• 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.

• 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.

• 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.

• 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.

• 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/or female.
• 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.
• Confirmed HCC (by imaging or histopathologically from biopsy specimen).
• No evidence of extrahepatic disease on any available imaging.
• Disease not amenable to curative surgery or transplantation or curative ablation.
• Disease must be amenable to TACE and anticipated to require no more than 4 TACE treatments to treat sites of disease within a ≤ 16-week period (Permitted modalities are DEB-TACE or cTACE (using an emulsion of Lipiodol® and a permitted chemotherapeutic agent as per institutional practice, followed by embolizing agents).
• Child-Pugh score class A to B7.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at enrollment 10. Patients with HBV infection, which is characterized by positive hepatitis B surface antigen (HBsAg) and/or hepatitis B core antibodies (anti-HBcAb) with detectable HBV DNA (≥ 10 IU/ml or above the limit of detection per local lab standard), must be treated with antiviral therapy, as per institutional practice. HBV antiviral therapy must be initiated prior to randomization and patients must remain on antiviral therapy for the study duration and for 6 months after the last dose of study medication. Patients must show evidence HBV stabilization or signs of viral response (e.g., reduction HBV DNA levels) prior to starting IP. Patients who test positive for anti-hepatitis B core (HBc) with undetectable HBV DNA (< 10 IU/ml or under the limit of detection per local lab standard) do not require antiviral therapy prior to randomization. These subjects 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 lab standard). HBV DNA detectable subjects must initiate and remain on antiviral therapy for the study duration and for 6 months after the last dose of study medication.
• Patients with HCV infection must have management of this disease per local institutional practice throughout the study. HCV diagnosis is characterized by the presence of detectable HCV ribonucleic acid (RNA) or anti-HCV antibody upon enrollment.
• At least 1 measurable intrahepatic lesion suitable for repeat assessments according to the following mRECIST criteria:
  • Liver lesions that show typical features of HCC on IV contrast-enhanced CT or MRI scans; i.e., hypervascularity in the arterial phase with washout in the portal or the late venous phase;
  • Viable, non-necrotic portion (arterial phase IV contrast-enhancing) that can be accurately measured at baseline as ≥ 10 mm in the longest diameter.
• Adequate organ and marrow function as defined below. Criteria “a,” “b,” “c,” and “f” may not be met with transfusions, infusions, or growth factor support administered within 14 days of starting the first dose:
  • Hemoglobin ≥ 9.0 g/dL;
  • Absolute neutrophil count ≥1000/µL;
  • Platelet count ≥ 75000/µL;
  • Total bilirubin ≤ 2.0 × the upper limit of normal (ULN);
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5 × ULN;
  • Albumin ≥2.8 g/dL;
  • International normalized ratio ≤1.6;
  • 2+ proteinuria or less urine dipstick reading;
  • Calculated creatinine clearance (CL) ≥ 30 mL/min as determined by Cockcroft-Gault (using actual body weight) or 24-hour urine creatinine CL.
  • Males: Creatinine CL = Weight (kg) × (140
    •Age) (mL/min) 72 × serum creatinine (mg/dL);
  • Females: Creatinine CL = Weight (kg) × (140
    •Age) × 0.85 (mL/min) 72 × serum creatinine (mg/dL). 
• Must have a life expectancy of at least 12 weeks.
• Upper Endoscopy to evaluate varices and risk of bleeding is required within 6 months of randomization.
• Body weight >30 kg

• Any history of nephrotic or nephritic syndrome.
• Clinically significant (e.g., active) cardiovascular disease, including:
  • Unstable angina within ≤ 6 months of randomization;
  • New York Heart Association Grade ≥ 2 congestive heart failure;
  • Poorly controlled cardiac arrhythmia despite medication (patient with rate controlled atrial fibrillation are eligible), or any clinically significant abnormal finding on resting ECG.
• Peripheral vascular disease Grade ≥ 3 (e.g., symptomatic and interfering with activities of daily living requiring repair or revision).
• Significant traumatic injury during 4 weeks prior to randomization.
• Known hereditary predisposition to bleeding or thrombosis; any prior or current evidence of bleeding diathesis.
• Systemic anticoagulation allowed, excluding Vitamin K antagonists.
• History of arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, within 6 months prior to randomization 
• Non-healing wound, active ulcer, or bone fracture. Patients with granulating incisions healing by secondary intention with no evidence of facial dehiscence or infection are eligible but require wound examinations every 3 weeks.
• History of abdominal fistula or GI perforation, nonhealed gastric ulcer that is refractory to treatment, or active GI bleeding within 6 months prior to enrollment.
• Patients who have had any kind of surgery in the past 28 days (biopsy from any type of surgery within 28 days is not an exclusion criteria. Nor are procedures to treat varices.) 
• Uncontrolled hypertension defined by a systolic pressure > 150 mmHg or diastolic pressure > 90 mmHg, with or without antihypertensive medication. Patients with initial blood pressure (BP) elevations are eligible if initiation or adjustment of antihypertensive medication lowers pressure to meet entry criteria.
• Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
• History of hepatic encephalopathy within past 12 months or requirement for medications to prevent or control encephalopathy (no lactulose, rifaximin, etc, if used for purposes of hepatic encephalopathy).
• Clinically meaningful ascites, defined as ascites requiring non-pharmacologic intervention (e.g., paracentesis) to maintain symptomatic control, within 6 months prior to the first scheduled dose:
  • Patients with ascites that has required pharmacologic intervention (e.g., diuretics) and who have been on stable doses of diuretics for ascites for ≥ 2 months are eligible;
  • Major portal vein thrombosis visible on baseline/eligibility imaging, patients with Vp3 and Vp4 are excluded.
• Patients with infiltrative-type HCC.
• History of allogeneic organ transplantation.
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn’s disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [eg, 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 (except for noted HBV or HCV as detailed above), symptomatic congestive heart failure, poorly controlled diabetes mellitus, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, active ILD, serious chronic GI conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
• History of another primary malignancy except for:
  • Malignancy treated with curative intent and with no known active disease ≥ 5 years before the first dose of IP and of low potential risk for recurrence;
  • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease;
  • Adequately treated carcinoma in situ without evidence of disease.
• History of leptomeningeal carcinomatosis.
• History of active primary immunodeficiency.
• 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 (positive HIV 1/2 antibodies).
• Patients co-infected with HBV and hepatitis D virus (HDV). (HBV infection is indicated by the presence of HBsAg and/or anti-HBcAb with detectable HBV DNA ≥ 10 IU/mL or above the limit of detection per local lab standard ; HDV positive infection is indicated by the presence of anti-HDV antibodies.)
• Any unresolved toxicity National Cancer Institute (NCI) CTCAE v 5.0 Grade ≥ 2 from previous anticancer therapy, with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria.
• Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
• History of allogeneic bone marrow transplant and active chronic graft versus host disease.
• Receipt of anti-PD-1, anti-PD-L1, or anti-CTLA-4 prior to the first dose of IP.
• Receipt of prior TACE, prior bland embolization, or prior radioembolization. Use of TACE or TAE as part of a curative therapy (e.g., in conjuntion with ablation or surgery) can be acceptable if it is used in the lesions where curative therapy was attempted. However, TACE or TAE cannot have been used as sole modalities in prior curative therapy.
• Receipt of prior systemic anticancer therapies for HCC.
• Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.
  • Note: Patients, if enrolled, should not receive live vaccine while receiving IP and up to 90 days after the last dose of IP.
• Current or prior use of immunosuppressive medication within 14 days before the first dose of IP. The following are exceptions to this criterion:
  • Intranasal, inhaled, 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 premedication for hypersensitivity reactions (e.g., CT scan premedication).
• Concurrent enrollment in another clinical study, unless it is an observational (noninterventional) clinical study or during the follow-up period of an interventional study.
• Prior randomization or treatment in a previous durvalumab clinical study regardless of treatment group assignment.
• 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 IP. Not engaging in sexual activity, as 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 (applies to both AstraZeneca staff and/or staff at the study site).

• Age ≥ 18 years  old.
• Life expectancy of at least 2 months.
• ECOG Performance Status ≤ 2.
• Patients must be able to swallow capsules.
• Adequate hematologic parameters, unless cytopenias are disease caused.
• Adequate renal, liver and cardiac function parameters.

• Patients with GVHD requiring systemic immunosuppressive therapy.
• Uncontrolled leptomeningeal disease, auto-immune hemolytic anemia and uncontrolled and clinical significant disease related metabolic disorde.r 
• Clinically significant intravascular coagulation. 
• Treatment with other investigational drugs within 14 days prior to first study treatment administration.

Inclusion Criteria
•Part 1:

• Patients must be informed about the study and fully consent to participation as demonstrated by signing the written informed consent form (ICF) before any screening procedures.
• Male or female patients 18 years or older at the time of consent.
• Confirmed diagnosis of MM per the revised IMWG diagnostic criteria.
• Patients with RRMM who have failed treatment with, are intolerant to, or are not candidates for available therapies that are known to confer clinical benefit.
• Must meet all of the following criteria for prior therapy:
  • Must be refractory to ≥ 1 proteasome inhibitor (PI), ≥ 1 immunomodulatory drug (IMiD), and ≥ 1 steroid;
  • Must either have received ≥ 3 prior lines of therapy or ≥ 2 prior lines of therapy if 1 line included a combination of PI and IMiD (prior treatment with an anti-CD38 therapy is permitted).
• With measurable disease, defined as ≥ 1 of the following:
  • Serum M-protein ≥ 500 mg/dL (≥ 5 g/L) on serum protein electrophoresis (SPEP);
  • Urine M-protein ≥ 200 mg/24 h on urine protein electrophoresis (UPEP).
  • Serum FLC assay result with an involved FLC level ≥ 10 mg/dL (≥ 100 mg/L) if serum FLC ratio is abnormal.
• Patients with serum M-protein, urine M-protein, or involved immunoglobulin FLC not meeting the measurable disease criteria above will be eligible if they have ≥ 1 of the following:
  • PET imaging with ≥ 1 plasmacytoma lesion with a single diameter of ≥ 2cm;
• • Bone marrow (BM) aspirate/biopsy with plasma cell percentage ≥ 30%
• With Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1.
• With normal QT interval corrected by the Fridericia method (QTcF) on screening electrocardiogram (ECG)[ QTcF of ≤ 450 millisecond (ms) in males or ≤ 470 ms in females].
• Must meet the following clinical laboratory criteria at entry:
  • Total bilirubin ≤1.5 x the upper limit of the normal range (ULN), except for Gilbert's syndrome (direct bilirubin must be < 2.0 x ULN);
  • Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤ 2.5 x ULN;
  • Estimated glomerular filtration rate (eGFR) ≥ 30 (mL/min/1.73 square meter [m^2]), using the modification of diet in renal disease (MDRD) equation;
  • Absolute neutrophil count (ANC) ≥ 1000 per cubic millimeter (/mm^3) (≥ 1.0*10^9 per liter [/L]); ≥ 750/mm^3 (≥ 0.75 x 10^9/L) may be acceptable for participants with > 50% of plasma cells in BM;
  • Platelet count ≥ 75,000/ mm^3 (≥ 75 x 10^9/L); ≥ 50,000/ mm^3 (≥ 50 X 10^9/L) may be acceptable for participants with > 50% of plasma cells in BM;
  • Hemoglobin ≥ 7.5 g/dL without transfusion within 7 days before the lab test;
  • Serum albumin ≥ 2.5 g/dL.
• Female patients who:
  • are postmenopausal for at least 1 year prior to screening; OR
  • are surgically sterile; OR
  • If they are of childbearing potential, agree to practice 1 highly effective method of contraception and 1 additional effective barrier method at the same time from study entry through 30 days after the last dose of study drug; OR
  • agree to practice true abstinence if in line with the preferred and usual lifestyle [periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable. Female and male condoms should not be used together].
• Male patients, even if surgically sterilized (postvasectomy) who:
  • Agree to practice effective barrier contraception during the entire study and through 90 days after the last dose of study drug; OR
  • Agree to practice true abstinence if in line with the preferred and usual lifestyle [periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods. Female and male condoms should not be used together].

