study drug. The exception is a single dose of radiation up to 8 Gray (equal to 800 RAD) with palliative intent for pain control up to 14 days before randomization.
• More than one prior chemotherapy regimen administered in the metastatic setting.
• Major surgery within 6 weeks prior to enrollment.
• Untreated or symptomatic brain metastasis.
• Women who are pregnant or breastfeeding.
• Gastrointestinal (GI) disorder(s) that, in the opinion of the Investigator, would significantly impede the absorption of an oral agent (e.g., intestinal occlusion, active Crohn’s disease, ulcerative colitis, extensive gastric and small intestine resection).
• Unable or unwilling to swallow study drug.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, clinically significant non-healing or healing wounds, symptomatic congestive heart failure (CHF) Class II or higher according to the New York Heart Association (NYHA) Functional Classification, unstable angina pectoris, clinically significant cardiac arrhythmia (see bevacizumab cardiac exclusions below), significant pulmonary disease (shortness of breath at rest or mild exertion), uncontrolled infection or psychiatric illness/social situations that would limit compliance with study requirements.
  • Known active infection with Human Immunodeficiency Virus (HIV), with measurable viral titer, and/or active infection with hepatitis B or C (patients who have had a hepatitis B virus (HBV) immunization are eligible);
  • Known active infection with SARS-CoV-2;
  • Clinically significant ascites or pleural effusions. 
• nown hypersensitivity to 5-FU/leucovorin.
• Known hypersensitivity to irinotecan.
• Abnormal glucuronidation of bilirubin; known Gilbert’s syndrome.
• Patients with a history of other malignancies except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix or prostate, or other solid tumors curatively treated with no evidence of disease for > 2 years.
• Any active disease condition that would render the protocol treatment dangerous or impair the ability of the patient to receive study drug.
• Any condition (e.g., psychological, geographical, etc.) that does not permit compliance with the protocol.
• Treatment with any of the drugs at the time of study treatment initiation.
• QT interval with Fridericia’s correction (QTcF) > 470 milliseconds (Vandenberk 2016). The QTcF should be calculated as the arithmetic mean of the QTcF on triplicate ECGs. In the case of potentially correctible causes of QT prolongation that are readily corrected (e.g., medications, hypokalemia), the triplicate ECG may be repeated once during Screening and that result may be used to determine eligibility.
• Planned concomitant use of medications known to prolong the QT/QTc interval according to institutional guidelines.
• Presence of risk factors for torsade de pointes, including family history of Long QT Syndrome or uncorrected hypokalemia.
• The following are exclusion criteria for bevacizumab:
  • History of cardiac disease: CHF Class II or higher according to the NYHA; active coronary artery disease, myocardial infarction within 6 months prior to study entry; unevaluated new onset angina within 3 months or unstable angina (angina symptoms at rest) or cardiac arrhythmias requiring anti-arrhythmic therapy, with the exception of patients who have been receiving therapy and are deemed by the Investigator to have stable/controlled disease;
  • Current uncontrolled hypertension (systolic blood pressure [BP] > 150 mmHg or diastolic pressure > 90 mmHg despite optimal medical management) and prior history of hypertensive crisis or hypertensive encephalopathy;
  • History of arterial thrombotic or embolic events (within 6 months prior to study entry);
  • Significant vascular disease (e.g., aortic aneurysm, aortic dissection, symptomatic peripheral vascular disease);
  • Evidence of bleeding diathesis or clinically significant coagulopathy;
  • Major surgical procedure (including open biopsy, significant traumatic injury, etc.) within 28 days, or anticipation of the need for major surgical procedure during the study, and minor surgical procedure (excluding placement of a vascular access device) within 7 days prior to study enrollment;
  • Proteinuria at Screening as demonstrated by urinalysis with proteinuria ≥ 2+ (patients discovered to have ≥ 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate ≤ 1g of protein in 24 hours to be eligible);
  • Abdominal fistula, GI perforation, peptic ulcer, or intra-abdominal abscess within the past 6 months;
  • Ongoing serious, non-healing wound, ulcer, or bone fracture;
  • Known hypersensitivity to any component of bevacizumab;
  • History of reversible posterior leukoencephalopathy syndrome (RPLS).
• Use of strong CYP3A4 or UGT1A1 inhibitors or strong CYP3A4 inducers. Patients currently receiving these agents who are able to switch to alternate therapy are not excluded. Inhibitors should be stopped at least 1 week prior to the first dose of protocol therapy and inducers should be stopped at least 2 weeks prior to initiation of protocol therapy.

Eligibility last updated 2/2/22. Questions regarding updates should be directed to the study team contact.

nclusion Criteria: 

• The subject has a histologic or cytologic diagnosis of a variant histology renal cell carcinoma including papillary, chromophobe, Xp.11 translocation, undifferentiated, or unclassified which is treatment naïve or has previously been treated with one systemic treatment line not containing any vascular endothelial growth factor antibody or vascular endothelial growth factor receptor tyrosine kinase inhibitors. The patient may have received treatment with immune checkpoint therapy including nivolumab as a single agent or nivolumab plus ipilimumab in combination. Previous treatment with mammalian target of rapamycin agents such as temsirolimus or everolimus is acceptable.
• Measurable disease per RECIST v1.1 as determined by the investigator. 
• The subject has had an assessment of all known disease sites; e.g., by computerized tomography (CT) scan, magnetic resonance imaging (MRI), bone scan as appropriate, within 28 days before the first dose of cabozantinib or sunitinib. 
• The subject is ≥ 18 years old on the day of consent.
• The subject has an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.
• Recovery to baseline or ≤ Grade 1 CTAE v.4.0 from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy;
• The subject has organ and marrow function and laboratory values as follows within 4 days before the first dose of cabozantinib or sunitinib:
  • The ANC ≥ 1500/mm^3 without colony stimulating factor support;
  • White blood cell count ≥ 2500/mm^3 (≥ 2.5 GI/L);
  • Platelets ≥ 100,000/mm^3;
  • Hemoglobin ≥ 9 g/dL; 
  • Bilirubin ≤ 1.5 x the ULN.  For subjects with known Gilbert's disease, bilirubin ≤ 3.0 x ULN;
  • Serum albumin ≥ 2.8 g/dl;
  • Serum creatinine ≤ 2.0 X ULN or calculated creatinine clearance ≥ 30 mL/min (≥ 0.5 mL/sec) using the Cockcroft-Gault equation:
  • Males: (140
    •age) x weight (kg)/(serum creatinine [mg/dL] × 72);
  • Females: [(140
    •age) x weight (kg)/(serum creatinine [mg/dL] × 72)] × 0.85;
  • Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) ≤ 3 X upper limit of normal (ULN). ALP ≤ 5 X ULN with documented bone metastases;
  • Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol).
• The subject is capable of understanding and complying with the protocol requirements and has signed the informed consent document.
• Sexually active subjects (men and women) must agree to use medically accepted barrier methods of contraception (e.g., male or female condom) during the course of the study and for 4 months after the last dose of study drug(s), even if oral contraceptives are also used. All subjects of reproductive potential must agree to use both a barrier method and a second method of birth control during the course of the study and for 4 months after the last dose of study drug(s).
• Female subjects of childbearing potential must not be pregnant at screening. Females of childbearing potential are defined as premenopausal females capable of becoming pregnant; i.e., females who have had any evidence of menses in the past 12 months, with the exception of those who had prior hysterectomy). However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, low body weight, ovarian suppression or other reasons.

• The subject has a variant histology that includes renal medullary carcinoma or collecting duct renal cell carcinoma. Any clear cell component in the tumor will lead to exclusion.
• Prior treatment with cabozantinib or sunitinib.
• Radiation therapy within 2 weeks. Systemic treatment with radionuclides within 6 weeks before the first dose of study treatment. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible.
• The subject has received any other type of investigational agent within 28 days before the first dose of study treatment.
• Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before the first dose of study treatment. Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of the start of study treatment.
• Concomitant anticoagulation with coumarin agents (e.g., warfarin).
• The subject has prothrombin time (PT)/INR or partial thromboplastin time (PTT) test ≥ 2.0 × the laboratory ULN within 7 days before the first dose of study treatment.
• The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:
• Cardiovascular disorders:
  • Congestive heart failure New York Heart Association Class 3 or 4, unstable angina pectoris, serious cardiac arrhythmias;
  • Uncontrolled hypertension defined as sustained blood pressure (BP) > 150 mm Hg systolic or > 100 mm Hg diastolic despite optimal antihypertensive treatment;
  • Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or other ischemic event, or thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 6 months before first dose;
• Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation:
  • The subject has evidence of tumor invading the GI tract, active peptic ulcer disease, inflammatory bowel disease (e.g., Crohn’s disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis, acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction;
  • Abdominal fistula, GI perforation, bowel obstruction, or intraabdominal abscess within 6 months before first dose.
    • Note: Complete healing of an intra-abdominal abscess must be confirmed before first dose
• Clinically significant hematemesis, or hemoptysis of > 0.5 teaspoon (2.5 ml) of red blood, or other history of significant bleeding (e.g., pulmonary hemorrhage) within 12 weeks before first dose.
• Other clinically significant disorders that would preclude safe study participation.
  • Serious non-healing wound/ulcer/bone fracture.
  • Uncompensated/symptomatic hypothyroidism.
  • Moderate- to- severe hepatic impairment (Child-Pugh B or C).
• Major surgery (e.g., GI surgery, removal or biopsy of brain metastasis) within 4 weeks before first dose of study treatment. Complete wound healing from major surgery must have occurred 2 month before first dose and from minor surgery (e.g., simple excision, tooth extraction) at least 10 days before first dose. Subjects with clinically relevant ongoing complications from prior surgery are not eligible.
• Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms per electrocardiogram (ECG) within 28 days before first dose of study treatment [add reference for Fridericia formula]. For patients with a bundle branch block the QTcR will be calculated as based on study by Rataharju PM et al. Am J Cardiol 2004;93:1017-1021(see local site documents in ePRTCL). If QTcR is > 500 ms the patient will be eligible for the study.
  • Note: If a single ECG shows a QTcF with an absolute value > 500 ms, two additional ECGs at intervals of approximately 3 min must be performed within 30 min after the initial ECG, and the average of these three consecutive results for QTcF will be used to determine eligibility.
• Pregnant or lactating females.
• Inability to swallow tablets.
• Previously identified allergy or hypersensitivity to components of the study treatment formulations.
• Diagnosis of another malignancy within 2 years before first dose of study treatment, except for superficial skin cancers, or localized, low grade tumors deemed cured and not treated with systemic therapy. Patients with Gleason 6 (3+3) prostate cancer with previous treatment or on active surveillance may also be allowed on protocol.
• The subject requires chronic concomitant treatment with strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John’s Wort).

• Patients must have histologically confirmed World Health Organization (WHO) grade II-III meningioma which has relapsed after prior radiation therapy with radiologically progressive or recurrent disease.
• Patients must have measurable disease, defined as at least 1 lesion that can be accurately measured in at least one dimension as >= 1 cm on brain MRI but with the maximum dimension =< 5 cm OR gross tumor volume < 20 cm^3. All relapsed disease would need to be eligible to be treated with reirradiation.
• Patients must have at least one prior surgery with available archival formalin-fixed paraffin-embedded (FFPE) tumor blocks of the initial or recurrent meningioma. If there are multiple tumor blocks from multiple surgeries, the most recent tumor block (and ideally of the relapsed tumor after initial radiation therapy) should be submitted. Annotation regarding whether the tumor block is before or after initial radiation therapy should be provided.
• Prior initial radiation therapy may include external beam radiation or radiosurgery, or combination of both. However, the total dose of prior radiation exposure to the site of recurrent tumor (for consideration of re-irradiation) cannot be more than 70 Gy. The duration since the previous radiation exposure to the site of reirradiation need to be at least 6 months.
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  •Leukocytes >= 3,000/mcL.
• Absolute neutrophil count >= 1,500/mcL.
• Platelets >= 100,000/mcL.
• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN).
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN.
• Creatinine =< 1.5 x institutional ULN OR glomerular filtration rate (GFR) >= 30 mL/min/1.73 m^2 for patients with creatinine levels above 1.5 x institutional normal.
• The effects of nivolumab and/or ipilimumab on the developing human fetus are unknown. For this reason and because radiation therapy is known to be teratogenic, women of childbearing potential (WOCBP) and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. WOCBP should use an adequate method to avoid pregnancy for 5 months after the last dose of investigational drug. Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 24 hours prior to the start of nivolumab. Women must not be breastfeeding. Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 7 months after the last dose of investigational product. Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile as well as azoospermic men) do not require contraception.
• Women of childbearing potential (WOCBP) is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes. In addition, women under the age of 55 must have a documented serum follicle stimulating hormone (FSH) level less than 40 mIU/mL.
• WOCBP receiving nivolumab will be instructed to adhere to contraception for a period of 5 months after the last dose of investigational product. Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 7 months after the last dose of investigational product. These durations have been calculated using the upper limit of the half-life for nivolumab (25 days) and are based on the protocol requirement that WOCBP use contraception for 5 half-lives plus 30 days and men who are sexually active with WOCBP use contraception for 5 half-lives plus 100 days
  •Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
• Ability to understand and the willingness to sign a written informed consent document.

