Ivosidenib and Venetoclax With or Without Azacitidine in Treating Participants With IDH1 Mutated Hematologic Malignancies
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|ClinicalTrials.gov Identifier: NCT03471260|
Recruitment Status : Recruiting
First Posted : March 20, 2018
Last Update Posted : May 21, 2019
|Condition or disease||Intervention/treatment||Phase|
|High Risk Myelodysplastic Syndrome IDH1 NP_005887.2:p.R132X Myeloproliferative Neoplasm Recurrent Acute Myeloid Leukemia Refractory Acute Myeloid Leukemia||Drug: Azacitidine Drug: Ivosidenib Other: Pharmacokinetic Study Drug: Venetoclax||Phase 1 Phase 2|
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)
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).
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||48 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase Ib/II Investigator Sponsored Study of the IDH1-Mutant Inhibitor Ivosidenib (AG120) With the BCL2 Inhibitor Venetoclax in IDH1-Mutated Hematologic Malignancies|
|Actual Study Start Date :||March 19, 2018|
|Estimated Primary Completion Date :||September 30, 2019|
|Estimated Study Completion Date :||September 30, 2019|
Experimental: Treatment (venetoclax, ivosidenib, azacitidine)
Participants receive venetoclax 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 IV over 30-60 minutes or SC on days 1-7. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Given IV or SC
Other Name: AG-120
Other: Pharmacokinetic Study
- Overall response rate (ORR) [ Time Frame: Up to 3 years ]Defined as complete response (CR), CR with incomplete blood count recovery (CRi), morphologic leukemia-free state (MLFS), and partial response (PR) based on revised International Working Group (IWG) response criteria. Analysis will be performed for enrolled subjects.
- Incidence of adverse events [ Time Frame: Up to 3 years ]Will be collected using leukemia adverse event guidelines.
- Dose-limiting toxicity [ Time Frame: Up to 56 days ]Defined as any grade 3 or 4, clinically significant non-hematologic adverse event or abnormal laboratory value.
- Response to therapy [ Time Frame: Up to 3 years ]Will be calculated.
- Duration of response [ Time Frame: From the date of initial response to first documented disease progression/relapse or death, assessed up to 3 years ]Will be calculated.
- Event-free survival [ Time Frame: From treatment initiation to date of documented treatment failure, relapse, or death from any cause, assessed up to 3 years ]Will be calculated.
- Overall survival [ Time Frame: Up to 3 years ]Will be calculated.
- Plasma concentrations and pharmacokinetic parameter [ Time Frame: Up to 3 years ]Will be tabulated for each subject, visit, and dose level, and summary statistics will be computed for each sampling time and each parameter.
- Peripheral blood and bone marrow aspirate samples [ Time Frame: Up to 3 years ]Biomarker assays may include, but are not limited to, BH3 profiling and characterization of BCL-2 and related proteins, IDH1 mutant status, serum R-2HG analysis, and assessment of the depth of response and monitoring of disease recurrence by assessment of minimal residual disease in the bone marrow.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03471260
|Contact: Courtney DiNardofirstname.lastname@example.org|
|United States, Illinois|
|Northwestern Medicine Cancer Center Delnor||Not yet recruiting|
|Geneva, Illinois, United States, 60134|
|Contact: Jessica K. Altman email@example.com|
|Principal Investigator: Jessica K. Altman|
|United States, Massachusetts|
|Dana-Farber Cancer Institute||Not yet recruiting|
|Boston, Massachusetts, United States, 02215|
|Contact: Richard M. Stone firstname.lastname@example.org|
|Principal Investigator: Richard M. Stone|
|United States, New York|
|Roswell Park Cancer Institute||Not yet recruiting|
|Buffalo, New York, United States, 14263|
|Contact: Eunice S. Wang email@example.com|
|Principal Investigator: Eunice S. Wang|
|United States, Ohio|
|Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center||Not yet recruiting|
|Cleveland, Ohio, United States, 44195|
|Contact: Hetty E. Carraway firstname.lastname@example.org|
|Principal Investigator: Hetty E. Carraway|
|United States, Texas|
|M D Anderson Cancer Center||Recruiting|
|Houston, Texas, United States, 77030|
|Contact: Courtney DiNardo 713-794-1141|
|Principal Investigator: Courtney DiNardo|
|Principal Investigator:||Courtney DiNardo||M.D. Anderson Cancer Center|