• Pre-registration Eligibility Criteria (Step 0)
• Submission of bone marrow aspirate and peripheral blood for MRD analysis is mandatory prior to registration; the bone marrow sample should be from the first aspiration (i.e. first pull). Aspirate needle should be redirected if needed to get first pull bone marrow aspirate. It should be initiated as soon as possible after pre-registration. The specimens should be sent to the HEME Biobank.
• Lumbar Puncture (Spinal Tap) and Intrathecal Methotrexate:
• Patients may receive the day 1 of course IA dose of intrathecal (IT) methotrexate during the prior-to-registration lumbar puncture (or the venous line placement) to avoid a second lumbar puncture. If the dose is administered prior to registration, then systemic chemotherapy must begin within 7 days of this IT chemotherapy.
• Registration Eligibility Criteria (Step 1)
• Morphologic diagnosis of precursor B-cell acute lymphoblastic leukemia (ALL) based on World Health Organization (WHO) criteria. Patients with Burkitt lymphoma/leukemia are not eligible.
• CD22-positive disease defined as CD22 expression by >= 20% of lymphoblasts by local hematopathology evaluation.
• Philadelphia chromosome/BCR-ABL1-negative ALL by cytogenetics, fluorescence in situ hybridization (FISH), and/or polymerase chain reaction (PCR). If any test is positive for Philadelphia chromosome/BCR-ABL1, then the patient is ineligible.
• No active central nervous system (CNS) leukemia (i.e. only CNS-1 disease allowed). Active CNS leukemia is defined as morphologic evidence of lymphoblasts in the cerebrospinal fluid (CSF), use of CNS-directed local treatment for active disease within 28 days prior to registration, symptomatic CNS leukemia (i.e. cranial nerve palsies or other significant neurological dysfunction) within the 28 days prior to registration, and/or known asymptomatic parenchymal CNS mass lesions; see below for additional guidance. Prophylactic intrathecal medication alone is not an exclusion.
• Categories of CNS Involvement for CNS Evaluation Prior to Registration:
• CNS 1: CSF has < 5 WBC/uL with cytospin negative for blasts; or >= 10 red blood cell (RBC)/uL with cytospin negative for blasts.
• CNS 2: CSF has < 5 WBC/uL with cytospin positive for blasts; or >= 10 RBC/uL with cytospin positive for blasts; or >= 10 RBC/uL, WBC/uL >= 5 but less than Steinherz/Bleyer algorithm with cytospin positive for blasts (see below).
• CNS 3: CSF has >= 5 WBC/uL with cytospin positive for blasts; or >= 10 RBC/uL, >= 5 WBC/uL and positive by Steinherz/Bleyer algorithm (see below); or clinical signs of CNS leukemia (such as facial nerve palsy, brain/eye involvement or hypothalamic syndrome). Steinherz/Bleyer Method of Evaluating Initial Traumatic Lumbar Punctures:
• If the patient has leukemia cells in the peripheral blood and the lumbar puncture is traumatic and contains >= 5 WBC/uL with blasts, the following algorithm should be used to define CNS disease: CSF WBC/CSF RBC > 2 x (Blood WBC/Blood RBC count)
• Patients with known or suspected testicular involvement by leukemia are allowed provided that the patient receives concomitant scrotal/testicular radiotherapy.
• Unilateral or bilateral testicular enlargement should be assessed by ultrasound or other imaging technique. Biopsy is recommended if clinical findings are equivocal or suggestive of hydrocele or a non-leukemic mass, but further assessments are per treating physician discretion.
• Not pregnant and not nursing.
• This study involves agents that have known genotoxic, mutagenic, and teratogenic effects. Therefore, for women of childbearing potential only, a negative pregnancy test done =< 7 days prior to registration is required.
• Eastern Cooperative Oncology Group (ECOG) performance status: 0-2
• No unstable cardiac disease such as myocardial infarction, angina pectoris, uncontrolled heart failure, or uncontrolled cardiac arrhythmia within 6 months of registration.
• No impaired cardiac function, defined as left ventricular ejection fraction (LVEF) < 45% or New York Heart Association (NYHA) stage III or IV congestive heart failure (CHF).
• Patients with known human immunodeficiency virus (HIV) infection are eligible if they have been on effective antiretroviral therapy with an undetectable viral load tested within 6 months of registration.
• Patients with hepatitis B virus (HBV) are eligible only if they meet all the following:
• On HBV-suppressive therapy.
• No evidence of active virus.
• No evidence of HBV-related liver damage.
• Patients with hepatitis C virus (HCV) are eligible only if they meet all the following:
• Successfully completed complete-eradication therapy with undetectable viral load.
• No evidence of HCV-related liver damage.
• No history of clinically relevant neurologic disorder such as epilepsy, seizure, aphasia, stroke, severe brain injury, structural brain abnormality, benign brain tumor, dementia, Parkinson's disease, movement disorder, cerebellar disease, or other significant CNS abnormalities.
• No prior additional malignancy (i.e. in addition to ALL) except adequately treated basal- or squamous-cell skin cancer, in situ cervical cancer, stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease-free for >= 2 years.
• No history of clinically significant ventricular arrhythmia, unexplained non-vasovagal syncope, or chronic bradycardic states such as sinoatrial block or higher degree of atrioventricular block unless a permanent pacemaker has been implanted.
• No history of chronic liver disease, including cirrhosis.
• No history of sinusoidal occlusion syndrome/veno-occlusive disease of the liver.
• No uncontrolled infection or recent history (within 4 months prior to registration) of deep tissue infections such as fasciitis or osteomyelitis.
• Total bilirubin, serum =< 1.5 x upper limit of normal (ULN)*
• Except in the event of: 1) Gilbert disease, in which case total bilirubin must be =< 2 x ULN, or 2) elevated bilirubin believed by investigator to be due to leukemic infiltration, in which case total bilirubin must be =< 2 x ULN.
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN
• Creatinine, serum =< 1.5 ULN OR creatinine clearance >= 40 mL/min
• QT interval by Fridericia's correction formula (QTcF) =< 470 msec
• Cohort 1 Patients Only
• Age >= 60 years.
• No prior treatment for ALL except a single dose of intrathecal chemotherapy, corticosteroids, hydroxyurea, and/or leukapheresis to reduce peripheral blast count and prevent ALL complications. Allowed therapy may be administered for no more than 14 days and must be completed >= 24 hours prior to the initiation of protocol therapy.
• No plan for allogeneic or autologous hematopoietic cell transplantation (HCT).
• Cohort 2 Patients Only:
• Age >= 18 years.
• Relapsed or refractory disease in salvage 1 or 2.
• No isolated extramedullary relapse.
• Prior allogeneic HCT permitted.
• Patients with prior allogeneic HCT must have completed transplantation >= 4 months prior to registration.
• Patients with prior allogeneic HCT must have no evidence of graft-versus-host disease and must have completed immunosuppressive therapy >= 30 days prior to registration.
• Prior treatment with inotuzumab ozogamicin, blinatumomab, other CD22-directed therapy, or other CD19-directed therapy is not allowed.
• Prior treatment with rituximab must be completed >= 7 days prior to registration.
• Prior treatment with other monoclonal antibodies must be completed >= 6 weeks prior to registration.
• Prior treatment for ALL must be completed >= 14 days prior to registration with the following exceptions: intrathecal chemotherapy, hydroxyurea, corticosteroids, 6-mercaptopurine, methotrexate, vincristine, and/or leukapheresis to reduce circulating absolute lymphoblast count to =< 10,000/uL or prevent complications related to ALL are allowed but must be completed >= 24 hours prior to the initiation of protocol therapy.
• Patients should have resolution of any acute non-hematologic toxicities of prior therapy to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0 grade =< 1.
• Peripheral blood absolute lymphoblast count =< 10,000/uL (treatment allowed as above to reduce blast count to =< 10,000/uL)

1. Subject has multiple myeloma, 18 years of age or older and subject or legally authorized representative is able to sign the informed consent form. 2. Subject had a subject-specific batch of idecabtagene vicluecel manufactured intended for commercial treatment; however, the final manufactured product was nonconforming and did not meet commercial release criteria. The Sponsor has determined that the nonconforming idecabtagene vicleucel may be released for use under the Expanded Access Protocol. 3. Remanufacturing is deemed not feasible or clinically inappropriate per assessment of the treating physician in discussion with the subject. 4. Subject is clinically stable, has recovered from any prior toxicities prior to receiving lymphodepleting chemotherapy, and has adequate bone marrow function to receive lymphodepleting chemotherapy 5. Females of childbearing potential must: 1. Have a negative pregnancy test as verified by the treating physician within 7 days prior to the first dose of lymphodepleting chemotherapy following institutional testing methodology practices. This applies even if the subject practices true abstinence from heterosexual contact. 2. Either commit to true abstinence from heterosexual contact or agree to use, and be able to comply with, effective contraception without interruption. Contraception methods must include 1 highly effective method from screening until at least 12 months after the lymphodepleting chemotherapy. 3. Agree to abstain from breastfeeding during study participation and for at least 12 months following lymphodepleting chemotherapy. 4. There are insufficient exposure data to provide any recommendation concerning the duration of contraception and the abstaining from breastfeeding following treatment with nonconforming idecabtagene vicluecel. Any decision regarding contraception and breastfeeding after infusion should be discussed with the treating physician. 6. Male subjects must: 1. Practice true abstinence or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential for at least 12 months after lymphodepleting chemotherapy even if the subject has undergone a successful vasectomy. 2. There are insufficient exposure data to provide any recommendation concerning the duration of contraception following treatment with nonconforming idecabtagene vicluecel. Any decision regarding contraception after infusion should be discussed with the treating physician. Subject must agree to not donate blood, organs, tissue, sperm or semen and egg cells for usage in other individuals for at least 1 year following lymphodepleting chemotherapy. There are insufficient exposure data to provide any recommendation concerning the duration of refraining from tissue donation following treatment with nonconforming idecabtagene vicluecel. Therefore, participants treated with nonconforming idecabtagene vicluecel should not donate blood, organs, tissues, and cells for transplantation. 1. Subject has a hypersensitivity to the active substance or to any of the excipients. 2. Subject should not experience a significant worsening in clinical status that would, in the opinion of the treating physician, either increase the risk of AEs associated with lymphodepleting chemotherapy or exclude them from treatment with nonconforming idecabtagene vicluecel. 3. Subject has any significant medical condition, laboratory abnormality, or psychiatric illness, sociologic or geographic condition that would prevent the subject from participating in the Expanded Access Protocol, complying with protocol requirements or confound the ability to interpret the data in the Investigator's judgement. 4. Subject has any condition and/or laboratory abnormality that places the subject at unacceptable risk if he/she were to participate in the Expanded Access Protocol based on the Investigator's judgement. 5. Pregnant or nursing women or has intention of becoming pregnant during the study.

