This phase Ib/II trial studies the side effects and best dose of pevonedistat and to see how well it works in combination with cytarabine and idarubicin in treating patients with acute myeloid leukemia. Pevonedistat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cytarabine and idarubicin, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Given pevonedistat, cytarabine, and idarubicin may work better in treating patients with acute myeloid leukemia.
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of pevonedistat in combination with cytarabine and idarubicin in newly diagnosed high-risk acute myeloid leukemia. (Phase Ib) II. To determine the composite complete response rate (complete remission \[CR\] or complete remission with incomplete blood count recovery \[CRi\]) of pevonedistat in combination with cytarabine and idarubicin in newly diagnosed high-risk acute myeloid leukemia. (Phase II) SECONDARY OBJECTIVES: I. To evaluate plasma pharmacokinetic (PK) profiles of pevonedistat when used in combination with cytarabine and idarubicin in the phase Ib part of the study. II. To evaluate the relapse free (RFS), overall survival (OS), safety and tolerability of pevonedistat in combination with cytarabine and idarubicin in the phase II part of the study. TERTIARY OBJECTIVES: I. To evaluate the pharmacodynamics (PD) effects of pevonedistat in combination with cytarabine and idarubicin in acute myelogenous leukemia (AML) blasts. II. To evaluate potential predictive biomarkers of response to pevonedistat in combination with cytarabine and idarubicin in AML. III. To determine the CR without minimal residual disease rate (CR MRD-) of pevonedistat in combination with cytarabine and idarubicin in newly diagnosed acute myeloid leukemia. OUTLINE: This is a phase Ib, dose escalation study of pevonedistat followed by a phase II study. INDUCTION: Patients receive idarubicin intravenously (IV) over 10-15 minutes on days 1-3, cytarabine IV over 1-3 hours on days 1-7, and pevonedistat IV over 60 minutes on days 1, 3, and 5. Patients with gross residual disease on day 14 bone marrow may receive a second course of induction chemotherapy. CONSOLIDATION: Patients who achieve CR and will not undergo bone marrow transplant receive cytarabine IV over 3 hours every 12 hours on days 1, 3, and 5. Treatment repeats every 28-35 days for 4 courses in the absence of disease progression or unaccepted toxicity. After completion of study treatment, patients are followed up for at least 30 days, and then every 3 months for 2 years.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
53
Given IV
Given IV
Correlative studies
Given IV
Correlative studies
University of Arizona Cancer Center - North Campus
Tucson, Arizona, United States
Los Angeles County-USC Medical Center
Los Angeles, California, United States
USC / Norris Comprehensive Cancer Center
Los Angeles, California, United States
University of Miami Miller School of Medicine-Sylvester Cancer Center
Miami, Florida, United States
Cleveland Clinic
Cleveland, Ohio, United States
Composite complete response rate
Response will be assessed according to the 2017 European Leukemia Net Guidelines. The composite complete response rate will be calculated as the percentage of patients who have CR or CRi. Wilson 95% confidence interval will be provided.
Time frame: Up to 2 years
Incidence of adverse events (Phase Ib)
Will be assessed by Common Terminology Criteria for Adverse Events version 4.03.
Time frame: Up to 22 days
Relapse-free survival (RFS)
RFS will be calculated as the date of achievement of a remission (CR or CRi) until the date of relapse (documented morphological recurrence (≥ 5% blasts on in the bone marrow, reappearance of blasts in the blood or development of extramedullary disease after CR) or death - whichever comes first; patients who are alive and have not progressed or recurred at the time of their last disease assessment, will be censored at that time. Survival curves will be plotted by the Kaplan-Meier (KM) method. Median RFS and their 95% confidence intervals, 1-year and 2- year survival rates and corresponding standard errors will be derived from the KM curves.
Time frame: From the date of achievement of a remission until the date of relapse or death from any cause, assessed up to 2 years
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