MYELOMATCH: A Screening Study to Assign People With Myeloid Cancer to a Treatment Study or Standard of Care Treatment Within myeloMATCH (MyeloMATCH Screening Trial)

PRIMARY OBJECTIVES:

I. Screening and Reassessment (MSRP): To evaluate the feasibility of MATCHBox receiving and organizing all data needed for assignment to a myeloMATCH clinical trial or Tier Advancement Pathway (TAP) within 72 hours of MDNet receipt of all required specimens for initial therapy and within 10 days for subsequent therapy.

II. Tier Advancement Pathway (TAP): To enable participants who are not matched to an investigational myeloMATCH treatment substudy to receive standard of care (SOC) while remaining on the MSRP to maintain access to later tiers of treatment substudies.

SECONDARY OBJECTIVES:

I. Screening and Reassessment (MSRP):

Ia. To describe the time to generation of all data required for treatment substudy (or TAP) assignment, time to treatment substudy (or TAP) assignment, percent assigned to a myeloMATCH treatment substudy, and the percent of screened participants who register to a myeloMATCH investigational treatment substudy or are assigned to TAP:

Iai. Separately within each tier of myeloMATCH treatment substudy and analogous TAP assignment; Ibi. Separately within each clinical basket of myeloMATCH treatment substudies; Ici. Over time, across and within the categories above.

II. Tier Advancement Pathway (TAP):

IIa. To evaluate participants for assignment to higher tier treatment substudies within myeloMATCH; IIb. To describe, within tier- and basket- levels of TAP, measurable residual disease (MRD) rates and clonal evolution; IIc. To describe, within tier- and basket- levels of TAP, remission status and overall survival of participants who receive standard of care therapy; IId. To obtain MDNet specimens for translational medicine and biobanking.

OUTLINE:

REGISTRATION: Patients undergo bone marrow aspiration and collection of blood on study. Patients' bone marrow and blood specimens undergo rapid genetic testing. Patients are then assigned to a specific substudy containing a therapy targeted to the patient's mutational profile. If there is no targetable mutation, the patient is placed on a substudy testing novel combinations that do not contain a target-specific drug. Patients who are not eligible for any MYELOMATCH substudy are assigned to TAP.

TAP: Patients continue SOC treatment and undergo continued bone marrow aspiration and blood collection for possible future substudy assignment.

TREATMENT: Patients are assigned to a specific treatment substudy.

MM1YA-CTG01: Younger patients (age 18-59 years) with intermediate risk acute myeloid leukemia (AML) are randomized to 1 of 3 arms.

ARM I: Patients receive daunorubicin intravenously (IV) on days 2-4, cytarabine IV continuously on days 2-8, and venetoclax orally (PO) once per day (QD) on days 1-11. Cycle is 28 days and treatment is given in the absence of disease progression or unacceptable toxicity. Based on a bone marrow aspiration assessment (completed at the discretion of the treating investigator), patients may receive reinduction consisting of daunorubicin IV on days 2-3, cytarabine IV continuously on days 2-6, and venetoclax PO QD on days 1-8. Cycle is 28 days and treatment is given in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspiration and collection of blood samples on study and as clinically indicated.

ARM II: Patients receive azacitidine IV or subcutaneously (SC) on days 1-7 or days 1-5 and 8-9 and venetoclax PO on days 1-28 of each cycle. Cycles repeat every 28 days for a total of 2 cycles, in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspiration and collection of blood samples on study and as clinically indicated.

ARM III: Patients receive daunorubicin IV on days 1-3 and cytarabine IV, continuously, on days 1-7. Cycle is 28 days and treatment is given in the absence of disease progression or unacceptable toxicity. Based on a bone marrow aspiration assessment (completed at the discretion of the treating investigator), patients may receive reinduction consisting of cytarabine IV, continuously, on days 1-5 and daunorubicin IV on days 1-2. Cycle is 28 days and treatment is given in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspiration and collection of blood samples on study and as clinically indicated.

MM1YA-S01: Younger patients (age 18-59 years) with high-risk AML are randomized to 1 of 5 arms.