Inclusion Criteria Part 2 (both RRMM and RRNHL patients):

• ECOG performance score of 0 or 1.
• Normal QTcF on screening ECG, defined as QTcF of ≤ 450 ms in males or ≤ 470 ms in females.
• Must meet the following clinical laboratory criteria at study entry:
  • Total bilirubin ≤ 1.5 x the ULN, except for Gilbert's syndrome (direct bilirubin must be < 2.0 x ULN);
  • Serum ALT and AST ≤ 2.5 x ULN;
  • eGFR ≥ 30 mL/min/1.73 m^2(MDRD equation);
  • ANC ≥ 1000 mm^3 (≥ 1.0 x 10^9 /L); a count of ≥ 750/mm^3 (≥ 0.75 x 10^9/L) may be acceptable for participant with > 50% of plasma cells in BM;
  • Platelet count ≥ 75,000/ mm63 (≥ 75 x 10^9/L); a value of ≥ 50,000/ mm3(≥ 50 x 10^9/L) may be acceptable for participants with > 50% of plasma cells in BM;
  • Hemoglobin ≥ 7.5 g/dL without transfusion within 7 days before the lab test;
  • Serum albumin ≥ 2.5 g/dL.
• Female patients who:
  • are postmenopausal for at least 1 year prior to screening; OR
  • are surgically sterile; OR
  • If they are of childbearing potential, agree to practice 1 highly effective method of contraception and 1 additional effective barrier method at the same time from study entry through 30 days after the last dose of study drug; OR
  • agree to practice true abstinence if in line with the preferred and usual lifestyle [periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable. Female and male condoms should not be used together].
• Male patients, even if surgically sterilized (postvasectomy) who:
  • Agree to practice effective barrier contraception during the entire study and through 90 days after the last dose of study drug; OR
  • Agree to practice true abstinence if in line with the preferred and usual lifestyle [periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable. Female and male condoms should not be used together].

Inclusion Criteria Part 2 for RRNHL patients:

• Pathologically confirmed diagnosis of the following NHL subtype based on local pathology report:
  • Mantle cell lymphoma (MCL) - Nodal MCL;
  • Diffuse large B-cell lymphoma (DLBCL), DLBCL- NOS, Plasmablastic lymphoma (PbL), Primary effusion lymphoma (PEL),  Primary effusion lymphoma (PMBL);
  • Follicular lymphoma;
  • Burkitt lymphoma (BL);
  • Peripheral T-cell lymphoma (PTCL) - PTCL-NOS (eligible at MTD/RPTD if biopsy evidence of CD38 positivity), Angioimmunoblastic T-cell lymphoma (AITL);
  • Extranodal NK/T-cell lymphoma (ENKTL)-nasal type.
• RRNHL, having failed treatment with, is intolerant to, or is determined not to be a candidate for available therapies considered standard of care (SOC) or are known to confer clinical benefit.
• At least 1 measurable site of disease according to the Lugano classification for lymphoma:
  • A measurable nodal lesion with longest diameter (LDi) greater than 1.5cm; OR
  • A measurable extranodal lesion with LDi greater than 1.0cm.
• Evidence of a CD38 positive tumor. Any of the following are acceptable:
  • Evidence of CD38 expression from most recent biopsy or blood sample [either flow cytometry (FCM) or immunohistochemistry (IHC)]; OR
  • The most recently archived tissue assessed for CD38 expression by IHC; OR
  • Fresh biopsy for CD38 expression assessment by IHC within 35 days of Cycle 1 Day 1; OR
  • Fresh blood sample with circulating NHL cells assessed by FCM within 35 days of Cycle 1 Day 1 (BM biopsy excisional lymph node biopsy, core biopsy of any involved organ are all acceptable methods, find needle aspirate is not. Any level of positive CD38 expression is eligible).

Inclusion Criteria Part 2 for RRMM patients:

• Confirmed diagnosis of MM per IMWG diagnosis criteria:
  • RRMM, having failed treatment with, is intolerant to, or is determined not to be a candidate for available therapies considered SOC or are known to confer clinical benefit.
• Must meet the following criteria for prior therapy:
  • Refractory or intolerant to ≥1 PI and ≥ 1 IMiD;
  • Receipt of ≥ 3 prior lines of therapy or ≥ 2 prior lines of therapy if 1 of those lines included a combination of a PI or IMiD (prior treatment with anti-CD38 therapy is permitted except for patients enrolled in the anti-CD38 therapy naïve cohort);
  • Daratumumab RR cohorts: RR to daratumumab at any time during treatment. Patients RR to other anti-CD38 therapies are excluded;
  • Anti-CD38 therapy naïve cohort: must not have received any prior anti CD-38 therapy.
• Measurable disease, defined as ≥ 1 of the following:
  • Serum M-protein ≥ 50 mg/dL (≥ 5 g/L) on SPEP;
  • Urine M-protein ≥ 200 mg/24 hours on UPEP.;
  • Serum FLC assay result with and involved FLC level ≥ 10 mg/dL (≥ 100mg/L), provided the serum FLC ratio is abnormal.
• Serum M-protein, urine M-protein or involved immunoglobulin FLC not meeting measurable disease criteria if at least 1 of the following criteria is met:
  • BM aspirate/biopsy showing plasma cell percentage ≥ 30%;
  • PET imaging showing at least 1 plasmacytoma lesion with a single diameter ≥ 2 cm.

Exclusion Criteria for Part 1 (RRMM patients only):

• With polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes (POEMS) syndrome, monoclonal gammopathy of unknown significance, smoldering myeloma, solitary plasmacytoma, amyloidosis, Waldenström macroglobulinemia, or Immunoglobulin M (IgM) myeloma.
• With sensory or motor neuropathy of NCI CTCAE V5 Grade ≥ 3.
• Have received final dose of any of the following treatments/procedures within the following interval before the first dose of MT-0169:
  • Myeloma-specific therapy, including PIs and IMiDs: 14 days;
  • Anti-CD38 (a) therapy: Isatuximab 90 days; daratumumab 60 days;
  • Corticosteroid therapy for myeloma: 7 days;
  • Radiation therapy for localized bone lesions: 14 days;
  • Major surgery:30 days;
  • Autologous stem cell transplant: 90 days;
  • Investigational therapy: 30 days.
• Have received an allogeneic stem cell transplant or organ transplantation.
• Have not recovered to Grade ≤ 1 or baseline, from adverse reactions to prior myeloma treatment or procedures (chemotherapy, immunotherapy, radiation therapy) excluding alopecia and Grade 2 neuropathy.
• With clinical signs of central nervous system (CNS) involvement of MM.
• With a history of myelodysplastic syndrome or another malignancy other than MM except for the following: any malignancy that has been in complete remission for 3 years, adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, or asymptomatic prostate cancer without known metastatic disease and not requiring therapy or requiring only hormonal therapy and with normal prostate-specific antigen level for ≥ 1 year before the start of study therapy.
• With known or suspected light chain amyloidosis of any organ (amyloid on the BM biopsy without other evidence of amyloidosis is acceptable).
• With any of the following cardiovascular conditions:
  • Congestive heart failure (NYHA) class ≥ II or left ventricular ejection fraction (LVEF < 40%, cardiac myopathy, active ischemia, or any other uncontrolled cardiac condition such as angina pectoris or myocardial infarction or clinically significant arrhythmia requiring therapy including anticoagulants within the past 6 months or at screening;
  • Resting tachycardia (heart rate of > 100 bpm) at screening;
  • Clinically significant uncontrolled hypertension at screening;
  • Cardiac MRI at screening demonstrates evidence of infiltrative disease of the myocardium.
• With a history of document significant pleural or pericardial effusions within 3 months before the start of treatment, including:
  • Pericarditis (any Grade);
  • Pericardial effusion (Grade ≥ 2);
  • Non-malignant pleural effusion (Grade ≥ 2);
  • Malignant pleural effusion (Grade ≥ 2).
• Patients with a history of noncardiogenic pulmonary edema associated with diffuse peripheral edema and a history of intravascular hypovolemia associated with systemic antineoplastic therapy.
• With chronic or active infection requiring systemic therapy, history of symptomatic viral infection that has not been fully cured.
  • With HIV and an undetectable viral load and CD4+ T-cell (CD4+) counts ≥ 350 cells/mL may be allowed but patient must be taking appropriate opportunistic infection prophylaxis if clinically relevant;
  • With positive HBV serology may be allowed if undetectable viral load, receiving antiviral prophylaxis for potential HBV reactivation per institutional guidelines;
  • With positive HCV serology may be allowed if quantitative PCR for plasma HCV RNA is below the lower limit of detection. Concurrent antiviral HCV treatment per institutional guidelines is allowed.
• Have received a live attenuated vaccine within 28 days of first dose of MT-0169.
• With a history of ≥ Grade 2 systemic inflammatory response syndrome (SIRS)/ cytokine release syndrome (CRS) reactions following infusion with any monoclonal antibodies or Chimeric Antigen Receptor (CAR) T therapy.
• With a chronic condition requiring systemic corticosteroids at > 10 mg/day of prednisone or equivalent.
• Are lactating and breastfeeding or have a positive serum pregnancy test during the screening period or patients of reproductive potential who are not employing an effective birth control.
• With a concurrent medical or psychiatric illness that would preclude study conduct and assessment including, but not limited to, uncontrolled medical conditions, uncontrolled and active infection, uncontrolled risk of bleeding, uncontrolled diabetes mellitus, pulmonary disease, alcoholic liver disease, or primary biliary cirrhosis.
• With known allergy or intolerance to any of the drugs used in the study or excipients in the MT-0169 formulation.
• With a history of hypersensitivity or serious toxic reaction to kanamycin or another aminoglycoside.

