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.

Brief Title

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

Official Title

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

Brief Summary

This phase Ib/II trial studies the side effects and best dose of venetoclax and how well it <br /> works when given together with ivosidenib with or without azacitidine, in treating patients <br /> with IDH1-mutated hematologic malignancies. Venetoclax and ivosidenib may stop the growth of <br /> cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in <br /> chemotherapy, such as azacitidine, work in different ways to stop the growth of cancer cells, <br /> either by killing the cells, by stopping them from dividing, or by stopping them from <br /> spreading. Giving ivosidenib and venetoclax with azacitidine may work better in treating <br /> 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.

Outcome Measures

Outcome measures are the tests that investigators perform to prove whether or not a treatment being tested in a clinical trial is having any effect.

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).