ARM I: Patients receive cytarabine IV continuously on days 1-7 and daunorubicin IV on days 1-3 per standard approach of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of cytarabine IV continuously on days 1-5 and daunorubicin IV on days 1-2. Patients undergo echocardiography (ECHO) or multigated acquisition (MUGA) scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.

ARM II: Patients receive cytarabine IV continuously on days 2-8 and daunorubicin IV on days 2-4 with venetoclax PO on days 1-11 of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of cytarabine IV continuously on days 2-6 and daunorubicin IV on days 2-3 with venetoclax PO on days 1-8. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.

ARM III: Patients receive azacitidine SC or IV on days 1-7 and venetoclax PO on days 1-28 of each cycle. Cycles repeat every 28 days for 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.

ARM IV: Patients receive daunorubicin and cytarabine liposome IV over 90 minutes on days 1, 3, and 5 of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of daunorubicin and cytarabine liposome IV over 90 minutes on days 1 and 3. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.

ARM V: Patients receive daunorubicin and cytarabine liposome IV over 90 minutes on days 1, 3, and 5 and venetoclax PO on days 1-14 of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of daunorubicin and cytarabine liposome IV over 90 minutes on days 1 and 3 and venetoclax PO on days 1-7. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.

MM2YA-EA01: Younger patients (age 18-59 years) with AML or secondary AML who have completed a tier 1 MyeloMATCH treatment study with complete remission (CR) or CR with partial hematologic recovery (CRh) and have detectable minimal residual disease (MRD) (> 0.1%) are randomized to 1 of 4 arms.

ARM A: Patients receive cytarabine IV on study. Patients undergo bone marrow aspiration and biopsy on study. Patients may also undergo ECHO and/or MUGA as clinically indicated.

ARM B: Patients receive cytarabine IV and venetoclax PO on study. Patients undergo bone marrow aspiration and biopsy on study. Patients may also undergo ECHO and/or MUGA as clinically indicated.

ARM C: Patients receive Vyxeos IV and venetoclax PO on study. Patients undergo bone marrow aspiration and biopsy on study. Patients may also undergo ECHO and/or MUGA as clinically indicated.

ARM D: Patients receive azacitidine IV or SC and venetoclax PO on study. Patients undergo bone marrow aspiration and biopsy on study. Patients may also undergo ECHO and/or MUGA as clinically indicated.

MM1OA-EA02: Patients are randomized to 1 of 3 regimens.

REGIMEN 1:

INDUCTION: Patients receive azacitidine IV or SC on days 1-7 and venetoclax PO on days 1-28 of each cycle. Treatment repeats every 28 days for up to 2 cycles or until patient achieves remission, whichever comes first, in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION: Patients receive azacitidine IV or SC on days 1-7 and venetoclax PO on days 1-28 of each cycle. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity.

REGIMEN 2:

INDUCTION: Patients receive azacitidine IV or SC on days 1-7 and venetoclax and gilteritinib PO on days 1-28 of each cycle. Treatment repeats every 28 days for up to 2 cycles or until patient achieves remission, whichever comes first, in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION: Patients receive azacitidine IV or SC on days 1-5, venetoclax PO on days 1-7 and gilteritinib PO on days 1-28 of each cycle. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity.

REGIMEN 3:

INDUCTION: Patients receive azacitidine IV or SC on days 1-7 and venetoclax PO on days 1-28, and gilteritinib PO on days 8-21 of each cycle. Treatment repeats every 28 days for up to 2 cycles or until patient achieves remission, whichever comes first, in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION: Patients receive azacitidine IV or SC on days 1-5, venetoclax PO on days 1-14 and gilteritinib PO on days 8-21 of each cycle. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity.

MM1MDS-A01: Patients are randomized to 1 of 2 regimens.

REGIMEN 1: Patients receive ASTX727 PO once daily (QD) on days 1-5 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who do not achieve a CR, CRL, or CRh at the end of cycle 6 may cross-over to Regimen 1. Patients who experience CR, PR, or stable disease (SD) any time after 4 cycles of treatment may be reassessed in order to go to a higher myeloMATCH tier assignment or to TAP. Patients also undergo bone marrow biopsy and aspiration throughout the study. Patients may also undergo optional buccal swab on study, and/or optional additional bone marrow aspiration and blood sample collection on study and at disease progression.