• Patients who have had chemotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study.
• Patients who have had radiation therapy (to the site of reirradiation) within 6 months prior to entering the study.
• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1); however, alopecia, sensory neuropathy =< grade 2, or other =< grade 2 not constituting a safety risk based on the investigator's judgment are acceptable.
• Patients who are receiving any other investigational agents.
• Patients who have previous treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab and/or ipilimumab.
• History of severe hypersensitivity reaction to any monoclonal antibody.
• Current use of immunosuppressive medication (EXCEPT for the following: Intranasal, inhaled, topical steroids, or local steroid injection [e.g. intra-articular injection]; systemic corticosteroids at doses =< 4 mg/day of dexamethasone or equivalent; steroids as premedication for hypersensitivity reactions [e.g., computed tomography (CT) scan premedication]).
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. However, patients with human immunodeficiency virus (HIV) on stable therapy with minimal viral loads and patients with hepatitis B and hepatitis C who have received treatment with minimal viral loads will be eligible.
• Pregnant women are excluded from this study because radiation therapy is teratogenic and that the effects of nivolumab and/or ipilimumab on the developing human fetus are unknown. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with nivolumab and/or ipilimumab, breastfeeding should be discontinued if the mother is treated with nivolumab and/or ipilimumab.
• Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids, should be excluded. These include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded because of the risk of recurrence or exacerbation of disease. Patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible. Patients with rheumatoid arthritis and other arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible
  •Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger (precipitating event).
• Prior organ transplantation including allogeneic stem cell transplantation. 
• Other severe acute or chronic medical conditions including immune colitis, inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis, or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior, or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
• Live vaccination within 4 weeks of the first dose of nivolumab and while on trial is prohibited except for administration of inactivated vaccines.

• Stratum 1 (IDH wild-type): Patients must be ≥ 3 years of age and ≤ 21 years of age at the time of enrollment.  Stratum 1 closed.
• Stratum 2 (IDH mutant): Patients must be ≥ 3 years of age and ≤ 25 years of age at the time of enrollment.
• Patients must have eligibility confirmed by rapid central pathology and central molecular screening reviews performed on APEC14B1:
  • Newly-diagnosed high-grade glioma such as anaplastic astrocytoma or glioblastoma;
  • Negative results for H3 K27M by immunohistochemistry (IHC);
  • Negative results for BRAFV600E mutation by next-generation sequencing (NGS).
• Patients must have histological verification of diagnosis.
• Patients with M+ disease (defined as evidence of neuraxis dissemination) are not eligible. Cerebrospinal fluid (CSF) cytology is not required but may be obtained if clinically indicated prior to study enrollment. If cytology is positive, the patient would be considered to have metastatic disease and would, therefore, be ineligible.
• Pre-operative and post-operative brain magnetic resonance imaging (MRI) with and without contrast must be obtained. The requirement for a post-operative MRI is waived for patients who undergo biopsy only. A spine MRI is not required, but may be obtained if clinically indicated. If the spine MRI is positive, the patient would be considered to have M+ disease (defined as neuraxis dissemination) and would be ineligible.
• Patients must have a performance status of ≥ 50 by Lansky or Karnofsky, corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2. Use Karnofsky for patients > 16 years of age and Lansky for patients ≤ 16 years of age. Patients who are unable to walk because of paralysis, but are up in a wheelchair will be considered ambulatory for the purposes of assessing the performance score.
• Peripheral absolute neutrophil count (ANC) ≥ 1,000/uL.
• Platelet count ≥ 100,000/uL (transfusion independent). 
• Hemoglobin ≥ 8.0 gm/dL (can be transfused). 
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 70 mL/min/1.73 m^2 OR a serum creatinine based on age/gender as follows:
  • 3 to < 6 years: 0.8 (male and female) maximum serum creatinine (mg/dL);
  • 6 to < 10 years: 1 (male and female) maximum serum creatinine (mg/dL); 
  • 10 to < 13 years: 1.2 (male and female) maximum serum creatinine (mg/dL);
  • 13 to < 16 years: 1.5 (male), 1.4 (female) maximum serum creatinine (mg/dL);
  • ≥ 16 years: 1.7 (male), 1.4 (female) maximum serum creatinine (mg/dL).
• Adequate Liver Function defined as:
  • Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age; and
  • SGPT (ALT) ≤ 135 U/L. For the purpose of this study, the ULN for SGPT is 45 U/L.
• Central Nervous System Function defined as:
  • Patients with seizure disorder may be enrolled if seizures are wellcontrolled (i.e., patients must not have required rescue medications for uncontrolled seizures within 14 days prior to enrollment).
• Patients with seizure disorder may be enrolled if seizures are well-controlled (i.e., patients must not have required rescue medications for uncontrolled seizures within 14 days prior to enrollment).
• Patients must be enrolled and protocol therapy must be projected to begin no later than 31 days after definitive diagnostic surgery (Day 0). 
• All patients and/or their parents or legal guardians must sign a written informed consent .
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met.

• Patients with the following histologies: 
  • Diffuse astrocytoma (grade 2);
  • Oligodendrogliomas (any grade);
  • Pleomorphic xanthoastrocytoma (PXA, any grade). 
• Patients with primary tumor location of brainstem or spinal cord.
• Patients with M+ disease (defined as neuraxis dissemination either by imaging or by cytology).
• Patients must not have received any prior tumor-directed therapy including radiation therapy, chemotherapy (tumor-directed therapy), molecularly targeted agents, or immunotherapy for the treatment of HGG other than surgical intervention.
• Lumbar CSF cytology is not required, but may be performed if clinically indicated prior to study enrollment. If lumbar CSF cytology is positive, the patient is considered to have M+ disease and is ineligible.
  • Note: False positive cytology can occur within 10 days of surgery.
• Patients with gliomatosis cerebri type 1 or 2. 
• Patients who are not able to receive protocol specified radiation therapy. 
• Patients must not be currently receiving other anti-cancer agents.
• Patients with known constitutional mismatch repair deficiency syndrome (CMMR-D)/biallelic mismatch repair deficiency (bMMRD). 
• Female patients who are pregnant are ineligible due to risks of fetal and teratogenic adverse events as seen in animal/human studies.
• Lactating females are not eligible unless they have agreed not to breastfeed their infants. 
• Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained.
• Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation and for 4 months after the last dose of veliparib.

Eligibility last updated 9/28/21. Questions regarding updates should be directed to the study team contact.

• Histologically confirmed CD30-positive PTCL (most subtypes allowed) or TMF per the revised World Health Organization 2016 classification (Swerdlow, 2016).
  Note: Patients must wait for central results before first dose of study drug.
• Cohorts A and B (PTCL cohorts):
  • measurable by the modified Lugano Classification (Cheson, 2014);
  • measurable disease of ≥1.5 cm diameter by computed tomography (CT), assessed locally for eligibility.
    • Note: Confirmation by fluorodeoxyglucose (FDG) avid disease by positron emission tomography (PET) recommended, if possible.
• Cohort C (TMF cohort):
  • measurable by the Olsen Criteria (Olsen, 2011) including at least 1 cutaneous lymphoma lesion ≥2 cm in diameter, assessed locally for eligibility.

Patients must have relapsed or refractory disease AND the following: 

• Cohorts A and B (PTCL cohorts):
  • patients must have received at least 1 prior line of systemic therapy. For patients with systemic ALCL, patients must have failed or be intolerant to brentuximab vedotin [BV]; Adcetris®.
• Cohort C (TMF cohort):
  • patients must have received at least 1 prior line of systemic therapy; and have exhausted systemic therapies with full approval for their treatment of transformed mycosis fungoides 
• Completion of treatment with any radiotherapy, chemotherapy, antibody, immunoconjugates and/or another investigational drug ≥4 weeks (or 5 half-lives of the drug, whichever is shorter) prior to first dose of study drug.
  Note: patients may be enrolled after a minimum of 2 weeks of radiation if radiation was for palliative intent to a single cutaneous lesion or single nodal region after discussion with the sponsor.
• Completion of an autologous hematopoietic stem cell transplantation at least 3 months prior to first dose of study drug (if applicable). 
• Resolution of any clinically significant previous therapy-related toxicity to ≤Grade 1 or to baseline if pre-existing condition (exception: patients with all grade alopecia and ≤Grade 2 peripheral neuropathy.
• Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1 (Appendix B).
• Life expectancy ≥12 weeks.
• Adequate laboratory functional values. Note: transfusions and growth factors allowed during screening; however, transfusion-dependency defined as requiring blood products ≥once per week is not allowed.

• Patients with the following subtypes of lymphoma:
  • T-cell prolymphocytic leukemia;
  • T-cell large granular lymphocytic leukemia;
  • Chronic lymphoproliferative disorder of NK cells;
  • Aggressive NK-cell leukemia;
  • Extranodal NK-/T-cell lymphoma;
  • Indolent T-cell lymphoproliferative disorder of the GI tract.
  • Adult T-cell leukemia/lymphoma (ATLL)
• Current evidence of central nervous system involvement.
• Has had an allogenic tissue hematopoietic cell/solid organ transplant within the last 3 years. Note: Patients who have had a transplant >3 years ago are eligible as long as there are no signs/symptoms of graft versus host disease (GvHD).
• Requirement for chronic systemic immunosuppressive therapy <12 weeks prior to the first dose of study drug for prophylaxis or management of conditions such as GvHD (e.g. mycophenolate, methotrexate, calcineurin inhibitor-based therapy, steroid doses that would require prolonged tapering for discontinuation).
• Major surgery ≤4 weeks prior to first dose of study drug.
• Any active, concurrent, significant illness or disease (other than T-cell lymphoma) or clinically significant findings including psychiatric and behavioral problems, medical history, and/or physical examination findings that would preclude the patient from participation in the study such as:
  • active infection requiring systemic therapy ≤10 days before the first dose of study drug
  • unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤6 months prior to first study drug, uncontrolled cardiac arrhythmia e.g. atrial fibrillation/flutter, cerebrovascular accidents ≤6 months before first dose of study drug
  • any severe or uncontrolled other disease or condition which might increase the risk associated with study participation
  • active Hepatitis B or Hepatitis C. Antiviral prophylaxis for chronic Hepatitis B virus infection may be used at the discretion of the investigator.
• Diagnosis of Human Immunodeficiency Virus (HIV) i.e. presence of HIV 1/2 antibodies
• Diagnosis of immunodeficiency or requirement for systemic steroid therapy or any other form of immunosuppressive therapy (outside of samples already mentioned in Exclusion Criterion number 4) <7 days prior to the first dose study drug. Topical steroid creams for symptomatic relief for patients in Cohort C (TMF) are exceptions to this rule. Also, the use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor/Medical Monitor.
• Any other malignancy known to be active, with the exception of treated cervical intraepithelial neoplasia and non-melanoma skin cancer.
• General intolerance of any protocol medication or its excipients
• Patient´s inability to appreciate the nature, meaning and consequences of the trial and to formulate his/her own wishes correspondingly.
• Patient is unwilling to comply with the protocol; including the required biopsies and PK sampling.
• Prior treatment with AFM13.

• Able to understand and comply with the study procedures, understand the risks involved in the study, and provide legally effective informed consent before the first study-specific procedure.
• Men or women ≥ 18 years with IPSS low risk or Int-1 MDS (all subjects). Subjects must have had at least 1 of the following disease-related criteria during the 8 weeks before randomization:
  • Red blood cell (RBC) transfusion dependence, defined as 2 or more units of RBC transfusions*;
  • Hb of ≤ 9.0 g/dL in at least 2 blood counts prior to randomization or in 1 blood count if RBC transfusion was received;
  • ANC of < 0.5×10^9 /L in at least 2 blood counts prior to randomization;
  • Platelet counts of < 50×10^9 /L in at least 2 blood counts prior to randomization.

*RBC transfusion administered for Hb levels ≤ 9.0 g/dL are counted.