1. Subject and/or LAR must understand and voluntarily sign an informed consent form prior to any study-related assessments/procedures being conducted. 2. Subject has relapsed and/or refractory large B-cell lymphoma and is, per the treating physician assessment, eligible for treatment with lisocabtagene maraleucel per the approved prescribing information. 3. Subject is ≥ 18 years of age at the time of signing the informed consent form. 4. Subject had a specific batch of lisocabtagene maraleucel manufactured intended for commercial treatment; however, the final manufactured product did not meet commercial release criteria. 5. Remanufacturing (eg, repeat leukapheresis and manufacturing) is deemed not feasible or clinically inappropriate per assessment of the treating physician in discussion with the subject. 6. Subject is clinically stable, has recovered from any toxicities prior to receiving lymphodepleting chemotherapy, and has adequate bone marrow function to receive lymphodepleting chemotherapy. The treating physician is advised to contact Medical Monitor in the event there is any concern regarding administration of lymphodepleting chemotherapy. 7. Females of childbearing potential must: 1. Have a negative pregnancy test as verified by the treating physician within 7 days prior to the first dose of lymphodepleting chemotherapy following institutional testing methodology practices. This applies even if the subject practices true abstinence from heterosexual contact. 2. Either commit to true abstinence from heterosexual contact or agree to use, and be able to comply with, effective contraception without interruption. Contraception methods must include 1 highly effective method from screening until at least 12 months after the nonconforming lisocabtagene maraleucel administration. 3. Agree to abstain from breastfeeding during study participation and for at least 12 months following nonconforming lisocabtagene maraleucel administration. 4. There are insufficient exposure data to provide any recommendation concerning the duration of contraception and the abstaining from breastfeeding following treatment with lisocabtagene maraleucel. Any decision regarding contraception and breastfeeding after infusion should be discussed with the treating physician. 8. Male subjects must: 1. Practice true abstinence or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential for at least 12 months after nonconforming lisocabtagene maraleucel administration even if the subject has undergone a successful vasectomy. 2. There are insufficient exposure data to provide any recommendation concerning the duration of contraception following treatment with lisocabtagene maraleucel. Any decision regarding contraception after infusion should be discussed with the treating physician 9. Subject must agree to not donate blood, organs, tissue, sperm or semen and egg cells for usage in other individuals for at least 1 year following nonconforming lisocabtagene maraleucel administration. 1. Subject has a hypersensitivity to the active substance or to any of the excipients. 2. Subject should not experience a significant worsening in clinical status that would, in the opinion of the treating physician, either increase the risk of adverse events associated with lymphodepleting chemotherapy, or exclude them from treatment with nonconforming lisocabtagene maraleucel. 3. Subject has any significant medical condition, laboratory abnormality, or psychiatric illness, sociologic or geographic condition that would prevent the subject from participating in the Expanded Access Protocol complying with protocol requirements in the Investigator's judgement. 4. Subject has any condition and/or laboratory abnormality that places the subject at unacceptable risk if he/she were to participate in the Expanded Access Protocol based on the Investigator's judgement 5. Pregnant or nursing women or has intention of becoming pregnant during the study. 6. Subjects with central nervous system (CNS)-only involvement by malignancy (note: subjects with secondary CNS involvement are allowed on study). 7. Subject has active hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection at the time of pretreatment evaluation 8. Subject has uncontrolled systemic fungal, bacterial, viral or other infection despite appropriate antibiotics or other treatment at the time of nonconforming lisocabtagene maraleucel administration. 9. Subject has presence of acute or chronic graft-versus-host disease (ie, GVHD) 10. Use of the following: 1. Therapeutic doses of corticosteroids (defined as > 20 mg/day prednisone or equivalent) within 72 hours prior to nonconforming lisocabtagene maraleucel administration. Physiologic replacement, topical, and inhaled steroids are permitted. 2. Low dose chemotherapy (eg, vincristine, rituximab, cyclophosphamide ≤ 300 mg/m2)given after leukapheresis to maintain disease control must be stopped ≥ 7 days prior to lymphodepleting chemotherapy. 3. Cytotoxic chemotherapeutic agents that are not considered lymphotoxic (see below) within 1 week of LD chemotherapy. Oral chemotherapeutic agents, including lenalidomide and ibrutinib, are allowed if at least 3 half-lives have elapsed prior to lymphodepleting chemotherapy. 4. Donor lymphocyte infusions within 6 weeks of nonconforming lisocabtagene maraleucel administration.

Inclusion Criteria
• Documented diagnosis of multiple myeloma (MM) and measurable disease.
• Received 1 to 2 prior lines of anti-myeloma therapy.
• Must have documented disease progression during or after their last anti-myeloma regimen.
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1 or 2. Exclusion Criteria
• Any condition that confounds the ability to interpret data from the study.
• Has plasma cell leukemia, Waldenstrom's macroglobulinemia or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), or clinically significant amyloidosis.
• Known central nervous system involvement with MM.
• Prior therapy with iberdomide.
• Other protocol-defined Inclusion/Exclusion criteria apply.

• Documented diagnosis of chronic lymphocytic leukemia (CLL) that requires treatment for CLL according to International Workshop for Chronic Lymphocytic Leukemia (iwCLL) 2018 criteria.
• Previously completed venetoclax + anti-CD20 antibody +/- X regimen as a fixed duration first-line (1L) therapy and achieved documented response, defined as complete remission, complete remission with incomplete marrow recovery, partial remission, or nodular partial remission.
• More than 24 months (Cohort 1) or 12-24 months (Cohort 2) have elapsed between last dose of venetoclax and disease progression after completion of 1L treatment.
•Received intervening treatment for CLL after completing previous treatment with a venetoclax + anti-CD20 antibody +/- X regimen.

• Patients must be less than 22 years of age at the time of study enrollment
• Patient must have one of the following:
• Patient has known or suspected relapsed/refractory (including primary refractory) AML
• This includes isolated myeloid sarcoma
• Patient has known or suspected relapsed/refractory (including primary refractory) myeloid leukemia of Down syndrome
• Patient has known or suspected relapsed ALL that meets one of the following criteria:
• Second or greater B-ALL medullary relapse, excluding KMT2Ar.
• Any first or greater B-ALL medullary relapse involving KMT2Ar.
• Any first or greater T-ALL medullary relapse with or without KMT2Ar.
• Patient has known or suspected relapsed/refractory (including primary refractory) mixed phenotype acute leukemia (MPAL)
• Patient has known or suspected de novo or relapsed/refractory (including primary refractory) treatment-related AML (t-AML) or treatment-related myelodysplastic syndrome (t-MDS)
• Patient has known or suspected de novo or relapsed/refractory (including primary refractory) myelodysplastic syndrome (MDS)
• Patient has known or suspected de novo or relapsed/refractory (including primary refractory) juvenile myelomonocytic leukemia (JMML)
• 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

1. 1 month of age up to < 18 years of age at the time of signing the informed consent. 2. Received HSCT within the past 6 months. 3. Diagnosis of TMA that persists despite initial management of any triggering condition. 4. Body weight ≥ 5 kilograms. 5. Female participants of childbearing potential and male participants with female partners of childbearing potential must use highly effective contraception starting at Screening and continuing until at least 8 months after the last dose of ravulizumab. 6. Participants must be vaccinated against meningococcal infections if clinically feasible, according to institutional guidelines for immune reconstitution after HSCT. Participants must be re-vaccinated against Haemophilus influenzae type b and Streptococcus pneumoniae if clinically feasible, according to institutional guidelines for immune reconstitution after HSCT. All participants should be administered coverage with prophylactic antibiotics according to institutional post-transplant infection prophylaxis guidances, including coverage against Neisseria meningitidis for at least 2 weeks after meningococcal vaccination. Participants who cannot receive meningococcal vaccine should receive antibiotic prophylaxis coverage against Neisseria meningitidis the entire Treatment Period and for 8 months following the final dose of ravulizumab. 1. Known familial or acquired 'a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13' deficiency (activity < 5%). 2. Known Shiga toxin-related hemolytic uremic syndrome. 3. Positive direct Coombs test. 4. Diagnosis or suspicion of disseminated intravascular coagulation. 5. Known bone marrow/graft failure. 6. Diagnosis of veno-occlusive disease (VOD). 7. Human immunodeficiency virus (HIV) infection (evidenced by HIV-1 or HIV-2 antibody titer). 8. Unresolved meningococcal disease. 9. Presence of sepsis requiring vasopressor support. 10. Pregnancy or breastfeeding. 11. Hypersensitivity to murine proteins or to 1 of the excipients of Ravulizumab. 12. Previously or currently treated with a complement inhibitor.

Group A
• Adult (18 years of age or older)
• No previous history of cancer
• Routine history of normal blood counts and vital signs
• Documented Informed Consent Group B
• Adult (18 years of age or older)
• Diagnosis of CLL with low disease burden defined as Rai stage 0 ((Lymphocytosis; no enlargement of the lymph nodes, spleen, or liver; red blood cell and platelet counts are near normal.)
• Treatment naïve
• Documented Informed Consent Group C
• Adult (18 years of age or older)
• Diagnosis of CLL with high systemic disease burden defined as infiltration of bone marrow causing cytopenia
• Treatment naïve
• Able/willing to have bone marrow aspiration
• Documented Informed Consent For all participants
• Prisoners
• Psychiatric inpatients or people who are institutionalized
• Minor (Less than 18 years of age)
• History of diabetes
• Cannot be on antihyperglycemic therapy
• Carbohydrate restricting diets: Atkins, Vegan, Ketogenic, etc.
• Females of child bearing potential
• Persons without decision-making capacity
• Person who cannot read/write English
• Not meeting inclusion criteria defined above

1. Age >18 years with no upper age limit 2. Confirmation of newly diagnosed multiple myeloma (MM) with 1-2 prior regimens utilized in induction that included an immunomodulatory agent (IMiD) and a proteasome inhibitor (PI) combined or in different regimens 3. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 4. Prior AHCT 100-180 days prior to initiation of protocol-directed therapy 5. MRD ≥ 10^-5 by clonoSEQ® NGS platform, determined 60-120 days after AHCT as part of the usual care. 6. No prior disease progression (either before or since AHCT) 7. Overall response (i.e post-AHCT compared to historical baseline prior to initiation of any therapy for MM) ≥ PR. 8. Measurable disease at the time of the initial diagnosis (i.e. prior to starting any therapy for MM) meeting at least one of the following criteria:
• Serum monoclonal (M) protein ≥1.0 g/dl
• 200 mg of M protein/24h in the urine
• Difference between involved and uninvolved free light chain ≥10 mg/dL and abnormal kappa to lambda ratio. 9. Adequate hepatic function evidenced by AST and ALT ≤ 3 x ULN and bilirubin ≤ 1.5 ULN. 10. Adequate bone marrow function evidenced by platelets ≥ 75,000 /mm3 (without transfusion of platelets in the prior 7 days) and absolute neutrophil count ≥ 1,000/mm3. 11. Creatinine clearance (CrCl) ≥ 40 mL/minute within 28 days prior to start of therapy either measured or calculated using standard Cockcroft and Gault formula (available in https://www.kidney.org/professionals/KDOQI/gfr_calculatorCoc ). 12. Females of childbearing potential (FCBP) must have two negative pregnancy tests as verified by the investigator and agree to ongoing pregnancy testing and to practice contraception during treatment. Male subjects must agree to practice contraception and refrain from donating sperm during treatment. 13. In line with the higher incidence of MM in Blacks, and to address the historical underrepresentation of ethnical minorities in MM trials, at least 25% of the enrolled patients will be of ethnical minorities. 14. Written informed consent in accordance with federal, local, and institutional guidelines. 1. Diagnosis of amyloidosis, POEMS, Waldenstrom's macroglobulinemia, plasma cell leukemia or smoldering multiple myeloma (i.e. never evolved to active myeloma). 2. Major surgery or radiotherapy within 28 days of starting protocol-directed treatment. 3. Acute active infection requiring treatment within 14 days of starting protocol-directed treatment. 4. Current or prior involvement of central nervous system by multiple myeloma. 5. MM refractory to prior CD38 monoclonal antibody therapy and/or to carfilzomib (prior exposure allowed). Refractoriness here is defined as not achieving at least a PR in a regimen containing the agent or disease progression < 60 days from last dose of the agent. 6. Pregnant or lactating females. 7. Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR. 8. Seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy). 9. Unstable angina or myocardial infarction within 4 months prior to starting protocol-directed treatment, NYHA Class II, III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities unless subject has a pacemaker. 10. A prolongation of QT interval on screening electrocardiogram (ECG) as defined by corrected QT interval (QTc) > 480 ms using Fridericia's QT correction formula. 11. Cerebrovascular disease manifested as prior stroke at any time or TIA in the 12 months prior to initiation of therapy. 12. Uncontrolled hypertension (per investigator assessment, despite optimal medical management) 13. Diagnosis of interstitial lung disease 14. Nonhematologic malignancy within the past 3 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, or localized thyroid cancer; b) carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason Grade 6 or less with stable prostate-specific antigen levels; or d) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder or benign tumors of the adrenal or pancreas. 15. Significant neuropathy (Grades 3-4, or Grade 2 with pain) within 28 days prior to starting protocol-directed treatment. 16. For regimen B
•Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib). 17. Contra indication or intolerance to required supportive care medications (Aspirin and Acyclovir) 18. Concomitant use of strong inhibitors or inducers of CYP3A4, P-gp, or BCRP, or BCRP substrate with a narrow therapeutic index, for at least 14 days or 5 half-lives (whichever is shorter). (consult https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interac tions-table-substrates-inhibitors-and-inducers ) 19. Any other clinically significant medical disease or condition that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent Diagnosis of amyloidosis, POEMS, Waldenstrom's macroglobulinemia.

1. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 2. A confirmed diagnosis of multiple myeloma (must have an M-component in serum and/or urine) 3. Measurable disease defined as: i. M-spike ≥ 500mg/dL, or ii. Urine protein M-spike of ≥ 200 mg/day, or iii. Serum free light chains ≥ 10 mg/dL, and an abnormal κ:λ ratio 4. Participant has documented relapsed or progressive MM on or after any regimen or who are refractory to the most recent line of therapy. i. Relapsed MM is defined as previously treated MM that progresses and requires initiation of salvage therapy but does not meet the criteria for refractory MM. ii. Refractory MM is defined as disease that is nonresponsive (failure to achieve minimal response or development of progressive disease) while on primary or salvage therapy or progresses within 60 days of last therapy. 1. Participants in Part 1 should have failed all other available options including having had ≥ 3 prior lines of therapy including a proteasome inhibitor, IMiD agent, and an anti-CD38 monoclonal antibody. 2. Participants in Part 2 should have had and failed ≥ 1 but ≤ 7 prior lines of therapy and will have had prior treatment with both a proteasome inhibitor and an IMiD agent. Note: A line of therapy consists of greater ≥ 1 complete cycle of a single agent, a regimen consisting of combination of several drugs, or a planned sequential therapy of various regimens. Induction therapy with consolidation and maintenance following stem cell transplant is considered a single line of therapy. 3. Prior treatment with carfilzomib is allowed but the patient must not be considered carfilzomib refractory and not have had carfilzomib within the past 6 months 5. Positivity for t(11;14) by validated fluorescence in situ hybridization (FISH) testing assay in a pre-defined laboratory a. fresh bone marrow aspirate sample must be collected at screening and sent to central laboratory for t(11;14) FISH testing. 6. Adequate organ function defined as: 1. Hemoglobin ≥ 8.0 g/dL, within 7 days before first dose of study treatment, independent of growth factor support and transfusions 2. Platelet count ≥ 75,000/μL, within 7 days before first dose of study treatment, independent of growth factor support and transfusions 3. Absolute neutrophil count (ANC) ≥ 1000/mm3 [ANC = (% of segmented neutrophils + % of segmented bands) x total WBC count within 7 days before first dose of study treatment 4. ALT and AST ≤ 3 x upper limit of normal (ULN) and total bilirubin ≤ 2.0 x ULN Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 45 mL/min/1.73 m2 calculated by the MDRD-6 formula. 1. Participant has any of the following conditions: 1. Non secretory MM (Serum free light chains < 10 mg/dL) 2. Solitary plasmacytoma 3. Active plasma cell leukemia (ie, either 20% of peripheral white blood cells or > 2.0 x 109/L circulating plasma cells by standard differential) 4. Waldenström macroglobulinemia 5. Amyloidosis. 6. Polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes (POEMS) syndrome 7. Uncontrolled diabetes (HbA1c > 7% or 53 mmol/mol or requiring insulin at study entry 8. Chronic respiratory disease that requires continuous oxygen 2. Significant cardiovascular disease, including but not limited to: 1. Myocardial infarction ≤ 6 months before screening 2. Ejection fraction ≤ 50% 3. Unstable angina≤ 3 months before screening 4. New York Heart Association Class III or IV congestive heart failure 5. History of clinically significant arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, or torsades de pointes) 6. Heart rate-corrected QT interval > 480 milliseconds based on Fridericia's formula 7. History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place 8. Uncontrolled hypertension at screening, defined as systolic blood pressure > 170 mmHg and diastolic blood pressure > 105 mmHg by ≥ 2 consecutive measurements 3. Known infection with human immunodeficiency virus (HIV) 4. Serologic status reflecting active viral hepatitis B (HBV) or viral hepatitis C (HCV) infection as follows: 1. Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). Participants with presence of HBcAb, but absence of HBsAg, are eligible if HBV DNA is undetectable (limitation of sensitivity < 20 IU/mL) ,), and if they are willing to undergo monthly monitoring for HBV reactivation. 2. Presence of HCV antibody. Participants with presence of HCV antibody are eligible if HCV RNA is undetectable (limitation of sensitivity < 15 IU/mL). Note: Other protocol defined Inclusion/Exclusion criteria may apply.

The main inclusion criteria include, but are not limited to the following:
• For aggressive B-cell malignancies MCL: Has histologically confirmed biopsy according to the 2016 World Health Organization (WHO) classification of neoplasms of the hematopoietic and lymphoid tissues and has relapsed or refractory disease after at least 2 prior systemic therapies including a Bruton's tyrosine kinase inhibition/inhibitor(s) (BTKi), and is post chimeric antigen receptor T (CAR-T) cell therapy or is ineligible for CAR-T cell therapy.
• For aggressive B-cell malignancies MCL Cohort C: Has histologically confirmed biopsy according to the 2016 World Health Organization (WHO) classification of neoplasms of the hematopoietic and lymphoid tissues and has relapsed or refractory disease after at least 1 prior systemic therapy and has no prior exposure to a non-covalent BTKi.
• For aggressive B-cell malignancies Richter transformation lymphoma (RTL): Has histologically confirmed biopsy according to the 2016 World Health Organization (WHO) classification of neoplasms of the hematopoietic and lymphoid tissues and has relapsed or refractory disease.
• For indolent B-cell malignancies FL and CLL: Has histologically confirmed biopsy and has relapsed or refractory disease after at least 2 prior systemic therapies and no other available therapy.
• Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization/allocation.
• Have an ECOG performance status of 0 to 2 assessed within 7 days before cycle 1 day 1.
• Has received solid organ transplant at any time.
• Has clinically significant (ie, active) cardiovascular disease: cerebral vascular accident/stroke (<6 months prior to enrollment), myocardial infarction (<6 months prior to enrollment), unstable angina (<6 months prior to enrollment), congestive heart failure (New York Heart Association Classification Class ≥II), or serious cardiac arrhythmia requiring medication.
• Has pericardial effusion or clinically significant pleural effusion.
• Has ongoing Grade >1 peripheral neuropathy.
• Has a demyelinating form of Charcot-Marie-Tooth disease.
• Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years.
• Participants with FL who have transformed to a more aggressive type of lymphoma.
• Has received prior systemic anticancer therapy within 5 half-lives or 4 weeks (if prior therapy was a monoclonal antibodies) or 2 weeks (if prior therapy was small molecules like kinase inhibitors) prior to the first dose of study intervention.
• Has received prior radiotherapy within 28 days of start of study intervention. Participants must have recovered from all radiation-related toxicities.
• Has ongoing corticosteroid therapy exceeding 30 mg daily of prednisone equivalent.
• Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention.
• Has known active central nervous system (CNS) lymphoma involvement or active CNS involvement by lymphoma.
• Has an active infection requiring systemic therapy.
• Has a known history of human immunodeficiency virus (HIV) infection.
• Active HBV or hepatitis C virus (HCV) infection.
• For Cohort C only: has any clinically significant gastrointestinal abnormalities that might alter absorption.

• Written informed consent and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
• Age ≥ 18 years at the time of consent.
• ECOG Performance Status of 0-2 within 10 days prior to registration.
• Low grade follicular lymphoma (grade 1-2 or 3A by WHO-HAEM4R and/or cFL by WHO-HAEM5). Specifically, grade 3B or FLBL will not be allowed. Must not have evidence of transformed lymphoma at the time of study enrollment.
• Stage II, III, or IV by Ann Arbor staging system.
• Meet the definition of high tumor burden follicular lymphoma as defined by Groupe d'Etude des Lymphomes Follicularies (GELF) Criteria or be defined as high risk by the follicular lymphoma international prognostic index (FLIPI) 1 or FLIPI 2. --GELF Criteria (Must meet ≥ 1 of the following)
• Any nodal or extranodal mass ≥ 7 cm in diameter
• Involvement of ≥ 3 nodal sites ≥ 3 cm
• Systemic or B symptoms
• Presence of serous effusion
• Splenic enlargement
• Risk of compression syndrome (epidural, ureteral, etc)
• Leukemic phase of disease
• Cytopenia deemed due to disease involvement (hemoglobin < 10, granulocyte count < 1.5×10^9/L, or platelet count < 100×10^9/L)
• In addition to meeting GELF criteria, must have at least one FDG-avid site on PET that measures 1.5 cm in at least one dimension of a nodal site or 1cm in at least one dimension for extranodal sites.
• Received no prior therapy except local radiation therapy (field did not exceed 2 adjacent nodal regions), single agent rituximab (limited to 4 doses), or steroids for symptom control in the 28 days preceding trial enrollment.
• Must have prior EZH2 testing already performed or have tissue available to perform retrospective EZH2 testing. If prior EZH2 results are not available, tissue must be submitted. Tissue block is preferred but unstained slides are also acceptable. Patients who have insufficient or suboptimal tissue must be willing to have a biopsy performed prior to starting study drugs. See Correlative Lab Manual for details.
• Demonstrate adequate organ function as defined below; all screening labs to be obtained within 28 days prior to registration.
• Hematological
• Platelets ≥ 50 K/dL
• Absolute Neutrophil Count (ANC) ≥ 1000 K/mm3
• Hemoglobin (Hgb) ≥ 8 g/dL
• Renal
• Calculated creatinine clearance ≥ 40 mL/min using the Cockcroft-Gault formula
• or Serum creatinine < 2 mg/dL
• Hepatic
• Bilirubin ≤ 1.5 × upper limit of normal (ULN)
• Aspartate aminotransferase (AST) ≤ 3 × ULN
• Alanine aminotransferase (ALT) ≤ 3 × ULN
• Coagulation ---International Normalized Ratio (INR) or Prothrombin Time (PT) Activated Partial Thromboplastin Time (aPTT) ≤ 2 × ULN
• Females of childbearing potential with a male partner able to father a child must have a negative serum or urine pregnancy test within 7 days prior to registration. See the protocol for definition of childbearing potential.
• Females of childbearing potential must be willing to abstain from vaginal intercourse or use an effective method(s) of contraception from the time of informed consent, during the study and for 6 months after the last dose of study drug(s). Males able to father a child must be willing to abstain from vaginal intercourse or to use an effective method(s) of contraception from initiation of treatment, during the study and for 3 months after the last dose of study drug(s). See the protocol.
• As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study.
• Active infection requiring systemic therapy with 4 weeks of study drug administration.
• Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study).
• Concurrent malignancy or malignancy within the last 3 years (except for ductal breast cancer in situ, non-melanoma skin cancer, prostate cancer not requiring treatment, and cervical carcinoma in situ) whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen are not eligible for this trial.
• Active central nervous system (CNS) metastases or leptomeningeal disease. NOTE: Subjects who are symptomatic and have not undergone prior brain imaging must undergo a head computed tomography (CT) scan or brain MRI within 28 days prior to registration to exclude brain metastases.
• Treatment with any investigational drug within 4 weeks prior to registration.
• Subjects who require chronic use of moderate or strong CYP3A4/5 inhibitors or inducers within 28 days prior to registration.
• Clinically significant acute infection requiring systemic antibacterial, antifungal, or antiviral therapy.
• Known Uncontrolled Human Immunodeficiency Virus infection. Testing not required. NOTE: If a subject is known to have HIV/AIDS, then they will be allowed on study with adequate antiviral therapy, no detectable viral load, and stable on antiviral treatment for ≥ 4 weeks prior to first dose of study drug(s).
• Known hepatitis C infection. Testing not required. NOTE: If hepatitis C antibody test is known positive, patients are excluded unless a hepatitis C virus ribonucleic acid (HCV RNA) is negative.
• Must be tested for hepatitis B within 28 days of registration: including hepatitis B surface antigen, hepatitis B surface antibody, hepatitis B core antibody. A positive hepatitis B core antibody should be followed by hepatitis B DNA PCR testing to confirm or rule out active infection. Patients with hepatitis B surface antigen and/or detectable hepatitis B DNA PCR are not allowed on study. Patients with a positive hepatitis B core antibody but negative hepatitis B surface antigen and hepatitis B DNA PCR will be allowed on study, but hepatitis B prophylactic treatment should be strongly considered.
• Clinically significant cardiovascular disease or cardiac insufficiency (New York Heart Association classes III-IV), cardiomyopathy, preexisting clinically significant arrhythmia, acute myocardial infarction within 3 months of enrollment, angina pectoris within 3 months of enrollment.