REGIMEN 2: Patients receive ASTX727 PO QD on days 1-5 and enasidenib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who experience CR, PR, or SD any time after 4 cycles of treatment may be reassessed in order to go to a higher myeloMATCH tier assignment or to TAP. Patients also undergo bone marrow biopsy and aspiration throughout the study. Patients may also undergo optional buccal swab on study, and/or optional additional bone marrow aspiration and blood sample collection on study and at disease progression.

MM1OA-S03: Patients are randomized to 1 of 2 arms.

ARM 1: Patients receive ASTX727 PO QD on days 1-5 and venetoclax PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, bone marrow aspiration, and bone marrow biopsy throughout the trial.

ARM 2: Patients receive ASTX727 PO QD on days 1-5, venetoclax PO QD on days 1-28, and enasidenib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, bone marrow aspiration, and bone marrow biopsy throughout the trial.

MM1YA-A04: Patients are randomized to 1 of 2 regimens.

REGIMEN 1: Patients receive gemtuzumab ozogamicin IV on days 1 and 4, cytarabine IV, continuously, on days 1-7 and daunorubicin IV on days 1-3 in the absence of disease progression or unacceptable toxicity. Patients then undergo standard of care consolidation/post-remission treatment at the discretion of the treating physician. Patients undergo echocardiography or MUGA scan during screening and bone marrow aspiration and biopsy and blood sample collection throughout the study. Patients may also undergo optional buccal swab collection throughout the study.

REGIMEN 2: Patients receive venetoclax PO QD on days 1-11, cytarabine IV, continuously, on days 2-8 and daunorubicin IV on days 2-4 in the absence of disease progression or unacceptable toxicity. Patients then undergo standard of care consolidation/post-remission treatment at the discretion of the treating physician. Patients undergo echocardiography or MUGA scan during screening and bone marrow aspiration and biopsy and blood sample collection throughout the study. Patients may also undergo optional buccal swab collection throughout the study.

MM3TCT-A03: Patients with matched donors are randomized to conditioning 1A or 1B. Patients with haploidentical or mismatched unrelated donors are randomized to conditioning 2A or 2B.

CONDITIONING 1A: Patients receive venetoclax PO QD on days -10 to -2, fludarabine IV on days -6 or -5 to -2 and busulfan IV on days -3 to -2 or twice daily (BID) on days -5 to -2 or melphalan IV on day -2. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity.

CONDITIONING 1B: Patients receive placebo PO QD on days -10 to -2, fludarabine IV on days -6 or -5 to -2 and busulfan IV on days -3 to -2 or BID on days -5 to -2 or melphalan IV on day -2. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity.

CONDITIONING 2A: Patients receive venetoclax PO QD on days -10 to -2, melphalan IV on day -6, fludarabine IV on days -5 to -2 and undergo total body irradiation once on day -1. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity.

CONDITIONING 2B: Patients receive placebo PO QD on days -10 to -2, melphalan IV on day -6, fludarabine IV on days -5 to -2 and undergo total body irradiation once on day -1. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: All patients without evidence of relapse at day +100 are re-randomized to maintenance I or II.

MAINTENANCE I: Patients receive venetoclax PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 1 year post transplant (9 cycles) in the absence of disease progression or unacceptable toxicity.

MAINTENANCE II: Patients receive placebo PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 1 year post transplant (9 cycles) in the absence of disease progression or unacceptable toxicity.

Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo positron emission tomography (PET) scan and/or computed tomography (CT) scan throughout the study.

MM1OA-MDS-A05: Patients are assigned to 1 of 3 cohorts.

COHORT A: Patients are randomized to 1 of 2 arms.

ARM 1: Patients receive ASTX727 PO QD on days 1-5 of each cycle and venetoclax PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients with CR, CRh, or CRi after cycle 4 continue treatment cycles every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow biopsy/aspiration and collection of blood samples throughout the trial.