• ECOG performance status of 0 to 2.
• Adequate organ function defined as follows:
  • Hepatic: Total or direct bilirubin ≤ 2 × upper limit of normal (ULN); aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT) ≤ 5 × ULN;
  • Renal: serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance or glomerular filtration rate ≥ 50 mL/min.
• Women of child-bearing potential (according to recommendations of the Clinical Trial Facilitation Group) must not be pregnant or breastfeeding and must have a negative pregnancy test at screening. Women of childbearing potential must agree to practice a highly effective contraceptive measure of birth control (as described in the protocol) and must agree not to become pregnant for 6 months after completing treatment; men with female partners of child-bearing potential must agree to practice a highly effective contraceptive measure of birth control (as described in the protocol) and must agree not to father a child while receiving treatment with ASTX727 and for at least 3 months after completing treatment.

• Treatment with any investigational drug or therapy within 2 weeks before study treatment, or 5 half-lives, whichever is longer, before the first dose of study treatment, or ongoing clinically significant AEs from previous treatment.
• Prior treatment with azacitidine, decitabine, or guadecitabine.
  Treatments for MDS, including erythropoietins, colony-stimulating factors (CSFs), thrombopoietins, chemotherapy, and immunosuppression including calcineurin inhibitors, glucocorticoids, etc., must be concluded 1 month prior to study treatment.
• Diagnosis of chronic myelomonocytic leukemia (CMML).
• Poor medical risk because of other conditions such as uncontrolled systemic diseases or active uncontrolled infections.
• Known significant mental illness or other condition, such as active alcohol or other substance abuse or addiction, that in the opinion of the investigator predisposes the subject to high risk of noncompliance with the protocol.
• Life-threatening illness, medical condition or organ system dysfunction, or other reasons including laboratory abnormalities, which, in the investigator’s opinion, could compromise the subject’s safety, interfere with the absorption or metabolism of ASTX727, or compromise the integrity of the study outcomes.
• Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, prostate cancer or breast cancer under control with hormone therapy, or other cancer from which the subject has been disease free for at least 1 year.
• Known active infection with human immunodeficiency virus or hepatitis viruses.

Eligibility last updated 3/18/22. Questions regarding updates should be directed to the study team contact.

Pre-registration – Inclusion Criteria Specific to Dose Escalation Cohort:

• Histological confirmation of either glioblastoma, IDH wildtype (GBM), anaplastic astrocytoma, IDH wildtype (AA) or non-small cell lung cancer (NSCLC).
• EGFR Status:
  • GBM/AA must have EGFR amplification and/or EGFRvIII mutation;
  • NSCLC must have confirmed activating EGFR mutation [including Del19, L858R, EGFRvIII, G719A, L861Q or trans triple mutations (Del19/T790M/C797S or L858R/T790M/C797S)].

Pre-registration – Inclusion Criteria Specific to Dose Expansion Cohorts:

• Glioblastoma, IDH wildtype/Anaplastic astrocytoma, IDH wildtype (GBM/AA) Cohort:
  • Diagnosis: Histological confirmation of either glioblastoma, IDH wildtype (GBM) or anaplastic astrocytoma, IDH wildtype (AA);
  • EGFR status: GBM/AA must have EGFR amplification and/or EGFRvIII mutation.
• Brain Tumor Penetration (BTP) Cohort:
  • Diagnosis: Histological confirmation of either glioblastoma, IDH wildtype (GBM) or anaplastic astrocytoma, IDH wildtype (AA);
  • EGFR status: GBM/AA must have been previously demonstrated to have EGFR amplification and/or EGFRvIII mutation based on any prior resection.
• Non-Small Cell Lung Cancer Leptomeningeal Metastases (NSCLC LM) cohort:
  • Diagnosis: Histological confirmation of non-small cell lung cancer (NSCLC);
  • EGFR status: NSCLC must have confirmed activating EGFR mutation (including Del19, L858R, EGFRvIII, G719A).

Registration
•Inclusion Criteria Specific to Dose Escalation Cohort:

• Previous treatments:
  • Patients with GBM/AA must have been previously treated with radiation and temozolomide;
  • Patients with NSCLC must have been previously treated with at least one line of single-agent therapy with an EGFR TKI (e.g., gefinib, erlotinib, afatinib, or osimertinib) and at least one line of chemotherapy (doublet chemotherapy such as carboplatin/paclitaxel, carboplatin/gemcitabine, cisplatin/paclitaxel, cisplatin/gemcitabine and other regimens listed in NCCN guideline or single agent such as pemetrexed, gemcitabine and taxanes).
• Radiographic progression:
  • Patients with GBM/AA must have radiographic progression based on RANO criteria;
  • Patients with NSCLC must have new or radiographic progression in the central nervous system (brain metastases and/or leptomeningeal metastases). Positive confirmation of CSF cytology is both necessary and sufficient to define the presence of leptomeningeal metastases for patients in this study. Patients with positive CSF cytology and brain metastases will be categorized as "leptomeningeal metastases."
• Measureable Disease.
• Performance Status:
  • ECOG 0 or 1. For patients with NSCLC with leptomeningeal metastases, ECOG 2 is also acceptable.

Registration
•Inclusion Criteria Specific to Dose Expansion Cohorts

• Glioblastoma, IDH wildtype/Anaplastic astrocytoma, IDH wildtype (GBM/AA) Cohort:
  • Previous treatments: Patients must have been previously treated with radiation and temozolomide;
  • Radiographic progression: Patients with GBM/AA must have radiographic progression based on RANO criteria;
  • Measurable disease; 
  • Performance status: ECOG 0 or 1 for patients with GBM/AA.
• Brain Tumor Penetration (BTP) Cohort:
  • Previous treatments: Patients must have been previously treated with radiation and temozolomide;
  • Radiographic progression: Patients with GBM/AA must have radiographic progression based on RANO criteria;
  • Therapeutic surgical resection of GBM/AA required as part of routine clinical care;
  • Performance status: ECOG 0 or 1.
• Non-Small Cell Lung Cancer Leptomeningeal Metastases (NSCLC LM) cohort:
  • Previous treatments: Patients must have had either: (a) no prior treatment with an EGFR TKI, or (b) previous EGFR TKI treatment (e.g. gefitinib, erlotinib, afatinib, or osimertinib) followed by central nervous system (CNS) disease progression without extra-CNS progression;
  • Radiographic progression: Patients must have new or radiographic progression of leptomeningeal metastases. Positive confirmation of CSF cytology is both necessary and sufficient to define the presence of leptomeningeal metastases for patients in this study;
  • For the NSCLC LM expansion cohort, patients must have both positive confirmation of CSF cytology and at least one site of leptomeningeal disease that can be assessed by magnetic resonance imaging (MRI) and which is suitable for repeat assessments as per the investigator’s discretion.
  • Performance Status: ECOG 0, 1, or 2.

Registration – Inclusion Criteria Common to Dose Escalation and Dose Expansion Cohorts:

• Age ≥18 years.
• Ability to understand and the willingness to sign a written informed consent document.
• Patients must have adequate organ and marrow function as defined by the following laboratory values obtained ≤ 14 days prior to registration:
  • Hemoglobin > 9.0 g/dL;
  • Leukocytes > 3.0 x 10^9/L;
  • Absolute neutrophil count > 1.5 x 10^9/L;
  • Platelets > 100 x 10^9/L;
  • INR < 1.5 x upper limit of normal (ULN)*;
  • aPTT < 1.5 x ULN*;
    • *Patients on a stable dose of anti-coagulation therapy will be allowed to participate if they have no signs of bleeding or clotting and the INR/PT and PTT/aPTT results are compatible with an acceptable risk-benefit ratio as per the investigator’s discretion.
  • Total bilirubin ≤1.5 x ULN and <3 mg/dL for patients with Gilbert's disease;
  • AST (SGOT) & ALT (SGPT) ≤3 x ULN or ≤ 5 x UNL if due to liver involvement by tumor;
  • Creatinine ≤ 1.5 x ULN or estimated glomerular filtration rate (eGFR) ≥ 60 mL/minute.
• Negative pregnancy test done ≤7 days prior to registration, for persons of childbearing potential only.
• Provision of signed and dated written informed consent prior to any study specific procedures, sampling, and analyses.
• Willingness to provide mandatory blood specimens and mandatory tissue specimens for correlative research.
• Willingness to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study; i.e., active treatment and clinical follow-up).
• Male and female patients of child bearing potential must be willing to use contraception (i.e., condoms, birth control) while on study and until 3 months after the last dose of study drug is taken.
• Must be willing to take light-protective measures during the study and for 2 weeks after their last dose of WSD0922-FU.
• Must have a minimum life expectancy of ≥ 3 months.
• Must be stable on no more than 2 mg of dexamethasone (or equivalent steroids) per day. Steroid dose should not be adjusted during cycle 1 of therapy.
• Must not take enzyme-inducing anticonvulsants treatment for at least 2 weeks prior to enrollment. Patients on enzyme-inducing anticonvulsants will be changed to non-enzyme inducing anticonvulsants. Drug-Drug Interactions (DDI) with proton pump inhibitor (PPI), H2 blockers or antacids have not been assessed; therefore it is suggested to avoid taking those drugs together with WSD0922-FU.
• Strong inducers and strong inhibitors of CYP3A should be discontinued at least 14 days prior to registration.

Registration – Exclusion Criteria for Dose Escalation and Dose Expansion

• Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:
  • Pregnant persons;
  • Nursing persons;
  • Persons of childbearing potential who are unwilling to employ adequate contraception.
• Any of the following prior therapies:
  • Any cytotoxic chemotherapy or other anticancer drugs for the treatment of advanced NSCLC from a previous treatment regimen ≤ 14 days prior to registration;
  • In patients with NSCLC, treatment with an EGFR TKI (e.g., erlotinib, gefitinib, afatinib or osimertinib) within 8 days or approximately 5 x half-life, whichever is the longer, prior to registration (if sufficient wash-out time has not occurred due to schedule or PK properties an alternative appropriate wash-out time based on known duration and time to reversibility of drug related adverse events could be agreed upon by the Investigator and Wayshine);
  • Radiation therapy to the brain ≤ 12 weeks prior to registration;
  • Patients with GBM/AA must not have received prior anti-EGFR or EGFRvIII therapies (erlotinib, gefitinib, afatinib, osimertinib, ABT-414, ABBV-221, AMG-595, AMG-596, etc.)
  •  
  • Patients with GBM/AA who have been treated with bevacizumab within the last four months are not eligible.
  • Received prior systemic biologic therapy (CAR-T, anti-PD-1 / anti-PD-L1, anti-CTLA-4, etc.) within 28 days prior to registration.
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens including uncontrolled hypertension and active bleeding diatheses, which in the investigator’s opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol. Screening for chronic conditions is not required.
• Subjects who are human immunodeficiency virus (HIV), hepatitis virus B (HBV), and/or hepatitis virus C (HCV) positive.
• Uncontrolled inter-current illness including, but not limited to:
  • Symptomatic CNS complications that require urgent neurosurgical or medical (e.g., mannitol) intervention;
  • Seizures requiring a change in anti-epileptic medications (addition of new anti-epileptic or increase in dose) ≤ 2 weeks of registration;
  • Known intracranial hemorrhage which is unrelated to tumor;
  • Significant medical or psychiatric illness that would interfere with compliance and ability to tolerate treatment as outlined in the protocol;
  • Illness/social situations that would limit compliance with study requirements.
• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm.
• Patients with a "currently active" second malignancy other than non-melanoma skin cancers and carcinoma-in-situ of the cervix. Patients are not considered to have a "currently active" malignancy if they have completed therapy and are free of disease for more than three years prior to registration.
• Any of the following cardiac criteria:
  • A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval > 480 milliseconds (ms) (CTCAE Grade 1) using Fredericia’s QT correction formula;
  • A history of additional risk factors for TdP (e.g., heart failure, hypokalemia, family history of Long QT Syndrome);
  • The use of concomitant medications that prolong the QT/QTc interval.
• Patients confirmed to have a cis double mutation (Del19/T790M or L858R/T790M) or cis triple mutation (Del19/T790m/C797S or L858R/T790M/C797S).
• Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease. History of hypersensitivity to active or inactive excipients of WSD0922-FU or drugs with a similar chemical structure or class to WSD0922-FU.
• Refractory nausea and vomiting if not controlled by supportive therapy, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of WSD0922-FU.
• Inadequate bone marrow reserve or organ function.
• Patients with NSCLC LM who are unable to undergo collection of CSF.

Eligibility last updated 6/8/22. Questions regarding updates should be directed to the study team contact.

