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

What's the purpose of this trial?

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.

This trial is currently open and accepting patients.

What will happen during the trial?

You may be able to join this trial if you:

The following criteria is a partial list of reasons why patients may be eligible to participate in this clinical trial. Further evaluation with a medical professional is required.

Inclusion Criteria:

* Eastern Cooperative Oncology Group (ECOG) performance status of =\< 2.
* 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 principal investigator (PI).
* Relapsed/refractory AML, or treatment-naive patients with AML who are not eligible for standard induction chemotherapy. Patients with high-risk myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN) (defined as \>= 10% bone marrow blasts, or intermediate or high risk by International Prostate Symptom Score \[IPSS\], Revised \[R\]-IPSS or Dynamic \[D\]-IPSS) may also be eligible after discussion with the PI
* Direct bilirubin =\< 2 x upper limit of normal (ULN) unless deemed to be related to underlying leukemia.
* Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) =\< 3 x ULN unless deemed to be related to underlying leukemia.
* Creatinine clearance \>= 30 ml/min based on the Cockcroft-Gault equation.
* Willing and able to provide informed consent.
* 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.
* 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:

* Patients with known allergy or hypersensitivity to ivosidenib or venetoclax.
* Patients who have previously received either ivosidenib or venetoclax.
* 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
* 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 central nervous system (CNS) leukemia. (2) use of hydroxyurea and/or one dose of cytarabine (up to 2 g/m\^2) for patients with rapidly proliferative disease is allowed before the start of study therapy and for the first four weeks on therapy.
* Patients receiving concomitant treatment with strong CYP3A4 inhibitors within 3 days of start of study therapy (including posaconazole and voriconazole).
* Patients receiving concomitant strong CYP3A inducers (avasimibe, carbamazepine, phenytoin, rifampin, rifabutin, St. John's wort) within 3 days of start of study therapy.
* 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).
* Patients with any severe gastrointestinal or metabolic condition which could interfere with the absorption of oral study medications.
* Patients with a concurrent active malignancy under treatment.
* Corrected QT (QTc) interval using Fridericia's formula (QTcF) \>= 450 msec. Bundle branch block and prolonged QTc interval are permitted after discussion with the PI.
* Known active hepatitis B (HBV) or hepatitis C (HCV) infection or known human immunodeficiency virus (HIV) infection.
* Subject has a white blood cell count \> 25 x 10\^9/L. (Note: Hydroxyurea is permitted to meet this criterion.)
* 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.

* Appropriate highly effective method(s) of contraception include oral or injectable hormonal birth control, intrauterine device (IUD), and double barrier methods (for example a condom in combination with a spermicide).

Additional Trial Information

Phase 1/2

Enrollment: 64 patients (estimated)

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Published Results

A phase Ib/II study of ivosidenib with venetoclax +/- azacitidine in IDH1-mutated myeloid malignancies

May 28, 2021

25 evaluable patients (DL1: 6, DL2: 6, DL3: 13) enrolled with a median follow-up of 16.1 months. Median age was 67 (range: 44-84). 84% (N=21) of patients had AML (ND: N=13 [TN: 8, sAML: 5], R/R: N=8), while 16% (N=4) had MDS. ELN risk was intermediate and adverse in 16% (N=4) and 56% (N=14). Median IDH1 VAF at enrollment was 22.7% (range: 5.1%-47.8%). Two patients had received a prior IDH1 inhibitor. The ORR was 92% (DL1: 67%, DL2: 100%, DL3: 100%). Composite CR (CRc: CR+CRi+CRh) was 84% (DL1: 67%, DL2: 100%, DL3: 85%) including 92% (TN: 100%, sAML: 80%), 63%, and 100% of patients with ND-AML, R/R-AML, or MDS. Median number of cycles received was 4 (DL1: 8.5, DL2: 6, DL3: 4) with ongoing responses in 62% (DL1: 33%, DL2: 50%, DL3: 82%) at 1-year. 8 patients transitioned to SCT (DL1: 0, DL2: 2, DL3: 6), and 8 patients remain on study (DL1: 2, DL2: 1, DL3: 5). 1-year OS was 68% for the entire study population (DL1: 50%, DL2: 67%, DL3: 78%), 71% in ND-AML (TN: 86%, sAML: 60%), 50% in R/R-AML, and 100% in MDS. Measurable residual disease negative CRc by multiparameter flow cytometry was attained in 60% (ND-AML: 67%, R/R-AML: 60%, MDS: 33%) correlating with improved OS (median OS: NR vs. 8.5 months, p-value: 0.038). Common grade 3/4 adverse events included febrile neutropenia (28%) and pneumonia (24%). Tumor lysis and differentiation syndrome occurred in two and four patients; all cases resolved with medical management.

Trial Locations

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Dana-Farber Cancer Institute (Main)

Boston, MA

Open and Accepting


Case Comprehensive Cancer Center Case Western Reserve University

Cleveland, OH

Open and Accepting


MD Anderson Cancer Center The University of Texas

Houston, TX

Open and Accepting
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