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

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ClinicalTrials.gov Identifier: NCT03471260
Recruitment Status : Recruiting
First Posted : March 20, 2018
Last Update Posted : December 15, 2022
Sponsor:
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Study Description
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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.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Hematopoietic and Lymphoid System Neoplasm Myelodysplastic Syndrome Myeloproliferative Neoplasm Recurrent Acute Myeloid Leukemia Refractory Acute Myeloid Leukemia Drug: Azacitidine Drug: Ivosidenib Drug: Venetoclax Phase 1 Phase 2

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : March 19, 2018
Estimated Primary Completion Date : September 30, 2023
Estimated Study Completion Date : September 30, 2023

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: 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.
 Drug: Azacitidine
Given IV or SC
Other Names:
  • 5 AZC
  • 5-AC
  • 5-Azacytidine
  • 5-AZC
  • Azacytidine
  • Azacytidine, 5-
  • Ladakamycin
  • Mylosar
  • Onureg
  • U-18496
  • Vidaza

Drug: Ivosidenib
Given PO
Other Names:
  • AG-120
  • Tibsovo

Drug: Venetoclax
Given PO
Other Names:
  • ABT-0199
  • ABT-199
  • ABT199
  • GDC-0199
  • RG7601
  • Venclexta
  • Venclyxto


Outcome Measures
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Primary Outcome Measures :
  1. Overall response rate (ORR) [ Time Frame: Up to 3 years ]
    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.

  2. Incidence of adverse events [ Time Frame: Up to 3 years ]
    Will be collected using leukemia adverse event guidelines.

  3. Dose-limiting toxicity [ Time Frame: Up to 56 days ]
    Defined as any grade 3 or 4, clinically significant non-hematologic adverse event or abnormal laboratory value.


Secondary Outcome Measures :
  1. Response to therapy [ Time Frame: Up to 3 years ]
    Will be calculated.

  2. Duration of response [ Time Frame: From the date of initial response to first documented disease progression/relapse or death, assessed up to 3 years ]
    Will be calculated.

  3. 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 ]
    Will be calculated.

  4. Overall survival [ Time Frame: Up to 3 years ]
    Will be calculated.


Other Outcome Measures:
  1. Plasma concentrations and pharmacokinetic parameter [ Time Frame: Up to 3 years ]
    Will be tabulated for each subject, visit, and dose level, and summary statistics will be computed for each sampling time and each parameter.

  2. Peripheral blood and bone marrow aspirate samples [ Time Frame: Up to 3 years ]
    Biomarker assays may include, but are not limited to, BH3 profiling and characterization of BCL-2 and related proteins, IDH1 mutant status, serum R-2HG analysis, and assessment of the depth of response and monitoring of disease recurrence by assessment of minimal residual disease in the bone marrow.


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 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).
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03471260


Contacts
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Contact: Courtney DiNardo 713-794-1141 cdinardo@mdanderson.org

Locations
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United States, Massachusetts
Dana-Farber Cancer Institute Active, not recruiting
Boston, Massachusetts, United States, 02215
United States, New York
Roswell Park Cancer Institute Not yet recruiting
Buffalo, New York, United States, 14263
Contact: Eunice S. Wang    716-845-2300    eunice.wang@roswellpark.org   
Principal Investigator: Eunice S. Wang         
United States, Ohio
Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center Recruiting
Cleveland, Ohio, United States, 44195
Contact: bhumika patel    216-444-8665    patelb3@ccf.org   
Principal Investigator: bhumika patel         
United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Courtney DiNardo    713-794-1141    cdinardo@mdanderson.org   
Principal Investigator: Courtney DiNardo         
Sponsors and Collaborators
M.D. Anderson Cancer Center
Investigators
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Principal Investigator: Courtney DiNardo M.D. Anderson Cancer Center
More Information
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Additional Information:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT03471260    
Other Study ID Numbers: 2017-0490
NCI-2018-00921 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2017-0490 ( Other Identifier: M D Anderson Cancer Center )
First Posted: March 20, 2018    Key Record Dates
Last Update Posted: December 15, 2022
Last Verified: December 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia
Neoplasms
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Hematologic Neoplasms
Myelodysplastic Syndromes
Myeloproliferative Disorders
Neoplasms by Histologic Type
Bone Marrow Diseases
Hematologic Diseases
 Neoplasms by Site
Azacitidine
Venetoclax
Ivosidenib
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors