Ivosidenib and Venetoclax With or Without Azacitidine in Treating Participants With IDH1 Mutated Hematologic Malignancies

Summary

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PRIMARY OBJECTIVES: I. To determine the safety and tolerability, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) of the combination of ivosidenib with venetoclax, with or without the addition of azacitidine, in IDH1-mutated patients with advanced hematologic malignancies. (Phase Ib...

PRIMARY OBJECTIVES: I. To determine the safety and tolerability, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) of the combination of ivosidenib with venetoclax, with or without the addition of azacitidine, in IDH1-mutated patients with advanced hematologic malignancies. (Phase Ib) II. To determine the overall response rate (ORR) including complete response, (CR), CR with incomplete blood count recovery (CRi), morphologic leukemia-free state (MLFS), and partial response (PR) of the combination of ivosidenib and venetoclax, with or without the addition of azacitidine, in IDH1-mutated patients with acute myeloid leukemia (AML). (Phase II) SECONDARY OBJECTIVES: I. Characterize the pharmacokinetic (PK) profiles of venetoclax and ivosidenib in combination in plasma samples (in Part 1b). II. To evaluate molecular and cellular biomarkers that may be predictive of antitumor activity and/or resistance to treatment including evaluation of 2HG, IDH1 VAF levels before, during and after treatment. II. To determine time to event endpoints including duration of response (DOR), event free survival (EFS) and overall survival (OS). EXPLORATORY OBJECTIVES: I. Evaluate minimal residual disease (MRD) using multiparameter flow cytometry, cytogenetics and molecular evaluation. II. Evaluate global gene expression profiles, deoxyribonucleic acid (DNA) methylation profiles, BH3 profiling and other potential prognostic markers to explore predictors of antitumor activity and/or resistance to treatment. OUTLINE: This is a phase Ib, dose-escalation study of venetoclax followed by a phase II study. Participants receive venetoclax orally (PO) daily on days 1-14. Participants also receive ivosidenib PO daily on days 15-28 of cycle 1 and days 1-28 of subsequent cycles. Participants may also receive azacitidine intravenously (IV) over 30-60 minutes or subcutaneously (SC) on days 1-7. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, participants are followed up at 30 days, and then monthly for 3 years.

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