• Participants with a cancer diagnosis: Documentation of disease:
• Histologic documentation: Histologically confirmed diagnosis of invasive cancer
• Stage: Stage I-IV per American Joint Committee on Cancer (AJCC) 7th edition, with the exception of patients with leukemia, lymphoma, and multiple myeloma
• For leukemia: Type (chronic lymphocytic leukemia [CLL], chronic myeloid leukemia [CML], acute lymphoblastic lymphoma [ALL], acute myeloid leukemia [AML])
• For lymphoma: Stage I-IV based on Ann Arbor staging
• For multiple myeloma: Stage I, II, III based on Revised International Staging System (RISS)
• One of the following tumor types:
• Colorectal
• Bladder
• Head and neck
• Hepatobiliary
• Lung
• Lymphoma
• Leukemia
• Ovary *** For these specific cancer types only, patients may be enrolled prior to histologic confirmation of malignancy. Sites are required to contact the study chairs to review appropriateness for enrollment
• Pancreas *** For these specific cancer types only, patients may be enrolled prior to histologic confirmation of malignancy. Sites are required to contact the study chairs to review appropriateness for enrollment
• Multiple myeloma
• Gastric, esophageal or gastroesophageal
• Breast
• Thyroid
• Kidney
• For these specific cancer types only, patients may be enrolled prior to histologic confirmation of malignancy. Sites are required to contact the study chairs to review appropriateness for enrollment
• Endometrium
• Prostate
• Melanoma *** For these specific cancer types only, patients may be enrolled prior to histologic confirmation of malignancy. Sites are required to contact the study chairs to review appropriateness for enrollment
• Sarcoma
• Participants with a cancer diagnosis: No prior definitive systemic or local anti-cancer intervention
• Participants with a cancer diagnosis: Age >= 40 and =< 75
• Participants with a cancer diagnosis: No known current pregnancy by self-report
• Participants with a cancer diagnosis: No known or prior history of in situ or invasive malignancy (excluding in situ non-melanoma skin cancers) other than the current cancer diagnosis
• Participants with a cancer diagnosis: Willingness to provide blood samples for research use
• Participants with a cancer diagnosis: Absence of medical contraindications to a research blood draw volume of 60 mL
• Participants with a cancer diagnosis: No history of organ transplantation
• Participants with a cancer diagnosis: Ability to read and comprehend English or Spanish * Eligibility is restricted to individuals who can comprehend and read English or Spanish given that participation in the study will require the ability to read and complete questionnaires that are available only in those two languages
• Participants without a cancer diagnosis and without suspicion of cancer: Age >= 40 and =< 75
• Participants without a cancer diagnosis and without suspicion of cancer: No known current pregnancy by self-report
• Participants without a cancer diagnosis and without suspicion of cancer: No known or prior history of in situ or invasive malignancy (excluding in situ non-melanoma skin cancers)
• Participants without a cancer diagnosis and without suspicion of cancer: Willingness to provide blood samples for research use
• Participants without a cancer diagnosis and without suspicion of cancer: Absence of medical contraindications to a research blood draw volume of 60 mL
• Participants without a cancer diagnosis and without suspicion of cancer: No history of organ transplantation
• Participants without a cancer diagnosis and without suspicion of cancer: Ability to read and comprehend English or Spanish * Eligibility is restricted to individuals who can comprehend and read English or Spanish given that participation in the study will require the ability to read and complete questionnaires that are available only in those two languages
• Participants with a high suspicion of cancer: High suspicion of ovarian cancer, pancreatic cancer, kidney cancer, or melanoma by clinical and/or radiological assessment, with plans for histologic or cytologic confirmation within 28 days after study blood draw * Examples of highly suspicious cases include: elevated CA125 and abnormal transvaginal ultrasound, suspicious renal or pancreatic mass on imaging, suspicious cutaneous lesion concerning for melanoma
• Participants with a high suspicion of cancer: Central review of radiology reports and/or clinical documentation conducted by study chairs
• Participants with a high suspicion of cancer: Age >= 40 and =< 75
• Participants with a high suspicion of cancer: No known current pregnancy by self-report
• Participants with a high suspicion of cancer: No known or prior history of in situ or invasive malignancy (excluding in situ non-melanoma skin cancers) other than the current cancer diagnosis
• Participants with a high suspicion of cancer: Willingness to provide blood samples for research use
• Participants with a high suspicion of cancer: Absence of medical contraindications to a research blood draw volume of 60 mL
• Participants with a high suspicion of cancer: No history or organ transplantation
• Participants with a high suspicion of cancer: Ability to read and comprehend English or Spanish * Eligibility is restricted to individuals who can comprehend and read English and Spanish given that participation in the study will require the ability to read and complete questionnaires that are available only in those two languages

• Patient must have measurable disease
• Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status between 0-2 OR patient must have Lansky performance status of >= 50% or Karnofsky performance status of >= 50%
• Patient must be deemed potentially eligible for a ComboMATCH Treatment Trial as assessed by the enrolling provider
• All patients must have sequencing results available from a National Cancer Institute (NCI) credentialed Designated Laboratory (DL)
• Patients must have locally advanced or advanced histologically documented solid tumors requiring therapy and meet one of the following criteria:
• Patients must have progressed on at least one line of standard systemic therapy OR
• Patients whose disease has no standard treatment that has been shown to prolong overall survival
• Patient must meet one of the following requirements:
• Patients 18 years and older who have tumor amenable to minimal risk image-guided or direct vision biopsy and must be willing and able to undergo a tumor biopsy to obtain samples for research if the patient is to enroll in a ComboMATCH treatment trial OR
• Patients 18 years and older who do not have disease that is biopsiable at minimal risk to the patient must confirm availability of an archival tumor tissue specimen for submission for research if the patient enrolls to a ComboMATCH Treatment Trial. This tumor tissue must meet the following criteria:
• Tissue must have been collected within 12 months prior to registration to the EAY191 Registration Trial
• Patient must not have had a Response Evaluation Criteria in Solid Tumors (RECIST) response (complete response [CR] or partial response [PR]) to any intervening therapy after collection of the tissue
• Formalin-fixed paraffin-embedded tumor tissue block(s) or slides must be available OR
• Patients under 18 years old must confirm availability of an archival tumor tissue specimen for submission for research if patient enrolls to a ComboMATCH Treatment Trial. This tumor tissue must meet the following criteria:
• Formalin-fixed paraffin-embedded tumor tissue block(s) or slides must be available
• NOTE: See specific ComboMATCH Treatment Trial protocol for tissue collection and management instructions. Performance of the mandatory research biopsy or submission of pre-trial formalin-fixed paraffin-embedded (FFPE) and collection and submission of the blood specimens for the integrated studies will be performed under the consent authority of the specific treatment trial protocol to which the patient is registered. No procedures to collect specimens for research only are to be performed for patients registered to the EAY191 Registration Trial only
• NOTE: Each ComboMATCH Treatment Trial contains specific eligibility criteria. If patient is found to not be eligible for the assigned ComboMATCH Treatment Trial, indication of ineligibility will trigger re-evaluation and potential assignment to another Treatment Trial

• ELIGIBILITY CRITERIA FOR PREREGISTRATION (TO STEP 0)
• Patient must be >= 18 and =< 75 years of age
• Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status between 0-3
• Patient must be newly diagnosed with B-ALL or is suspected to have ALL
• Patient must have BCR-ABL1 positive disease. The diagnosis of ALL and the presence of BCR-ABL translocation must be confirmed centrally. Patients can be registered and begin Step 1 therapy while awaiting central laboratory eligibility confirmation
• NOTE: Bone marrow aspirate and/or peripheral blood specimen must be submitted to the American College of Radiology Imaging Network (ECOG-ACRIN) Leukemia Laboratory at MD Anderson Cancer Center to determine patient's eligibility for registration to Step 1 or confirm patient evaluability. Centrally fluorescence-activated cell sorting (FACS) analysis will be performed to determine B-ALL and to exclude acute myeloid leukemia (AML) or acute bi-phenotypic leukemia and baseline BCR-ABL status will be determined by fluorescent in situ hybridization (FISH). The ECOG-ACRIN Leukemia Laboratory will forward results within 48 hours of receipt of the specimen to the submitting institution. Bone marrow aspirate is to be from first pull (initial or re-direct). Specimens must contain sufficient blast cells. In cases where the bone marrow aspiration may be inadequate, or the bone marrow examination has already been performed prior to study consent and enrollment on Step 0, peripheral blood may be submitted, given that adequate circulating blasts are present (> 10%). If a diagnosis of BCR-ABL positive B-ALL has already been established by local Clinical Laboratory Improvement Act (CLIA) certified laboratories, the patient may be registered to Step 1 without waiting for central confirmation
• Patient must not have a diagnosis of BCR/ABL T-ALL
• Patient must not have received chemotherapy for B-ALL. Patients who received up to five days of hydroxyurea or steroids of any kind with the aim to reduce disease burden prior to study registration to Step 1 are eligible
• Patients who started any kind of TKI prior to study registration to Step 1 are allowed to proceed on the study if they received no more than 14 days of TKI
• Patient must not have unstable epilepsy that requires treatment
• Patients with lymphoid blast crisis CML are not eligible
• ELIGIBILITY CRITERIA FOR REGISTRATION TO STEP 1
• Patient must have a diagnosis of Philadelphia chromosome positive (Ph+) ALL that has been determined locally and bone marrow and/or peripheral blood was sent and receipt confirmed for central confirmation or determined centrally by the ECOG-ACRIN Leukemia Laboratory at MD Anderson Cancer Center
• Patient must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used. All patients of childbearing potential must have a blood test or urine study within 14 days prior to registration to rule out pregnancy. A patient of childbearing potential is defined as any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy, or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
• Patients must not expect to conceive or father children by using accepted and effective method(s) of contraception or by abstaining from sexual intercourse from the time of step 1 registration, while on study treatment, and until at least six months after the last dose of study treatment
• Total bilirubin =< 3 mg/dL (patients with Gilbert's syndrome must have a total bilirubin =< 5 mg/dL) (obtained =< 28 days prior to step 1 registration)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X the institutional upper limit of normal (ULN) (obtained =< 28 days prior to step 1 registration)
• Estimated creatinine clearance > 45 mL/min (based on Cockcroft-Gault equation) (obtained =< 28 days prior to step 1 registration)
• Patients with acute organ dysfunction at step 1 registration, which may be attributed to leukemia can be registered regardless of lab results at presentation. Such patients will be allowed to register and can start Arm A steroid + TKI therapy but will only be allowed to proceed to Step 2 randomization if the eligibility criteria outlined is met
• Patients who presented with no evidence of acute organ dysfunction but during Step 0 experienced a rise in liver enzymes which investigator suspects to be a side effect of any of prescribed drugs, are allowed to be registered regardless of the level of liver enzymes. Step 2 Randomization must be withheld until the eligibility criteria outline is met but no more than 14 days after concluding Arm A therapy
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable or on suppressive therapy, if indicated
• Patients with a history of hepatitis C virus (HCV) infection must have an undetectable HCV viral load and if indicated, on treatment
• Patients with a prior malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• Patient must not have active concomitant malignancy. Patients on chronic hormonal therapy for breast or prostate cancer or patients treated with maintenance with targeted agents but are in remission with no evidence for the primary malignancies are eligible
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients must be class 2B or better. An ECHO/MUGA is required.
• Investigators must confirm which TKI patient is to receive
• NOTE: Patients with known T315I mutation status should receive ponatinib treatment
• NOTE: In situations due to insurance coverage issues and the pre-selected TKI is not immediately available, patients can receive dasatinib or imatinib during Step 1. The investigator must re-specify dasatinib or ponatinib prior to Step 2 randomization and from then on patients must receive the pre-selected TKI only
• ELIGIBILITY CRITERIA FOR RANDOMIZATION TO STEP 2
• Patient must have completed at least 7 and no more than 21 days of protocol-treatment on Arm A prior to step 2 randomization. (Days in which arm A therapy was withheld for any reason are not counted)
• NOTE: First day of steroids prescription after registration will be considered as the first day of study therapy. The selected TKI must be initiated prior to randomization
• Patients who presented with acute organ dysfunction within 2 weeks of registration to step 1 must have total bilirubin =< 2 X institutional upper limit of normal (ULN)
• AST(SGOT)/ ALT(SGPT) =< 2 X the institutional upper limit of normal (ULN)
• Estimated creatinine clearance > 45 mLg/min (based on Cockcroft-Gault equation)
• Investigators must confirm which TKI patient is to receive.
• NOTE: Patients with known T315I mutation status should receive ponatinib treatment
• For patients under age 70, intended chemotherapy regimen must have been determined prior to randomization
• Patient must not have active central nervous system (CNS) involvement by leukemic blasts. Patients with signs of CNS involvement at presentation are eligible for randomization if clearance of blasts from the cerebrospinal fluid (CSF) is demonstrated
• Patients must have resolved any serious infectious complications related to therapy
• Any significant medical complications related to therapy must have resolved
• ELIGIBILITY CRITERIA FOR REGISTRATION TO STEP 3 (RE-INDUCTION)
• Institution has received centralized MRD results confirming positive status
• Patients who presented with acute organ dysfunction within 2 weeks of registration to step 1 must have total bilirubin =< 2 X institutional ULN
• Patients who presented with acute organ dysfunction must have AST (SGOT)/ALT (SGPT) =< 2 X institutional upper limit of normal (ULN)
• Patients who presented with acute organ dysfunction must have an estimated creatinine clearance > 45 mL/min (based on Cockcroft-Gault equation)
• Investigators must confirm which TKI patient is to receive
• NOTE: Patients with known T315I mutation status should receive ponatinib treatment
• For patients under age 70 and previously assigned to Arm C, intended chemotherapy regimen must have been determined
• Step 3 (Re-Induction): Patients must have resolved any serious infectious complications related to therapy
• Step 3 (Re-Induction): Any significant medical complications related to therapy must have resolved
• Patient must not have complaints of symptoms and/or have clinical and/or radiological signs that indicate an uncontrolled infection or any other concurrent medical condition that could be exacerbated by the treatment or would seriously complicate compliance with the protocol

