• 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.

• 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.

• 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.

Inclusion Criteria
•Registration:

• Women of age ≥ 18 years.
• Histological confirmation of invasive breast carcinoma.
• Stage I-III breast cancer
• Estrogen receptor (ER) positive disease according to ASCO/CAP guidelines as ER≥1% positive nuclear staining.
• Completion of all planned cancer treatments prior to registration:
  • surgical resection of breast and nodal surgery;
  • NOTE: Reconstructive surgery does not have to be completed
  • adjuvant radiation therapy, if needed; and
  • neoadjuvant and/or adjuvant chemotherapy, if needed.
• Post-menopausal defined as
• Age ³60 and amenorrhea >12 consecutive months OR
• Previous bilateral oophorectomy OR
• Age <60 and amenorrhea >12 consecutive months and documented follicle stimulating hormone (FSH) level within post-menopausal range according to institutional standard
• NOTE: Patients who did not meet these criteria at time of diagnosis and received pre-operative (neoadjuvant) or post-operative (adjuvant) chemotherapy will not be allowed to participate.
• ECOG Performance Status (PS) 0, 1, or 2 .
• The following laboratory values obtained ≤14 days prior to registration:
  • Hemoglobin ≥ 8.0 g/dL;
  • Absolute neutrophil count (ANC) ≥ 1500/mm^3;
  • Platelet count ≥ 70,000/mm^3;
  • Total bilirubin ≤ 1.5 x ULN;
  • Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤ 3 x ULN.
• Ability to swallow oral medication.
• Provide written informed consent.
• Willingness to provide mandatory blood specimens for correlative research.
• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).

Exclusion Criteria
•Registration:

• Pre-menopausal women receiving ovarian function suppression (goserelin, leuprolide, etc.).
• Stage IV (metastatic) breast cancer.
• HER2 positive breast cancer as defined by:
  • HER2 IHC ≥ 3+;
  • HER2/CEP17 ≥ 2.0;
  • HER2/CEP17 < 2.0 and average HER2 copy number of ≥ 6.0. signals/cell
• Prior endocrine therapy for this breast cancer.
• Exceptions:
  • Pre-operative aromatase therapy (anastrozole, letrozole, or exemestane)  and last treatment was ≥ 4 weeks prior to registration; OR
  • Pre-operative tamoxifen therapy and last treatment was ≥ 12 weeks prior to registration.
• Currently receiving any of the following cancer-directed therapies:
  • Radiation therapy;
  • Systemic therapy such as chemotherapy (standard or investigational);
  • Bisphosphonate therapy started < 4 weeks prior to registration.
• NOTE: If patient is currently on bisphosphonate therapy she must be on stable dose for ≥ 4 weeks prior to registration.
• Patients not currently taking bisphosphonates will be allowed to start bisphosphonate therapy after completion of anastrozole (1mg and 10 mg daily (if given)). Information regarding bisphosphonate therapy will be collected.
• Current use of systemic or topical exogenous estrogen or progesterone (menopausal hormone replacement therapy [HRT]).
• Prior ovarian function suppression (leuprolide, goserelin, etc).
• Inability to provide informed consent.
• History of contralateral DCIS or invasive breast cancer.
• NOTE: Exception allowed if:
  • Patient did not receive adjuvant endocrine therapy; OR
  • Patient received adjuvant endocrine therapy but has been off treatment for at least 6 months prior to registration.
• Concurrent active malignancy or history of malignancy ≤ 3 years prior to registration.
• NOTE: Exceptions allowed for successfully treated cervical carcinoma in situ, lobular carcinoma in situ of the breast, papillary thyroid cancer, or non-melanoma skin cancer.
• Prior prevention therapy with an aromatase inhibitor or a SERM.
• Exception: Therapy with a SERM (tamoxifen or raloxifene) is allowed if patient has been off treatment for ≥ 6 months prior to registration.

