This phase Ib trial studies the side effects and best dose of navtemadlin when given together with the standard chemotherapy drugs cytarabine and idarubicin in patients with acute myeloid leukemia. Navtemadlin may stop the growth of cancer cells by blocking a protein called MDM2 that is needed for cell growth. Chemotherapy drugs, 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. Giving navtemadlin with cytarabine and idarubicin may stabilize cancer for longer when compared to giving usual treatments alone.
PRIMARY OBJECTIVE: I. To evaluate the toxicities of navtemadlin (KRT-232 \[AMG 232\]), cytarabine and idarubicin hydrochloride (idarubicin), and to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of KRT-232 (AMG 232), cytarabine and idarubicin. SECONDARY OBJECTIVES: I. To observe and record anti-tumor activity. II. To evaluate the pharmacokinetic (PK) profiles of KRT-232 (AMG 232), cytarabine and idarubicin when used in combination. III. To evaluate p53 signaling induced by KRT-232 (AMG 232), cytarabine and idarubicin. IV. To correlate KRT-232 (AMG 232), cytarabine and idarubicin exposure with pharmacodynamics endpoints (efficacy, toxicity, changes in p53 signaling). EXPLORATORY OBJECTIVES: I. To evaluate the response rate (RR) and progression free survival (PFS) of KRT-232 (AMG 232), cytarabine and idarubicin in acute myeloid leukemia (AML). II. To evaluate potential predictive biomarkers, including MTF2 and H3K27me3, of response to KRT-232 (AMG 232), cytarabine and idarubicin in AML. III. To evaluate the pharmacodynamic (PD) effects of KRT-232 and induction chemotherapy in AML blasts. OUTLINE: This is a dose-escalation study of navtemadlin. Patients receive navtemadlin orally (PO) once daily (QD) on days 1-7, cytarabine intravenously (IV) twice daily (BID) over 3 hours on days 1-7, and idarubicin IV over 10-15 minutes on days 1-3. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients with residual disease may receive cytarabine IV BID over 3 hours for 5 days and idarubicin IV over 10-15 minutes for 2 days starting between days 14-21 of cycle 1 or the second cycle of navtemadlin, cytarabine, and idarubicin. Patients who achieve a complete response (CR) or a CR with incomplete hematologic recovery (CRi) in either cycle 1 or 2 may receive cytarabine IV BID over 3 hours on days 1, 3, and 5 for 3-4 additional 28 to 35-day cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and then every 3 months for 2 years, then every 6 months thereafter.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
24
Los Angeles General Medical Center
Los Angeles, California, United States
USC / Norris Comprehensive Cancer Center
Los Angeles, California, United States
Northwestern University
Chicago, Illinois, United States
University of Maryland/Greenebaum Cancer Center
Baltimore, Maryland, United States
Laura and Isaac Perlmutter Cancer Center at NYU Langone
New York, New York, United States
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, United States
Incidence of adverse events
Toxicity will be coded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Based on the toxicity observed, a derived variable, the occurrence of dose limiting toxicity, will be created. Toxicities will be tabulated and reported according to dose level, grade, type, cycle, and attribution and, if numbers permit, by whether the patient had newly diagnosed or previously treated acute myeloid leukemia (AML). Cumulative incidence curves will be used to estimate the proportion of patients who will discontinue therapy for reasons of toxicity or general inability to tolerate the regimen. The data from all patients treated at the recommended phase 2 dose (RP2D), will be combined for a final summary and listing of toxicities observed.
Time frame: Up to 30 days after the last dose of navtemadlin
Pharmacokinetic (PK) profile of navtemadlin in combination with cytarabine and idarubicin
Will be quantitatively measured using liquid chromatography/tandem mass spectrometric (LC/MS/MS) method developed by the Analytical Pharmacology Core Laboratory at the Sidney Kimmel Comprehensive Cancer Center (SKCCC) at Johns Hopkins. For navtemadlin, the individual PK parameters from a single dose will be estimated for concentration maximum (Cmax), area under the curve (AUC), half-life (T1/2), apparent clearance (Cl/F), and apparent volume of distribution (V/F) using non-compartmental or compartmental PK methods with the software WinNonlin. Advanced population PK methods may be employed to assess the link between drug exposure and biological effects and efficacy.
Time frame: Pre-treatment and 1, 3, 5, 8, and 24 hours post-treatment on cycle 1, day 1 (1 cycle = 28-35 days)
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