Exclusion Criteria for Part 2 NHL patients only:

• With known CNS lymphoma (exception allowed if history of CNS disease and evidence of SD on neuroimaging separated in time by at least 4 weeks and within 4 weeks of Cycle 1 Day 1).   
• Have received a final dose of any of the following treatments/procedures within the following minimum interval before the first dose of MT-0169:
  • Nitrosoureas: 6 weeks;
  • Chemotherapy: 4 weeks;
  • Small molecules (< 0.9 kDa): 5 half-lives or at least 2 weeks:
  • Therapeutic antibodies: 4 weeks;
  • Radio/toxin -immunoconjugates: 12 weeks;
  • Radiation therapy to a target lesion (measurable disease): 4 weeks
  • Radiation therapy to a nontarget lesion (radiation therapy to non-target lesions may be permitted): 2 weeks
  • Investigational chemotherapeutic agents or antibodies: 4 weeks
  • Daratumumab: 60 days
  • Isatuximab: 90 days
  • (MCL) Bruton's tyrosine kinase inhibitors: 2 weeks or 5 half-lives, whichever is longer
  • Major surgery (determined by the principal investigator with the Sponsor): 4 weeks
  • Autologous stem cell transplant: 100 days
  • Allogenic stem cell transplant: 180 days (patients with graft vs host disease > Grade 1 will be excluded).
• With a history of myelodysplastic syndrome or malignancy (other than NHL) except for the following: any malignancy in complete remission for 3 years, adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, or asymptomatic prostate cancer without known metastatic disease and not requiring therapy or requiring only hormonal therapy and with normal prostate-specific antigen level for ≥ 1 year before the start of study therapy.

Exclusion Criteria for Part 2 RRMM patients only:

• With POEMS syndrome, monoclonal gammopathy of unknown significance, smoldering myeloma, solitary plasmacytoma, amyloidosis, Waldenström macroglobulinemia, IgM myeloma.
• Have received a final dose of any of the following treatments/procedures within the following interval before the first dose of MT-0169:
  • Myeloma-specific therapy, including PIs and IMiDs: 14 days;
  • Anti-CD38 therapy
    •Isatuximab: 90 days;
  • Anti-CD38 therapy
    •Daratumumab: 60 days;
  • Corticosteroid therapy for myeloma: 7 days;
• • Radiation therapy for localized bone lesions: 14 days;
  • Major surgery: 30 days;
  • Autologous stem cell transplant: 90 days;
  • Investigational therapy: 30 days.
• Have received an allogenic stem cell or organ transplant.
• With clinical signs of CNS involvement of MM.
• With a history of myelodysplastic syndrome or another malignancy other than MM except or any malignancy in complete remission for 3 years, adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, or asymptomatic prostate cancer without known metastatic disease and not requiring therapy or requiring only hormonal therapy and with normal prostate-specific antigen level for >1 year before the start of study therapy.
• With known or suspected light chain amyloidosis of any organ (amyloid on BM biopsy without other evidence of amyloidosis is acceptable).

Exclusion Criteria for Part 2 (both RRMM and NHL patients):

• Failed to recover to Grade ≤ 1 or baseline from adverse reactions to prior treatment or procedures (chemotherapy, immunotherapy, radiation therapy) excluding alopecia and stable Grade 2 neuropathy.
• With any of the following cardiovascular conditions:
  • Congestive heart failure (NYHA) class ≥ II LVEF < 40%, cardiac myopathy, active ischemia, or any other uncontrolled cardiac condition such as angina pectoris or myocardial infarction or clinically significant arrhythmia requiring therapy including anticoagulants within the past 6 months or at screening;
  • Resting tachycardia (heart rate of >100 bpm) at screening;
  • Clinically significant uncontrolled hypertension at screening;
  • Cardiac MRI at screening demonstrating infiltrative disease of the myocardium 12. With a history of documented significant pleural or pericardial effusions, specifically any of the following within 3 months before the start of study treatment:
  • Pericarditis (any grade);
  • Pericardial effusion (Grade ≥ 2);
  • Non-malignant pleural effusion (Grade ≥ 2); OR
  • Malignant pleural effusion (Grade ≥ 3).
• With a history of noncardiogenic pulmonary edema associated with peripheral edema and a history of intravascular hypovolemia associated with antineoplastic therapy.
• With chronic or active infection requiring systemic therapy and a history of symptomatic viral infection that is not fully controlled or cured. The following exceptions apply for those with positive serologies of HIV, HBV, or HCV:
  • With HIV and undetectable viral load and CD4+ T-cell (CD4+) counts ≥ 350 cells/mL may be enrolled, but must be taking appropriate opportunistic infection prophylaxis, if clinically relevant;
  • With positive HBV serology are eligible if they have an undetectable viral load and the patient will receive antiviral prophylaxis for potential HBV reactivation per institutional guidelines;
  • With positive HCV serology are eligible if qPCR for plasma HCV RNA is below the lower limit of detection. Concurrent antiviral HCV treatment per institutional guidelines is allowed.
• Have received a live attenuated vaccine within 28 days of the first dose of MT-0169.
• With a history of Grade ≥ 2 SIRS/CRS reactions following infusion with any mAbs or CAR T therapy.
• With a chronic condition requiring systemic corticosteroids ≥ 10 mg/day of prednisone or equivalent.
• With a known allergy or intolerance to any of the drugs in the study or excipients in the MT-0169 formulation.
• Are lactating and breastfeeding or have a positive serum pregnancy test during the screening period or male or female patients of reproductive potential who are not employing effective birth control.
• With a concurrent medical or psychiatric illness that would preclude study conduct and assessment including, but not limited to, uncontrolled medical conditions, uncontrolled and active infection, uncontrolled risk of bleeding, uncontrolled diabetes mellitus, pulmonary disease, alcoholic liver disease, or primary biliary cirrhosis.
• With a history of hypersensitivity or serious toxic reactions to kanamycin or another aminoglycoside.

• Histologically or cytologically confirmed solid tumor malignancy that is advanced or metastatic or is surgically unresectable. 
• Radiographically measurable disease (per RECIST v1.1 or RANO for primary brain tumors). Tumor lesions located in a previously irradiated area or in an area subjected to other loco-regional therapy are considered measureable if progression has been clearly demonstrated in the lesion. 
• Documentation of an FGFR1-3 gene mutation or translocation. 
• Objective progression after at least 1 prior therapy and no therapy available that is likely to provide clinical benefit. Participants who are intolerant to or decline the approved therapy are eligible only if they have no therapy available that is likely to provide clinical benefit. 
• Eastern Cooperative Oncology Group performance status 0 to 2.
• Baseline archival tumor specimen (if < 12 months from date of screening) or willingness to undergo a pretreatment tumor biopsy to obtain the specimen. Must be a tumor block or approximately 15 unstained slides from biopsy or resection of primary tumor or metastasis. 
• Willingness to avoid pregnancy or fathering children.

• Prior receipt of a selective FGFR inhibitor in the past 6 months. 
• Receipt of anticancer medications or investigational drugs for any indication or reason within 28 days before first dose of pemigatinib. 
• Cannot be a candidate for potentially curative surgery. 
• Current evidence of clinically significant corneal or retinal disorder as confirmed by ophthalmologic examination. 
• Radiation therapy administered within 2 weeks of enrollment/first dose of study treatment.
• Untreated brain or central nervous system (CNS) metastases or brain or CNS metastases that have progressed (e.g., evidence of new or enlarging brain metastasis or new neurological symptoms attributable to brain or CNS metastases). 
• Known additional malignancy that is progressing or requires active treatment. 
• History of calcium and phosphate hemostasis disorder or systemic mineral imbalance with ectopic calcification of soft tissues.
• Clinically significant or uncontrolled cardiac disease. 
• Active chronic or current infectious disease requiring systemic antibiotic, antifungal, or antiviral treatment within 2 weeks before enrollment (participants with asymptomatic chronic infections on prophylactic treatment are allowed). 
• Evidence of active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (defined as elevated transaminases or cirrhosis; chronic HBV/HCV infection with no cirrhosis and no elevated transaminases is allowed). 
• Known HIV infection. 
• Use of any potent CYP3A4 inhibitors or inducers or moderate CYP3A4 inducers within 14 days or five half-lives (whichever is longer) before the first dose of study drug/treatment. 
• Women who are pregnant or breastfeeding.

• Signed written informed consent granted prior to initiation of any study-specific procedures. 
• 18 years of age and older.
• For the dose escalation cohorts, relapsed or refractory subjects with a diagnosis of B-cell NHL, CLL/SLL and WM who have received at least two prior systemic therapies . Subjects must have failed or are intolerant to standard therapies and cannot be a candidate for standard salvage regimens. Subjects with low grade lymphoma must be progressing and requiring treatment.. 
• For the expansion cohorts, the following criteria must be met:
  • Cohort A: Relapsed/Refractory (R/R) CLL/SLL subjects with at least 2 prior systemic therapies and previously treated with a covalent BTKi who must have a documented BTK mutation on C481 residue;
  • Cohort B: R/R CLL/SLL subjects who have failed or were intolerant to a BTKi with documentation of the absence of BTK mutation on C481 residue. In this study, intolerance to standard therapy is defined as having experienced a grade 3 or higher adverse event that was caused by the standard therapy and resulted in treatment discontinuation;
  • Cohort C: Richter's transformation subjects who have failed at least one prior therapy;
  • Cohort D: Follicular Lymphoma (FL) subjects who have failed at least 2 prior systemic therapies and are histology grade 1, 2, or 3A;
  • Cohort E: Mantle Cell Lymphoma (MCL) subjects who have failed at least 2 prior systemic therapies;
  • Cohort F: Marginal Zone Lymphoma (MZL) subjects who have failed at least 2 prior systemic therapies;
  • Cohort G: High-grade B-cell lymphoma subjects who have failed at least 2 prior systemic therapies and have known MYC and BCL2 and/or BCL6 translocations;
  • Cohort H: Waldenström macroglobulinemia (WM) subjects who have failed at least 2 prior systemic therapies.
• Disease status requirement: 
  • For CLL subjects, symptomatic disease that mandates treatment (Hallek et al. 2018); 
  • For B-cell NHL subjects, measurable disease by imaging scan;
  • For WM, serum immunoglobulin M (IgM) with a minimum IgM level of ≥ 2 times the upper limit of normal (ULN). 
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. 
• Good organ function:
  • Creatinine clearance of ≥ 60 mL/min as estimated by the Cockcroft-Gault equation or by 24-hour urine collection;
  • Total bilirubin ≤ 1.5 x institutional ULN (total bilirubin of ≤ 3 x institutional ULN in subjects with documented Gilbert's syndrome);
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × institutional ULN;
  • Platelet count ≥ 50,000/µL;
  • Absolute neutrophil count (ANC) ≥ 1000/µL;
  • Hemoglobin (Hgb) ≥ 8.0 g/dL, stable for ≥ 1 week.
• For men and women of child-bearing potential, willing to use adequate contraception (e.g., latex condom, cervical cap, diaphragm, abstinence, etc.) for the entire duration of the study.
• Female subjects of child-bearing potential must have a negative serum pregnancy test within 14 days of the first day of drug dosing.
• Ability to swallow oral medications without difficulty.