• Adult and pediatric (from birth to 18 year old) patients.
• Patients with locally advanced or metastatic solid tumor harboring an NTRK gene fusion. NTRK (NTRK1, NTRK2, and NTRK3) gene fusions will be identified locally. Acceptable methods of detection of NTRK gene fusion include NGS, fluorescence in situ hybridization (FISH), reverse-transcription polymerase chain reaction (rt-PCR) or any other genomic testing able to detect NTRK gene fusion. If a pan-TRK IHC method is used, this result needs to be accompanied with the results using one of the other methods noted above. 
• Life expectancy of at least 3 months based on clinical judgement.
• Decision to treat with larotrectinib made by the treating physician prior to study enrollment.
• Signed informed consent form.
• For patients under legal age, signed assent by the patient (where applicable) and parental/legal guardian signed informed consent is required.

• Any contraindications as listed in the local approved product information.
• Pregnancy.
• Participation in an investigational program with interventions outside of routine clinical practice.
• Prior treatment with larotrectinib or other kinase inhibitor with TRK inhibition.
• Patients with NTRK gene amplification or NTRK point mutation.

STEP 1 REGISTRATION

• If this will be the first patient from a registering site to receive a given RT modality (3DCRT vs. IMRT), the site must first submit pre-RT planning documents within 3 days of Step 1 registration and receive approval from Imaging and Radiation Oncology Core (IROC) before randomizing the patient to Step 2. If this will not be the first patient to receive a specific RT modality, the patient should be immediately randomized to Step 2 on the same day. 

