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

NCT ID: NCT03471260

Last Updated: 2025-10-03

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 96 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-03-19
• Study Completion Date: 2027-09-30

Brief Summary

This phase Ib/II trial studies the side effects and best dose of venetoclax and how well it works when given together with ivosidenib with or without azacitidine, in treating patients with IDH1-mutated hematologic malignancies. Venetoclax and ivosidenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as azacitidine, 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 ivosidenib and venetoclax with azacitidine may work better in treating patients with hematologic malignancies compared to ivosidenib and venetoclax alone.

Detailed 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 and after treatment.

III. 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.

Patients receive venetoclax orally (PO) daily on days 1-14. Patients also receive ivosidenib PO daily on days 15-28 of cycle 1 and days 1-28 of subsequent cycles. Patients 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, patients are followed up at 30 days, and then monthly for 3 years.

Conditions

Acute Myeloid Leukemia; Hematopoietic and Lymphoid System Neoplasm; Myelodysplastic Syndrome; Myeloproliferative Neoplasm; Recurrent Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Treatment (venetoclax, ivosidenib, azacitidine)

Patients receive venetoclax PO daily on days 1-14. Patients also receive ivosidenib PO daily on days 15-28 of cycle 1 and days 1-28 of subsequent cycles. Patients 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.

Group Type: EXPERIMENTAL

Azacitidine

Intervention Type: DRUG

Given IV or SC

Ivosidenib

Intervention Type: DRUG

Given PO

Venetoclax

Intervention Type: DRUG

Given PO

Interventions

Azacitidine

Given IV or SC

Intervention Type: DRUG

Ivosidenib

Given PO

Intervention Type: DRUG

Venetoclax

Given PO

Intervention Type: DRUG

Other Intervention Names

5 AZC; 5-AC; 5-Azacytidine; 5-AZC; Azacytidine; Azacytidine, 5-; Ladakamycin; Mylosar; Onureg; U-18496; Vidaza; AG-120; Tibsovo; ABT-0199; ABT-199; ABT199; GDC-0199; RG7601; Venclexta; Venclyxto

Eligibility Criteria

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).

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

M.D. Anderson Cancer Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Courtney DiNardo, MD

Role: PRINCIPAL_INVESTIGATOR

M.D. Anderson Cancer Center

Locations

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

Site Status: RECRUITING

Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center

Cleveland, Ohio, United States

Site Status: RECRUITING

Oregon Health and Science University

Portland, Oregon, United States

Site Status: RECRUITING

M D Anderson Cancer Center

Houston, Texas, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Courtney DiNardo, MD

Role: CONTACT

cdinardo@mdanderson.org

713-794-1141

Facility Contacts

Jacqueline S. Garcia, MD

Role: primary

Jacqueline_Garcia@DFCI.HARVARD.EDU

617-632-2168

Hetty Carraway, MD

Role: primary

carrawh@ccf.org

216-445-5899

Curtis Lachowiez, MD

Role: primary

lundbert@ohsu.edu

503-346-0010

Courtney DiNardo

Role: primary

cdinardo@mdanderson.org

713-794-1141

References

DiNardo CD, Marvin-Peek J, Loghavi S, Takahashi K, Issa GC, Jen WY, Daver NG, Reville PK, Short NJ, Sasaki K, Mullin JK, Bradley CA, Borthakur G, Maiti A, Alvarado Y, Pemmaraju N, Abbas HA, Hammond DE, Haddad F, Bravo GM, Chien KS, Yilmaz M, Kornblau SM, Jabbour E, Ravandi F, Kadia T, Garcia-Manero G, Konopleva MY, Kantarjian HM. Outcomes of Frontline Triplet Regimens With a Hypomethylating Agent, Venetoclax, and Isocitrate Dehydrogenase Inhibitor for Intensive Chemotherapy-Ineligible Patients With Isocitrate Dehydrogenase-Mutated AML. J Clin Oncol. 2025 Aug 20;43(24):2692-2699. doi: 10.1200/JCO-25-00640. Epub 2025 Jun 13.

Reference Type: DERIVED

PMID: 40513054 (View on PubMed)

Wilde L, Kasner M. Whom should we treat with novel agents? Specific indications for specific and challenging populations. Hematology Am Soc Hematol Educ Program. 2021 Dec 10;2021(1):24-29. doi: 10.1182/hematology.2021000228.

Reference Type: DERIVED

PMID: 34889407 (View on PubMed)

Related Links

http://www.mdanderson.org

M D Anderson Cancer Center

Other Identifiers

NCI-2018-00921

Identifier Type: REGISTRY

Identifier Source: secondary_id

2017-0490

Identifier Type: OTHER

Identifier Source: secondary_id

2017-0490

Identifier Type: -

Identifier Source: org_study_id