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Trial record 10 of 46 for:    Venetoclax AND Bcl-

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

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ClinicalTrials.gov Identifier: NCT03471260
Recruitment Status : Recruiting
First Posted : March 20, 2018
Last Update Posted : May 21, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

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 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.

Condition or disease Intervention/treatment Phase
High Risk Myelodysplastic Syndrome IDH1 NP_005887.2:p.R132X Myeloproliferative Neoplasm Recurrent Acute Myeloid Leukemia Refractory Acute Myeloid Leukemia Drug: Azacitidine Drug: Ivosidenib Other: Pharmacokinetic Study 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.

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 48 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : March 19, 2018
Estimated Primary Completion Date : September 30, 2019
Estimated Study Completion Date : September 30, 2019


Arm Intervention/treatment
Experimental: Treatment (venetoclax, ivosidenib, azacitidine)
Participants 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.
Drug: Azacitidine
Given IV or SC
Other Names:
  • 5 AZC
  • 5-AC
  • 5-Azacytidine
  • 5-AZC
  • Azacytidine
  • Azacytidine, 5-
  • Ladakamycin
  • Mylosar
  • U-18496
  • Vidaza

Drug: Ivosidenib
Given PO
Other Name: AG-120

Other: Pharmacokinetic Study
Correlative studies
Other Names:
  • PHARMACOKINETIC
  • PK Study

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




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.



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 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).

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, Illinois
Northwestern Medicine Cancer Center Delnor Not yet recruiting
Geneva, Illinois, United States, 60134
Contact: Jessica K. Altman       j-altman@northwestern.edu   
Principal Investigator: Jessica K. Altman         
United States, Massachusetts
Dana-Farber Cancer Institute Not yet recruiting
Boston, Massachusetts, United States, 02215
Contact: Richard M. Stone       rstone@partners.org   
Principal Investigator: Richard M. Stone         
United States, New York
Roswell Park Cancer Institute Not yet recruiting
Buffalo, New York, United States, 14263
Contact: Eunice S. Wang       eunice.wang@roswellpark.org   
Principal Investigator: Eunice S. Wang         
United States, Ohio
Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center Not yet recruiting
Cleveland, Ohio, United States, 44195
Contact: Hetty E. Carraway       carrawh@ccf.org   
Principal Investigator: Hetty E. Carraway         
United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Courtney DiNardo    713-794-1141      
Principal Investigator: Courtney DiNardo         
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Courtney DiNardo M.D. Anderson Cancer Center

Additional Information:
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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT03471260     History of Changes
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 )
P30CA016672 ( U.S. NIH Grant/Contract )
First Posted: March 20, 2018    Key Record Dates
Last Update Posted: May 21, 2019
Last Verified: May 2019

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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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Venetoclax
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Myeloproliferative Disorders
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Azacitidine
Ivosidenib
Glycine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors
Glycine Agents
Neurotransmitter Agents
Physiological Effects of Drugs