STEP 2 RANDOMIZATION

• If patient required review of pre-RT planning, randomization must occur within 14 days of initial registration. 
• Patients must have histologically proven, T2-T4a N0M0 urothelial carcinoma of the bladder within 70 days prior to randomization. Patients with mixed urothelial carcinoma will be eligible for the trial, but the presence of small cell carcinoma will make a patient ineligible. Patients with lymph nodes ≥ 1.0 cm in shortest cross-sectional diameter on imaging (computed tomography [CT]/magnetic resonance imaging [MRI]) must have a biopsy of the enlarged lymph node showing no tumor involvement within 70 days prior to randomization. These patients may be suitable for neoadjuvant chemotherapy and radical cystectomy and are eligible for this trial if they seek out a bladder sparing treatment strategy, however patients who have received prior systemic chemotherapy for bladder cancer are not eligible for the trial. 
• Patients must undergo a transurethral resection of bladder tumor (TURBT) within 70 days prior to randomization. In a situation where a patient is referred from outside to the enrolling institution, patient must have a repeat cystoscopy by the urologist who will be following the patient on the clinical trial to assess the adequacy of the prior TURBT. Patient may then undergo repeat TURBT if deemed necessary as standard of care by the treating urologist. Patients may have either completely or partially resected tumors as long as the treating urologist attempted maximal resection. Patient must not have T4b disease. 
• Patients must undergo radiological staging within 70 days prior to randomization. Imaging of chest, abdomen, and pelvis must be performed using CT or MRI. Patients must not have evidence of T4bN1-3 disease. Eligibility is based on the local radiology report. 
• Patients with hydronephrosis are eligible if they have unilateral hydronephrosis and kidney function meets criteria specified. 
• Patients must not have had urothelial carcinoma or histological variant at any site outside of the urinary bladder within the previous 24 months except Ta/T1/carcinoma in situ (CIS) of the upper urinary tract including renal pelvis and ureter if the patient had undergone complete nephroureterectomy. 
• Patients must not have diffuse CIS based on cystoscopy and biopsy. 
• Patient must be planning to receive one of the protocol specified chemotherapy regimens.
• All adverse events associated with any prior surgery and intravesical therapy must have resolved to Common Terminology Criteria for Adverse Events (CTCAE) grade ≤ 2 prior to randomization. 
• Patient must not have received any systemic chemotherapy for their bladder cancer. 
• Patient must not have had prior pelvic radiation. 
• Patients must not have received prior treatment for muscle invasive bladder cancer including neoadjuvant chemotherapy for the current tumor. 
• Patients must not have received any systemic therapy (including, but not limited to, interferon alfa-2b, high dose IL-2, pegylated interferon [PEG-IFN], anti-PD-1, anti-PD-L1), for non-muscle invasive bladder cancer. Prior intravesical BCG, interferon, and intravesical chemotherapy are allowed. 
• Patients must not have received any of the following prohibited therapies within 28 days prior to randomization or be planning to receive any of the following prohibited therapies during protocol treatment: 
  • Anti-cancer systemic chemotherapy or biological therapy not specified in the protocol
  • Immunotherapy not specified in this protocol;
  • Systemic or intravesical use of any non-study anti-cancer agent (investigational or non-investigational);
  • Investigational agents other than atezolizumab;
  • Live vaccines: Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, shingles, yellow fever, rabies, bacillus Calmette-Guerin (BCG), and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed. Prior administration of intravesical BCG is allowed;
  • Glucocorticoids for any purpose other than to modulate symptoms from an event of suspected immunologic etiology. The use of physiologic doses of corticosteroids (defined as 10 mg prednisone) are acceptable, however site investigators should consult with the study chair for any dose higher than 10 mg prednisone. Dexamethasone 4 mg iv with chemotherapy to prevent nausea is allowed;
  • RANKL infusion: Concurrent denosumab (which binds the cytokine RANKL) for any known indication is prohibited due to interaction with study medication. 
• Patients must not have a major surgical procedure within 28 days prior to randomization. If patient had any surgical procedure then they should have recovered to full presurgical performance status and surgical adverse events should have resolved to grade ≤ 2. TURBT is not considered a major surgical procedure. 
• Patients must not have received treatment with systemic immunosuppressive medications (including, but not limited to, prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 14 days prior to randomization. Exceptions: 
  • Patients may have received acute, low dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea);
  • The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed. Physiological doses equivalent of 10 mg prednisone daily are allowed. Short term steroids given as antiemetic therapy; e.g., 4 mg dexamethasone or equivalent once a week, is allowed. 
• Patients must not have received a live, attenuated vaccine within 4 weeks prior to randomization or anticipate that such a live, attenuated vaccine will be required while on protocol treatment and up to 5 months after the last dose of protocol treatment. 
  • Inactivated influenza vaccination should be given during influenza season only (approximately October to March). Patients must not receive live, attenuated influenza vaccine within 4 weeks prior to randomization or while on protocol treatment and up to 5 months after the last dose of protocol treatment. 
• Patients must not have undergone prior allogeneic bone marrow transplantation or prior solid organ transplantation. 
• Patient may or may not be radical cystectomy candidates.
• Absolute neutrophil count (ANC) ≥ 1,500/microliter (mcL) (within 28 days prior to randomization). 
• Platelets ≥ 100,000/mcL (within 28 days prior to randomization).
• Hemoglobin ≥ 9 g/dL (within 28 days prior to randomization).
• Total bilirubin ≤ 1.5 x institutional upper limit of normal (IULN) (except patients with Gilbert's syndrome, who must have a total bilirubin < 3.0 mg/dL) (within 28 days prior to randomization). 
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 2.5 x IULN (within 28 days prior to randomization). 
• Patients must not have clinically significant liver disease that precludes patient from treatment regimens prescribed on the study (including, but not limited to, active viral, alcoholic or other autoimmune hepatitis, cirrhosis or inherited liver disease). 
• Patients must have adequate renal function as evidenced by calculated creatinine clearance ≥ 25 mL/min. The creatinine used to calculate the clearance result must have been obtained within 28 days prior to randomization. 
• Patients must have Zubrod performance status ≤ 2. 
• Patients must have a baseline electrocardiography (ECG) performed within 30 days prior to randomization. 
• Patient must not have history of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis. 
• Patients must not have an active infection requiring oral or IV antibiotics within 14 days prior to randomization. Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are not eligible. If patient develops urinary tract infection after TURBT they must have recovered from the infection prior to registration.
• Patients must not have active autoimmune disease that has required systemic treatment in past two 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. Autoimmune diseases include, but are not limited to, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Bell's palsy, Guillain-Barré syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, Graves' disease treated with methimazole or glomerulonephritis. 
• Patient must not have a history of active tuberculosis. 
• If patient has a known history of hepatitis B virus (HBV) or hepatitis C virus (HCV), they must meet the following criteria within 28 days prior to randomization. 
  • Patients with past or resolved hepatitis B infection (defined as having a negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible;
  • Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA). 
• Patients who are known to be positive for human immunodeficiency virus (HIV) are eligible only if they have all of the following: 
  • A stable regimen of highly active anti-retroviral therapy (HAART);
  • No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections;
  • A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard PCR-based tests within 28 days prior to randomization.
• No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for two years. Patients with localized prostate cancer who are being followed by an active surveillance program are also eligible. 
• Female patients of childbearing potential must have a serum pregnancy test prior to randomization. Patients must not be pregnant or nursing due to the potential teratogenic side effects of the protocol treatment. 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, for the duration of protocol treatment, and for 5 months (150 days) after the last dose of all study drugs. A woman is considered to be of "reproductive potential" if she has had a menses at any time in the preceding 12 consecutive months. 
• Patients must not be known to be allergic to Chinese hamster egg or ovary cell products and must not have any known major allergic reactions to any study drug. 
• Patients must be offered the opportunity to participate in specimen banking for future studies. 
• Patients who can complete Patient-Reported Outcome instruments in English or Spanish must agree to complete the EORTC QLQ-C30, the EORTC QLQ-BLM30, the EPIC-26 (bowel domain only), and the EQ-5D-5L per protocol schedule of assessment. 
• As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system.