• Participants must have a confirmed diagnosis of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) (collectively referred to as CLL throughout) according to the 2018 International Workshop on CLL. Participants must have been diagnosed within 18 months prior to registration
• Participants must have CLL-International Prognostic Index (CLL-IPI) score >= 4 and/or complex cytogenetics (defined as 3+ chromosomal abnormalities)
• Cytogenetic AND/OR FISH analyses must be completed at a Clinical Laboratory Improvement Act (CLIA)-approved (or laboratories accredited under Accreditation Canada Diagnostics to conduct FISH analyses) laboratory within 18 months prior to registration. FISH panel should use probes to detect for abnormalities in chromosomes 13q, 12, 11q, and 17p
• TP53 mutation status from an next generation sequencing (NGS) test performed at any CLIA-approved (or laboratories accredited under Accreditation Canada Diagnostics) lab (if completed) must be obtained within 18 months prior to registration. This sequencing test is distinct from FISH studies for del(17p)
• Immunoglobulin heavy chain locus variable (IgVH) mutational status from an NGS test performed at any CLIA-approved lab (or laboratories accredited under Accreditation Canada Diagnostics) must be obtained prior to registration (at any time prior to registration)
• Serum beta-2 microglobulin level must be obtained within 28 days prior to registration
• Participants must not meet any of the IWCLL specified criteria for active CLL therapy
• Treatment with high dose corticosteroids and/or intravenous immunoglobulin for autoimmune complications of CLL must be complete at least 4 weeks prior to enrollment
• Steroids used for treatment of conditions other than CLL/SLL must be at a dose of at most 20 mg/day of prednisone or equivalent corticosteroid at the time of registration
• Prior therapy with anti CD20 monoclonal antibodies is not allowed
• Participants must not have received or be currently receiving any prior CLL-directed therapy, including non-protocol-related therapy, anti-cancer immunotherapy, experimental therapy (with exception of agents approved for emergency access use for the prevention or treatment of COVID-19), or radiotherapy
• Participants must not be receiving or planning to receive any other investigational agents before completing protocol therapy
• Participants must be >= 18 years of age
• Participants must have Eastern Cooperative Oncology Group (ECOG) performance status =< 2
• Platelet count >= 100,000/mm^3 within 28 days prior to registration
• Absolute neutrophil count (ANC) >= 1,000/mm^3 within 28 days prior to registration
• Creatinine clearance >= 30mL/min (by Cockcroft Gault) within 28 days prior to registration
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3.0 x upper limit of normal (ULN) within 28 days prior to registration
• Total bilirubin =< 2.0 x ULN (or 5.0 x ULN if the participant has a history of Gilbert's disease), within 28 days prior to registration
• Participants must be able to take oral medications
• Human immunodeficiency virus (HIV)-infected participants on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• Participants with history of malignancy are allowed providing the cancer has not required active treatment within 2 years prior to registration (hormonal therapy is permissible). The following exceptions are permissible: basal cell, squamous cell skin, or non-melanomatous skin cancer, in situ cervical cancer, superficial bladder cancer not treated with intravesical chemotherapy or Bacillus Calmette-Guerin (BCG) within 6 months, localized prostate cancer requiring no more than chronic hormonal therapy, or localized breast cancer requiring no more than chronic hormonal therapy
• Participants must not have current, clinically significant gastrointestinal malabsorption, in the opinion of treating doctor
• Participants must not have cirrhosis
• Obinutuzumab has been associated with hepatitis reactivation. Participants must not have uncontrolled active infection with hepatitis B or C. Participants with latent hepatitis B infection must agree to take prophylaxis during and for 6 months following active protocol therapy with V-O.
• Active infection with hepatitis B or C:
• Active infection is defined as detectable hepatitis B deoxyribonucleic acid (DNA) or hepatitis C ribonucleic acid (RNA) by quantitative polymerase chain reaction (PCR).
• Latent infection with hepatitis B:
• Latent infection is defined as meeting all of the following criteria:
• Hepatitis B surface antigen positive
• Anti-hepatitis B total core antibody positive
• Anti-hepatitis IgM core antibody undetectable
• Hepatitis B PCR undetectable
• Participants with latent hepatitis B infection must agree to take prophylaxis with anti-hepatitis agents during and for 6 months following active protocol therapy with V-O.
• Participants who have received intravenous immunoglobulin (IVIG) therapy within 6 months who are hepatitis B core total antibody positive but PCR undetectable are not mandated to take prophylaxis
• Participants must not have had major surgery within 30 days prior registration or minor surgery within 7 days prior to registration. Examples of major surgery include neurosurgical procedures, joint replacements, and surgeries that occur inside the thoracic or abdomino-pelvic cavities. Examples of minor surgery include dental surgery, insertion of a venous access device, skin biopsy, or aspiration of a joint. If a participant has had a bone marrow biopsy for diagnosis or evaluation of CLL, this will not exclude the patient from registration to the study. If there is a question about whether a surgery is major or minor, this should be discussed with the Study Chair
• Participants must not have known bleeding disorders (e.g., von Willebrand's disease or hemophilia)
• Participants must not have a history of stroke or intracranial hemorrhage within 6 months prior to enrollment
• Participants must not require continued therapy with a strong inhibitor or inducer of CYP3A4/5, as venetoclax is extensively metabolized by CYP3A4/5
• Participants must not have uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura
• Participants must not have any currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification
• Participants must not have a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to enrollment
• Participants must not be pregnant or nursing, as there are no safety data available for these drug regimens during pregnancy. Women/men of reproductive potential must have agreed to use an effective contraceptive method. A woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation. However, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures
• Participants must agree to have specimens submitted for translational medicine (MRD) and specimens must be submitted as outlined
• Participants must be offered participation in banking for future research. With patient's consent, specimens must be submitted as outlined
• Participants who are able to complete patient reported outcome (PRO) forms in English, Spanish, French, German, Russian or Mandarin must agree to participate in the quality of life assessments. (Those participants who are unable to read and write in English, Spanish, French, German, Russian or Mandarin may be registered to S1925 without contributing to the quality of life portion of the study.)
• Participants must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines
• NOTE: As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system

To be eligible to participate in the randomized trial, an individual must meet all the following criteria: 1. Provision of signed and dated informed consent form for the randomized trial by patient and/or legal guardian. 2. Age ≤25 years old at time of randomized trial consent. 3. Confirmed diagnosis of idiopathic SAA, defined as: 1. Bone marrow cellularity <25%, or <30% hematopoietic cells. 2. Two of three of the following (in peripheral blood): neutrophils <0.5 x 10^9/L, platelets <20 x 10^9/L, absolute reticulocyte count <60 x 10^9/L or hemoglobin <8 g/dL. 4. No suitable fully matched related donor available (minimum 6/6 match for HLA-A and B at intermediate or high resolution and DRB1 at high resolution using DNA based typing). 5. At least 2 unrelated donors noted on NMDP search who are well matched (9/10 or 10/10 for HLA-A, B, C, DRB1, and DQB1 using high resolution). 6. In the treating physician's opinion, no obvious contraindications precluding them from BMT or IST. 1. Presence of Inherited bone marrow failure syndromes (IBMFS). The diagnosis of Fanconi anemia must be excluded by diepoxybutane (DEB) or equivalent testing on peripheral blood or marrow. Telomere length testing should be sent on all patients to exclude Dyskeratosis Congenita (DC), but if results are delayed or unavailable and there are no clinical manifestations of DC, patients may enroll. If patients have clinical characteristics suspicious for Shwachman-Diamond syndrome, this disorder should be excluded by pancreatic isoamylase testing or gene mutation analysis (note: pancreatic isoamylase testing is not useful in children <3). Other testing per center may be performed to exclude IBMFS. 2. Clonal cytogenetic abnormalities or Fluorescence In-Situ Hybridization (FISH) pattern consistent with pre- myelodysplastic syndrome (pre-MDS) or MDS on marrow examination. 3. Known severe allergy to ATG. 4. Prior allogeneic or autologous stem cell transplant. 5. Prior solid organ transplant. 6. Infection with human immunodeficiency virus (HIV). 7. Active Hepatitis B or C. This only needs to be excluded in patients where there is clinical suspicion of hepatitis (e.g., elevated LFTs). 8. Female patients who are pregnant or breast-feeding. 9. Prior malignancies except resected basal cell carcinoma or treated cervical carcinoma in situ. 10. Disease modifying treatment prior to study enrollment, including but not limited to use of androgens, eltrombopag, romiplostim, or immune suppression. Note: Supportive care measures such as G-CSF, blood transfusion support and antibiotics are allowable

• Histologically confirmed diagnosis of peripheral T-cell lymphoma (PTCL) with < 10% CD30 expression by immunohistochemistry in the following subtypes (by local review): nodal T-cell lymphoma with T-follicular helper (TFH) phenotype (TFH-PTCL), follicular T-cell lymphoma, PTCL-not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma (AITL), enteropathy associated T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma
• Patients with expression of CD30 in >= 10% of the tumor (based on local immunohistochemistry review) regardless of histology will not be permitted
• Patients with a diagnosis of other PTCL subtype histologies other than those specified in the inclusion criteria are excluded including large cell transformation of mycosis fungoides
• Patients will be stratified by presence or absence of TFH phenotype (i.e. diagnosis of AITL, TFH-PTCL, follicular T-cell lymphoma) based on local review of pathology. Determination of TFH phenotype can be defined by expression of two or more of the following markers CD10, BCL6, CXCL13, ICOS, and PD1 by immunohistochemistry
• Measurable disease as defined by the Lugano criteria
• No prior systemic therapy for lymphoma (excluding corticosteroids)
• Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown. Therefore, for women of childbearing potential only, a negative urine or serum pregnancy test done =< 7 days prior to registration is required
• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2
• Platelet count >= 75,000/mm^3 (>= 50,000/mm^3 if secondary to bone marrow involvement from lymphoma per investigator assessment; the first 12 patients on each arm of the study must have platelets >= 75,000/mm^3 regardless of bone marrow involvement)
• Absolute neutrophil count (ANC) >= 1,000/mm^3
• Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) or alanine aminotransferase (ALT)/serum glutamate pyruvate transaminase (SGPT) =< 3.0 x upper limit of normal (ULN) * Except in subjects with documented liver involvement by lymphoma
• Calculated creatinine clearance >= 30 mL/min by Cockcroft-Gault formula
• Total bilirubin =< 2.0 x ULN * Except in cases of Gilbert's Syndrome or documented liver or pancreatic involvement by lymphoma
• Archival tissue must be available for submission
• Patients known to have HTLV 1/2 are excluded
• Patients with known central nervous system involvement are excluded
• No active viral infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C. Those who are seropositive (e.g. hepatitis B core antibody [Ab] positive) are permitted if they are negative by polymerase chain reaction (PCR). Those who are seropositive for hepatitis B and are negative for hepatitis B virus (HBV) deoxyribonucleic acid (DNA) by PCR must receive concomitant hepatitis B directed antiviral therapy. Those who have hepatitis C Ab positivity who have completed curative therapy for hepatitis C with negative hepatitis C PCR are eligible
• Patients with history of HIV are eligible if they have an undetectable viral load for at least 6 months
• No active uncontrolled systemic fungal, bacterial or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy and/or other treatment). Patients with Epstein-Barr virus (EBV) viremia related to their lymphoma are permitted
• No concurrent malignancy requiring active therapy within the last 3 years with the exception of basal cell carcinoma limited to the skin, squamous cell carcinoma limited to the skin, carcinoma in situ of the cervix, breast or localized prostate cancer. Adjuvant hormonal therapy for cancer previously treated for curative intent is permitted
• Patients must have documented left ventricular ejection fraction of >= 45%
• No significant active cardiac disease within the previous 6 months including:
• New York Heart Association (NYHA) class III or IV congestive heart failure
• Unstable angina or angina requiring surgical or medical intervention; and/or
• Myocardial infarction
• No contraindication to any drug in the chemotherapy regimen, including neuropathy >= grade 2
• Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed on this study. Patients on strong CYP3A4 inhibitors must discontinue the drug for 14 days prior to registration on the study. Chronic concomitant treatment with strong CYP3A4 inducers is not allowed. Patients must discontinue the drug 14 days prior to the start of study treatment