ARM 2: Patients receive ASTX727 PO QD on days 1-5 of each cycle, venetoclax PO QD on days 1-28 of each cycle, and olutasidenib PO BID on days 1-28 of each cycle. Cycles repeat every 28 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients with CR, CRh, or CRi after cycle 4 continue treatment cycles every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow biopsy/aspiration and collection of blood samples throughout the trial.

COHORT B: Patients are randomized to 1 of 2 arms.

ARM 3: Patients receive ASTX727 PO QD on days 1-5 of each cycle and olutasidenib PO BID on days 1-28 of each cycle. Cycles repeat every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients with CR continue treatment cycles every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow biopsy/aspiration and collection of blood samples throughout the trial.

ARM 4: Patients receive ASTX727 PO QD on days 1-5 of each cycle. Cycles repeat every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients without CR after cycle 6 may then cross-over to Arm 3. Patients with CR, as well as patients without CR but deriving clinical benefit after cycle 6 continue treatment cycles every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow biopsy/aspiration and collection of blood samples throughout the trial.

COHORT C: Patients receive olutasidenib PO BID on days 1-28 of each cycle. Cycles repeat every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients deriving clinical benefit after cycle 6 continue treatment cycles every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow biopsy/aspiration and collection of blood samples throughout the trial.

MM1MDS-CTG02: This is a dose-escalation study of luspatercept in combination, dependent upon arms assignments, with fixed dose epoetin alfa or emavusertib. Patients are randomized to 1 of 3 arms.

ARM 1: Patients receive luspatercept SC on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow aspiration and blood sample collection throughout the study.

ARM 2: Patients receive luspatercept SC on day 1 and epoetin alfa SC once weekly (QW) for each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow aspiration and blood sample collection throughout the study.

ARM 3: Patients receive luspatercept SC on day 1 and emavusertib PO BID on days 1-21 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow aspiration and blood sample collection throughout the study.

Inclusion criteria

• Participants must be suspected to have previously untreated acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Participants with AML cannot have a history of previously treated myeloproliferative neoplasms (MPN) or MDS.
• Participants must be >= 18 years of age.
• Participants must not have received prior anti-cancer therapy for AML or MDS.

• Note: Hydroxyurea to control the white blood cell count (WBC) is allowed.
• Note: Prior erythroid stimulating agent (ESA) is not considered prior therapy for the purposes of eligibility. Participants must not be currently receiving any cytarabine-containing therapy other than up to 1 g/m^2 of cytarabine, which is allowed for urgent cytoreduction.
• Participants are allowed prior use of hydroxyurea, all-trans retinoic acid (ATRA), BCR-ABL directed tyrosine kinase inhibitor, erythropoiesis-stimulating agent, thrombopoietin receptor agonist and lenalidomide, with a maximum limit of 1 month of exposure.

• Note: Participants receiving hydroxyurea prior to treatment substudy or TAP assignment must agree to discontinue hydroxyurea within 24 hours before beginning substudy or TAP treatment.
• Participants must not have a prior or concurrent malignancy that requires concurrent anti-cancer therapy

• Note: active hormonal therapy is allowed
• Participants must have a Zubrod Performance Status evaluation within 28 days prior to registration.
• Participants must agree to have translational medicine specimens submitted.
• Participants must be offered the opportunity to participate in specimen banking.

• Note: Specimens must be collected and submitted following the initial paper-based process and subsequently via the Precision Medicine Specimen Tracking Forms in Medidata Rave instance for the MyeloMATCH MSRP.
• Participants must be informed of the investigational nature of this study and must sign and give 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.
• The master screening and reassessment protocol (MSRP) should only be used in sites where the relevant AML treatment substudies are open or if the site is willing to follow the MSRP Tier Advancement Pathway (TAP) for patients in the event that the site does not have the relevant study open and transfer to another site that does have the study open. For example, if a site does not have a myeloMATCH Tier 1 study for older AML open for enrollment, such older AML patients should only be consented for the MSRP if the site is willing to treat the patient with standard of care on TAP or is willing to transfer the patient to a center with a study open that the patient would otherwise match to.