• Age ≥ 18 years old.
• Histological confirmation of advanced biliary tract cancers including cancers originating in the gallbladder who have received at least one line of systemic anticancer therapy. Note: Patients who have either progressed on or are intolerant to the prior therapy can be included in this study.
• Measurable disease as defined by RECIST criteria.
  • NOTE: Tumor lesions in a previously irradiated area are not considered measurable disease. Disease that is measurable by physical examination only is not eligible.
• ECOG Performance Status (PS) of 0 or 1).
• The following laboratory values obtained ≤ 21 days prior to registration.
  • Absolute neutrophil count (ANC) ≥ 1500/mm3;
  • Platelet count ≥ 100,000/mm3;
  • Total bilirubin ≤ 1.5 × upper limit of normal (ULN);
  • spartate transaminase (AST) or alanine transaminase (ALT) ≤ × ULN;
  • Creatinine ≤ 1.5 × ULN.
• Negative pregnancy test done ≤ days prior to registration, for persons of childbearing potential only.
• Provide written informed consent.
• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).
• Willingness to provide mandatory blood and tissue specimens for correlative research.

• Any of the following because this study involves an agent that has potential genotoxic, mutagenic and teratogenic effects:
  • Pregnant persons;
  • Nursing persons;
  • Persons of childbearing potential who are unwilling to employ adequate contraception for at least 3 months after the last dose of the study drug.
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
• Immunocompromised patients and patients known to be HIV positive and currently receiving antiretroviral therapy.
  • NOTE: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm ≤ 21 days prior to registration.
• Receiving any anticancer therapy for biliary tract cancer ≤ 21 days prior to registration.
• Other active malignancy requiring treatment in ≤ 6 months prior to registration.
  • EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix.
    • NOTE: If there is a history of prior malignancy, they must not be receiving other specific treatment for their cancer.
• History of myocardial infarction ≤6 months prior to registration, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias.
• Previous treatment with irinotecan or irinotecan-based chemotherapy for biliary tract cancers.

• Capable of giving signed informed consent including compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol. For participants <18 years of age (or the legal minimum age in the relevant country) their legal guardian must give informed consent. Pediatric participants will be included in age-appropriate discussion in order to obtain assent.
• Participant must be ≥ 10 years of age at the time of signing the informed consent. Participant scheduled to receive clinical drug product supply must also weigh ≥ 40 kg. For participant scheduled to receive commercial drug product supply and weighing < 40kg, the Investigator must also consult with the Medical Monitor prior to inclusion.
• Participant has a diagnosis of synovial sarcoma or myxoid/round cell liposarcoma, confirmed by local histopathology and with evidence of translocation per below: – for synovial sarcoma, the presence of a translocation between SYT on the X chromosome and SSX1, SSX2 or, SSX4 on chromosome 18 (may be presented in the pathology report as t (X;18)) is required; – for myxoid/round cell liposarcoma, the presence of a translocation t (12;16)(q13;p11) or the variant translocation t (12;22)(q13;q12) is required.
• Participant has high-risk locally advanced (i.e. deeply seated, high grade, positive margins, large [≥5 cm], or locally recurrent) synovial sarcoma or myxoid/round cell liposarcoma.
• Participant with synovial sarcoma or myxoid/round cell liposarcoma who is:
  • Newly diagnosed, previously untreated; OR
  • Relapsed after surgery or radiotherapy for localized disease; OR
  • Relapsed 1 year after adjuvant/neoadjuvant therapy for localized disease.
• Male or female. Contraception requirements will apply at the time of leukapharesis and treatment.A representative tumor tissue specimen (archived or fresh biopsy) with associated pathology report should be available to perform NY-ESO-1 antigen expression analysis, unless a recent NY-ESO-1 expression test result from the same designated central laboratory, following the same procedures, has already been performed under a separate GSK-sponsored protocol or under another substudy. 

All the Inclusion Criteria in 1-7 must apply again prior to leukapheresis. In addition, the following criteria must also apply:

• Life expectancy ≥ 24 weeks.
• Participant has advanced (metastatic or unresectable) synovial sarcoma or myxoid/round cell liposarcoma. Unresectable refers to a tumor lesion in which clear surgical excision margins cannot be obtained without leading to significant functional compromise.
• Participant must be positive for HLA-A*02:01, HLA-A*02:05, and/or HLA-A*02:06 alleles by a validated test in a designated central lab prior to leukapheresis.
  • NOTE: An HLA test result from the same designated central laboratory, following the same procedures, and performed under a separate GSK-sponsored protocol or under another substudy is acceptable.
• Participant’s tumor has been pathologically reviewed by a designated central laboratory with confirmed positive NY-ESO-1 expression defined as:
  • 30% of cells that are 2+ or 3+ by immunohistochemistry.
  • NOTE: A NY-ESO-1 expression test result from the same designated central laboratory, following the same procedures, and performed under a separate GSKsponsored protocol or under another substudy is acceptable.
• Left ventricular ejection fraction ≥ 45% with no evidence of clinically significant pericardial effusion.
• Performance status: for participants 60, or for participants < 16 and Lansky > 60, or for participants ≥ 16 and < 18 years of age, Karnofsky > 60, or for participants or for participants ≥ 18 years of age, Eastern Cooperative Oncology Group (ECOG) of 0-1.
• Participant must have adequate organ function and blood cell counts, within 7 days prior to the day of leukapheresis procedure (or first day of lymphodepletion during Treatment fitness assessment), as indicated by the following laboratory values.
• Hematological
• Absolute Neutrophil count (ANC) ≥1.5 x10^9 /L (without granulocute coloty-stimulating support);
• Absolute Lymphocyte count (ALC) ≥ 0.5 x 10^9 /L;
• Hemoglobin ≥ 8 g/dL or ≥ 5.6 mmol/L.
• Platelets ≥ 100 x10^9 /L (not achieved by transfusion).
• Creatinine clearance ≥ 40 mL/min.
• Participants who are ≥ 18 and < 65 years of age must be assessed either:
  • by 24-hour urine creatinine collection; OR
  • by using Serum Creatinine (Scr) via an estimated creatinine clearance calculated as below: Step 1: estimated glomerular filtration rate (GFR) to be obtained from the Chronic kidney disease Epidemiology Collaboration (CKD-EPI) formula [Levey, 2009]:
  • Estimated GFR (mL/min/1.73m^2 ) = 141 × min(Scr/κ, 1), α × max(Scr/κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 [if black] where:
  • Scr is serum creatinine in mg/dL, κ is 0.7 for females and 0.9 for males, α is -0.329 for females and -0.411 for males, min(Scr/κ,1) indicates the minimum of Scr/κ or 1, max(Scr/κ,1) indicates the maximum of Scr/κ or 1, and Age is in years.
  • Step 2: correction factor to be applied per the American National Kidney Foundation in order to obtain the estimated creatine clearance in mL/min Estimated CrCl (mL/min) = Estimated GFR (mL/min/1.73 m^2 ) × BSA (m2 ) / 1.73 m^2.
• Participants ≥ 65 years of age must have renal function measured either by 24-hour urine creatinine collection or by nuclear medicine EDTA GFR measurement, according to standard practice at the treating institution.  Participants <18 years of age must have renal function measured either by 24-hour urine creatinine collection or by nuclear medicine EDTA GFR measurement or by serum creatinine collection, according to standard practice at the treating institution.
• Participants < 18 years of age must have GFR ≥ 70mL/min/1.73m^2 OR have a serum creatinine based on age/gender as follows:
  • Age Maximum serum creatinine (mg/dL) Male Female
  • Age 10 to < 13 years > 1.2
  • Age 13 to < 16 years > Male 1.5  | Female 1.4
  • Age 16 to < 18 years > Male 1.7 | Female 1.4
• Hepatic
• Total bilirubin
• Participants with Gilbert’s Syndrome (only if direct bilirubin ≤ 35%) | ≤ 1.5 x ULN (isolated bilirubin ≤ 1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%)
• ALT ≤ 2.5 x ULN (or ≤ 5 x ULN if documented history of liver metastases)
• Coagulation
• International normalized ratio (INR) OR prothrombin time (PT)
• Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants Nutritional status.
• Albumin ≥ 3.5 g/dL
  • Participants may be transfused or receive growth factor treatment to meet minimum hematologic values up to 7 days prior to determining eligibility;
  • Adequate Organ Function will be reassessed for eligibility prior to lymphodepletion: if, upon consultation with the Medical Monitor, there is evidence from laboratory values that recovery from last anti-cancer treatment is underway, hematology labs may be considered acceptable and requirements waved to proceed with lymphodepletion.
• Participant is fit for leukapheresis and has adequate venous access for the cell collection.
• Male or female. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• Male Participants: Male participants are eligible to participate if they agree to the following during the intervention period starting at the first dose of chemotherapy for at least 12 months after receiving the T-cell infusion, or 4 months after there is no evidence of persistence/ gene modified cells in the participant’s blood, whichever is longer. Refrain from donating sperm Plus, either: Be abstinent from heterosexual or homosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent OR Must agree to use contraception/barrier as detailed below:
  • Agree to use a male condom and should also be advised of the benefit for a female partner to use a highly effective method of contraception when having sexual intercourse with a woman of childbearing potential (WOCBP) who is not currently pregnant (as a condom may break or leak);
  • Agree to use male condom when engaging in any activity that allows for passage of ejaculate to another person.
• Female Participants: A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
  • Is not a WOCBP; OR
  • Is a WOCBP who will agree to use a barrier method (male condom) and use a contraceptive method that is highly effective (with a failure rate of < 1% per year) during the intervention period and for at least 12 months after receiving the T-cell infusion, or 4 months after there is no evidence of persistence/ gene modified cells in the participant’s blood, whichever is longer.  WOCBP should also agree not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The Investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention.
  • A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours before any dose of study intervention. If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. The Investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
• Female participants of childbearing potential (FCBP) must have a negative urine or serum pregnancy test.
• Safety assessments will be reassessed again prior to lymphodepletion. Treatment fitness will be established in consultation with Medical Monitor.

In addition, the following criteria must also apply:

• Participant has measurable disease according to RECIST v1.1.
• Supportive radiotherapy has not affected > 25% of bone marrow.
• A biopsy (excisional, incisional, or core) of non-target tumor tissue obtained within 90 days prior to initiating lymphodepleting chemotherapy is mandatory if cleanically feasible. This biopsy will be used as baseline for biomarker analyses. If it is not feasible to obtain a fresh biopsy, an archival tumor tissue (FFPE block) taken after completion of the participant’s last line of therapy, preferably within 90 days prior to initiating lymphodepleting chemotherapy, may be accepted at the discretion of the Medical Monitor (or designee). For participants who already provided a fresh biopsy for antigen expression and did not receive any supportive or intermediate anti-cancer therapy, the screening biopsy will be used for baseline.

• Participant has been previously treated for advanced (metastatic or unresectable) synovial sarcoma or myxoid/round cell liposarcoma.
• Central nervous system (CNS) metastases.
• Any other prior malignancy that is not in complete remission.
• Exceptions include:
  • completely resected non-melanoma skin cancer, or successfully treated in situ carcinoma (e.g., melanoma in situ, basal cell carcinoma, prostate cancer in-situ, periosteal osteosarcoma);
  • previous malignancies that have been definitively treated, and have been in remission for 5 years may be enrolled upon consultation with sponsor Medical Monitor or designee.
• Previous treatment with genetically engineered NY-ESO-1 specific T cells.
• Previous NY-ESO-1 vaccine or NY-ESO-1 targeting antibody.
• Prior gene therapy using an integrating vector.
• Previous allogeneic hematopoietic stem cell transplant.
• Clinically significant systemic illness: a. serious active infections or significant cardiac, pulmonary, hepatic or other organ dysfunction, that in the judgment of the Investigator would compromise the participant’s ability to tolerate protocol therapy or significantly increase the risk of complications; OR
• Prior or active demyelinating disease. Please note in particular that mandatory washout period restrictions must be respected before starting leukapheresis.

