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Study of Venetoclax With the mIDH1 Inhibitor Ivosidenib (AG120) in IDH1-Mutated Hematologic Malignancies

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03471260
Recruitment Status : Recruiting
First Posted : March 20, 2018
Last Update Posted : January 7, 2019
Agios Pharmaceuticals, Inc.
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:

There are 2 parts to this clinical research study: Part 1 (dose escalation) and Part 2 (dose expansion).

The goal of Part 1 of this clinical research study is to find the highest tolerable dose of the combination of ivosidenib (AG-120) and venetoclax that can be given to patients with relapsed (has come back) or refractory (has not responded to treatment) acute myeloid leukemia (AML) with an IDH1 mutation (a type of genetic change).

The goal of Part 2 is to learn if the highest tolerable dose of ivosidenib and venetoclax found in Part 1 can help to control the disease.

The safety of this drug combination will be studied in both parts.

This is an investigational study. Ivosidenib is not FDA approved or commercially available. Venetoclax is FDA approved and commercially available for the treatment of a certain type of chronic lymphocytic leukemia (CLL). It is considered investigational to use ivosidenib in combination with venetoclax to treat AML.

The study doctor can explain how the study drugs are designed to work.

Up to 48 patients will be enrolled on this study. All will take part at MD Anderson.

Condition or disease Intervention/treatment Phase
Other Diseases of Blood and Blood-forming Organs Advanced Hematologic Malignancies Acute Myeloid Leukemia Drug: Ivosidenib Drug: Venetoclax Phase 1 Phase 2

  Show Detailed Description

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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 2019
Estimated Study Completion Date : September 2019

Arm Intervention/treatment
Experimental: Ivosidenib + Venetoclax

Participants take Venetoclax by mouth 1 time each day on Days 1-14 of each 28 day cycle.

Participants take Ivosidenib by mouth once each day starting with Day 15 of Cycle 1.

Drug: Ivosidenib
Dose Escalation and Dose Expansion Phase: Ivosidenib 500 mg by mouth once each day starting with Day 15 of Cycle 1.
Other Name: AG120

Drug: Venetoclax

Dose Escalation Phase Starting Dose: 400 mg by mouth one time each day on Days 1-14 of each 28 day cycle.

Dose Expansion Phase Starting Dose: Maximum tolerated dose from Dose Escalation Phase.

Other Names:
  • ABT-199
  • GDC-0199

Primary Outcome Measures :
  1. Incidence and Severity of Adverse Events using Common Toxicity Criteria v 4.0 [ Time Frame: Start of drug combination up to 30 days after drug combination stopped ]
  2. Dose-Limiting Toxicity (DLT) [ Time Frame: 56 days ]
    Dose-limiting toxicity (DLT) defined as any grade 3 or 4, clinically significant non-hematologic adverse event or abnormal laboratory value occurring during the first two cycles on study that cannot be attributed by the investigator to a clearly identifiable cause such as disease progression, underlying illness, concurrent illness, or concomitant medication.

  3. Overall Response Rate (ORR) Defined by CR + CRi + PR + MLFS, CR Rate, CR/CRi Rate [ Time Frame: 3 years ]
    ORR assessed based on revised IWG response criteria for AML (Cheson et al, JCO 2003).

Secondary Outcome Measures :
  1. Evaluate Molecular and Cellular Biomarkers That May be Predictive of Antitumor Activity and/or Resistance to Treatment by Assessment of the Depth of Response and Monitoring of Disease Recurrence by Assessment of MRD in the Bone Marrow [ Time Frame: Baseline up to 30 days after study drug combination stopped ]

    Blood drawn at various time points.

    The effects of the combination compared not only to historical outcomes in matched groups of patients, but also at the molecular and cellular level by correlating with karyotype and molecular mutation profile. The NGS gene panel performed on the screening BM aspirate and the progression/relapse BM aspirate.

  2. Duration of Response (DOR) [ Time Frame: 3 years ]
    Duration of response defined as the number of days from the date of initial response to the date of first documented disease progression/relapse or death, whichever occurs first.