• Participant has documented NF1 mutation or a diagnosis of neurofibromatosis type 1 (NF1) using National Institute of Health (NIH) Consensus Conference criteria inclusive of the presence of a plexiform neurofibroma (PN). 
• Participant has a PN that is causing significant morbidity. 
• Participant has a PN that cannot be completely surgically removed.
• Participant has a target tumor that is amenable to volumetric MRI analysis. 
• Participant is willing to undergo a tumor biopsy pre- and end of treatment if ≥ 18 years of age. 
• Participant has adequate organ and bone marrow function.
• Participant can swallow capsules whole if the capsule dosage form is being utilized. This criterion does not apply if participant is utilizing the dispersible tablet dosage form of study treatment;

• Participant has abnormal liver function or history of liver disease.
• Participant has lymphoma, leukemia or any malignancy within the past 5 years (except for resected basal/squamous skin carcinomas without metastases within 3 years). 
• Participant has breast cancer within 10 years.
• Participant has active optic glioma or other low-grade glioma requiring treatment. 
• Participant has abnormal QT interval corrected or other heart disease within 6 months.
• Participant has a history of retinal pathology, risk factors for retinal vein occlusion or has a history of glaucoma. 
• Participant has known malabsorption syndrome or gastrointestinal conditions that would impair absorption of PD-0325901. 
• Participant has received NF1 PN-targeted therapy within 45 days. 
• Participant has received radiation therapy within 6 months or has received radiation to the orbit at any time. 
• Participant is unable to undergo or tolerate MRI.
• Participant has active bacterial, fungal or viral infection.
• Participant has experienced other severe acute or chronic medical or psychiatric conditions within 1 year.