• Had immunotherapy, radiotherapy, radioimmunotherapy, biological therapy, chemotherapy, or treatment with an investigational product within 5 half-lives or four weeks (whichever is shorter) prior to treatment initiation, or oral therapy within 5 half-lives or one week (whichever is shorter) prior to treatment initiation. 
• Transformation of FL to a more aggressive subtype of lymphoma or grade 3b FL.
• Subjects currently being treated with the following drugs:
  • CYP 2C9 substrates with a narrow therapeutic index (such as warfarin, phenytoin);
  • CYP 2C8 substrates with a narrow therapeutic index (such as paclitaxel);
  • CYP 2C19 substrates with a narrow therapeutic index (such as S-mephenytoin);
  • CYP 2D6 substrates with a narrow therapeutic index (such as thioridazine, pimozide);
  • P-gp substrates with a narrow therapeutic index (such as digoxin)
    • Note: A washout period of at least 5 times the half-life after the last dose of any of the above treatments is required for a subject to be eligible for study enrollment. 
• Prior allogeneic bone marrow transplant. 
• Active central nervous system (CNS) involvement. 
• Pregnant or breast-feeding women. 
• Has significant, ongoing co-morbid conditions which would preclude safe delivery of the study drug. 
• Uncontrolled illness including but not limited to ongoing or active infection, symptomatic congestive heart failure (New York Heart Association [NYHA] Class III or IV heart failure), unstable angina pectoris, cardiac arrhythmia, cardiac infarction in the past six months, and psychiatric illness that would limit compliance with study requirements. 
• QTc prolongation (defined as a QTc > 450 msecs) or other significant electrocardiogram (ECG) abnormalities including 2nd degree atrioventricular (AV) block type II, 3rd degree AV block, or bradycardia (ventricular rate less than 50 beats/min). If the screening ECG has a QTc > 450 msecs, the ECG can be submitted for a centralized, cardiologic evaluation. 
• Active human immunodeficiency virus (HIV) infection, Hepatitis B, or Hepatitis C infection. 
• Other medical or psychiatric illness or organ dysfunction which, in the opinion of the Investigator, would either compromise the subject's safety or interfere with the evaluation of the safety of the study agent.
• History of prior cancer within < 1 year, except for basal cell or squamous cell carcinoma of the skin, cervical cancer in situ or other in situ carcinomas.

• Patients at risk for HCC with either an imaging diagnosis of HCC by ceCT or ceMRI (LI-RADS 5) confirmed by a board-certified abdominal radiologist or biopsy-proven HCC confirmed by a hepatobiliary pathologist.
• No prior treatment for HCC.
• Subjects who may or may not be expected to undergo surgical resection of the hepatic lesion(s) and/or liver transplant.
• Male or female with age greater than 18 years.
• Patients with the capacity to give informed consent and willingness to provide a written consent.

• Subjects requiring emergent surgery for a ruptured/bleeding HCC.
• Bilirubin > 3.0mg/dL, which is a contraindication for Gadoxetate, the MRI contrast agent.
• Pregnant and/or breast-feeding subjects. A negative pregnancy test within 48 hours of the PET scan.
• Subjects with higher than the weight/size limitations of PET/MRI scanner.
• Subjects with contraindication to MRI including:
  • Subjects who have a heart pacemaker;
  • Subjects who have a metallic foreign body (metal sliver) in their eye, or who have an aneurysm clip in their brain;
  • Subjects who have implanted devices with magnets;
  • Subjects who have other implanted electronic devices;
  • Subjects who have deep brain stimulator;
  • Subjects who have vagal nerve stimulator.
  • Subjects with cochlear (ear) or auditory implants.
• Subjects with history of allergic response to radiocontrast media.
• Subjects with known history of claustrophobia.

Newly-Diagnosed

• Age ≥ 18 years.
• Histologically confirmed Grade IV GBM, inclusive of gliosarcoma (WHO criteria; IDH wild-type by immunohistochemistry [IHC] or sequencing for IDH) established following either a surgical resection or biopsy. An MRI scan with the required imaging sequences performed within 21 days prior to randomization preferably. The post-operative MRI scan performed within 96 hours of surgery or the MRI scan performed for radiation therapy planning may serve as the MRI scan performed during screening if all required imaging sequences were obtained.
• Karnofsky performance status ≥ 60%. performed within a 14-day window prior to randomization.
• Availability of tumor tissue representative of GBM from definitive surgery or biopsy.

Recurrent

• Age ≥ 18 years.
• Histologically confirmed Grade IV GBM, inclusive of gliosarcoma (WHO criteria; IDH wild-type by immunohistochemistry [IHC] or sequencing for IDH) at first or second recurrence after initial standard, control or experimental therapy that includes at a minimum radiation therapy (RT).
• Evidence of recurrent disease demonstrated by disease progression using slightly modified Response Assessment in Neuro-Oncology (RANO) criteria.
• Two scans to confirm progression are required: at least 1 scan at the time of progression and 1 scan prior to the time of progression.
• Karnofsky performance status ≥ 70% performed within a 14-day window prior to randomization.
• Availability of tumor tissue representative of GBM from initial definitive surgery and/or, recurrent surgery, if performed.

Newly-Diagnosed

• Received any prior treatment for glioma including:
  • Prior prolifeprospan 20 with carmustine wafer;
  • Prior intracerebral, intratumoral, or cerebral spinal fluid (CSF) agent;
  • Prior radiation treatment for GBM or lower-grade glioma;
  • Prior chemotherapy or immunotherapy for GBM or lower-grade glioma. Receiving additional, concurrent, active therapy for GBM outside of the trial.
• Extensive leptomeningeal disease.
• QTc > 450 msec if male and QTc > 470 msec if female.
• History of another malignancy in the previous 2 years, with a disease-free interval of < 2 years. Patients with prior history of in situ cancer or basal or squamous cell skin cancer are eligible.

Recurrent

• Early disease progression prior to 3 months (12 weeks) from the completion of RT.
• More than 2 prior lines for chemotherapy administration. (NOTE: In the 1st line adjuvant setting, combination of temozolomide (TMZ) with an experimental agent, is considered one line of chemotherapy).
• Received any prior treatment with lomustine, agents part of any of the experimental arms, and bevacizumab or other vascular endothelial growth factor (VEGF) or VEGF receptor-mediated targeted agent.
• Any prior treatment with prolifeprospan 20 with carmustine wafer.
• Any prior treatment with an intracerebral agent.
• Receiving additional, concurrent, active therapy for GBM outside of the trial.
• Extensive leptomeningeal disease.
• QTc > 450 msec if male and QTc > 470 msec if female.
• History of another malignancy in the previous 2 years, with a disease-free interval of < 2 years. Patients with prior history of in situ cancer or basal or squamous cell skin cancer are eligible.

Eligibility last updated 2/16/22. Questions regarding updates should be directed to the study team contact.

• Adult subjects with large B-cell lymphoma, including Diffuse large B-cell lymphoma (DLBCL) not otherwise specified, Primary mediastinal large B-cell lymphoma (PMBCL), High-grade B-cell lymphoma (HGBL), and Diffuse large B-cell lymphoma (DLBCL) arising from Follicular lymphoma (FL).
• Subjects must have relapsed disease after 2 or more lines of systemic therapy, OR chemorefractory disease defined as the following: No response to first-line therapy, including the following: PD as best response to first therapy, SD as best response after ≥ 4 cycles of first-line therapy (eg, 4 cycles of R-CHOP), with SD duration no longer than 6 months from the last dose of therapy, Note: Subjects who are intolerant to first-line chemotherapy are excluded OR No response to ≥ 2 lines of therapy, including the following: PD as best response to most recent therapy, SD as best response after ≥ 2 cycles of last line of therapy.
• Subjects must have received adequate prior therapy including at a minimum: Anti-CD20 monoclonal antibody unless investigator determines that tumor is CD20 negative, and An anthracycline-containing chemotherapy regimen, Subjects with transformed FL must have chemorefractory disease after transformation to DLBCL.
• At least 1 measurable lesion according to the International Working Group (IWG) Lugano Classification {Cheson 2014}. Lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy.
• Magnetic resonance imaging of the brain showing no evidence of CNS lymphoma.
• At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed since any prior systemic therapy at the time the subject is planned for leukapheresis, except for systemic inhibitory/stimulatory immune checkpoint therapy. At least 3 half-lives must have elapsed from any prior systemic inhibitory/stimulatory immune checkpoint molecule therapy at the time the subject is planned for leukapheresis (eg, ipilimumab, nivolumab, pembrolizumab, atezolizumab, OX40 agonists, 4-1BB agonists).
• Toxicities due to prior therapy must be stable and recovered to Grade ≤ 1 (except for clinically nonsignificant toxicities such as alopecia).
• Age 18 or older.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Additional Inclusion Criteria may apply.

• History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (eg, cervix, bladder, breast) or FL unless disease free for at least 3 years.
• History of Richter’s transformation of chronic lymphocytic leukemia.
• Autologous stem cell transplant (SCT) within 6 weeks of planned axicabtagene ciloleucel infusion.
• History of allogeneic stem cell transplantation.
• Prior CD19 targeted therapy or prior CAR T cell therapy.
• History of PAP.
• History of severe, immediate hypersensitivity reaction attributed to aminoglycosides.
• Presence of fungal, bacterial, viral, or other infection that is uncontrolled or requiring intravenous antimicrobials for management. Simple urinary tract infection and uncomplicated bacterial pharyngitis are permitted if responding to active treatment and after consultation with the Kite medical monitor.
• Known history of human immunodeficiency virus (HIV) infection, hepatitis B (HBsAg positive) or hepatitis C (anti-HCV positive) infection. A history of hepatitis B or hepatitis C infection is permitted if the viral load is undetectable per quantitative polymerase chain reaction (PCR) and/or nucleic acid testing.
• Additional Exclusion Criteria may apply.

