Clinical Trials /

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

NCT03471260

Description:

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 participants 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.

Related Conditions:
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
  • Myeloproliferative Neoplasm
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Ivosidenib and Venetoclax With or Without Azacitidine in Treating Participants With IDH1 Mutated Hematologic Malignancies
  • 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

Clinical Trial IDs

  • ORG STUDY ID: 2017-0490
  • SECONDARY ID: NCI-2018-00921
  • SECONDARY ID: 2017-0490
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03471260

Conditions

  • High Risk Myelodysplastic Syndrome
  • IDH1 NP_005887.2:p.R132X
  • Myeloproliferative Neoplasm
  • Recurrent Acute Myeloid Leukemia
  • Refractory Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
Azacitidine5 AZC, 5-AC, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, U-18496, VidazaTreatment (venetoclax, ivosidenib, azacitidine)
IvosidenibAG-120Treatment (venetoclax, ivosidenib, azacitidine)
VenetoclaxABT-0199, ABT-199, ABT199, GDC-0199, RG7601, VenclextaTreatment (venetoclax, ivosidenib, azacitidine)

Purpose

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 participants 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.

      II. 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.

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (venetoclax, ivosidenib, azacitidine)ExperimentalParticipants 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.
  • Azacitidine
  • Ivosidenib
  • Venetoclax

Eligibility Criteria

        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 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) 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
             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) or hydroxyurea 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, i.e. 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. a) 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).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate (ORR)
Time Frame:Up to 3 years
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Response to therapy
Time Frame:Up to 3 years
Safety Issue:
Description:Will be calculated.
Measure:Duration of response
Time Frame:From the date of initial response to first documented disease progression/relapse or death, assessed up to 3 years
Safety Issue:
Description:Will be calculated.
Measure: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
Safety Issue:
Description:Will be calculated.
Measure:Overall survival
Time Frame:Up to 3 years
Safety Issue:
Description:Will be calculated.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

May 18, 2020