• Male and female.
• Provision of signed and dated written informed consent form (ICF) and any locally required authorization (e.g., Health Insurance Portability and Accountability Act in the US, EU Data Privacy Directive in the EU) obtained from the patient (or legal representative / impartial witness where mandated & allowed by local regulations) prior to any mandatory study-specific procedures, sampling, and analyses, including screening evaluations.
• Age ≥ 18 years at the time of screening. For patients aged < 20 years and enrolled in Japan, a written informed consent should be obtained from the patient and his or her legally acceptable representative. Patients aged < 21 years must not be enrolled in Egypt or Singapore.
• Histologically or cytologically (or radiologically for patients undergoing curative ablation) confirmed HCC, newly diagnosed, and successfully completed curative therapy (resection or ablation). (a) Hepatic resection and have the following pathologic and/or radiologic findings from surgery: (i) Any size with microvascular invasion (clear pathologic assessment on microvascular invasion: Yes or No) and/or satellite tumor (ii) 3 or less tumors, with at least one > 5 cm (iii) 4 or more tumors, ≤ 5 cm each (b) Ablation (radiofrequency or microwave, cryoablation, or PEI per institutional standard. Embolisation (e.g., TACE/TAE) is acceptable so long as it is part of the local planned ablative process) where all curative procedures are completed within a 12 week window, and have the following radiologic findings prior to ablation: (i) Solitary tumor, 3 to 5 cm (ii) 2 to 4 tumors, ≤ 5 cm each (iii) Exclude patients with 5 or more tumors.
• Patients must be randomized within 12 weeks of completion of curative hepatic resection, or final curative ablation procedure.
• Imaging to confirm disease-free status within 28 days prior to randomization.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1 at enrollment.
• Child-Pugh score of 5 or 6. 8 Patients with active HBV infection (as characterized by positive hepatitis B virus surface antigen [HBsAg] and/or anti-hepatitis B core antibodies (HBcAbs) with detectable HBV deoxyribonucleic acid (DNA) [≥10 IU/mL or above the limit of detection per local laboratory]) must receive antiviral therapy at least after enrollment (sign of ICF) per institutional practice. Patients must remain on antiviral therapy for the study duration and for 6 months after the last dose of study treatment. Patients must show evidence of HBV stabilization or signs of viral response (e.g., reduction HBV DNA levels) prior to randomization. Patients who test positive for anti-HBcAb with undetectable HBV DNA (< 10 IU/mL or under the limit of detection per local laboratory) do not require antiviral therapy. These patients will be tested at every cycle to monitor HBV DNA levels and initiate antiviral therapy if HBV DNA is detected (≥ 10 IU/mL or above the limit of detection per local laboratory). Patients with detectable HBV DNA during the study must initiate and remain on antiviral therapy for the study duration and for 6 months after the last dose of study treatment.
• Patients with active HCV infection (as characterized by the presence of detectable HCV ribonucleic acid (RNA)) must be managed per local institutional practice for the study duration.
• Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. A definition of post-menopausal.
• Adequate organ and marrow function, as defined below. Criteria “a,” “b,” “c,” and “f” cannot be met with transfusions, infusions, or growth factor support administered within 14 days of starting the first dose:
  • Hemoglobin ≥ 9 g/dL;
  •  Absolute neutrophil count ≥ 1000/µL;
  • Platelet count ≥ 65000/µL;
  • Total bilirubin (TBL) ≤ 2.0 × upper limit of normal (ULN);
  • Aspartate aminotransferase (AST) and ALT ≤ 5 × ULN;
  •  Albumin ≥ 2.8 g/dL;
  • International normalized ratio ≤ 1.6 (for patients receiving Warfarin, please consult with the study physician);
  • Urine protein 2+ or less;
  • Tested blood urea nitrogen or creatinine ≤ 1.5 × ULN or calculated creatinine clearance (CL) ≥ 51 mL/min as determined by the Cockcroft-Gault formula (using actual WT) or 24-hour urine creatinine CL;
  • Males: Creatinine CL (mL/min)=WT (kg) × (140
    •Age) 72 × serum creatinine (mg/dL); Females:  Creatinine CL (mL/min) = WT (kg) × (140
    •Age) × 0.85 72 × serum creatinine (mg/dL).