  3. Event Free Survival (EFS) [ Time Frame: Start of study treatment up to 3 years ]
    Event-free survival defined as the number of days from the date of treatment initiation to the date of documented treatment failure, relapse, or death from any cause, whichever occurs first.

  4. Overall Survival (OS) [ Time Frame: Start of study treatment up to 3 years ]
    OS assessed based on revised IWG response criteria for AML (Cheson et al, JCO 2003)

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Age >/= 18 years.
  2. Eastern Cooperative Oncology Group (ECOG) performance status of </= 2.
  3. 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 PI.
  4. Relapsed/refractory AML. Treatment-naïve patients who are not eligible for standard induction chemotherapy may also be eligible after discussion with the PI if in the best interest of the patient. Patients with high-risk MDS or MPN (defined as >/ = 10% bone marrow blasts) may also be eligible after discussion with the PI.
  5. Baseline cardiac ejection fraction must be >/= 40 %
  6. Adequate hepatic function (direct bilirubin </= 2 x ULN, ALT and/or AST </= 3x ULN) unless deemed to be related to underlying leukemia.
  7. Adequate renal function including creatinine clearance >/= 30 ml/min based on the Cockcroft-Gault equation.
  8. Willing and able to provide informed consent
  9. 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.
  10. 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:

  1. Patients with known allergy or hypersensitivity to AG120 or venetoclax.
  2. Patients who have previously received either AG120 or venetoclax
  3. 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.
  4. 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 CNS leukemia. (2) use of hydroxyurea and/or one dose of cytarabine (up to 2 g/m2) or hydroxyurea for patients with rapidly proliferative disease is allowed before the start of study therapy and for the first four weeks on therapy.
  5. Patients receiving concomitant treatment with strong CYP3A4 inhibitors within 3 days of start of study therapy (including posaconazole and voriconazole)
  6. Patients receiving concomitant strong CYP3A inducers (avasimibe, carbamazepine, phenytoin, rifampin, rifabutin, St. John's wort) within 3 days of start of study therapy.
  7. Patients with active graft-versus-host-disease (GVHD) status post stem cell transplant, i.e. patients requiring therapy more than chronic steroid immunosuppression and/or phototherapy for chronic skin GVHD will be excluded
  8. Patients with any severe gastrointestinal or metabolic condition which could interfere with the absorption of oral study medications.
  9. Patients with a concurrent active malignancy under treatment.
  10. QTc interval using Fridericia's formula (QTcF) >/= 450 msec. Bundle branch block and prolonged QTc interval are permitted after discussion with the PI
  11. Known active hepatitis B (HBV) or Hepatitis C (HCV) infection or known HIV infection.
  12. Subject has a white blood cell count > 25 x 10^9/L. (Note: Hydroxyurea is permitted to meet this criterion.)
  13. 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, 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 identifier (NCT number): NCT03471260

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Contact: Courtney DiNardo, MD 713-794-1141

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United States, Texas
University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
Agios Pharmaceuticals, Inc.
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Principal Investigator: Courtney DiNardo, MD M.D. Anderson Cancer Center

Additional Information:
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Responsible Party: M.D. Anderson Cancer Center Identifier: NCT03471260     History of Changes
Other Study ID Numbers: 2017-0490
NCI-2018-00921 ( Registry Identifier: NCI CTRP )
First Posted: March 20, 2018    Key Record Dates
Last Update Posted: January 7, 2019
Last Verified: January 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by M.D. Anderson Cancer Center:
Other diseases of blood and blood-forming organs
Advanced hematologic malignancies
Acute myeloid leukemia
IDH1 mutation

Additional relevant MeSH terms:
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Leukemia, Myeloid
Leukemia, Myeloid, Acute
Hematologic Diseases
Neoplasms by Histologic Type
Pathologic Processes
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Glycine Agents
Neurotransmitter Agents
Physiological Effects of Drugs