In addition, participants are not eligible for leukapharesis if any of the following criteria apply: 

• Participant has history of chronic or recurrent (within the last year prior to leukapheresis) severe autoimmune or immune mediated disease (e.g., Crohn’s disease, systemic lupus) requiring steroids or other immunosuppressive treatments.
• Uncontrolled intercurrent illness including, but not limited to:
  • Ongoing or active infection;
  • Clinically significant cardiac disease defined by congestive heart failure New York Heart Association (NYHA) Class 3 or Class 4;
  • Uncontrolled clinically significant arrhythmia;
  • Acute coronary syndrome (angina or myocardial infarction) in last 6 months;
  • Interstitial lung disease (participants with existing pneumonitis as a result of radiation are not excluded; however, participants cannot be oxygen dependent).
• Current active liver or biliary disease (with the exception of Gilbert’s syndrome or asymptomatic gallstones, liver metastases or otherwise stable chronic liver disease per Investigator assessment).
  • NOTE: Stable chronic liver disease should generally be defined by the absence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, oesophageal or gastric varices, persistent jaundice or cirrhosis.
• QTc > 480 msec.
  • NOTES: The QTc is the QT interval corrected for heart rate according to Bazett’s formula (QTcB), Fridericia’s formula (QTcF), and/or another method, machine-read or manually over-read. The specific formula that will be used to determine eligibility for an individual participant should be determined prior to initiation of the study. In other words, several different formulae cannot be used to calculate the QTc for an individual participant and then the lowest QTc value used to include or discontinue the participant from the trial. For purposes of data analysis, QTcB, QTcF, another QT correction formula, or a composite of available values of QTc will be used as specified in the Reporting and Analysis Plan (RAP).
• Participant has a history of allergic reactions attributed to compounds of similar chemical or biologic composition to cyclophosphamide, fludarabine, other agents used in the study.
• Pregnant or breastfeeding females (due to risk to fetus or newborn).
• Any prior treatment-related toxicities must be CTCAE (Version 5.0) ≤ Grade 1 at the time of initiating study intervention (except for non-clinically significant toxicities e.g., alopecia, vitiligo). Participants with Grade 2 toxicities that are deemed stable or irreversible (e.g., chemotherapy related arthritis or tendinitis, skin discoloration or erythema) can be enrolled.
• Other standard of care lines of therapy are allowed only if guidelines and washout periods.
• Investigational treatment within 30 days or 5 half-lives (whichever is shorter) prior to leukapheresis. Investigational vaccines (other than NY-ESO-1 vaccines that are not allowed) must follow the washout period. Exceptions to this rule must be evaluated by the Investigator in agreement with the Sponsor’s Medical Monitor (or designee).
• Participant has active infection with HIV, HBV, HCV, EBV, CMV, syphilis, or HTLV as defined below:
  • Positive serology for HIV;
  • Active hepatitis B infection as demonstrated by test for hepatitis B surface antigen. Participants who are hepatitis B surface antigen negative but are hepatitis B core antibody positive must have undetectable hepatitis B DNA and receive prophylaxis against viral reactivation;
  • Active hepatitis C infection as demonstrated by hepatitis C RNA test. Participants who are HCV antibody positive will be screened for HCV RNA by any RT PCR or bDNA assay. If HCV antibody is positive, eligibility will be determined based on a negative Screening RNA value;
  • Positive test for syphilis (spirochete bacterium);
  • Positive serology for HTLV 1 or 2.
• Has known psychiatric or substance abuse disorders that would interfere with cooperating with the requirements of the study. Treatment fitness will be established in consultation with Medical Monitor. Please note in particular that mandatory washout period restrictions must be respected before starting lymphodepletion.

In addition, participants cannot proceed with lymphodepletion or treatment if any of the following criteria apply:

• Participant has received cytotoxic therapy within 3 weeks prior to lymphodepleting chemotherapy.
• Systemic corticosteroids or any other immunosuppressive therapy within 2 weeks prior to lymphodepleting chemotherapy.
  • NOTE: Isolated doses of systemic corticosteroids are permitted to manage acute allergic reactions. Use of inhaled or topical steroids is not exclusionary.
• Participant has received radiotherapy to the target lesions within 3 months prior to lymphodepletion. A lesion with unequivocal progression may be considered a target lesion regardless of time from last radiotherapy dose.
  • NOTE: There is no washout period for palliative radiation to non-target lesions.
• Participant has received an anti-cancer vaccine within 2 months in the absence of tumor response. The participant should be excluded if their disease is responding to an experimental vaccine given within 6 months.
• Participant has received live vaccine within 4 weeks prior to lymphodepletion or intends to receive live vaccine during the 3 month period following administration of GSK3377794.
• Participant has received immune therapy (monoclonal antibody therapy, checkpoint inhibitors) within 4 weeks of lymphodepletion.
• Participant had major surgery ≤ 28 days of first dose of study intervention.

• Age ≥ 11 years and ≤ 45 years on the date of randomisation.
• Histologically or cytologically confirmed germ cell tumour (non-seminoma or seminoma); or exceptionally raised tumour markers (AFP ≥ 1000ng/mL and/or HCG ≥ 5000 IU/L) without histologic or cytologic confirmation in the rare case where pattern of metastases consistent with GCT, high tumour burden, and a need to start therapy urgently.
• Primary arising in testis, ovary, retro-peritoneum, or mediastinum.
• Metastatic disease or non-testicular primary.
• Intermediate or poor prognosis as defined by IGCCC classification3 (modified with different LDH criteria for intermediate risk non-seminoma, and inclusion of ovarian primaries)..
• Adequate bone marrow function with ANC ≥1.0 x 10^9/L, Platelet count ≥100 x 10^9/L.
• Adequate liver function where bilirubin must be ≤ 1.5 x ULN, except participants with Gilbert's Syndrome where bilirubin must be ≤ 2.0 x ULN; ALT and AST must be ≤ 2.5 x ULN, except if the elevations are due to hepatic metastases, in which case ALT and AST must be ≤ 5 x ULN.
• Adequate renal function with estimated creatinine clearance of ≥ 60 ml/min according to the Cockcroft-Gault formula, unless calculated to be < 60 ml/min or borderline in which case GFR should be formally measured; e.g., with EDTA scan.
• ECOG Performance Status of 0, 1, 2, or 3 10. Study treatment both planned and able to start within 14 days of randomisation. Willing and able to comply with all study requirements, including treatment, timing and nature of required assessments. Able to provide signed, written informed consent

• Other primary malignancy (EXCEPT adequately treated non-melanomatous carcinoma of the skin, germ cell tumour, or other malignancy treated at least 5 years previously with no evidence of recurrence).
• Previous chemotherapy or radiotherapy, except:
  • pure seminoma relapsing after adjuvant radiotherapy or adjuvant chemotherapy with 1-2 doses of single agent carboplatin;
  • non-seminoma and poor prognosis by IGCCC criteria or stage IV malignant ovarian germ cell tumour in the rare case where low-dose induction chemotherapy is given prior to registration because patient is not fit enough to receive protocol chemotherapy (e.g., organ failure, vena cava obstruction, overwhelming burden of disease). Acceptable regimens include cisplatin 20 mg/m 2 days 1-2 and etoposide 100 mg/m 2 days 1-2; carboplatin AUC 3 days 1-2 and etoposide 100 mg/m 2 days 1-2; or baby-BOP.43 Patients must meet all other inclusion and exclusion criteria at the time of registration;
  • Participants who need to start therapy urgently prior to completing study-specific baseline investigations may commence study chemotherapy prior to registration and randomisation. Such patients must be discussed with the coordinating centre prior to registration, and must be registered within 10 days of commencing study chemotherapy.
• Significant cardiac disease resulting in inability to tolerate IV fluid hydration for cisplatin.
• Significant co-morbid respiratory disease that contraindicates the use of bleomycin.
• Peripheral neuropathy ≥ grade 2 or clinically significant sensorineural hearing loss or tinnitus.
• Concurrent illness, including severe infection that may jeopardize the ability of the participant to undergo the procedures outlined in this protocol with reasonable safety.
• Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation. Women of childbearing potential must have a negative pregnancy test done within 7 days prior to registration.
• Known allergy or hypersensitivity to any of the study drugs.
• Presence of any psychological, familial, sociological or geographical condition that in the opinion of the investigator would hamper compliance with the study protocol and follow-up schedule, including alcohol dependence or drug abuse.

Eligibility last updated 9/7/21. Questions regarding updates should be directed to the study team contact.

Registration
•

• Age ≥ 18 years old.
• Newly diagnosed, untreated, histologically confirmed diffuse large B-cell lymphoma expressing the CD20 antigen, with ANY of the following:
  • Non-GCB subtype by Hans algorithm
  • Myc expression ≥40% by IHC
  • Bcl-2 expression ≥50% by IHC
  • Myc expression ≥40% AND Bcl-2 expression ≥50% by IHC (double expressor)
  • MYC rearrangement by FISH
• Or high-grade B-cell lymphoma MYC with MYC rearrangement AND BCL2 and/or BCL6 rearrangement (double-hit or triple-hit lymphoma) but not a candidate for more aggressive chemotherapy (such as CODOX-M-IVAC)
  • NOTE: Patients with a new diagnosis of concurrent DLBCL and an indolent lymphoma (previously undiagnosed, such as follicular lymphoma or marginal zone lymphoma) are eligible. However, patients with a known prior diagnosis of indolent lymphoma with new transformation to DLBCL (i.e., transformed lymphoma) are not eligible.
• Ann Arbor Stages II (bulky disease; i.e., ≥ 5 cm, or not a candidate for combined modality treatment with R-CHOP plus radiotherapy), III, or IV (See Appendix I for Ann Arbor Staging).
• Measurable disease (at least 1 lesion of ≥ 1.5 cm in one diameter) as detected by CT or the CT images of PET/CT. Skins lesions can be used if the area is ≥ 2 cm in at least one diameter and photographed with a ruler.
• ECOG Performance Status (PS) 0, 1 or 2.
• The following laboratory values obtained ≤14 days prior to registration:
  • Absolute neutrophil count (ANC) ≥1500/mm^3;
  • Platelet count 100,000/mm^3;
  • Total bilirubin ≤ 1.5 upper limit of normal (ULN), or if total bilirubin is > 1.5 ULN, the direct bilirubin must be normal;
  • Aspartate transaminase (AST) 3 ULN (≤ 5 ULN for patients with direct liver involvement by lymphoma);
  • Alkaline phosphatase ≤ 3 ULN, unless evidence of the direct liver involvement by lymphoma, then ≤ 5 ULN;
  • Calculated creatinine clearance of ≥ 30 mL/min using the Cockcroft-Gault formula below:

    • Creatinine clear for males =     (140
      •age) x weight in Kg
                                                   72 x serum creatinine in mg/dL

    • Creatinine clear for females = (140
      •age) x weight in Kg x 0.85
                                                      72 x serum creatinine in mg/dL

• Negative urine pregnancy test done ≤ 7 days prior to registration, for persons of childbearing potential only.
  • NOTE: If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• Persons of childbearing potential must agree to use one reliable form of birth control.
• Provide written informed consent.
• Willingness to provide mandatory research blood specimens for banking.
• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).

Registration
•Exclusion Criteria

• Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:
  • Pregnant persons;
  • Nursing persons (lactating persons are eligibile provided that they aree not to breast feel while taking parscaclisib);
  • Persons of childbearing potential who are unwilling to employ adequate contraception.
• Primary CNS lymphoma, or parenchymal, meningeal or cerebrospinal fluid involvement with malignant lymphoma cells.
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
• Immunocompromised patients and patients known to be HIV positive and currently receiving antiretroviral therapy (except for patients on effective antiretroviral therapy with undetectable viral load within 6 months).
  • NOTE: If evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be undetectable on suppressive therapy if indicated.
  • NOTE: If history of hepatitis C virus (HCV) infection, HCV viral load must be undetectable.
• Uncontrolled intercurrent illness including, but not limited to:
  • ongoing or active infection;
  • symptomatic congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias;
  • unstable angina pectoris;
  • cardiac arrhythmia;
  • ongoing inflammatory bowel disease (such as ulcerative colitis) or other colitis requiring active treatment;
  • oxygen dependent baseline lung disease (such as interstitial lung disease or COPD);
  • or psychiatric illness/social situations that would limit compliance with study requirements.
• Received or receiving any other agent which would be considered as a treatment for the lymphoma (with the exception of corticosteroid).
• Other active malignancy requiring therapy such as radiation, chemotherapy or immunotherapy. Patients on hormonal therapy for treated breast or prostate cancer are permitted if they meet other eligibility criteria.
  • EXCEPTIONS: Localized non-melanotic skin cancer or any cancer that in the judgment of the investigator has been treated with curative intent (e.g., disease-free survival equal or more than 5 years) and will not interfere with the study treatment plan and response assessment.
  • NOTE: If there is a history of prior malignancy, they must not require therapy such as radiation, chemotherapy or immunotherapy for their cancer.
• History of myocardial infarction ≤ 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias.
• ≥ 25% of bone marrow radiated for other diseases.
• Ejection fraction of < 45% by either MUGA or ECHO.

All clinical and laboratory studies to determine eligibility must be performed within 7 days prior to enrollment unless otherwise indicated. Laboratory values used to assess eligibility must be no older than seven (7)  days at the start of therapy.

Laboratory tests need not be repeated if therapy starts within seven (7) days of obtaining labs to assess eligibility. Exception: repeat AFP MUST be sent within 48 hours prior to starting chemotherapy and  preferably on the same day that chemotherapy starts. However, the AFP result is NOT required prior to starting therapy.