• Are ≥ 18 (or ≥ 20 in Japan and Taiwan or age legally considered to be an adult) years of age at the time of signing the informed consent. In Japan, a participant aged < 20 years of age but ≥ 18 years of age may participate if written informed consent from his/her parent or guardian is provided in addition to the participant’s written informed consent.
• Are participants with histologically or cytologically confirmed locally advanced or metastatic BTC, including intrahepatic CCA, extrahepatic CCA, gallbladder cancer, and ampulla of Vater’s cancer. The histological origin of ampullary carcinomas (intestinal, pancreaticobiliary, or other) will be collected.
• Naïve to chemotherapy, immunotherapy, and interventional radiological treatment (transarterial chemo-embolization, transarterial embolization, transarterial infusion) for locally advanced or metastatic BTC. Participants whose disease has recurred ≥ 6 months after completion of neoadjuvant or adjuvant treatments will be considered eligible.
• Availability of tumor tissue (primary or metastatic) (fresh or archival biopsies) before the first administration of study intervention. Availability of tumor tissue is mandatory except for the safety run-in part. Brush cytology and cell blocks are not acceptable. Tumor tissue (fresh or archival) must be suitable for biomarker assessment as described in the Laboratory Manual.
• At least 1 measurable lesion according to RECIST 1.1. Participants in the safety run-in part do not require a measurable lesion at baseline.
• ECOG PS of 0 or 1 at study entry and at Week 1, Day 1 prior to dosing.
• Life expectancy of ≥ 12 weeks, as judged by the Investigator.
•  Adequate hematological function defined by white blood cell count ≥ 2.0 × 10^9 /L with absolute neutrophil count ≥ 1.5 × 10^9 /L, lymphocyte count ≥ 0.5 × 10^9 /L, platelet count ≥ 100 × 10^9 /L, and hemoglobin (Hgb) ≥ 9 g/dL (participants may have been transfused) at study entry and at Week 1 Day 1 prior to dosing.
  • Previously transfused participants are allowed in the study with a stable Hgb of ≥ 9 g/dL at the time of study entry.
• Adequate hepatic function defined by a total bilirubin level ≤ 1.5 × upper limit of normal (ULN), an aspartate aminotransferase level ≤ 3.0 × ULN, and an alanine aminotransferase level ≤ 3.0 × ULN. For participants with liver involvement, aspartate aminotransferase ≤ 5.0 × ULN and alanine aminotransferase ≤ 5.0 × ULN are acceptable.
• Adequate renal function defined by an estimated creatinine clearance (CrCl) > 50 mL/min according to the Cockcroft-Gault formula or by measure of CrCl from 24-hour urine collection.
  • CrCl (mL/min) = (140-age) × weight (kg) / (72 × serum creatinine Cr[jaffe]);
  • If female, × 0.85 ;
  • If creatinine is measured by the enzymatic method, add 0.2 and use as Cr[jaffe] = 0.2 + Cr[enzyme].
• Albumin ≥ 2.8 g/dL.
• Adequate coagulation function defined as prothrombin time or international normalized ratio ≤ 1.5 × ULN unless the participant is receiving anticoagulant therapy.
• Hepatitis B virus (HBV) deoxyribonucleic acid (DNA) positive participants must be treated and on a stable dose of antivirals (e.g., entecavir, tenofovir, or lamivudine; adefovir or interferon is not allowed) at study entry and with planned monitoring and management including baseline HBV DNA quantity according to appropriate labeling guidance. Participants receiving active hepatitis C virus (HCV) therapy must be on a stable dose at study entry and with planned monitoring and management according to appropriate labeling guidance of approved antiviral.
• Are male or female:
  • Male Participants Agree to the following during the intervention period and for at least 4 months after the last dose of study intervention (35 days corresponding to the time needed to eliminate any study interventions; e.g., 5 terminal half-lives plus 90 days for spermatogenic cycle):
    • Refrain from donating sperm PLUS, either:  Abstain from any activity that allows for exposure to ejaculate; OR
    • Use a male condom:  When having sexual intercourse with a woman of childbearing potential who is not currently pregnant, and advise her to use a highly effective contraceptive method with a failure rate of < 1% per year since a condom may break or leak;
    • When engaging in any activity that allows for exposure to ejaculate.
  • Female participants are not pregnant or breastfeeding and at least 1 of the following conditions applies: Not a woman of childbearing potential; OR
  • If a woman of childbearing potential, agree to use a highly effective contraceptive method (i.e., with a failure rate of < 1% per year), preferably with low user dependency for the following time periods: 
    Before the first dose of study intervention(s), if using hormonal contraception:
    • Has completed at least one 4-week cycle of an oral contraceptive pill and has either had or has begun her menses; OR
    • Has used a depot contraceptive or extended-cycle contraceptive for at least 28 days and has a documented negative pregnancy test using a highly sensitive assay;
    • During the intervention period;
    • After the study intervention period (i.e., after the last dose of study intervention is administered) for at least 65 days (time needed to eliminate any study interventions, eg, 5 terminal half-lives plus 30 days for a menstrual cycle), and as indicated in the respective label (Summary of Product Characteristics [SmPC]) for gemcitabine and cisplatin. Participants have to agree to the following:
      • Women of childbearing potential should refrain from donating eggs from the start of dosing until 2 months after discontinuing study intervention.
      • The Investigator evaluates the effectiveness of the contraceptive method in relationship to the first dose of study intervention.
    • Have a negative serum or highly sensitive urine pregnancy test, as required by local regulations, within 24 hours before the first dose of study intervention. If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required.
    • The Investigator reviews the medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a female with an early, undetected pregnancy.
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the Informed Consent Form (ICF) and this protocol.

• Previous and/or intercurrent cancers. With the exception of: curatively-treated cancers with no recurrence in > 3 years or early cancers treated with curative intent, including but not limited to cervical carcinoma in situ, superficial, noninvasive bladder cancer, basal cell carcinoma, squamous cell carcinoma in situ, or endoscopically resected gastrointestinal cancers limited in mucosal layer.
• Rapid clinical deterioration not related to malignancy which, in the opinion of the Investigator, may predispose to inability to tolerate treatment or study procedures at study entry and at Week 1 Day 1 prior to dosing.
• Participants with symptomatic central nervous system (CNS) metastases are excluded. Participants with a history of treated CNS metastases (by surgery or radiation therapy) are not eligible unless they are judged to have fully recovered from treatment.
• Receipt of any organ transplantation, including allogeneic stem-cell transplantation, but with the exception of transplants that do not require immunosuppression (e.g., corneal transplant, hair transplant).
• Significant acute or chronic infections including:
  • Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (testing at Screening is not required). If an Investigator has a strong suspicion of HIV infection without known history for a participant in screening, but the participant refuses testing, discuss with Medical Monitor to assess eligibility.
    • Note: HIV testing is not mandated for study inclusion; however, if it is performed at any point in screening or while on study, a site must consent the participant for HIV testing as per local standard guidance.
    • Active tuberculosis (presence of clinical symptoms, physical or radiographic findings of active tuberculosis).
    • Uncontrolled biliary infection. Biliary tract obstruction should be released by stenting or percutaneous transhepatic biliary drainage (PTBD). Participants with biliary obstruction should have adequate biliary drainage with no evidence of ongoing infection without antibiotics treatment at the time of enrollment as well as on Cycle 1 Day 1.
    • Active bacterial, fungal, or viral infection (with the exception of hepatitis B and hepatitis C) requiring systemic therapy at study entry and at Week 1 prior to dosing.
• Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent:
  • Participants with type 1 diabetes, vitiligo, alopecia, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible. 
  • Participants requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses ≤ 10 mg of prednisone or equivalent per day.
  • Administration of steroids for other conditions through a route known to result in a minimal systemic exposure (topical, intranasal, intra-ocular, or inhalation) is acceptable.
• History of, or concurrent, interstitial lung disease.
• Known history of hypersensitivity reactions to bintrafusp alfa or its products or known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3 National Cancer Institute [NCI]-Common Terminology Criteria for Adverse Events [CTCAE] Version 5.0), any history of anaphylaxis, or recent (within 5 months) history of uncontrolled asthma.
• Clinically significant cardiovascular/cerebrovascular disease as follows: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (New York Heart Association Classification ≥ Class II), or serious cardiac arrhythmia.
• Other severe, acute, or chronic medical conditions, including immune colitis, inflammatory bowel disease, immune pneumonitis, or psychiatric conditions, including recent (within the past year) or active suicidal ideation or behavior. Participants with history of bleeding diathesis or recent major bleeding events considered by the Investigator as high risk for study intervention are also excluded.
• Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days before randomization.
• Participants who are candidates for liver transplantation and who can receive the transplantation within a medically acceptable period.
• Concurrent treatment with nonpermitted drugs. Participants who have completed prior adjuvant therapy > 6 months prior to randomization are eligible.
• Prior therapy with any antibody/drug targeting T-cell coregulatory proteins (immune checkpoints), including but not limited to anti-PD-1, anti-PD-L1, anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody, or anti-4-1BB antibody is not allowed, inclusive of localized administration of such agents.
• Prior therapy with any antibody/drug targeting TGFβ/TGFβ receptor.
• Radiation within 28 days other than focal palliative bone-directed radiotherapy.
• Systemic therapy with immunosuppressive agents within 7 days before the start of study intervention; or use of any investigational drug within 28 days before the start of study intervention.
• Live vaccine administration within 4 weeks of study intervention administration.
• Unable to tolerate CT or magnetic resonance imaging (MRI) in the opinion of the Investigator and/or allergy to contrast material.

Other Exclusions:

• Major surgery within 28 days before the start of study intervention (excluding prior diagnostic biopsy and stenting/PTBD for the purpose of releasing biliary tract obstruction).
• Pregnancy or breastfeeding.
• Known alcohol or drug abuse.
• Legal incapacity or limited legal capacity.

• Recurrent or progressive advanced stage non-small cell lung cancer (no small cell component) with most recent treatment being an FDA approved immune checkpoint inhibitor (pembrolizumab, atezolizumab, or nivolumab).
  • NOTE: Pathology reports documenting the diagnosis of NSCLC are required to be reviewed to confirm outside diagnosis.
• Sufficient tumor tissue available from original diagnosis or subsequent biopsy for analysis of estrogen receptor and aromatase.
• Tumor block or a minimum of 5 unstained slides.
• Failed at least 1 prior FDA approved treatment for advanced NSCLC. 
• Measureable disease by RECIST version 1.1.
• Post-menopausal defined as:
  • Age ≥ 55 years and 1 year or more of amenorrhea;
  •  Age < 55 years and 1 year or more of amenorrhea with an estradiol assay < 20 pg/mL;
  • Surgical menopause with bilateral oophorectomy.
• ECOG performance status 0, 1 or 2.
• Life expectancy of 3 months or more in the opinion of the enrolling investigator and documented in the medical record. 
• Adequate organ function within 14 days of study enrollment defined as: 
• Hematology:
  • Absolute neutrophil count (ANC) ≥ 1500/mm³;
  • Platelets ≥ 100,000/mm³;
  • Hemoglobin ≥ 8 g/dL.
• Biochemistry: 
  • Total Bilirubin within normal institutional limits.
  • AST/SGOT and ALT/SGPT ≤ 2.5 x upper limit of normal (ULN), except if there is known hepatic metastasis, wherein transaminases may be ≤ 5 x institutional ULN.
  • Serum creatinine ≤ 1.5 mg/dl or glomerular filtration rate > 50 ml/min.
• Must have recovered to CTCAE v 4 Grade 1 or better from the acute effects of any prior surgery, chemotherapy or radiation therapy. Chronic residual toxicity (i.e., peripheral neuropathy) is permitted. 
• A minimum time period must elapse between the end of a previous treatment and start of study therapy: 
  • 1 week from the completion of radiation therapy for brain metastases;
  • 4 weeks from the completion of chemotherapy or any experimental therapy;
  • 4 weeks from prior major surgery (such as open biopsy or significant traumatic injury).
• Voluntary written consent before any research related procedures or therapy.

