Induction and Consolidation With Fludarabine, Cytarabine, Idarubicin, and Venetoclax for the Treatment of Acute Myeloid Leukemia

Description

PRIMARY OBJECTIVE:

I. Assess the efficacy of treatment based on rates of measurable residual disease negative composite complete remission (CRc-MRD-) determined using multiparameter flow cytometry (MFC).

SECONDARY OBJECTIVES:

I. Assess the efficacy of treatment based on complete response (CR) disease remission.

II. Assess the efficacy of treatment based on overall clinical response. III. Assess the safety of treatment. IV. Assess survival in the absence of treatment failure, hematologic relapse, or progressive disease.

V. Assess patient survival after commencing study therapy. VI. Assess the delay in hematopoietic stem cell transplant (HSCT) referral and consultation for transition to HSCT.

VII. Assess the efficacy of treatment based on transitioning to HSCT. VIII. Assess disease response after transplant among participants who proceed to HSCT.

IX. Assess risk of post-transplant infection among participants who proceed to HSCT.

X. Assess risk of post-transplant graft versus host disease (GVHD) among participants who proceed to HSCT.

XI. Assess survival in the absence of post-HSCT GVHD and relapse among participants who proceed to HSCT.

EXPLORATORY OBJECTIVES:

I. Evaluate the depth of response with measurable residual disease (MRD) testing and compare methods of determining MRD status.

II. Evaluate survival of measurable residual disease negative (MRD-) patients with CR versus CR with partial or incomplete hematologic recovery.

III. Assess participant quality of life (QoL) using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ C30).

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM 1:

INDUCTION: Patients receive fludarabine intravenously (IV) over 30 minutes and cytarabine IV over 4 hours on days 2, 3, 4, 5, and 6, idarubicin IV over 15-30 minutes on days 4, 5, and 6, and venetoclax orally (PO) once daily (QD) on days 3-9 of each cycle. Cycles repeat every 28 days for up to 1 cycle in the absence of disease progression or unacceptable toxicity. Patients achieving CR, CR with partial hematologic recovery (CRh), CR with incomplete blood count recovery (CRi), or morphologic leukemia-free state (MLFS) after one induction cycle proceed to consolidation. Patients achieving partial response (PR) after one induction cycle may proceed to consolidation at the investigator’s discretion. Patients with ≥ 5% blasts after one cycle of induction may receive a second cycle of induction therapy.

CONSOLIDATION: Patients receive fludarabine IV over 30 minutes and cytarabine IV over 4 hours on days 2, 3, and 4 of each cycle, idarubicin IV over 15-30 minutes on days 4, 5, and 6 of either cycles 3 and 6 or cycles 4 and 7, and venetoclax PO QD on days 3-9 of each cycle. Cycles repeat every 28 days for up to 6 post-induction cycles in the absence of disease progression or unacceptable toxicity.

ARM 2:

INDUCTION: Patients receive cytarabine IV on days 1-7 and daunorubicin IV on days 1-3 of each cycle. Cycles repeat every 28 days for up to 1 cycle in the absence of disease progression or unacceptable toxicity. Patients achieving CR, CRh, CRi, or MLFS after one induction cycle proceed to consolidation. Patients achieving PR after one induction cycle may proceed to consolidation at the investigator’s discretion. Patients with ≥ 5% blasts after one induction cycle may receive a second cycle of induction therapy.

CONSOLIDATION: Participants receive cytarabine IV over 3 hours twice daily (BID) on days 1, 3, and 5 of each cycle. Cycles repeat every 28 days for up to 4 post-induction cycles in the absence of disease progression or unacceptable toxicity.

Additionally, all patients undergo echocardiography (ECHO) or multigated acquisition (MUGA) scan during screening and on study as clinically indicated. Patients also undergo bone marrow aspiration and biopsy and blood sample collection throughout the trial.

After completion of study treatment, patients are followed up at 30 days and then every 3 months for 2 years.