If a post-enrollment lab value is outside the limits of eligibility, or laboratory values are > 7 days old, then the following laboratory evaluations must be re-checked within 48 hours prior to initiating therapy:

• CBC with differential, bilirubin, ALT (SGPT) and serum creatinine. If the recheck is outside the limits of eligibility, the patient may not receive protocol therapy and will be considered off protocol therapy.  Imaging studies, if applicable, must be obtained within 2 weeks prior to start of  protocol therapy (repeat the tumor imaging if necessary). For patients with upfront resection, imaging must be obtained within 28 days prior to the start of therapy (repeat tumor imaging if necessary).
• Patients must be ≤ 30 years of age at the time of diagnosis.
• Patients in Group F must have a Body Surface Area (BSA) ≥ 0.6 m2.
• Patients must have a performance status corresponding to ECOG scores of 0, 1, or 2. Use Karnofsky for patients > 16 years of age and Lansky for patients ≤ 16 years of age.
• Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
• Patients must be newly diagnosed with histologically-proven primary pediatric hepatic malignancies including hepatoblastoma or hepatocellular carcinoma.
• Patients with a diagnosis of hepatocellular neoplasm, not otherwise specified, should be classified and treated per hepatoblastoma treatment arms.
  • Please note: All patients with histology as assessed by the institutional pathologist consistent with pure small cell undifferentiated (SCU) HB will be required to have testing for INI1/SMARCB1 by IHC according to  the practices at the institution.
• Patients with histology consistent with pure SCU must have positive INI1/SMARCB1 staining.
• In emergency situations when a patient meets all other eligibility criteria and has had baseline required observations, but is too ill to undergo a biopsy safely, the patient may be enrolled without a biopsy.  Clinical situations in which emergent treatment may be indicated include, but are not limited to, the following circumstances:
  • Anatomic or mechanical compromise of critical organ function by tumor (e.g., respiratory distress/failure, abdominal compartment syndrome, urinary obstruction, etc.).
  • Uncorrectable coagulopathy.  For a patient to maintain eligibility for AHEP1531 when emergent treatment is given, the following must occur:
    • The patient must have a clinical diagnosis of hepatoblastoma, including an elevated alphafetoprotein (AFP), and must meet all AHEP1531 eligibility criteria at the time of emergent treatment.
    • Patient must be enrolled on AHEP1531 prior to initiating protocol therapy.
• A patient will be ineligible if any chemotherapy is administered prior to AHEP1531 enrollment.
  • Note: If the patient receives AHEP1531 chemotherapy emergently PRIOR to undergoing a diagnostic biopsy, pathologic review of material obtained in the future during either biopsy or surgical resection must either confirm the diagnosis of hepatoblastoma or not reveal another pathological diagnosis to be included in the analysis of the study aims.
• Patients may have had surgical resection of the hepatic malignancy prior to enrollment. All other anti-cancer therapy for the current liver lesion is prohibited.
• Adequate renal function for patients receiving chemotherapy (Groups A2, B, C, D, E2, F), defined as:
  • Creatinine clearance or radioisotope GFR ≥ 60 mL/min/1.73 m2 or a serum creatinine based on age/gender as follows:
    • 1 month to < 6 months | Male 0.4 | Female 0.4
    • 6 months to < 1 year | Male 0.5 | Female 0.5
    • 1 to < 2 years | Male 0.6 | Female 0.6
    • 2 to < 6 years | Male 0.8 | Female 0.8
    • 6 to < 10 years | Male 1.0 | Female 1.0
    • 10 to < 13 years | Male 1.2 | Female 1.2
    • 13 to < 16 years | Male 1.5 | Female 1.4
    • ≥ 16 years | Male 1.7 | Female 1.4

  • The threshold creatinine values in this Table were derived from the Schwartz formula for estimating GFR utilizing child length and stature data published by the CDC.

• Adequate liver function defined as:
  • Total bilirubin ≤ 5 x upper limit of normal (ULN) for age; and
  • SGOT (AST) or SGPT (ALT) < 10 x upper limit of normal (ULN) for age.
• Adequate cardiac function for patients on doxorubicin-containing regimens (Groups C, D, E2, and F), which must be assessed within 8 weeks prior to study enrollment, is defined as:
  • Shortening fraction of ≥ 28% by echocardiogram; or
  • Ejection fraction of ≥ 47% by echocardiogram or radionuclide angiogram;
  • Group F patients only: QT/QTc interval ≤ 450 milliseconds for males and ≤ 470 milliseconds for females.
• Adequate pulmonary function for patients receiving chemotherapy (Groups A2, B, C, D, E2, F), defined as:
  • Normal pulmonary function tests (including DLCO) if there is clinical indication for determination (e.g., dyspnea at rest, known requirement for supplemental oxygen).
• For patients who do not have respiratory symptoms or requirement for supplemental oxygen, PFTs are NOT required.

• Prior chemotherapy or tumor directed therapy (i.e., radiation therapy, biologic agents, local therapy (embolization, radiofrequency ablation, and laser); therefore, patients with a pre-disposition syndrome who have a prior malignancy are not eligible.
• Patients who are currently receiving another investigational drug.
• Patients who are currently receiving other anticancer agents.
• Patients with uncontrolled infection.
• Patients who previously received a solid organ transplant, other than those who previously received an orthotopic liver transplantation (OLT) as primary treatment of their hepatocellular carcinoma.
• Patients with hypersensitivity to any drugs on their expected treatment arm.
• Treatment Group specific exclusion criteria:
• Group C:
  • Patients who have known deficiency of dihydropyrimidine dehydrogenase (DPD).
• Group D:
  • Patients with chronic inflammatory bowel disease and/or bowel obstruction.
  • Patients with concomitant use of St. John’s wort, which cannot be stopped prior to the start of trial treatment.
• Group F:
  • Patients with peripheral sensitive neuropathy with functional impairment.
  • Patients with a personal or family history of congenital long QT syndrome.
• Pregnancy and Breast Feeding
  •These criteria apply ONLY to patients who will receive chemotherapy (all groups other than Groups A1 and E1).
• Female patients who are pregnant, since fetal toxicities and teratogenic effects have been noted for several of the study drugs.
• A pregnancy test is required for female patients of childbearing potential.
• Lactating females who plan to breastfeed their infants.
• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation.
• Note for Group F:
  • Patients of childbearing potential should use effective birth control during treatment with sorafenib and for at least 2 weeks after stopping treatment.

Main Cohort Key

Eligibility last updated 7/8/22. Questions regarding updates should be directed to the study team contact.

PRIOR TO STEP 1 REGISTRATION

• Histologically proven diagnosis of adenocarcinoma or squamous cell carcinoma of the thoracic esophagus or gastroesophageal junction (Siewert I-II).
• Stage I-IVA, excluding T4b, according to the American Joint Committee on Cancer (AJCC) 8th edition based on the following diagnostic workup:
  • History/physical examination;
  • Whole-body fludeoxyglucose F-18 (FDG)-positron emission tomography (PET)/computed tomography (CT) with or without (+/-) contrast (preferred) or chest/abdominal (include pelvic if clinically indicated) CT with contrast.
• For patients who DID NOT receive induction chemotherapy, scan must occur within 30 days prior to Step 1 registration.
• For patients who DID receive induction chemotherapy, scan must occur: 
  • Within 30 days after final induction chemotherapy dose; OR
  • Within 30 days prior to Step 1 registration.
    • Note: Patients who had prior endoscopic mucosal resection (EMR) with a diagnosis of AJCC stage I-IVA, excluding T4b, esophageal cancer are eligible.
• Surgical consultation to determine whether or not the patient is a candidate for resection after completion of chemoradiation.
• Induction chemotherapy for the current malignancy prior to concurrent chemoradiation allowed if last dose is no more than 90 days and no less than 10 days prior to Step 1 registration.
• Zubrod performance status 0, 1, or 2.
• Absolute neutrophil count (ANC) (within 30 days prior to Step 1 registration):
  • For patients who DID NOT receive induction chemotherapy: ANC ≥ 1,500 cells/mm^3;
  • For patients who DID receive induction chemotherapy: ANC ≥ 1,000 cells/mm^3.
• Platelets (within 30 days prior to Step 1 registration):
  • For patients who DID NOT receive induction chemotherapy: Platelets ≥ 100,000/uL;
  • For patients who DID receive induction chemotherapy: Platelets ≥ 75,000/uL.
• Hemoglobin ≥ 8.0 g/dl.
  • Note: The use of transfusion or other intervention to achieve Hgb ≥ 8.0 g/dl is acceptable (within 30 days prior to Step 1 registration).
• Creatinine clearance > 50 mL/min estimated by Cockcroft-Gault formula (within 30 days prior to Step 1 registration).
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (within 30 days prior to Step 1 registration).
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN (within 30 days prior to Step 1 registration). 
• Negative pregnancy test (serum or urine) within 14 days prior to Step 1 registration for women of child bearing potential.
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry.

• Cervical esophageal cancers arisen from 15-18 cm from the incisors. 
• Patients with T4b disease according to the AJCC 8th edition.
• Definitive clinical or radiologic evidence of metastatic disease.
• Any active malignancy within 2 years of study registration that may alter the course of esophageal cancer treatment. 
• Prior thoracic radiotherapy that would result in overlap of radiation therapy fields.
• Severe, active co-morbidity defined as follows: 
  • Active uncontrolled infection requiring IV antibiotics at the time of Step 1 registration;
  • Symptomatic congestive heart failure, unstable angina, or cardiac arrhythmia not controlled by pacer device at the time of Step 1 registration; 
  • Myocardial infarction within 3 months prior to Step 1 registration.
• Pregnant and/or nursing females. 
• Human immunodeficiency virus (HIV) positive with CD4 count < 200 cells/microliter. Note that patients who are HIV positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count ≥ 200 cells/microliter within 30 days prior to registration.
  • Note also that HIV testing is not required for eligibility for this protocol. This exclusion criterion is necessary because the treatments involved in this protocol may be significantly immunosuppressive.

PRIOR TO STEP 2 REGISTRATION

• Unable to obtain confirmation of payment coverage (insurance or other) for either possible radiation treatment.

PRIOR TO STEP 1 REGISTRATION

• Histologically proven diagnosis of adenocarcinoma or squamous cell carcinoma of the thoracic esophagus or gastroesophageal junction (Siewert I-II).
• Stage I-IVA, excluding T4b, according to the American Joint Committee on Cancer (AJCC) 8th edition based on the following diagnostic workup:
  • History/physical examination;
  • Whole-body fludeoxyglucose F-18 (FDG)-positron emission tomography (PET)/computed tomography (CT) with or without (+/-) contrast (preferred) or chest/abdominal (include pelvic if clinically indicated) CT with contrast.
• For patients who DID NOT receive induction chemotherapy, scan must occur within 30 days prior to Step 1 registration.
• For patients who DID receive induction chemotherapy, scan must occur: 
  • Within 30 days after final induction chemotherapy dose; OR
  • Within 30 days prior to Step 1 registration.
    • Note: Patients who had prior endoscopic mucosal resection (EMR) with a diagnosis of AJCC stage I-IVA, excluding T4b, esophageal cancer are eligible.
• Surgical consultation to determine whether or not the patient is a candidate for resection after completion of chemoradiation.
• Induction chemotherapy for the current malignancy prior to concurrent chemoradiation allowed if last dose is no more than 90 days and no less than 10 days prior to Step 1 registration.
• Zubrod performance status 0, 1, or 2.
• Absolute neutrophil count (ANC) (within 30 days prior to Step 1 registration):
  • For patients who DID NOT receive induction chemotherapy: ANC ≥ 1,500 cells/mm^3;
  • For patients who DID receive induction chemotherapy: ANC ≥ 1,000 cells/mm^3.
• Platelets (within 30 days prior to Step 1 registration):
  • For patients who DID NOT receive induction chemotherapy: Platelets ≥ 100,000/uL;
  • For patients who DID receive induction chemotherapy: Platelets ≥ 75,000/uL.
• Hemoglobin ≥ 8.0 g/dl.
  • Note: The use of transfusion or other intervention to achieve Hgb ≥ 8.0 g/dl is acceptable (within 30 days prior to Step 1 registration).
• Creatinine clearance > 50 mL/min estimated by Cockcroft-Gault formula (within 30 days prior to Step 1 registration).
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (within 30 days prior to Step 1 registration).
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN (within 30 days prior to Step 1 registration). 
• Negative pregnancy test (serum or urine) within 14 days prior to Step 1 registration for women of child bearing potential.
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry.