• Known active CNS disease.
• If patient has history of brain metastases, the brain lesions must have been treated with radiation and/or surgery.
• Patients should be neurologically stable and requiring ≤ 10mg oral prednisone equivalence of steroids per day.
• Any toxicity from immune-related toxicity from prior immune therapy that would preclude further treatment with anti-PD-1/PDL-1 inhibitor or ongoing IR toxicity ≥ Grade 2.
• Requiring > 10 mg prednisone equivalence of steroids per day for immune-related toxicity.
• Inability or unwilling to swallow study drug.
• Any gastrointestinal condition causing malabsorption or obstruction (e.g., celiac sprue, gastric bypass surgery, strictures, adhesions, history of small bowel resection, blind loop syndrome).
• Currently using hormone replacement therapy (oral or patch) or/and phytoestrogen supplements (i.e., black cohosh).
• Known hypersensitivity to exemestane or its excipients.
• Any serious underlying medical condition that, in the opinion of the enrolling physician, would impair the ability of the patient to receive protocol treatment.
• Prior malignancy, with the exception of curatively treated squamous cell or basal carcinoma of the skin or in situ cervical cancer, unless there is a 3-year disease-free interval.
• Concomitant use of strong CYP3A4 inducers such as rifampicin, phenytoin, carbamazepine, phenobarbital, or St. John's wort as these may significantly reduce the availability of exemestane.

• Recurrent or progressive advanced stage non-small cell lung cancer (no small cell component) with most recent treatment being an FDA approved immune checkpoint inhibitor (pembrolizumab, atezolizumab, or nivolumab).
  • NOTE: Pathology reports documenting the diagnosis of NSCLC are required to be reviewed to confirm outside diagnosis.
• Sufficient tumor tissue available from original diagnosis or subsequent biopsy for analysis of estrogen receptor and aromatase.
• Tumor block or a minimum of 5 unstained slides.
• Failed at least 1 prior FDA approved treatment for advanced NSCLC. 
• Measureable disease by RECIST version 1.1.
• Post-menopausal defined as:
  • Age ≥ 55 years and 1 year or more of amenorrhea;
  •  Age < 55 years and 1 year or more of amenorrhea with an estradiol assay < 20 pg/mL;
  • Surgical menopause with bilateral oophorectomy.
• ECOG performance status 0, 1 or 2.
• Life expectancy of 3 months or more in the opinion of the enrolling investigator and documented in the medical record. 
• Adequate organ function within 14 days of study enrollment defined as: 
• Hematology:
  • Absolute neutrophil count (ANC) ≥ 1500/mm³;
  • Platelets ≥ 100,000/mm³;
  • Hemoglobin ≥ 8 g/dL.
• Biochemistry: 
  • Total Bilirubin within normal institutional limits.
  • AST/SGOT and ALT/SGPT ≤ 2.5 x upper limit of normal (ULN), except if there is known hepatic metastasis, wherein transaminases may be ≤ 5 x institutional ULN.
  • Serum creatinine ≤ 1.5 mg/dl or glomerular filtration rate > 50 ml/min.
• Must have recovered to CTCAE v 4 Grade 1 or better from the acute effects of any prior surgery, chemotherapy or radiation therapy. Chronic residual toxicity (i.e., peripheral neuropathy) is permitted. 
• A minimum time period must elapse between the end of a previous treatment and start of study therapy: 
  • 1 week from the completion of radiation therapy for brain metastases;
  • 4 weeks from the completion of chemotherapy or any experimental therapy;
  • 4 weeks from prior major surgery (such as open biopsy or significant traumatic injury).
• Voluntary written consent before any research related procedures or therapy.

• Known active CNS disease.
• If patient has history of brain metastases, the brain lesions must have been treated with radiation and/or surgery.
• Patients should be neurologically stable and requiring ≤ 10mg oral prednisone equivalence of steroids per day.
• Any toxicity from immune-related toxicity from prior immune therapy that would preclude further treatment with anti-PD-1/PDL-1 inhibitor or ongoing IR toxicity ≥ Grade 2.
• Requiring > 10 mg prednisone equivalence of steroids per day for immune-related toxicity.
• Inability or unwilling to swallow study drug.
• Any gastrointestinal condition causing malabsorption or obstruction (e.g., celiac sprue, gastric bypass surgery, strictures, adhesions, history of small bowel resection, blind loop syndrome).
• Currently using hormone replacement therapy (oral or patch) or/and phytoestrogen supplements (i.e., black cohosh).
• Known hypersensitivity to exemestane or its excipients.
• Any serious underlying medical condition that, in the opinion of the enrolling physician, would impair the ability of the patient to receive protocol treatment.
• Prior malignancy, with the exception of curatively treated squamous cell or basal carcinoma of the skin or in situ cervical cancer, unless there is a 3-year disease-free interval.
• Concomitant use of strong CYP3A4 inducers such as rifampicin, phenytoin, carbamazepine, phenobarbital, or St. John's wort as these may significantly reduce the availability of exemestane.

• Have active, relapsed or refractory AML. Active, relapsed or refractory AML is defined as any one of the following:
  • primary induction failure (PIF) after 2 or more cycles of therapy; or
  • first early relapse after a remission duration of fewer than 6 months; or
  • relapse refractory to salvage combination therapy; or
  • second or subsequent relapse (Schmid, 2006).
• Have documented CD45 expression by leukemic cells via flow cytometry (a “blast gate” on CD45 vs. side scatter analysis consist.nt with AML);
• Be ≥ 55 years of age.
• Have a circulating blast count of less than 10,000/mm^3 (control with hydroxyurea is allowed).
• Have a calculated creatinine clearance (Cockroft-Gault equation) > 50 mL/min.
• Have adequate hepatic function (direct bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT), defined as ≤ 2 times the upper limit of normal [ULN]).
• Have a Karnofsky score ≥ 70.
• Have an expected survival of > 60 days.
• Have a central venous catheter line in place prior to study treatment administration.
• Have 8/8 allele-level, related or unrelated, HSC donor matching at human leukocyte antigen (HLA)-A, HLA-B, HLA-C, and DRB1 with a donor who is medically cleared.
• Syngeneic donors that meet these criteria are allowed.
• Women of childbearing potential, be surgically sterile or agree to practice abstinence or utilize acceptable contraception (intrauterine, injectable, transdermal, or combination oral contraceptive) through 1-year post transplant; Males who are sexually active with women of childbearing potential must be surgically sterile or using an acceptable method of contraception (defined as barrier methods in conjunction with spermicides) from time of screening through 12 weeks after last dose of study drug.
• Be able to understand the study procedures, agree to participate in the study program, and voluntarily provide written Informed Consent.

Exclusion Criteria: 

• Have circulating HAMA noted on initial screening.
• Have received prior radiation to maximally tolerated levels to any critical normal organ.
• Have active leukemic central nervous system (CNS) involvement, as defined by any leukemic blasts detected in the cerebrospinal fluid (CSF) by morphology or flow cytometry and/or any chloromas detected by CNS imaging.
• Have previously received a HCT (includes both allogeneic and autologous HCT).
• Clinically significant cardiac disease (NYHA Class III or IV); clinically significant arrhythmia; i.e., ventricular tachycardia, ventricular fibrillation, or “Torsade de Pointes”. Myocardial infarction with uncontrolled angina within 6 months, congestive heart failure, or clinically significant cardiomyopathy.
• Have abnormal QTcF (> 450 milliseconds) after electrolytes have been corrected (at least two different ECG readings and at least 15 minutes between readings). Subjects with paced rhythm or prolonged QTcF may be exempt from this exclusion if considered eligible for transplant per treating physician clinical judgment, with optional cardiology consultation.
• Have current or prior positive test results for human immunodeficiency virus (HIV) or hepatitis B (HBV) or C. Subjects who have positive HBV test results due to having been previously vaccinated against hepatitis B, as evidenced by negative hepatitis B surface antigen (HBsAg), negative anti- hepatitis B core protein (HBc) and positive antibody to the HBsAg (anti-HBs) are not excluded; Subjects who have positive hepatitis test results with adequate organ function as defined in the protocol are not excluded.
• Have active serious infection uncontrolled by antibiotics or antifungals.
• Have acute promyelocytic leukemia and the associated cytogenetic translocation t(15;17).
• Have active malignancy within 2 years of entry. Active malignancy is defined as those malignancies requiring treatment with anti-cancer therapy or in the event of indolent malignancies, having measurable disease.  Exceptions to this exclusion include:
  • myelodysplastic syndrome;
  • treated non-melanoma skin cancer;
  • completely resected Stage 0 or 1 melanoma no less than 1 year from resection;
  • carcinoma in situ or cervical intraepithelial neoplasia;
  • successfully treated organ-confined prostate cancer with no evidence of progressive disease based on prostate specific antigen (PSA) levels and are not on active therapy;
• Have a perceived inability to tolerate diagnostic or therapeutic procedures, particularly treatment in radiation isolation.
• Currently receiving any other active investigational agents.

• Adult patients, 18 years or older.
• Previous participation in an Astex-sponsored ASTX727 clinical trial (including, but not limited to studies ASTX727-01, ASTX727-02, and ASTX727-04) in which the subject was treated with ASTX727 and was still on active treatment with ASTX727 at the time of study completion as determined by Astex. 
• Subject is considered to be benefitting from ASTX727 treatment in the opinion of the treating investigator at the time of parent study completion (subjects must not be withdrawn from the parent study until eligibility for this study is confirmed). 
• Subject is able to understand and comply with the study procedures and understands the risks involved in the study. 
• Subject provides written informed consent before undergoing any study-specific procedure.
• Women of childbearing potential must not be pregnant or breastfeeding and must have a negative pregnancy test at screening. Women of childbearing potential must agree to practice 2 highly effective contraceptive methods of birth control and must agree not to become pregnant for 6 months after completing treatment; men with female partners of childbearing potential must agree to practice 2 highly effective contraceptive measures and must agree not to father a child while receiving ASTX727 and for at least 3 months after completing ASTX727 treatment.

• Any subject who, in the opinion of the investigator, may have other conditions, organ dysfunction, or for whom safety data from parent study participation suggests the risks of continuing treatment with ASTX727 may outweigh the benefits.

• 18 years of age or older.
• Able to read, write and understand English.
• Undergoing chemotherapy, radiation therapy, CAR-T, or bone marrow transplant for a cancer diagnosis within the previous 3 years or have metastatic cancer.
• A mean score of at least 1.1 on the Cancer and Treatment Distress (CTxD) or at least one item rated at a 3 (often true) or 4 (nearly all the time).
• A minimum score of 3 on the PC-PTSD-5.
• Denial of suicidal ideation or intent, with no evidence of psychotic behavior.
• Participants must be willing and able to travel to Mayo Clinic outside of normally scheduled visits to participate in the study.

• Individuals under 18 years of age.

