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 daily (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. Additionally, patients undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) during screening.

ARM II: Patients receive azacitidine IV or subcutaneously (SC) on days 1-7 or days 1-5 and 8-9 and venetoclax PO QD 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. Additionally, patients undergo ECHO or MUGA during screening.

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. Additionally, patients undergo ECHO or MUGA during screening.

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 ECHO or 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 of each cycle and venetoclax PO on days 1-28 of each cycle. Treatment repeats every 28 days for up to 2 cycles or until bone marrow assessment shows at least an MLFS response or better ("better" defined as CR, CRi, CRh), 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 bone marrow assessment shows at least an MLFS response or better ("better" defined as CR, CRi, CRh), 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 bone marrow assessment shows at least an MLFS response or better ("better" defined as CR, CRi, CRh), 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 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.

• Time to MDNet generating all data required for treatment substudy or TAP assignment [Time frame: Within 72 hours of MDNet receipt of specimens for initial therapy or within 10 days for subsequent therapy]
• Time to treatment substudy or TAP assignment [Time frame: Within 72 hours of MDNet receipt of specimens for initial therapy or within 10 days for subsequent therapy]
• Percent assigned to a myeloMATCH clinical trial [Time frame: Within 72 hours of MDNet receipt of specimens for initial therapy or within 10 days for subsequent therapy]
• Percent of screened participants who register to a treatment substudy [Time frame: Within 72 hours of MDNet receipt of specimens for initial therapy or within 10 days for subsequent therapy]
• Assignment to higher tier treatment substudies within myeloMATCH [Time frame: Within 72 hours of MDNet receipt of specimens for initial therapy or within 10 days for subsequent therapy]
• Adverse events [Time frame: Within 72 hours of MDNet receipt of specimens for initial therapy or within 10 days for subsequent therapy]
• Minimal residual disease (MRD) response [Time frame: Within 72 hours of MDNet receipt of specimens for initial therapy or within 10 days for subsequent therapy]
• Time-to-event outcomes for exploratory analysis [Time frame: Within 72 hours of MDNet receipt of specimens for initial therapy or within 10 days for subsequent therapy]
• Performance status [Time frame: Within 72 hours of MDNet receipt of specimens for initial therapy or within 10 days for subsequent therapy]