• History of deep vein thrombosis, pulmonary embolism, or any other significant thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis are not considered “significant”) during the 3 months prior to randomization.
• History of significant bleeding disorders, vasculitis, or a significant bleeding episode from the GI tract within 3 months prior to study randomization.
• History of GI perforation and/or fistulae within 6 months prior to randomization.
• Any history of nephrotic or nephritic syndrome.
• Evidence of symptomatic congestive heart failure (New York Heart Association II to IV) or symptomatic or poorly controlled cardiac arrhythmia.
• History of arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, within 6 months prior to randomization.
• Uncontrolled arterial hypertension defined by a systolic pressure ≥ 150 mm Hg or diastolic pressure ≥ 90 mm Hg despite standard medical management.
• Serious or non-healing wound, peptic ulcer, or bone fracture within 28 days prior to randomization.
• Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
• Evidence, by Investigator assessment, of varices at risk of bleeding on upper endoscopy or contrast-enhanced cross-sectional imaging undertaken at the screening visit, or within 6 months (24 weeks) of randomization.
• Evidence of distant metastasis (except regional lymph node metastases related to the disease under study, per Appendix F), co-existing malignant disease or macrovascular invasion on baseline imaging.
• History of hepatic encephalopathy within 12 months prior to randomization or requirement for medications to prevent or control encephalopathy (no lactulose, rifaximin, etc, if used for purposes of hepatic encephalopathy).
• Evidence of portal vein thrombosis, visible on baseline/eligibility imaging, and patients with Vp1, Vp2, Vp3 and Vp4 (benign portal vein thrombosis is allowed, where not related to tumor thrombus, and anti-thrombotics may be used as needed).
• Clinically meaningful ascites, defined as ascites requiring non-pharmacologic intervention (e.g., paracentesis) to maintain symptomatic control, within 6 months prior to the first dose of study treatment. (a) Patients with ascites who have required pharmacologic intervention (e.g., diuretics) and who have been on stable doses of diuretics for ascites for ≥ 2 months before randomization are eligible.
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis [except for diverticulosis], systemic lupus erythematosus, sarcoidosis syndrome, or Wegener syndrome [e.g., granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, and uveitis]). The following are exceptions to this criterion:
  • Patients with vitiligo or alopecia;
  • Patients with hypothyroidism (e.g., following Hashimoto syndrome), stable on hormone replacement;
  • Any chronic skin condition that does not require systemic therapy;
  • Patients without active disease in the last 5 years may be included but only after consultation with the Study Physician;
  • Patients with celiac disease controlled by diet alone.
  • Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, active interstitial lung disease (ILD), serious chronic GI conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirements, substantially increase the risk of incurring AEs or compromise the ability of the patient to give written informed consent.
  • History of another primary malignancy except for the following:
    • Prostate cancer of pathologic stage less than or equal to T2cN0M0 determined from a prior prostatectomy without biochemical recurrence and who, in the opinion of the Investigator, are not deemed to require active intervention, or patients with incidental histologic findings of prostate cancer that has not been treated prior to the study and who do not require specific therapy for prostate cancer beyond the surgery described in the Clinical Study Protocol and also are considered to be at low risk for recurrence per the Investigator;
    • Malignancy treated with curative intent and with no known active disease ≥ 5 years before the first dose of study treatment and of low potential risk for recurrence;
    • Adequately treated non-melanoma skin cancer or lentigo malignant without evidence of disease;
    • Adequately treated carcinoma in situ without evidence of disease;
    • Patients with another primary malignancy that is not active or expected to be clinically relevant in the next 5 years may be considered further to discussion with the Study Physician.
• Active infection, including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice) or human immunodeficiency virus (HIV; positive for HIV 1/2 antibodies).
• Active co-infection with both HBV and hepatitis D virus.
• Known allergy or hypersensitivity to any of the study treatments or any of the study treatment excipients.
• History of aneurysm (Patients with a capped aneurysm may be included but only after consultation with the Study Physician).
• Major surgery (as defined by the Investigator) within 28 days prior to randomization, or central venous access device placement within 7 days prior to randomization (biopsy from any type of surgery within 28 days is not an exclusion criteria, nor are procedures to treat varices).
• Receipt of routine treatment for chronic condition with nonsteroidal anti-inflammatory agents (e.g., indomethacin, ibuprofen, naproxen, or similar agents) or other anti-platelet agents (e.g., clopidogrel, ticlopidine, dipyridamole, or anagrelide). Require minimum washout period of 5 days prior to randomization. Low dose aspirin (≤ 325 mg/day) is permitted. Prohibited concomitant medications with exceptions.
• Receipt of prior systemic anticancer therapy for HCC.
• History of allogeneic organ transplantation or those who are on a waiting list for liver transplantation.
• Receipt of live attenuated vaccine within 30 days prior to the first dose of study treatment.
  • Note: Patients, if enrolled, should not receive live vaccine while receiving study treatment and up to 90 days after the last dose of study treatment.
• Current or prior use of immunosuppressive medication within 14 days before the first dose of study treatment. The following are exceptions to this criterion:
  • Intranasal, inhalational, topical steroids, or local steroid injections (e.g., intra-articular injection);
  • Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent;
  • Steroids as pre-medication for hypersensitivity reactions (e.g., CT-scan premedication).
• Receipt of treatment with herbal medications labelled for the treatment of HCC (e.g., Huaier) within 14 days prior to first dose of study treatment.
• Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ highly effective birth control from screening to 6 months after the last dose of study treatment. Not engaging in sexual activity, per the patient’s preferred and usual lifestyle, for the total duration of the treatment and 6 months after the last dose of study treatment is an acceptable practice.
• Judgment by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions, and requirements.
• Involvement in the planning and/or conduct of the study for both AstraZeneca staff and/or staff at the study site.

Eligibility last updated 10/7/21. Questions regarding updates should be directed to the study team contact.