• Age > 22 years (minimum age approved for use).
• Polypoid (0-Is) and non-polypoid (0-IIa, 0-IIb and 0-IIc) lateral spreading lesions according to Paris classification.
• Colorectal lesions situated between 5 and 15 cm from the dentate line.
• Colorectal mucosal lesions ranging from 1.5 to 7 cm in maximum diameter.
• Colorectal subepithelial lesions < 2 cm in size.
• Absence of uncorrectable bleeding disorder or coagulopathy (platelet count > 50,000 and INR < 1.5).
• Ability to give informed consent.

• Inability to receive general anesthesia.
• Presence of medical conditions for which a transanal approach is contraindicated (e.g., anal stricture, radiation proctopathy).
• Excavated (0-III) colorectal lesions according to Paris classification.
• Suboptimal colon preparation.
• Clinical discretion of the provider.

• Biopsy-proven histological diagnosis of localized prostate cancer (pT2 or specimen confined pT3).
• Having undergone radical prostatectomy (open or laparoscopic) with bilateral pelvic lymph node dissection.
• Negative surgical margins on final specimen.
• Men that decline adjuvant therapy.
• Detectable serum PSA of 0.1 ng/mL or >.
• 24 months or less since radical prostatectomy at time of study screening.

• Unable or unwilling to provide informed consent.
• Treated prior to surgery with any form of hormone, antiandrogen, or androgen deprivation therapy.
• Treated prior to surgery with any form of chemotherapy or radiotherapy.
• Medical conditions/history that precludes subjects from following a fasting regimen including, but not limited to:
  • Diabetes Mellitus.
• On hormone therapy (Casodex, GnRH agonist/antagonist).

• Age ≥ 18 years.
• Histological confirmation of adenocarcinoma of the pancreas (head, body, or tail of pancreas).
• Imaging consistent with T1-4, N0-2,  M0 pancreas cancer, including potentially resectable, borderline resectable, or unresectable disease as per NCCN classification. When CT of the chest, abdomen, and pelvis are performed, this must be with contast per pancreas protocol. Imaging with a PET/MRI alone is acceptable on study. If a PET/CT is performed, a separate pancreas protocol CT is required for inclusion.
  • *Note: Imaging must be done prior to initiation of radiotherapy and does not need to be completed at time of enrollment.
• Must have received neoadjuvant chemotherapy at the discretion of medical oncology.
• Medical oncology consultation to confirm that patient is an appropriate candidate for concurrent chemotherapy, and surgical oncology consultation for confirmation of resection status.
  • Note: Consultation must be completed prior to initiation of radiotherapy and does not need to be completed at time of enrollment.
• Patients who have received previous chemotherapy for pancreatic cancer are allowed to participate in this study, unless they experienced a previous allergic reaction to the drugs used in this study.
• Planned to receive CRT, consisting of PBT or IMRT (45 Gy/15 fractions) with concurrent chemotherapy with 5 FU or Capecitabine.
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1 or Karnofsky Performance Status 70-100. 
• Willing to sign consent onto the Mayo Clinic Radiotherapy Patient Outcomes Registry and Biobanking study, IRB 15-000136*.
  • *Patients do not need to agree to Biobank blood draw. 
• Able to complete standard of care clinical questionnaire(s) by themselves or with assistance.

• Presence of non-regional nodal involvement or distant metastatic disease (M1).
• Prior radiotherapy resulting in overlap of radiation treatment fields.
• History of prior malignancy < 2 years of enrollment, except non-melanotic skin cancer or carcinoma-in-situ of the cervix.
• Immunocompromised patients and patients known to be HIV positive and not currently receiving antiretroviral therapy. 
  • Note: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial.
• Receiving any investigational agent concurrent with CRT which would be considered as a treatment for the primary neoplasm.
• Any of the following because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects:
  • Pregnant women;
  • Nursing women;
  • Men or women of childbearing potential who are unwilling to employ adequate contraception.
• Co-morbid systemic or psychiatric illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.        
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

• 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 7 days at the start of therapy.
• Laboratory tests need not be repeated if therapy starts within 7 days of obtaining labs to assess eligibility.
• If a post-enrollment lab value is outside the limits of eligibility, or laboratory values are > 7 days old, then laboratory evaluations must be re-checked within 48 hours prior to initiating therapy. If the recheck is outside the limits of eligibility, the patient may not receive protocol therapy and will be considered off protocol therapy.
• A pre- and post-operative brain MRI with and without contrast, and a baseline spine MRI with contrast, must be obtained prior to enrollment. The requirement for post-operative MRI is waived for patients who undergo biopsy only.
• Patients must be ≥ 3 years and ≤ 21 years of age at the time of enrollment.
• Patients must have eligibility confirmed by Rapid Central Pathology and Molecular Screening Reviews performed on APEC14B1:
  • Newly diagnosed high-grade glioma with BRAFV600-mutation;
  • Positive or negative results for H3 K27M by immunohistochemistry (IHC)
  • Histologically confirmed high-grade glioma (WHO Grade III or IV) including but not limited to: anaplastic astrocytoma (AA), anaplastic pleomorphic xanthoastrocytoma (aPXA), anaplastic gangliogliomas (aGG), glioblastoma (GB), and high-grade astrocytoma, NOS.
• Patients must have had histologic verification of a high-grade glioma diagnosis. CSF cytology by lumbar puncture must be done if clinically indicated and determined to be safe prior to study enrollment. If cytology proves positive, the patient would be considered to have metastatic disease and would, therefore, be ineligible.
• A pre- and post-operative brain MRI with and without contrast and a baseline spine MRI with contrast must be obtained prior to enrollment. The requirement for a post-operative MRI is waived for patients who undergo biopsy only. If the spine MRI is positive, the patient would be considered to have metastatic disease and would be ineligible.
• 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. See https://www.cogmembers.org/site/pages/default.aspx?page=Prot_reference_materials under Standard Sections for Protocols.
• Adequate Bone Marrow Function defined as:
  • Peripheral absolute neutrophil count (ANC) ≥ 1000/µL;
  • Platelet count ≥ 100,000/µL (transfusion independent);
  • Hemoglobin ≥ 8.0 g/dL (may receive RBC transfusions).
• Adequate Renal Function defined as:
  • Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73 m^2; or
  • A serum creatinine based on age/gender as follows:
  • 3 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 GFR32 utilizing child length and stature data published by the CDC.
  • 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 a seizure disorder may be enrolled if their seizures are well controlled while on non-enzyme inducing anticonvulsants permitted on this study.
• Patients must be enrolled and protocol therapy must be projected to begin no later than 31 days after definitive surgery (Day 0). If a biopsy only was performed, the biopsy date will be considered the date of definitive surgery. For patients who have a biopsy or incomplete resection at diagnosis followed by additional surgery, the date of the last resection will be considered the date of definitive surgery.

• Patients with intrinsic brainstem or primary spinal cord tumors will be excluded.
• Patients with metastatic disease (defined as neuraxis dissemination either by imaging or by cytology) will be excluded.
• Patients must not have received any prior tumor-directed therapy including chemotherapy, radiation therapy, immunotherapy, or bone marrow transplant for the treatment of HGG other than surgical intervention and/or corticosteroids.
• Previous treatment with dabrafenib or another RAF inhibitor, trametinib or another MEK inhibitor, or an ERK inhibitor.
• Patients with a history of a malignancy with confirmed activating RAS mutation.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to dabrafenib, trametinib, and their excipients.
• Uncontrolled medical conditions (e.g., diabetes mellitus, hypertension, liver disease, or uncontrolled infection), psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol; or unwillingness or inability to follow the procedures required in the protocol.
• Presence of active gastrointestinal (GI) disease or other condition (e.g., small bowel or large bowel resection) that will interfere significantly with the absorption of drugs.
• History of Hepatitis B Virus, or Hepatitis C Virus infection (patients with laboratory evidence of cleared Hepatitis B Virus and/or Hepatitis C Virus may be enrolled).
• History or current diagnosis of cardiac disease indicating significant risk of safety for patients participating in the study such as uncontrolled or significant cardiac disease, including any of the following:
  • Recent myocardial infarction (within the last 6 months);
  • Uncontrolled congestive heart failure;
  • Unstable angina (within last 6 months);
  • Clinically significant (symptomatic) or known, uncontrolled cardiac arrhythmias (e.g., sustained ventricular tachycardia, and clinically significant second or third degree AV block without a pacemaker) except sinus arrhythmia within the past 24 weeks prior to the first dose of study treatment;
  • Coronary angioplasty or stenting (within last 6 months);
  • Intra-cardiac defibrillators;
  • Abnormal cardiac valve morphology (≥ Grade 2) documented by echocardiogram.
• Patients with a history or current evidence of retinal vein occlusion (RVO) or central serous retinopathy (CSR), or predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension).
• Patients with presence of interstitial lung disease or pneumonitis.
• Female patients who are pregnant are ineligible since there is yet no available information regarding human fetal or teratogenic toxicities.
• Lactating females are not eligible unless they have agreed not to breastfeed their infants for the duration of the study and for 4 months following discontinuation of study therapy.
• Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained.
• Sexually active patients of reproductive potential (male or female) are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation and for 4 months following discontinuation of study therapy. Male patients (including those who have had a vasectomy) taking dabrafenib and trametinib combination therapy must use a condom during intercourse while on study and for 16 weeks after stopping treatment, and should not father a child during these periods. Women of childbearing potential should use. effective non-hormonal contraception during therapy and for 4 weeks following discontinuation of dabrafenib and at least 4 months following the last dose of trametinib in patients taking combination therapy.  Women should be advised that dabrafenib may decrease the efficacy of hormonal contraceptives and an alternate method of contraception, such as barrier methods, should be used.
• All patients and/or their parents or legal guardians must sign a written informed consent.
• All institutional, FDA, and NCI requirements for human studies must be met.

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

For Patients with CLL

• Confirmed diagnosis of chronic lymphocytic leukemia (CLL).
• Must have received at least two (2) prior therapy regimens.
• Patients with Richter's transformation should have failed standard therapy.

For Patients with NHL

• Histologically confirmed diagnosis of B- or T-cell non-Hodgkins lymphoma (NHL).
• Must have a site of disease amenable to biopsy, and be suitable and willing to undergo study required biopsies at screening and during therapy.
• The histologic subtypes of NHL that are permitted in the dose escalation part were specified.
• Must have received at least two (2) prior therapy regimens.
• Patients with indolent lymphoma must have received and failed standard-of-care therapy or be intolerant or ineligibile to approved therapies and must be in need of therapeutic intervention.
• Patients with prior CART T-cell therapy will be permitted on this trial 30 days after CART infusion and meet protocol defined inclusion/exclusion criteria.