• Cervical esophageal cancers arisen from 15-18 cm from the incisors. 
• Patients with T4b disease according to the AJCC 8th edition.
• Definitive clinical or radiologic evidence of metastatic disease.
• Any active malignancy within 2 years of study registration that may alter the course of esophageal cancer treatment. 
• Prior thoracic radiotherapy that would result in overlap of radiation therapy fields.
• Severe, active co-morbidity defined as follows: 
  • Active uncontrolled infection requiring IV antibiotics at the time of Step 1 registration;
  • Symptomatic congestive heart failure, unstable angina, or cardiac arrhythmia not controlled by pacer device at the time of Step 1 registration; 
  • Myocardial infarction within 3 months prior to Step 1 registration.
• Pregnant and/or nursing females. 
• Human immunodeficiency virus (HIV) positive with CD4 count < 200 cells/microliter. Note that patients who are HIV positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count ≥ 200 cells/microliter within 30 days prior to registration.
  • Note also that HIV testing is not required for eligibility for this protocol. This exclusion criterion is necessary because the treatments involved in this protocol may be significantly immunosuppressive.

PRIOR TO STEP 2 REGISTRATION

• Unable to obtain confirmation of payment coverage (insurance or other) for either possible radiation treatment.

PRIOR TO STEP 1 REGISTRATION

• Histologically proven diagnosis of adenocarcinoma or squamous cell carcinoma of the thoracic esophagus or gastroesophageal junction (Siewert I-II).
• Stage I-IVA, excluding T4b, according to the American Joint Committee on Cancer (AJCC) 8th edition based on the following diagnostic workup:
  • History/physical examination;
  • Whole-body fludeoxyglucose F-18 (FDG)-positron emission tomography (PET)/computed tomography (CT) with or without (+/-) contrast (preferred) or chest/abdominal (include pelvic if clinically indicated) CT with contrast.
• For patients who DID NOT receive induction chemotherapy, scan must occur within 30 days prior to Step 1 registration.
• For patients who DID receive induction chemotherapy, scan must occur: 
  • Within 30 days after final induction chemotherapy dose; OR
  • Within 30 days prior to Step 1 registration.
    • Note: Patients who had prior endoscopic mucosal resection (EMR) with a diagnosis of AJCC stage I-IVA, excluding T4b, esophageal cancer are eligible.
• Surgical consultation to determine whether or not the patient is a candidate for resection after completion of chemoradiation.
• Induction chemotherapy for the current malignancy prior to concurrent chemoradiation allowed if last dose is no more than 90 days and no less than 10 days prior to Step 1 registration.
• Zubrod performance status 0, 1, or 2.
• Absolute neutrophil count (ANC) (within 30 days prior to Step 1 registration):
  • For patients who DID NOT receive induction chemotherapy: ANC ≥ 1,500 cells/mm^3;
  • For patients who DID receive induction chemotherapy: ANC ≥ 1,000 cells/mm^3.
• Platelets (within 30 days prior to Step 1 registration):
  • For patients who DID NOT receive induction chemotherapy: Platelets ≥ 100,000/uL;
  • For patients who DID receive induction chemotherapy: Platelets ≥ 75,000/uL.
• Hemoglobin ≥ 8.0 g/dl.
  • Note: The use of transfusion or other intervention to achieve Hgb ≥ 8.0 g/dl is acceptable (within 30 days prior to Step 1 registration).
• Creatinine clearance > 50 mL/min estimated by Cockcroft-Gault formula (within 30 days prior to Step 1 registration).
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (within 30 days prior to Step 1 registration).
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN (within 30 days prior to Step 1 registration). 
• Negative pregnancy test (serum or urine) within 14 days prior to Step 1 registration for women of child bearing potential.
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry.

• Cervical esophageal cancers arisen from 15-18 cm from the incisors. 
• Patients with T4b disease according to the AJCC 8th edition.
• Definitive clinical or radiologic evidence of metastatic disease.
• Any active malignancy within 2 years of study registration that may alter the course of esophageal cancer treatment. 
• Prior thoracic radiotherapy that would result in overlap of radiation therapy fields.
• Severe, active co-morbidity defined as follows: 
  • Active uncontrolled infection requiring IV antibiotics at the time of Step 1 registration;
  • Symptomatic congestive heart failure, unstable angina, or cardiac arrhythmia not controlled by pacer device at the time of Step 1 registration; 
  • Myocardial infarction within 3 months prior to Step 1 registration.
• Pregnant and/or nursing females. 
• Human immunodeficiency virus (HIV) positive with CD4 count < 200 cells/microliter. Note that patients who are HIV positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count ≥ 200 cells/microliter within 30 days prior to registration.
  • Note also that HIV testing is not required for eligibility for this protocol. This exclusion criterion is necessary because the treatments involved in this protocol may be significantly immunosuppressive.

PRIOR TO STEP 2 REGISTRATION

• Unable to obtain confirmation of payment coverage (insurance or other) for either possible radiation treatment.

• Patients must have histologically confirmed (biopsy-proven) diagnosis of mantle cell lymphoma (MCL), with documented cyclin D1 (BCL1) expression by immunohistochemical stains and/or t(11;14) by cytogenetics or FISH. 
• Patients must have measurable or evaluable disease as defined as a lymph node measuring >1.5 cm in any dimension or splenomegaly with spleen >15 cm in craniocaudal dimension. 
• Age ≥ 60 years. 
• No intention to undergo consolidation with high dose chemotherapy and autologous stem cell rescue (Autologous Stem Cell Transplant) in first remission
• ECOG performance status of 0-2. 
• Ability to understand and willingness to sign Institutional Review Board (IRB)-approved informed consent. 
• Willing to provide mandatory tissue samples (if sufficient tissue available), bone marrow and blood samples for research purposes. 
• Adequate organ function as measured by the following criteria, obtained ≤ 2 weeks prior to registration: 
  • Absolute Neutrophil Count (ANC) ≥ 1000/mm³;
  • Hemoglobin ≥ 8 g/dL;
  • Platelets ˃75,000/mm³;
  • Creatinine clearance ≥ 40 mL/min, calculated with the use of 24-hour creatinine clearance or by Cockcroft-Gault formula;
  • Total Bilirubin ≤ 1.5 x Upper Limit of Normal (ULN) or ≤ 3 x ULN for patients with documented Gilbert's syndrome;
  • Aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) ≤ 2.5 x ULN. 
• All females of childbearing potential (not surgically sterilized and between menarche and 1 year post menopause) must have a blood test to rule out pregnancy within 2 weeks prior to registration. 
• Women must not be pregnant or breastfeeding. Females of childbearing potential who are sexually active with a non-sterilized male partner and sexually active men must agree to use 2 methods of adequate contraception (hormonal plus barrier or 2 barrier forms) prior to study entry, for the duration of study participation, and for 12 months after last dose of therapy. Method of contraception must be documented. 
• Patients should not have prior chemotherapy, radiotherapy or immunotherapy for lymphoma.
• Corticosteroids used for other non-lymphomatous conditions will be allowed.
• Corticosteroids no greater than 1 mg/kg prednisone (or equivalent) given for ≤ 14 days will be allowed for treatment of lymphoma related symptoms.

• Patients should not have prior chemotherapy, radiotherapy or immunotherapy for lymphoma. 
• Patients must have no recent (< 1 year) history of malignancy except for the following:
  • adequately treated non-melanoma skin cancer;
  • adequately treated Stage I melanoma of the skin;
  • in situ cervical cancer;
  • low grade prostate adenocarcinoma (Gleason grade ≤ 6) managed with observation and stable for 6 months. 
• Patients should not have known evidence of central nervous system (CNS) lymphoma. 
• Patients must not have received a prior allogeneic stem cell transplant or solid organ transplant (except for cornea) for any indication. 
• Patients must have no active, uncontrolled infections. 
• Patients must not have active hepatitis B or be chronic carriers of hepatitis B. This is defined as patients with hepatitis B surface antigen (HBsAg) positive. Patients with prior exposure to hepatitis B (hepatitis B core antibody (anti-HBc) positive AND HBsAg negative) are allowed with a protective level hepatitis B surface antibody AND a negative hepatitis B viral load by polymerase-chain reaction (PCR). 
• Patients must not have active hepatitis C (HCV) as defined by a hepatitis C viral load detectable by PCR. Patients with a negative HCV antibody are assumed to have a negative HCV viral load. Patients with a positive HCV antibody must have a negative hepatitis C viral load by PCR. Prior treatment for an active HCV infection will be allowed as long as the hepatitis C viral load by PCR is negative.
• Patients must not have known active Human Immunodeficiency Virus (HIV). Testing not required in absence of clinical suspicion. 
• Patients must not have evidence of significant, uncontrolled concomitant diseases, including psychiatric diseases, that could affect compliance with the protocol or interpretation of results or that could increase risk to the patient.
• Patients must not have conditions that preclude oral administration or absorption of medications through the GI tract, including but not limited to the inability to swallow pills or malabsorption syndromes. 
• Patients must not have known allergies to both xanthine oxidase inhibitors and rasburicase. 
• Patients must not require the use of warfarin. Blood thinners of other classes are permitted.
• Patient may not receive the following agents within 7 days prior to the first dose of venetoclax: 
  • Strong and moderate CYP3A inhibitors
  • Strong and moderate CYP3A inducers
  • Strong and moderate P-gp inhibitors 
• Patients must not have consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges), or star fruit within 3 days prior to the first dose of venetoclax.

Registration Criteria: 

• Any patient undergoing bone marrow biopsy with suspicion of or known diagnosis of acute myeloid leukemia (AML) will be asked to sign a Prescreening Consent to allow for centralized testing of bone marrow/peripheral blood samples.

Eligibility Criteria: 

• Patient must have previously untreated FLT3 mutated Non M3 AML (FLT3-TKD or FLT3-ITD allowed).

  • NOTE: Standard of care induction 7+3 chemotherapy may start prior to randomization using same regimen and doses as defined in Section 5.2.1 while awaiting prescreening test results.

• Patient must have had no prior systemic therapy for AML, except as noted below:
  • Hydroxyurea and emergent leukapheresis or preemptive treatment with retinoic acid prior to exclusion of Acute Promyelocytic Leukemia (APL) allowed. 
  • Prior therapy for myelodysplastic syndrome (MDS) or myeloproliferative neoplasms (MPN) (e.g., thalidomide or lenalidomide, interferon, jakafi, cytokines, 5-azacytidine or decitabine, histone deacetylase inhibitors). 

  • Initiation of standard of care 7+3 induction chemotherapy using same regimen and doses as defined in protocol (Section 5.2.1) while awaiting prescreening test results.

• Patient may not have hypomethylating agent within 21 days. 
• Patient may not have M3 AML. 
• Patient may not have AML with known Core Binding Factor -t(8;21), inv(16), t(16;16). 

  • NOTE: If results return with known Core Binding Factor –t(8;21), inv(16), t(16;16) after patient is registered, patient may be allowed to remain on-study per investigator’s discretion after discussion with PrECOG.

• Patient may not have known active Central Nervous System (CNS) leukemia. 

  • NOTE: -Prophylaxis with intrathecal chemotherapy is allowed prior to or during induction/consolidation.

    - If prophylactic lumbar puncture is performed, recommend scheduling so results are available prior to Day 8 or wait until Day 21 to perform.

• Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-3. 
• Patient must be age ≥ 18 years to ≤ 70 years. 
• Patient must be able to understand and willing to sign Institutional Review Board (IRB)-approved informed consent. 
• Patient must be willing to provide mandatory bone marrow and blood samples for research. 
• Patient must have adequate organ function as measured by the following criteria, obtained ≤ 48 hours prior to randomization except ECG and left ventricular ejection fraction (LVEF) which can be done ≤ 2 weeks prior to randomization: 
• Serum creatinine ≤ 1.5x institutional upper limit of normal (ULN), or if serum creatinine outside normal range, then glomerular filtration rate (GFR) > 40 mL/min as measured by Cockcroft-Gault formula. 
• Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ≤ 3x ULN, unless secondary to leukemia. 
• Serum total or direct bilirubin <2 mg/dL, unless due to Gilbert's, hemolysis or leukemic infiltration. 
• Fridericia-Corrected QT Interval (QTcF) interval ≤ 500 msec (using Friderica's correction). 
• Left Ventricular Ejection Fraction > 45%.
• The patient may not be known to have hypokalemia and/or hypomagnesemia that does not respond to supplementation.
• A female patient is eligible to participate if she is not pregnant and at least one of the following conditions apply: 
  • Not a woman of childbearing potential (WOCBP); or
  • WOCBP who agrees to follow the contraceptive guidance throughout the treatment period and for at least 180 days after the final study drug administration.
• Female patient must agree not to breastfeed or donate ova starting at treatment and throughout the study period, and for at least 180 days after the final study drug administration. 
• A male patient must agree not to donate sperm starting at treatment and throughout the study period, and for at least 120 days after the final study drug administration. 
• A male patient with female partner(s) of child-bearing potential must agree to use contraception during the treatment period, and for at least 120 days after the final study drug administration. 
• Male patient with a pregnant or breastfeeding partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy or time partner is breastfeeding throughout the treatment period, and for at least 120 days after the final study drug administration. 
• Patient may not have another malignancy that could interfere with the evaluation of safety or efficacy of this combination. 
• Patient may not have a history of Long QT Syndrome. 
• Patient may not have evidence of uncontrolled angina, severe uncontrolled ventricular arrhythmias, electrocardiographic evidence of acute ischemia, or congestive heart failure (CHF) New York Heart Association (NYHA) Class 3 or 4. Patient may also not have a history of CHF NYHA Class 3 or 4 in the past, unless a prescreening echocardiogram (ECHO) or multigated acquisition scan (MUGA) performed within 2 weeks prior to study entry with results of left ventricular ejection fraction > 45%.
• Patient may not have had major surgery or radiation therapy within 4 weeks of registration. 
• Patient may not require treatment with concomitant drugs that are strong inducers of CYP3A. 
• Patient with a known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent are not eligible. 
• Patient with known gastrointestinal (GI) disease or prior GI procedure that could interfere with the oral absorption or tolerance of gilteritinib or midostaurin including difficulty swallowing are not eligible. 
• Patient with any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of the treatment according to the protocol are not eligible. 
• Patient may not participate in any other therapeutic clinical trials, including those with other investigational agents not included in this trial during treatment on this study without prior approval from PrECOG.