• Patient must have enrolled onto EAY191 and must have been given a treatment assignment to ComboMATCH to EAY191-N4 based on the presence of an actionable mutation as defined in EAY191
• Patients must be enrolled on the ComboMATCH Master Registration Trial EAY191
• Patients must have RAS pathway mutations as determined by the ComboMATCH screening assessment
• Cohort 1: Patients with histologically confirmed RAS pathway mutant ovarian, primary peritoneal, or fallopian tube ("ovarian") cancer (activating mutations in KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, or inactivating mutations in NF1)
• Cohort 2: Patients with histologically confirmed RAS pathway mutant endometrial cancer (activating mutations in KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, or inactivating mutations in NF1).
• Patients must have disease that can be safely biopsied and agree to a pre-treatment biopsy, if disease cannot be safely biopsied, or have archival tissue available from within 12 months prior to registration on the ComboMATCH Registration Trial (EAY191)
• Patients must have progressed after first-line treatment for recurrent or persistent disease
• Patients with ovarian cancer should not be eligible for further platinum-based therapy
• Patients with endometrial cancer must have received or been offered an immune oncology agent (alone or in combination with lenvatinib) unless there are existing contraindications for immune oncology agents or lenvatinib
• Patients may have received unlimited prior therapy
• Patients must have measurable and biopsiable disease. Measurable disease is defined by RECIST 1.1 as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded). Each lesion must be > 10 mm when measured by CT, magnetic resonance imaging (MRI) or caliper measurement by clinical exam; or > 20 mm when measured by chest x-ray. Lymph nodes must be > 15 mm in short axis when measured by CT or MRI
• Patients must have at least one "target lesion" separate from the lesion to be biopsied to be used to assess response on this protocol as defined by RECIST version 1.1. Tumors within a previously irradiated field will be designated as "non-target" lesions unless progression is documented or a biopsy is obtained to confirm persistence at least 90 days following completion of radiation therapy
• Prior therapy must have been completed at least four weeks prior to registration
• Age >= 18
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1 or 2
• Hemoglobin (Hgb) >= 9.5 g/dL with no blood transfusion in the past 28 days (within 14 days prior to registration)
• Platelets >= 100,000/mcl (within 14 days prior to registration)
• Absolute neutrophil count (ANC) >= 1,500/mcl (within 14 days prior to registration)
• Patients must have creatinine clearance estimated of >= 50 mL/min using the Cockcroft-Gault equation or based on a 24 hour urine test (within 14 days prior to registration)
• Total bilirubin level =< 1.5 x institutional upper limit of normal (ULN) or =< 3 x ULN in the presence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia) (within 14 days prior to registration)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN (within 14 days prior to registration)
• Patients must be able to swallow and retain oral medications and be without gastrointestinal illnesses that would preclude absorption of selumetinib or olaparib
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better
• Women of childbearing potential (WOCBP) must agree to use two forms of birth control (hormonal or barrier method of birth control; abstinence) during the study and for 12 weeks after completing treatment
• Non-sterilized male partners of WOCBP (including males sterilized by a method other than bilateral orchidectomy e.g., vasectomy) who intend to be sexually active with a female partner must be using an acceptable method of contraception such as male condom plus spermicide (condom alone in countries where spermicides are not approved) from the time of screening throughout the total duration of the study and the drug washout period (at least 16 weeks after the last dose of study intervention) to prevent pregnancy in a partner. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. Vasectomized (i.e., sterile) males are considered fertile and should still use a male condom plus spermicide as indicated above during the clinical study
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration are eligible for this trial
• Patients with evidence of chronic hepatitis B virus (HBV) infection must have an undetectable HBV viral load on suppressive therapy, if indicated
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate central nervous system (CNS) specific treatment is not required and is unlikely to be required during the first cycle of therapy
• Patients with treated brain metastases are eligible if follow-up brain imaging after CNS-directed therapy shows no evidence of progression
• Extra caution should be taken with olaparib, as it crosses the blood brain barrier and can cause edema in brain metastases
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information
• Patients who have received any MEK inhibitors
• Patients who have progressed while receiving a PARP inhibitor
• Patients who have received chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to registration
• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia
• Patients with uncontrolled intercurrent illness
• Patients with >= grade 2 neuropathy within 14 days of registration
• Patients with severe (Child-Pugh C) liver dysfunction
• Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to olaparib and selumetinib or any excipients thereof
• Concomitant use of known strong (e.g., phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate CYP3A inducers (e.g., bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents
• Supplementation with vitamin E greater than 100% of the daily recommended dose. Any multivitamin containing vitamin E must be stopped prior to study enrollment even if less than 100% of the daily recommended dosing for vitamin E
• Vitamin E must not be taken in the 7 days prior to initiation of treatment with selumetinib
• Concomitant use of known strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or known moderate CYP3A inhibitors (e.g. ciprofloxacin, erythromycin, diltiazem, Fluconazole, verapamil). The required washout period prior to starting olaparib is at least 14 days or 5 half-lives (whichever is longer) before the first dose of study medication
• Concomitant use of strong CYP2C19 inhibitors (e.g., ticlopidine) or moderate CYP2C19 inhibitors (e.g., omeprazole). The required washout period prior to starting selumetinib is at least 14 days or 5 half-lives (whichever is longer) before the first dose of study medication
• Have received or are receiving an investigational medicinal product (IMP) or other systemic anti-cancer treatment (including chemotherapy, immunotherapy, targeted therapy, biologic therapy, tumor embolization, or monoclonal antibodies) within 4 weeks prior to registration, or within a period during which the IMP or systemic target treatment has not been cleared from the body (e.g., a period of 5 'half-lives'), whichever is longer
• Known myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)
• Patients who have had previous organ transplant, allogenic bone marrow transplant or double umbilical cord blood transplantation
• Patients who have had whole blood transfusion within 28 days prior to registration
• Patients with ophthalmological conditions as follows:
• Current or past history of retinal pigment epithelial detachment/central serous retinopathy or retinal vein occlusion.
• Intraocular pressure >21 mmHg (or ULN adjusted by age) or uncontrolled glaucoma (irrespective of intraocular pressure [IOP]). Subjects with known glaucoma and increased IOP who do not have meaningful vision (light perception only or no light perception) and are not experiencing pain related to the glaucoma, may be eligible after discussion with the study chair
• Patients with any other significant abnormality on ophthalmic examination should be discussed with the study chair for potential eligibility
• Ophthalmological findings secondary to long-standing optic pathway glioma (such as visual loss, optic nerve pallor or strabismus) or longstanding orbito-temporal plexiform neurofibroma (PN) (such as visual loss, strabismus) will NOT be considered a significant abnormality for the purposes of the study
• Patients with severe, active co-morbidity defined as any of the following:
• History and/or confirmed pneumonitis
• Uncontrolled hypertension (blood pressure [BP] >= 150/90 mmHg despite medical therapy)
• Acute coronary syndrome within 6 months prior to registration
• Uncontrolled atrial fibrillation
• Known family history of long QT syndrome
• Women who are pregnant or unwilling to discontinue nursing

• Patients must be 5 to 60 years of age at the time of enrollment
• Patients with newly diagnosed untreated histologically confirmed classic Hodgkin lymphoma (cHL) (nodular sclerosis, mixed cellularity, lymphocyte-rich, or lymphocyte-depleted, or not otherwise specified [NOS]) with stage I or II disease
• Patients must have bidimensionally measurable disease (at least one lesion with longest diameter >= 1.5 cm)
• Patients must have a whole body or limited whole body PET scan performed within 42 days prior to enrollment. PET-CT is strongly preferred. PET-MRI allowed if intravenous contrast enhanced CT is also obtained
• Pediatric patients (age 5-17 years) must have an upright posteroanterior (PA) chest X-ray (CXR) for assessment of bulky mediastinal disease. Adult patients must have either a CXR or CT chest
• Patients >= 18 years must have a performance status corresponding to Zubrod scores of 0, 1 or 2
• Patients =< 17 years of age must have a Lansky performance score of >= 50
• Pediatric patients (age 5-17 years): A serum creatinine based on age/gender as follows (within 7 days prior to enrollment):
• 2 to < 6 years (age): 0.8 mg/dL (male), 0.8 mg/dL (female)
• 6 to < 10 years (age): 1 mg/dL (male), 1 mg/dL (female)
• 10 to < 13 years (age): 1.2 mg/dL (male), 1.2 mg/dL (female)
• 13 to < 16 years (age): 1.5 mg/dL (male), 1.4 mg/dL (female)
• >= 16 years (age): 1.7 mg/dL (male), 1.4 mg/dL (female) OR a 24 hour urine creatinine clearance >= 50 mL/min/1.73 m^2 (within 7 days prior to enrollment) OR a glomerular filtration rate (GFR) >= 50 mL/min/1.73 m^2 (within 7 days prior to enrollment). GFR must be performed using direct measurement with a nuclear blood sampling method OR direct small molecule clearance method (iothalamate or other molecule per institutional standard)
• Note: Estimated GFR (eGFR) from serum or plasma creatinine, cystatin C or other estimates are not acceptable for determining eligibility
• For adult patients (age 18 years or older) (within 7 days prior to enrollment): Creatinine clearance >= 30 mL/min, as estimated by the Cockcroft and Gault formula or a 24-hour urine collection. The creatinine value used in the calculation must have been obtained within 28 days prior to registration. Estimated creatinine clearance is based on actual body weight
• Total bilirubin =< 2 x upper limit of normal (ULN) (within 7 days prior to enrollment)
• Unless due to Gilbert's disease, lymphomatous involvement of liver or vanishing bile duct syndrome
• Aspartate aminotransferase (AST) =< 3 x ULN (within 7 days prior to enrollment)
• Unless due to Gilbert's disease, lymphomatous involvement of liver or vanishing bile duct syndrome
• Alanine aminotransferase (ALT) =< 3 x ULN (within 7 days prior to enrollment)
• Unless due to Gilbert's disease, lymphomatous involvement of liver or vanishing bile duct syndrome
• Shortening fraction of >= 27% by echocardiogram (ECHO), multigated acquisition scan (MUGA), or functional cardiac imaging scan (within 7 days prior to enrollment) or ejection fraction of >= 50% by radionuclide angiogram, ECHO, MUGA, or cardiac imaging scan (within 7 days prior to enrollment)
• Diffusion capacity of the lung for carbon monoxide (DLCO) >= 50% of predicted value as corrected for hemoglobin by pulmonary function test (PFT) (within 7 days prior to enrollment). If unable to obtain PFTs, the criterion is: a pulse oximetry reading of > 92% on room air
• Known human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• Patients with nodular lymphocyte predominant Hodgkin lymphoma
• Patients with a history of active interstitial pneumonitis or interstitial lung disease
• Patients with a diagnosis of inherited or acquired immunodeficiency that is poorly controlled or requiring active medications, such as primary immunodeficiency syndromes or organ transplant recipients
• Patients with any known uncontrolled intercurrent illness that would jeopardize the patient's safety such as infection, autoimmune conditions, cardiac arrhythmias, angina pectoris, and gastrointestinal disorders affecting swallowing and/or absorption of pills
• Patients with a condition requiring systemic treatment with either corticosteroids (defined as equivalent to > 10 mg daily prednisone for patients >= 18 years or > 0.5 mg/kg [up to 10 mg/day] for patients < 18 years) or other immunosuppressive medications within 14 days prior to enrollment
• Note: Replacement therapy such as thyroxine, insulin, or physiologic corticosteroid for adrenal or pituitary insufficiency is not considered a form of systemic treatment. Inhaled or topical steroids, and adrenal replacement doses (=< 10 mg daily for patients >= 18 years or =< 0.5 mg/kg [up to 10 mg/day] prednisone equivalents) are permitted in the absence of active autoimmune disease
• Note: Steroid use for the control of Hodgkin lymphoma symptoms is allowable, but must be discontinued by cycle 1, day 1
• Patients with peripheral neuropathy > grade 1 at the time of enrollment or patients with known Charcot-Marie-Tooth syndrome
• Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen
• Administration of prior chemotherapy, radiation, or antibody-based treatment for cHL
• Prior solid organ transplant
• Prior allogeneic stem cell transplantation
• Live vaccine within 30 days prior to planned day 1 of protocol therapy (e.g., measles, mumps, rubella, varicella, yellow fever, rabies, bacillus calmette guerin [BCG], oral polio vaccine, and oral typhoid). Administration of messenger ribonucleic acid (mRNA) vaccines are permitted
• Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test within 28 days prior to enrollment is required for female patients of childbearing potential
• Lactating females who plan to breastfeed their infants starting with the first dose of study therapy and for at least 6 months after the last treatment
• Sexually active patients of reproductive potential who have not agreed to use a highly effective contraceptive method (failure rate of < 1% per year when used consistently and correctly) for the duration of their study drug therapy. Following therapy, patients will be advised to use contraception as per institutional practice or as listed below for investigational agents, whichever is longer
• Men and women of childbearing potential must continue contraception for a period of 6 months after last dose of brentuximab vedotin
• Women of child-bearing potential (WOCBP) must continue contraception for a period of at least 5 months after the last dose of nivolumab
• 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