Exclusion Criteria:

Applicable to both CLL and NHL

• History of anaphylactic or other severe hypersensitivity/infusion reactions to ADCs, monoclonal antibodies (mAbs) and/or their excipients such that the patient in unable to tolerate immunoglobulin/monoclonal antibody administration.
• Any prior history of treatment with maytansine (DM1 or DM4)-based ADC.
• Known intolerance to a maytansinoid.
• Patients with any active or chronic corneal disorders.
• Patients who have any other condition that precludes monitoring of the retina or fundus.
• Patients with active CNS involvement are excluded, except if the CNS involvement has been effectively treated and provided that local treatment was > 4 weeks before enrollment. Patients that have been effectively treated for CNS disease and are stable under systemic therapy may be enrolled provided all other inclusion and exclusion criteria are met.
• Impaired cardiac function or clinically significant cardiac disease.
• Known history of Human Immunodeficiency Virus (HIV) infection, Active Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection.

• Age ≥ 18 years on day of signing informed consent.
• Specific by tumor cohorts:
  • For the HCC cohort, confirmed diagnosis of inoperable HCC by histology or clinical/radiological criteria:
    • No prior therapy with a PD-(L)1 immune checkpoint inhibitor (prior sorafenib is permitted);
    • No or one prior line of systemic therapy only;
    • Child Pugh Score A or B7.
  • For the NSCLC cohort, histologically confirmed diagnosis of advanced and/or metastatic NSCLC in which radiological progression has been demonstrated during therapy with a PD(L)1 immune CPI and for which no existing options are felt to provide clinical benefit (only one line of PD-(L)1 therapy is permitted). Progression during or following 1 or more prior regimen(s) and no more than 3 prior therapeutic regimens for metastatic disease.
  • For the melanoma cohorts, histologically confirmed diagnosis of advanced and/or metastatic melanoma in which radiological progression has been demonstrated during therapy with a PD(L)1 immune CPI and for which no existing options are considered to provide clinical benefit (only one line of PD(L)1 therapy is permitted). Progression on ipilimumab is not required.
    • For the IT melanoma cohort:
      • At least one tumor lesion amenable to repeated IT injection via palpation or ultrasound. Injection of deep visceral lesions is not permitted;
      • Agrees to provide a newly obtained biopsy of injected and witness lesions prior to start of study treatment, and to repeat biopsies twice during study treatment, and to providing the acquired tissue for biomarker analysis. Tissue obtained for the biopsy must not be previously irradiated, but a new or progressing lesion in the radiation field is acceptable.
    • For the endometrial cancer cohort, histologically confirmed diagnosis of advanced and/or metastatic endometrioid endometrial adenocarcinoma. Eligible patients will not have had any prior systemic therapy in the metastatic setting.
• For patients treated with prior anti-PD-(L)1 therapy:
  • Last dose of anti-PD-(L)1 must be within 12 weeks of initiating study treatment.;
  • Patient must have received at least 4 doses on q2w, 3 doses on q3w or 2 doses on q4w schedule of the previous anti-PD-(L)1 therapy;
  • Progression on prior anti-PD-(L)1 therapy must be defined by:
    • Documented radiographic progression on a single radiographic scan, if treatment with anti-PD-(L)1 was ≥ 16 weeks;
    • Documented radiographic progression on two consecutive radiographic scans at least 4 weeks apart, if treatment with anti-PD-(L)1 therapy was between 8
      •16 weeks; if radiographic progression is accompanied with clinical progression, then a single scan assessment may be used;
    • If progression was only in lymph nodes, biopsy to provide histological confirmation of progression in the lymph node is required.
• Measurable disease based on RECIST 1.1.

Patients meeting any of the following exclusion criteria at Screening/Day-1 of first dosing will not be enrolled in the study.

• Availability of and patient acceptance of an alternative curative therapeutic option.
• Recent or ongoing serious infection, including any active Grade 3 or higher per the National Institute of Cancer Common Terminology Criteria for Adverse Events Version 5.0 (NCI CTCAE, v5.0) viral, bacterial, or fungal infection within 2 weeks of registration.
• Known seropositivity for and with active infection by the human immunodeficiency virus (HIV):
  • Patients who are seropositive for HIV but are receiving antiviral therapy and show non-detectable viral load and a normal CD4 T cell count for at least 6 months are eligible;
  • Seropositive for and with evidence of active viral infection with hepatitis B virus (HBV);
  • Patients who are hepatitis B surface antigen (HBsAg) negative and HBV viral DNA negative are eligible;
  • Patients who had HBV but have received an antiviral treatment and show non-detectable viral DNA for 6 months are eligible;
  • Patients who are seropositive because of HBV vaccine are eligible.
• Seropositive for and with active viral infection with hepatitis C virus (HCV):
  • Patients who had HCV but have received an antiviral treatment and show no detectable HCV viral DNA for 6 months are eligible.
• Known history of active or latent TB (bacillus tuberculosis).
• Any concomitant serious health condition, which, in the opinion of the investigator, would place the patient at undue risk from the study, including uncontrolled hypertension and/or diabetes, clinically significant pulmonary disease (e.g., chronic obstructive pulmonary disease requiring hospitalization within 3 months) or neurological disorder (e.g., seizure disorder active within 3 months).
• Prior therapy within the following timeframe before the planned start of study treatment as follows:
  • Small molecule inhibitors, and/or other investigational agent: ≤ 2 weeks or 5 half-lives, whichever is shorter;
  • Chemotherapy, other monoclonal antibodies, antibody-drug conjugates, or other similar experimental therapies:
    • ≤ 3 weeks or 5 half-lives, whichever is shorter;
    • Antibody drug conjugates and radioimmunoconjugates or other similar experimental therapies ≤ 6 weeks or 5 half-lives, whichever is shorter.
• New York Heart Association (NYHA) classification III or IV, known symptomatic coronary artery disease, or symptoms of coronary artery disease on systems review, or known cardiac arrhythmias (atrial fibrillation or supraventricular tachycardia).
• Any known or suspected active organ-threatening autoimmune disease, such as inflammatory bowel disease, autoimmune hepatitis, lupus, or pneumonitis, with the exception of hypothyroidism and type 1 diabetes that are controlled with treatment .
• Immunodeficiency or immunosuppression.
• History of Grade 3 or 4 immune-mediated adverse reaction to immune CPIs.
• Toxicities from previous therapies that have not resolved to a Grade 1 or less.
• History of non-infectious pneumonitis that required steroids, or current pneumonitis.

• Have a projected life expectancy of at least 12 weeks, as assessed by the Investigator.
• Have histological confirmation of AML by World Health Organization (WHO) 2016 criteria and are either:
  • refractory to intensive induction chemotherapy; OR
  • relapsed after intensive induction chemotherapy or stem cell transplant; OR
  • relapsed after or refractory to treatment with molecularly targeted and/or low-intensity chemotherapeutic regimens.
• Have an Eastern Cooperative Oncology Group (ECOG) Performance status of 0 to 2.
• Have adequate renal function as demonstrated by measured or calculated creatinine clearance ≥ 60 mL/min.
• Have adequate liver function as demonstrated by:
  • Aspartate aminotransferase (AST) ≤ 2.5 × upper limit of normal (ULN);
  • Alanine aminotransferase (ALT) ≤ 2.5 × ULN;
  • Bilirubin ≤ 1.5 × ULN
    •unless considered due to leukemic organ involvement.
• Women of child-bearing potential (according to recommendations of the Clinical Trial Facilitation Group [CTFG]) must not be pregnant or breastfeeding and must have a negative pregnancy test at screening.

• Poor medical risk in the investigator's opinion because of systemic diseases in addition to the cancer under study, for example, uncontrolled infections.
• Known clinically active central nervous system (CNS) leukemia.
• BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast crisis).
• Diagnosis of acute promyelocytic leukemia (M3 AML or APML).
• Second malignancy currently requiring active therapy, except breast or prostate cancer stable on or responding to endocrine therapy.
• Graft Versus Host Disease (GVHD), or any GVHD requiring treatment with immunosuppression. Any GVHD treatment (including calcineurin inhibitors) must be discontinued at least 28 days prior to Day 1 of study treatment.
• Presence of persistent toxicities of Grade > 1 from prior treatment including chemotherapy, targeted therapy, immunotherapy, experimental agents, radiation, and surgery (except for alopecia).
• Hypersensitivity to decitabine, ASTX727, ASTX660, or any of their excipients.
• Liver cirrhosis, or chronic liver disease Child-Pugh Class B or C.
• Life-threatening illness, significant organ system dysfunction, or other condition that, in the investigator's opinion, could compromise participant safety, or the integrity of study outcomes, or interfere with the absorption or metabolism of ASTX660 or ASTX727.
• History of, or at risk for, cardiac disease.
• Known human immunodeficiency virus (HIV), active hepatitis B virus (HBV), or active hepatitis C virus (HCV) infection (participants with laboratory evidence of no active replication will be permitted).
• Known significant mental illness or other conditions, such as active alcohol or other substance abuse that, in the opinion of the investigator, predispose the participant to high risk of noncompliance with the protocol treatment or assessments.
• Treated with any investigational therapy within 2 weeks of the first dose of study treatment or treatment with a myelosuppressive therapy within 4 weeks of the first dose of study treatment.
• In Parts 1 and 2, prior treatment with decitabine for more than 2 cycles. In Part 3, any treatment with an HMA (azacitidine or decitabine, for more than one cycle).
• Inability to swallow oral medication or inability or unwillingness to comply with the administration requirements related to ASTX660-02.
  • Note: G-tube administration is not allowed.

• Adult females 13-45 years of age.
• Mild or moderate von Willebrand disease (VWF:RCo < 0.50 IU/ml, past bleeding.
• Menorrhagia and a PBAC > 100 in at least one of the last two menstrual cycles.
• Regular menses, at least every 21-35 days.
• Willingness to have blood drawn/
• No prior history of an allergic reaction or anaphylaxis to rVWF or TA.
• Willingness to avoid ASA and nonsteroidal anti-inflammatory agents (NSAIDS) during the study.
• Willingness to comply with randomization to rVWF or TA study arms.
• Willingness to keep a personal diary of menorrhagia bleeding frequency duration and severity by pictorial blood assessment chart, and any drugs or hemostatic agents taken.
• Willingness to make 4 visits, undergo blood sampling for coagulation studies, and accept randomization of two therapies for each of four consecutive menstrual cycles, including an end-of-study visit.
• Willingness to use “double-barrier” method of contraception during the study.

• Any bleeding disorder other than von Willebrand disease; or past thrombotic disease
• Pregnant or lactating, or use of hormones or oral contraceptives, and contraceptive implants in past 3 months.
• Platelet count < 100,000/ul.
• Use of immunomodulatory or experimental drugs.
• Surgery within the past 8 weeks.
• Concomitant use of antiplatelet drugs, anticoagulants, dextran, aspirin or NSAIDs.
• Treatment with DDAVP, cryoprecipitate, whole blood, plasma and plasma derivatives containing VWF within 5 days of study.
• Inability to comply with study requirements.
• Hypothyroidism as defined by elevated TSH.
• Iron deficiency as defined by low serum ferritin, unless iron replacement has been initiated.
• History of renal disease.