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Phase Ib/II Investigator Initiated Study of the IDH1-Mutant Inhibitor Ivosidenib (AG120) With the BCL2 Inhibitor Venetoclax +/- Azacitidine in IDH1-Mutated Hematologic Malignancies


Description

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

Trial Eligibility

Inclusion Criteria: 1. Age \> 18 years. 2. ECOG performance status of \< 2. 3. IDH1-R132 mutated disease status as assessed by local laboratory. 2HG-producing IDH1 variants outside of R132 (i.e. R100) may be eligible after discussion with the PI. 4. Relapsed/refractory AML, or treatment-naïve patients with AML who are not eligible for standard induction chemotherapy. Patients with high-risk MDS, MDS/MPN or MPN (defined as \> 10% bone marrow blasts, or intermediate or high risk by IPSS, R-IPSS or D-IPSS) that have failed standard therapy may also be eligible after discussion with the PI. 5. Adequate hepatic function (direct bilirubin \< 2 x ULN, ALT and/or AST \< 3x ULN) unless deemed to be related to underlying leukemia. 6. Adequate renal function including creatinine clearance \> 30 ml/min based on the Cockcroft-Gault equation. 7. Willing and able to provide informed consent 8. In the absence of rapidly proliferative disease, the interval from prior treatment to time of initiation will be at least 7 days for cytotoxic or non-cytotoxic (immunotherapy) agents. 9. Male subjects must agree to refrain from unprotected sex and sperm donation from initial study drug administration until 90 days after the last dose of study drug. Exclusion Criteria: 1. Patients with known allergy or hypersensitivity to ivosidenib or venetoclax. 2. Patients who have previously received either ivosidenib or venetoclax. 3. Patients with any concurrent uncontrolled clinically significant medical condition including infection, laboratory abnormality, or psychiatric illness, which could place the patient at unacceptable risk of study treatment. 4. The use of other chemotherapeutic agents or anti-leukemic agents is not permitted during study with the following exceptions (1) intrathecal chemotherapy for prophylactic use or for controlled CNS leukemia. (2) use of hydroxyurea and/or one dose of cytarabine (up to 2 g/m2) for patients with rapidly proliferative disease is allowed before the start of study therapy and for the first four weeks on therapy. 5. Patients receiving concomitant strong CYP3A inducers (avasimibe, carbamazepine, phenytoin, rifampin, rifabutin, St. John's wort) within 3 days of start of study therapy. 6. Patients with active graft-versus-host-disease (GVHD) status post stem cell transplant (patients without active GVHD on chronic suppressive immunosuppression and/or phototherapy for chronic skin GVHD are permitted after discussion with the PI). 7. Patients with any severe gastrointestinal or metabolic condition which could interfere with the absorption of oral study medications. 8. Patients with a concurrent active malignancy under treatment. 9. QTc interval using Fridericia's formula (QTcF) \> 450 msec. Bundle branch block and prolonged QTc interval are permitted after discussion with the PI. 10. Known active hepatitis B (HBV) or Hepatitis C (HCV) infection or known HIV infection. 11. Subject has a white blood cell count \> 25 x 10⁹/L. (Note: Hydroxyurea is permitted to meet this criterion.) 12. Nursing women, women of childbearing potential (WOCBP) with positive urine pregnancy test, or women of childbearing potential who are not willing to maintain adequate contraception a. Appropriate highly effective method(s) of contraception include oral or injectable hormonal birth control, IUD, and double barrier methods (for example a condom in combination with a spermicide).

Study Info

Organization

M.D. Anderson Cancer Center


Primary Outcome

Overall response rate (ORR)


Outcome Timeframe Up to 3 years

NCTID NCT03471260

Phases PHASE1,PHASE2

Primary Purpose TREATMENT

Start Date 2018-03-19

Completion Date 2025-09-30

Enrollment Target 96

Interventions

DRUG Azacitidine

DRUG Ivosidenib

DRUG Venetoclax

Locations Recruiting

Dana-Farber Cancer Institute

United States, Massachusetts, Boston


Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center

United States, Ohio, Cleveland


M D Anderson Cancer Center

United States, Texas, Houston


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