• PATIENT INCLUSION CRITERIA FOR ENROLLMENT:
• 6 months to < 22 years at enrollment
• Diagnosed with ALL, AML, or MDS or mixed phenotype acute leukemia (MPAL) for which an allogeneic hematopoietic stem cell transplant is indicated. Complete Remission (CR) status will not be confirmed at the time of enrollment. CR as defined in these sections is required to proceed with the actual HCT treatment plan
• Has not received a prior allogeneic hematopoietic stem cell transplant
• Does not have a suitable human leukocyte antigen (HLA)-matched sibling donor available for stem cell donation
• Has an eligible haploidentical related family donor based on at least intermediate resolution HLA typing
• Patients who also have an eligible 8/8 MUD adult donor based on confirmatory high resolution HLA typing are eligible for randomization to Arm A or Arm B.
• Patients who do not have an eligible MUD donor are eligible for enrollment to Arm C
• 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
• Co-Enrollment on other trials
• Patients will not be excluded from enrollment on this study if already enrolled on other protocols for treatment of high risk and/or relapsed ALL, AML, MPAL and MDS. This is including, but not limited to, COG AAML1831, COG AALL1821, the EndRAD Trial, as well as local institutional trials. We will collect information on all co-enrollments
• Patients will not be excluded from enrollment on this study if receiving immunotherapy prior to transplant as a way to achieve remission and bridge to transplant. This includes chimeric antigen receptor (CAR) T cell therapy and other immunotherapies
• PATIENT INCLUSION CRITERIA TO PROCEED TO HCT:
• Karnofsky Index or Lansky Play-Performance Scale >= 60 on pre-transplant evaluation. Karnofsky scores must be used for patients >= 16 years of age and Lansky scores for patients =< 16 years of age (within 4 weeks of starting therapy)
• A serum creatinine based on age/gender as follows: 6 months to < 1 year: 0.5 mg/dL (Male); 0.5 mg/dL (Female) 1. to < 2 years: 0.6 mg/dL (Male); 0.6 mg/dL (Female) 2. to < 6 years: 0.8 mg/dL (Male); 0.8 mg/dL (Female) 6 to < 10 years: 1 mg/dL (Male); 1 mg/dL (Female) 10 to < 13 years: 1.2 mg/dL (Male); 1.2 mg/dL (Female) 13 to < 16 years: 1.5 mg/dL (Male); 1.4 mg/dL (Female) >= 16 years: 1.7 mg/dL (Male); 1.4 mg/dL (Female)
• OR
• A 24 hour urine Creatinine clearance >= 60 mL/min/1.73 m^2
• OR
• A glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2. GFR must be performed using direct measurement with a nuclear blood sampling method OR direct small molecule clearance method (iothalamate or other molecule per institutional standard)
• Note: Estimated GFR (eGFR) from serum creatinine, cystatin C or other estimates are not acceptable for determining eligibility
• Serum glutamic-oxaloacetic transaminase (SGOT) aspartate aminotransferase [AST] or serum glutamate pyruvate transaminase (SGPT) aminotransferase [ALT] < 5 x upper limit of normal (ULN) for age
• Total bilirubin < 2.5 mg/dL, unless attributable to Gilbert's Syndrome
• Shortening fraction of >= 27% by echocardiogram or radionuclide scan (MUGA)
• OR
• Ejection fraction of >= 50% by echocardiogram or radionuclide scan (MUGA), choice of test according to local standard of care
• Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and corrected carbon monoxide diffusing capability (DLCO) must all be >= 50% of predicted by pulmonary function tests (PFTs).
• For children who are unable to perform for PFTs (e.g., due to age or developmental delay), the criteria are: no evidence of dyspnea at rest, oxygen (O2) saturation (Sat) > 92% on room air by pulse oximetry, not on supplemental O2 at rest, and not on supplemental O2 at rest
• MPAL in first complete remission (CR1) for whom transplant is indicated. Examples include those patients who are poorly responsive to ALL therapy (end of induction failure( IF-MPAL) to ALL induction (see IF-MPAL note below), end of induction MRD ≥ 5% or end-of-consolidation MRD > 0.01%), as well as patients treated with AML therapy
• IF-MPAL: additional criterion for Induction failure for MPAL ONLY as per ALL1732:
• An increasing number of circulating leukemia cells on 3 or more consecutive CBCs obtained at daily or longer intervals following day 8 of Induction therapy and prior to day 29 with confirmation by flow cytometry OR development of new sites of extramedullary disease, or other laboratory or clinical evidence of refractory disease or progression prior to the end of Induction evaluation (note that residual testicular disease at the end of Induction is an exception)
• MPAL in > second complete remission (CR2)
• ALL high-risk in CR1 for whom transplant is indicated. Examples include: induction failure, treatment failure as per minimal residual disease by flow cytometry > 0.01% after consolidation and not eligible for AALL1721 or AALL1721 not available/unwilling to enroll, hypodiploidy (< 44 chromosomes) with MRD+ > 0.01% after induction, persistent or recurrent cytogenetic or molecular evidence of disease during therapy requiring additional therapy after induction to achieve remission (e.g. persistent molecular BCR-ABL positivity), T cell ALL with persistent MRD > 0.01% after consolidation.
• ALL in CR2 for whom transplant is indicated. Examples include: B-cell: early (=< 36 months from initiation of therapy) bone marrow (BM) relapse, late BM relapse (>= 36 months) with MRD >= 0.1% by flow cytometry after first re-induction therapy; T or B-cell: early (< 18 months) isolated extramedullary (IEM), late (>= 18 months) IEM, end-Block 1 MRD >= 0.1%; T-cell or Philadelphia chromosome positive (Ph+): BM relapse at any time
• ALL in >= third complete remission (CR3)
• Patients treated with chimeric antigen receptor T-cells (CART) cells for whom transplant is indicated. Examples include: transplant for consolidation of CART, loss of CART persistence and/or B cell aplasia < 6 months from infusion or have other evidence (e.g., MRD+) that transplant is indicated to prevent relapse
• AML in CR1 for whom transplant is indicated. Examples include those deemed high risk for relapse as described in AAML1831:
• FLT3/ITD+ with allelic ratio > 0.1 without bZIP CEBPA, NPM1
• FLT3/ITD+ with allelic ratio > 0.1 with concurrent bZIP CEBPA or NPM1 and with evidence of residual AML (MRD >= 0.05%) at end of Induction
• Presence of RAM phenotype or unfavorable prognostic markers (other than FLT3/ITD) per cytogenetics, fluorescence in situ hybridization (FISH), next generation sequencing (NGS) results, regardless of favorable genetic markers, MRD status or FLT3/ITD mutation status
• AML without favorable or unfavorable cytogenetic or molecular features but with evidence of residual AML (MRD >= 0.05%) at end of Induction
• Presence of a non-ITD FLT3 activating mutation and positive MRD (>= 0.05%) at end of Induction 1 regardless of presence of favorable genetic markers.
• AML in >= CR2
• MDS with < 5% blasts by morphology and flow cytometry (if available) on the pre-transplant bone marrow evaluation
• Complete remission (CR) is defined as < 5% blasts by morphology and flow cytometry (if available) on the pre-transplant bone marrow evaluation with minimum sustained absolute neutrophil count (ANC) of 300 cells/microliter for 1 week or ANC > 500 cells/microliter. We will be collecting data from all approaches to MRD evaluation performed including NGS and polymerase chain reaction (PCR). It is strongly recommended that MPAL be evaluated using multidimensional flow cytometry and/or (KMT2Ar) qt PCR. It is strongly recommended that MPAL be evaluated using multidimensional flow cytometry and/or (KMT2Ar) qt PCR
• DONOR ELIGIBILITY CRITERIA:
• Matched Unrelated Donors: Unrelated donor candidates must be matched at high resolution at a minimum of 8/8 alleles (HLA-A, -B, -C, -DRB1). One-antigen HLA mismatches are not permitted. HLA matching of additional alleles is recommended according to National Marrow Donor Program (NMDP) guidelines, but will be at the discretion of local centers
• Haploidentical Matched Family Members:
• Minimum match level full haploidentical (at least 5/10; HLA-A, -B, -C, -DRB1, -DQB1 alleles). The following issues (in no particular order) should be considered in choosing a haploidentical donor:
• Absent or low patient donor-specific antibodies (DSA)
• Mean fluorescence intensity (MFI) of any anti-donor HLA antibody by solid phase immunoassay should be < 2000. Donors with higher levels are not eligible.
• If a screening assay against pooled HLA antigens is used, positive results must be followed with specificity testing using a single antigen assay. The MFI must be < 2000 unless the laboratory has validated higher threshold values for reactivity for HLA antigens (such as HLA-C, -DQ, and -DP), that may be enhanced in concentration on the single antigen assays. Donor anti- recipient antibodies are of unknown clinical significance and do not need to be sent or reported.
• Consult with Study Chair for the clinical significance of any recipient anti-donor HLA antibody.
• If centers are unable to perform this type of testing, please contact the Study Chair to make arrangements for testing.
• If killer immunoglobulin testing (KIR) is performed: KIR status by mismatch, KIR-B, or KIR content criteria can be used according to institutional guidelines.
• ABO compatibility (in order of priority):
• Compatible or minor ABO incompatibility
• Major ABO incompatibility
• CMV serostatus:
• For a CMV seronegative recipient: the priority is to use a CMV seronegative donor when feasible
• For a CMV seropositive recipient: the priority is to use a CMV seropositive donor when feasible
• Age: younger donors including siblings/half-siblings, and second degree relatives (aunts, uncles, cousins) are recommended, even if < 18 years
• Size and vascular access appropriate by center standard for peripheral blood stem cell (PBSC) collection if needed
• Haploidentical matched family members: screened by center health screens and found to be eligible
• Unrelated donors: meet eligibility criteria as defined by the NMDP or other unrelated donor registries. If the donor does not meet the registry eligibility criteria but an acceptable eligibility waiver is completed and signed per registry guidelines, the donor will be considered eligible for this study
• Human immunodeficiency virus (HIV) negative
• Not pregnant
• MUD donors and post-transplant cyclophosphamide haplo donors should be asked to provide BM. If donors refuse and other donors are not available, PBSC is allowed. TCR-alpha beta/CD19 depleted haplo donors must agree to donate PBSC
• Must give informed consent:
• Haploidentical matched family members: Institution standard of care donor consent and Protocol-specific Donor Consent for Optional Studies
• Unrelated donors: standard NMDP Unrelated Donor Consent
• PATIENT EXCLUSION CRITERIA FOR ENROLLMENT:
• Patients with genetic disorders (generally marrow failure syndromes) prone to secondary AML/ALL/MPAL with known poor outcomes because of sensitivity to alkylator therapy and/or TBI are not eligible (Fanconi Anemia, Kostmann Syndrome, Dyskeratosis Congenita, etc). Patients with Downs syndrome because of increased toxicity with intensive conditioning regimens.
• Patients with any obvious contraindication to myeloablative HCT at the time of enrollment
• Female patients who are pregnant are ineligible as many of the medications used in this protocol could be harmful to unborn children and infants
• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation
• PATIENT EXCLUSION CRITERIA TO PROCEED TO HCT:
• Patients with uncontrolled fungal, bacterial, viral, or parasitic infections are excluded. Patients with history of fungal disease during chemotherapy may proceed if they have a significant response to antifungal therapy with no or minimal evidence of disease remaining by computed tomography (CT) evaluation
• Patients with active central nervous system (CNS) leukemia or any other active site of extramedullary disease at the time of initiation of the conditioning regimen are not permitted.
• Note: Those with prior history of CNS or extramedullary disease, but with no active disease at the time of pre-transplant workup, are eligible
• Pregnant or breastfeeding females are ineligible as many of the medications used in this protocol could be harmful to unborn children and infants

• Confirmed diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and active disease clearly documented to initiate therapy.
• Deletion (Del) (17p) status, tumor protein 53 (TP53) mutation status, immunoglobulin heavy chain gene (IGHV) mutation status and Bruton's tyrosine kinase (BTK)-C481 mutation status results required before randomization for Part 2 participants only.
• Relapsed or refractory to at least 1 prior available therapy.
• Have at least 1 marker of disease burden.
• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 within 7 days before randomization.
• Has a life expectancy of at least 3 months.
• Has the ability to swallow and retain oral medication.
• Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and have undetectable HBV deoxyribonucleic acid (DNA) viral load before randomization.
• Participants with history of hepatitis C virus (HCV) infection are eligible if HCV ribonucleic acid (RNA) viral load is undetectable at screening.
• Participants with human immunodeficiency virus (HIV) who meet ALL eligibility criteria.
• Participants with adequate organ function with specimens collected within 7 days before the start of study intervention.
• If capable of producing sperm, participant agrees to eliminate Nemtabrutinib: 12 days, Venetoclax: 1 month (30 days), Rituximab (rituximab biosimilar): not applicable; abstains from penile-vaginal intercourse as their preferred and usual lifestyle; OR uses prescribed contraception.
• Participant assigned female sex at birth are eligible to participate if not pregnant or breastfeeding and are not a person of childbearing potential (POCBP) OR is a POCBP and uses a contraceptive method that is highly effective, has a negative highly sensitive pregnancy test, and abstains from breastfeeding.
• Has an active hepatitis B virus/ hepatitis C virus (HBV/HCV) infection.
• Has gastrointestinal (GI) dysfunction that may affect drug absorption.
• Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
• Has diagnosis of Richter Transformation or active central nervous system (CNS) involvement by CLL/SLL.
• Has an active infection requiring systemic therapy, such as intravenous (IV) antibiotics, during screening.
• HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease and/or acquired immune deficiency syndrome (AIDS)-defining opportunistic infection in the past 12 months before screening.
• Has QT interval corrected (QTc) prolongation or other significant electrocardiogram (ECG) abnormalities.
• Has a known allergy/sensitivity to nemtabrutinib or contraindication to venetoclax/rituximab (or rituximab biosimilar), or any of the excipients.
• Has history of severe bleeding disorders (eg, hemophilia).
• Has received prior systemic anticancer therapy within 5 half-lives or 4 weeks (if prior therapy was a monoclonal antibody) before randomization.
• Has received prior B-cell lymphoma 2 inhibitor(s) (BCL2i) including venetoclax or Non-covalent Bruton's tyrosine kinase inhibitor (BTKi).
• Is currently being treated with p-glycoprotein (P-gp) substrates with a narrow therapeutic index, cytochrome P450 3A (CYP3A) strong or moderate inducers or CYP3A strong inhibitors.
• Has received a live or live attenuated vaccine within 30 days before the first dose of study intervention.
• Has received an investigational agent or has used an investigational device within 4 weeks before study intervention administration.
• Has a known psychiatric or substance use disorder that would interfere with the participant's ability to cooperate with the requirements of the study.
• Participants who have not adequately recovered from major surgery or have ongoing surgical complications.