• At least 18 years of age.
• Evidence of a response (partial response or better based on investigator's determination of response by International Myeloma Working Group [IMWG] criteria) to daratumumab-containing therapy with response duration of at least 4 months.
• Participants must have progressed from or be refractory to their last line of treatment. Relapsed or refractory disease as defined as:
  • Relapsed disease is defined as an initial response to previous treatment, followed by confirmed progressive disease (PD) by IMWG criteria greater than (>) 60 days after cessation of treatment;
  • Refractory disease is defined as less than (<) 25 percent (%) reduction in M-protein or confirmed PD by IMWG criteria during previous treatment or > 60 days after cessation of treatment.
• Received 1 to 3 prior line(s) of treatment of which one contained daratumumab, and completed daratumumab at least 3 months prior to randomization. A single line of therapy may consist of 1 or more agents, and may include induction, hematopoietic stem cell transplantation, and maintenance therapy. Radiotherapy, bisphosphonate, or a single short course of corticosteroids (no more than the equivalent of dexamethasone 40 milligram per day [mg/day] for 4 days) would not be considered prior lines of therapy.
• Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1, or 2.
• Women of childbearing potential must have a negative urine or serum pregnancy test at screening within 14 days prior to randomization.

• Previous treatment with daratumumab within the last 3 months prior to randomization.
• Discontinuation of daratumumab due to a daratumumab-related adverse event (AE).
• History of malignancy (other than multiple myeloma) unless all treatment of that malignancy was completed at least 2 years before consent and the patient has no evidence of disease. Further exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or breast, or other non-invasive lesion, that in the opinion of the investigator, with concurrence with the sponsor's medical monitor, is considered cured with minimal risk of recurrence within 3 years.
• Allergies, hypersensitivity, or intolerance to daratumumab, hyaluronidase, monoclonal antibodies (mAbs), human proteins, or their excipients, or known sensitivity to mammalian-derived products. Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib).
• Participant is:
  • Known to be seropositive for human immunodeficiency virus (HIV) with one or more of the following: not receiving highly active antiretroviral therapy (ART), had a change in ART within 6 months of the start of screening, receiving ART that may interfere with study treatment, cluster of differentiation (CD)4 count < 350 (unit: cells per cubic millimeter of blood) at screening, acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection within 6 months of start of screening, and not agreeing to start ART and be on ART > 4 weeks plus having HIV viral load <400 copies/milliliters (mL) at end of 4-week period (to ensure ART is tolerated and HIV controlled;
  • Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Participants with resolved infection (example: participants who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) deoxyribonucleic acid (DNA) levels. Those who are PCR positive will be excluded;
  • Known to be seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy).

Eligibility last updated 10/14/21. Questions regarding updates should be directed to the study team contact.

• The subject must consent to take precautionary measures to prevent Newcastle Disease Virus (NDV) transmission to humans and birds.
• Subjects must have histologic documentation of advanced solid tumor and received and have progressed, are refractory, or are intolerant to standard therapy for the specific tumor type. All subjects are required to have had at least one prior line of treatment in the recurrent or metastatic setting.
• Subjects must have at least 1 measurable lesion.
• All subjects must consent to provide tumor tissue for correlative studies.
• ECOG performance status of 0 to 1.
• Adequate organ function.
• Use of highly effective contraception (females) or male condom plus spermicide (males).

• Rapidly progressing disease defined as a subject that cannot tolerate a break of at least 8 weeks from systemic anticancer therapy. 
• Primary central nervous system (CNS) disease is excluded.
• Subjects who have received prior immunotherapy will require varying washout times prior to the first dose of MEDI5395.
• Unresolved toxicities from prior anticancer therapy.
• History of severe allergic reactions to any of the study drug components.
• Infectious disease exclusions including tuberculosis, Human immunodeficiency virus (HIV), hepatitis A, B or C, active bacterial, fungal or viral infections plus receipt of live attenuated vaccine prior to first dose of MEDI5395.
• (NOTE: Subjects with hepatitis B/C with undetectable virus load and are on medications may be permitted). 
• Any conditions requiring use of any systemic immunosuppressant including systemic corticosteroids, methotrexate, azathioprine, tumor necrosis factor (TNF) inhibitor, and/or interleukin 6 (IL-6) blockers.
• Active autoimmune disease or chronic inflammatory condition (Exceptions include vitiligo, alopecia, hypothyroidism on stable treatment, diverticulosis, controlled celiac disease and chronic skin conditions not requiring systemic therapy).
• Active acquired immune-deficiency states.
• Subjects who are regularly exposed to poultry or birds.
• Current active hepatitis or biliary disease (except for Gilbert's syndrome, asymptomatic gallstones, or stable chronic liver disease).
• Clinically significant pulmonary disease and cardiac disease.
• Any condition that, in the opinion of the investigator, would interfere with evaluation of the investigational product or interpretation of subject safety or study results.

• Documented diagnosis of relapsed/refractory multiple myeloma (MM) with measurable disease (serum, urine, or free light chain [FLC]) per International Myeloma Working Group (IMWG) criteria.
• At least 3 prior lines of MM therapy, including a proteasome inhibitor, immunomodulatory agent, and anti-CD38 antibody (unless contraindicated), and refractory to the last treatment line.
• Eastern Cooperative Oncology Group (ECOG) 0 or 1.
• Absence of donor (product)-specific anti-HLA antibodies.
• Adequate hematologic, renal, hepatic, pulmonary, and cardiac function.

• Current or history of Central Nervous System (CNS) involvement of myeloma or plasma cell leukemia.
• Clinically significant CNS disorder.
• Current or history of thyroid disorder.
• Autologous stem cell transplant within the last 6 weeks, or any allogeneic stem cell transplant.
• Prior treatment with anti-BCMA therapy, any gene therapy, any genetically modified cell therapy, or adoptive T cell therapy.
• History of HIV infection or acute or chronic active hepatitis B or C infection.
• Patients unwilling to participate in an extended safety monitoring period.

Additional Exclusion Criteria for Nirogacestat plus ALLO-715 Cohorts:

• Inability to swallow tablets.
• Subject has known malabsorption syndrome or preexisting gastrointestinal conditions that may impair absorption of nirogacestat.
• Use of strong/moderate CYP3A4 inhibitors, and strong CYP3A4 inducers within 14 days before starting nirogacestat.
• Use of concomitant medications that are known to prolong the QT/QTcF interval.

Eligibility last updated 3/24/22. Questions regarding updates should be directed to the study team contact.

• Patients must have histologically or cytologically confirmed stage IV non-squamous non‐small cell lung cancer (NSCLC) (includes M1a, M1b stage disease, American Joint Committee on Cancer [AJCC] 8th edition). Patients with T4NX disease (stage IIIB and IIIC) with nodule in ipsilateral lung lobe are eligible if they are not candidates for combined chemotherapy and radiation/
• Patients must have PD-L1 expression Tumor Proportion Score (TPS) ≥ 1% in tumor cells. If PD-L1 expression TPS is unevaluable or the testing could not be completed, the patients are not eligible. The assay must have been performed by a Clinical Laboratory Improvement Act (CLIA) (or equivalent) certified laboratory.
• Patients must have measurable or non-measurable disease. The presence of malignant pleural fluid alone is sufficient to satisfy this eligibility criterion. Baseline imaging assessments and measurements used to evaluate all measurable or non-measurable sites of disease must be done within 4 weeks prior to study registration.
  • NOTE: If patient receives pemetrexed, follow institutional guidelines to drain fluids.
• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. 
• Patients must NOT have received the following: 
  • Prior systemic chemotherapy or immunotherapy for advanced metastatic NSCLC. Patients treated with any prior checkpoint inhibitors for metastatic lung cancer are ineligible. Chemotherapy for non-metastatic disease (e.g., adjuvant therapy) or immunotherapy for locally advanced stage III disease is allowed if at least 6 months have elapsed between the last dose of the prior therapy and study registration. Local therapy, e.g. palliative radiation, is allowed as long as a period of 14 days has passed between completion of local therapy and study registration;
  • Methotrexate (MTX) given in low doses for non-malignant conditions with last dose at least 14 days prior to date of registration will be allowed. Other low dose chemotherapeutics for non-malignant conditions will be considered, but review by the study chair is required.
• Patients with known EGFR mutations (except exon 20 insertion), BRAF mutations (V600) or ALK or ROS1 translocations that can be treated with oral tyrosine kinase inhibitors are excluded.
• Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression. Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy.
• Patients are eligible if off steroids for at least 14 days prior to protocol treatment.
• Anticonvulsants are allowed.
• Patients with prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
• Patients must not have known pre-existing and clinically active interstitial lung disease, or a known history of (non infectious) pneumonitis that required steroids, or current pneumonitis.
• Patients must not have significant gastrointestinal disorders with diarrhea as a major symptom (e.g,. Crohn's disease, malabsorption, etc.). 
• Patients must not have history of auto-immune condition requiring ongoing or intermittent systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better
• Patients must not have any other concomitant serious illness or organ system dysfunction that in the opinion of the investigator would either compromise patient safety or interfere with the evaluation of the safety of the study drug.
• Patients must not receive any other investigational agents during the course of therapy.
• Women must not be pregnant or breast-feeding due to potential harm to the fetus or infant from cytotoxic chemotherapy and the unknown risk of MK-3475 (pembrolizumab). Patients must also not expect to conceive or father children from the time of registration, while on study treatment, and until at least 120 days after the last dose of study treatment:
  • All females of childbearing potential must have a blood test or urine study within 72 hours prior to registration to rule out pregnancy;
  • A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: has achieved menarche at some point; has not undergone a hysterectomy or bilateral oophorectomy; or has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
• Women of childbearing potential and sexually active males must use an accepted and effective method of contraception or abstain from sexual intercourse from time of registration, while on study treatment, and continue for 120 days after the last dose of study treatment.
• Absolute neutrophil count (ANC) ≥ 1500/mm^3 (within 14 days of randomization).
• Platelets ≥ 100,000/mm^3 (within 14 days of randomization).
• Prothrombin time (PT)/international normalized ratio (INR) ≤ 1.5 Or if patient on therapeutic anticoagulation, PT/INR ≤ 3.0 (within 14 days of randomization).
• Partial thromboplastin time (PTT) ≤ institutional upper limit of normal (ULN) OR, if patient is on therapeutic anticoagulation, PTT must be ≤ 1.5 x ULN (within 14 days of randomization).
• Total bilirubin ≤ 1.5 mg/dL (obtained within 14 days of randomization).
• Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) < 5 x upper limit of normal (ULN) (obtained within 14 days of randomization)
  •Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 5 x upper limit of normal (ULN) (obtained within 14 days of randomization).
• Calculated creatinine clearance ≥ 45ml/min to be eligible to receive pemetrexed (obtained within 14 days prior to randomization). 
• Serum creatinine ≤ 1.5 x institutional upper limit of normal (ULN) (obtained within 14 days prior to randomization).
• Patients must not have a known history of active tuberculosis (TB).
• Patients must not have a diagnosis of immunodeficiency or receive systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of protocol treatment.
• Patients must not have received a live vaccine within 30 days prior to randomization. Seasonal flu vaccines that do not contain live virus are permitted.
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.