1. Adult participants must be 18 years of age or older 2. Advanced or metastatic solid tumors excluding primary central nervous system (CNS) tumors 3. Have documented evidence of genetic alterations conferring homologous recombination deficiency 4. Participant must have progressed on at least one prior line of therapy in the advanced or metastatic setting that is considered an appropriate standard of care, or for which the participant has documented intolerance 1. Known primary CNS malignancy 2. Impairment of GI function or GI disease that may significantly alter the absorption of IDE161 3. Have active, uncontrolled infection 4. Clinically significant cardiac abnormalities 5. Major surgery within 4 weeks prior to enrollment 6. Radiation therapy within 2 weeks prior to enrollment 7. Systemic cytotoxic chemotherapy within 4 weeks prior to enrollment 8. Radioimmunotherapy within 6 weeks of enrollment 9. Treatment with a therapeutic antibody within 4 weeks prior to enrollment 10. Treatment with an anti-cancer small molecule within 5 half-lives (t1/2), or 2 weeks, whichever is shorter

• Alive (per medical record)
• Diagnosed with cancer in the past 3 years
• Received care from a participating oncology clinic in the past year
• Has a current tobacco use status
• Does not have a preferred language other than English (missing language preference will be included).
• Valid address that is not a correctional facility or residential treatment/care facility.
• No flag for patient cognitive impairment, activated health care power of attorney, or other health care agent (e.g., legally authorized representative) in the EHR. The following additional inclusion criteria must be met for inclusion in the CET
• Smoked combustible cigarettes in the past month.
• Able to speak and understand English.
• Willing to set a date to quit smoking in the next 60 days.
• Willing to receive smoking treatment information.
• Willing to complete study activities.
• No current suicidal ideation.
• Suicide attempt in the past year.
• Currently receiving treatment for bipolar disorder, schizophrenia, schizoaffective disorder, or psychotic disorder.
• Incarceration.
• Unable to provide informed consent to treatment (i.e., cannot answer questions about study procedures or risks after hearing about the study).

1. Male or female participants ≥18 years of age 2. Dose Escalation Phase (Part 1): 1. Participants must have a pathologically confirmed diagnosis of an advanced or metastatic solid tumor with a documented RAS, NF1, or RAF mutations. A molecular pathology report documenting mutational status of RAS, NF1, or RAF must be available. 2. Progressed despite standard therapies, and received at least 1 prior line of anticancer therapy.
• Participants with a documented mutation in BRAF V600E or V600K must have received approved treatments known to provide clinical benefit prior to study entry. 3. Participants enrolled in the DCC-3116 and sotorasib cohort (Cohort D) must have a KRAS G12C mutation. 3. Dose Expansion Phase (Part 2): 1. Cohort 1: Patients with Pancreatic Ductal Adenocarcinoma (PDAC).
• Pathologically confirmed PDAC with a documented mutation in KRAS.
• Received only 1 prior line of systemic therapy in the advanced or metastatic setting. 2. Cohort 2: Patients with Non-Small Cell Lung Cancer (NSCLC)
• Pathologically confirmed NSCLC with a documented mutation in KRAS, NRAS, NF1, or BRAF.
• Received at least 2 prior lines but no more than 4 prior lines of systemic therapy in the advanced or metastatic setting. 3. Cohort 3: Patients with Colorectal Cancer (CRC)
• Pathologically confirmed CRC with a documented mutation in KRAS, NRAS, NF1, or BRAF.
• Received at least 2 prior lines of systemic therapy in the advanced or metastatic setting. 4. Cohort 4: Patients with Melanoma
• Pathologically confirmed melanoma with a documented mutation in NRAS.
• Received at least 1 but not more than 2 prior lines of systemic therapy in the advanced or metastatic setting that included T-cell checkpoint inhibitor-based therapy.
• Have not received prior MEK inhibitor therapy. 5. Cohort 5: Patients with KRAS G12C mutant NSCLC
• Pathologically confirmed NSCLC with a documented mutation in KRAS G12C.
• Received at least 1 prior line but no more than 3 prior lines of systemic therapy in the advanced or metastatic setting.
• Have not received prior sotorasib or other KRAS G12C inhibitor therapy. 4. Must provide a fresh tumor biopsy from a primary or metastatic cancer lesion that can be biopsied with acceptable risk as determined by the Investigator, and an archival tumor tissue sample, if available. If a fresh tumor biopsy is not possible, then an archival tumor tissue sample must be provided. 5. Eastern Cooperative Oncology Group (ECOG) score of 0 to 2 (Dose Escalation) or 0 to 1 (Dose Expansion) at Screening 6. Adequate organ function and bone marrow function. 7. If a female of childbearing potential must have a negative pregnancy test prior to enrollment and agree to follow the contraception requirements. 8. Male participants must agree to follow contraception requirements. 9. Must provide signed consent to participate in the study and is willing to comply with study-specific procedures. 1. Must not have received the following within the specified time periods prior to the first dose of study drug: 1. Prior therapies (anticancer or therapies given for other reasons) that are known strong or moderate inhibitors or inducers of CYP3A4 or P-gp including certain herbal medications (eg, St. John's Wort): 14 days or 5× the half-life of the medication (whichever is longer) 2. All other prior anticancer therapies or any therapy that is investigational for the participant's condition with a known safety and PK profile: 14 days or 5× the half-life of the medication (whichever is shorter) 3. Investigational therapies with unknown safety and PK profile: 28 days. If there is enough data on the investigational therapy to assess the risk for drug.-drug interactions and late toxicities of prior therapy as low, the Sponsor's Medical Monitor may approve a shorter washout of 14 days 4. Grapefruit or grapefruit juice: 14 days 2. Have not recovered from all toxicities from prior therapy according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). 3. Presence or history of central nervous system (CNS) metastases or leptomeningeal disease, with some exceptions 4. New York Heart Association Class III or IV heart disease, active ischemia, or any other uncontrolled cardiac condition such as angina pectoris, clinically significant cardiac arrhythmia requiring therapy, uncontrolled hypertension, congestive heart failure, or myocardial infarction within 6 months prior to the first dose of study drug. 5. Prolongation of the QT interval corrected by Fridericia's formula (QTcF) based on repeated demonstration of QTcF >450 ms in males or >470 ms in females at screening, or history of long QT syndrome. 6. Left ventricular ejection fraction (LVEF) <50% at Screening 7. Systemic arterial thrombotic or embolic events 8. Systemic venous thrombotic events 9. Malabsorption syndrome 10. Bone disease that requires ongoing treatment or has required treatment. 11. Major surgery within 4 weeks of the first dose of study drug. All surgical wounds must be healed and free of infection or dehiscence before the first dose of the study drug. 12. Any other clinically significant comorbidities. 13. For participants receiving DCC-3116 and trametinib combination or DCC-3116 and binimetinib combination: previous treatment with trametinib or binimetinib that resulted in treatment discontinuation due to intolerability as a result of an adverse event (AE) that was considered related to trametinib or binimetinib. 14. For participants receiving DCC-3116 and sotorasib combination in Dose Escalation Part 1: previous treatment with sotorasib that resulted in treatment discontinuation due to intolerability as a result of an adverse event (AE) that was considered related to sotorasib. 15. For participants receiving DCC-3116 and sotorasib combination: Use of proton pump inhibitors (PPIs) and H2 receptor antagonists that cannot be discontinued 3 days prior to the start of study drug administration. 16. Known allergy or hypersensitivity to any component of the investigational drug products. 17. Known human immunodeficiency virus unless the following requirements are met: 1. CD4 count >350/µL 2. No AIDS-defining opportunistic infection in the last 12 months 3. Stable anti-retroviral regimen with medications that are not prohibited by the protocol for at least 4 weeks with HIV viral load less than 400 copies/mL prior to enrollment. 18. Known active hepatitis B, active hepatitis C infection or if the participant is taking medications that are prohibited per protocol. 19. If female, the participant is pregnant or lactating. 20. Ongoing participation in an interventional study. 21. For participants receiving DCC-3116 and binimetinib combination: Known Gilbert's syndrome

Key
• Patients must have a documented NPM1 mutation or KMT2A rearrangement and have either newly diagnosed or relapsed/refractory AML
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
• Adequate liver, renal, and cardiac function according to protocol defined criteria
• A female of childbearing potential must agree to use adequate contraception from the time of screening through 180 days following the last dose of study intervention. A male of childbearing potential must agree to use abstinence or adequate contraception from the time of screening through 90 days following the last dose of study intervention Key
• Diagnosis of either acute promyelocytic leukemia or blast chronic myelomonocytic leukemia
• Known history of BCR-ABL alteration
• Advanced malignant hepatic tumor [for patients receiving ven/aza combination]
• Administration of live attenuated vaccines within 14 days prior to, during, or after treatment until B-cell recovery
• Active central nervous system (CNS) involvement by AML.
• Clinical signs/symptoms of leukostasis or WBC > 25,000 / microliter. Hydroxyurea and/or leukapheresis are permitted to meet this criterion
• Not recovered to Grade ≤1 (NCI-CTCAE v5.0) from all nonhematological toxicities except for alopecia
• Known clinically active human immunodeficiency virus, active hepatitis B or active hepatitis C infection
• For newly diagnosed cohorts: received prior chemotherapy for leukemia, except hydroxyurea and/or leukapheresis to control leukocytosis, prior treatment with all-transretinoic acid for initially suspected acute promyelocytic leukemia, or non-HMA therapy for prior myelodysplastic syndrome
• For relapsed/refractory cohorts: received chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy that is considered to be investigational < 14 days prior to the first dose of ziftomenib or within 5 drug half-lives prior to the first dose of study drug
• Uncontrolled intercurrent illness including, but not limited to, cardiac illness as defined in the protocol
• Mean corrected QT interval corrected for heart rate by Fredericia's formula (QTcF) >480 ms on triplicate ECGs
• Uncontrolled infection
• Women who are pregnant or lactating
• An active malignancy and currently receiving chemotherapy for that malignancy or disease that is uncontrolled/progressing

The main inclusion criteria include but are not limited to the following:
• Confirmed diagnosis of CLL/SLL and active disease clearly documented to have a need to initiate therapy.
• Has at least 1 marker of disease burden.
• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 within 7 days before randomization.
• Has the ability to swallow and retain oral medication.
• Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and have undetectable HBV deoxyribonucleic acid (DNA) viral load before randomization.
• Participants with history of hepatitis C virus (HCV) infection are eligible if HCV ribonucleic acid (RNA) viral load is undetectable at screening.
• Participants with human immunodeficiency virus (HIV) who meet ALL eligibility criteria. The main exclusion criteria include but are not limited to the following:
• Has an active hepatitis B virus/ hepatitis C virus (HBV/HCV) infection.
• Has gastrointestinal (GI) dysfunction that may affect drug absorption.
• Has diagnosis of Richter Transformation or active central nervous system (CNS) involvement by CLL/SLL.
• Has had acquired immune deficiency syndrome (AIDS)-defining opportunistic infection in the past 12 months before screening.
• Has clinically significant cardiovascular disease.
• Has hypersensitivity to nemtabrutinib or contraindication to ibrutinib or acalabrutinib, or any of the excipients.
• Has history of severe bleeding disorder.
• Has history of second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years.
• Has received any systemic anticancer therapy for CLL/SLL.
• Is currently being treated with p-glycoprotein (P-gp) substrates with a narrow therapeutic index, cytochrome P450 3A (CYP3A) strong or moderate inducers or CYP3A strong inhibitors.
• Received prior radiotherapy within 2 weeks of start of study intervention, or radiation-related toxicities, requiring corticosteroids.
• Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed.
• Has received an investigational agent or has used an investigational device within 4 weeks before study intervention administration.
• Has diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study medication.
• Has active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid) is allowed.
• Has active infection requiring systemic therapy.
• Participants who have not adequately recovered from major surgery or have ongoing surgical complications.