Clinical Trials /

Glutaminase Inhibitor CB-839 and Azacitidine in Treating Patients With Advanced Myelodysplastic Syndrome

NCT03047993

Description:

This phase I/II trial studies the side effects of glutaminase inhibitor CB-839 in combination with azacitidine in treating patients with myelodysplastic syndrome that has spread to other places in the body. Glutaminase inhibitor CB-839 and azacitidine may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Related Conditions:
  • Acute Myeloid Leukemia
  • Chronic Myelomonocytic Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: CB-839 + Azacitidine for Treatment of Myelodysplastic Syndrome (MDS)
  • Official Title: Phase Ib/II Study of the Glutaminase Inhibitor CB-839 in Combination With Azacitidine in Patients With Advanced Myelodysplastic Syndrome

Clinical Trial IDs

  • ORG STUDY ID: 2016-0636
  • SECONDARY ID: R01CA206210-01
  • SECONDARY ID: NCI-2018-01243
  • NCT ID: NCT03047993

Conditions

  • Myelodysplastic Syndrome
  • Other Diseases of Blood and Blood-forming Organs

Interventions

DrugSynonymsArms
CB-839CB-839 + Azacitidine
Azacitidine5-azacytidine, 5-aza, Vidaza, 5-AZC, AZA-CR, Ladakamycin, NSC-102816, AzacytidineCB-839 + Azacitidine

Purpose

The goal of this clinical research study is to learn if CB-839 given in combination with azacitidine can help to control the disease in patients with myelodysplastic syndrome (MDS). The safety of this drug combination will also be studied. This is an investigational study. CB-839 is not FDA approved or commercially available. It is currently being used for research purposes only. Azacitidine is FDA approved and commercially available for the treatment of MDS. Its use in combination with CB-839 is investigational. The study doctor can explain how the study drugs are designed to work. Up to 46 participants will be enrolled on this study. All will take part at MD Anderson.

Detailed Description

      Study Drug Administration:

      Every study cycle is 28 days.

        -  You will take CB-839 by mouth 2 times per day while you are on study. You should take
           each dose with food, and about 12 hours apart.

        -  You will receive azacitidine by vein over about 10-40 minutes, or as an injection under
           the skin about 1 hour after taking CB-839 on Days 1-7 of every cycle. If needed, you may
           receive azacitidine at your local doctor's office.

      It is important that you tell the study doctor about any drugs you are taking during the
      study. This includes prescription drugs, over-the-counter drugs, natural or herbal medicines,
      alternative medicines, and vitamins.

      Length of Study:

      You may continue taking the study drugs for as long as the doctor thinks it is in your best
      interest. You will no longer be able to take the study drugs if the disease gets worse, if
      intolerable side effects occur, or if you are unable to follow study directions.

      Your participation on the study will be over after the End-of-Study visit.

      Study Visits:

      You may visit your regular home doctor for any study visits in which PD or PK testing is not
      taking place. However, you will need to come to MD Anderson on Day 1 of each cycle in order
      to get your supply of CB-839.

      On Day 1 of Cycle 1:

        -  You will have a physical exam.

        -  Blood (about 2 tablespoons) will be drawn for routine tests and pharmacokinetic (PK)
           testing before the dose of CB-839. PK testing measures the amount of study drug in the
           body at different time points.

        -  Blood (about 8 teaspoons) will be drawn for biomarker testing, including genetic
           biomarkers. Biomarkers are found in the blood/tissue and may be related to your reaction
           to the study drug.

        -  You will have two EKGs within 2-4 hours after the dose.

      On Days 8, 15, and 22 of Cycle 1:

        -  You will have a physical exam.

        -  Blood (about 2 tablespoons) will be drawn for routine testing.

      On Day 1 of Cycles 2 and 3, and Day 15 of Cycle 1, blood (about 1 tablespoon) will be drawn
      for PK testing before the dose. You should not take the morning dose of CB-839 at home before
      the clinic visits.

      On Day 1 of Cycle 2 and beyond:

        -  You will have a physical exam.

        -  Blood (about 1 tablespoon) will be drawn for routine and biomarker testing, including
           genetic biomarkers.

      You will have a bone marrow biopsy and aspirate for biomarker and pharmacodynamic (PD)
      testing and to check the status of the disease on Day 1 of Cycles 1,2,4,6 and every 3 cycles
      after that. PD testing measures how the level of study drug in your body may affect the
      disease.

      End-of-Study Visit:

      Within 28 days of the last dose of the study drugs:

        -  You will have a physical exam.

        -  Blood (about 2 tablespoons) will be drawn for routine tests.

        -  You will have an EKG.

        -  You will have a bone marrow biopsy and aspirate for biomarker and PD testing. You may
           also have blood (about 2 tablespoons) drawn for this sample instead.

        -  If you can become pregnant, blood (about 1 tablespoon) or urine will be collected for a
           pregnancy test.
    

Trial Arms

NameTypeDescriptionInterventions
CB-839 + AzacitidineExperimentalPhase 1b: Participants take CB-839 at Starting Level by mouth 2 times per day while on the study. Participants receive Azacitidine by vein or as an injection under the skin about 1 hour after taking CB-839 on Days 1-7 of every 28 day cycle. Phase II: Participants receive CB-839 at RP2D Level by mouth 2 times per day of every 28 day cycle while on the study. Participants receive Azacitidine by vein or as an injection under the skin about 1 hour after taking CB-839 on Days 1-7 of every 28 day cycle. Participants continue on study therapy unless they have evidence of progressive disease or unacceptable toxicity.
  • CB-839
  • Azacitidine

Eligibility Criteria

        Inclusion Criteria:

          1. Signed, informed consent must be obtained prior to any study specific procedures.

          2. 2. Subjects must be >/= 18 years of age at the time of informed consent

          3. Subjects with a histologically confirmed diagnosis of MDS, including both MDS and
             RAEB-T (AML with 20-30% blasts and multilineage dysplasia by FAB criteria) by World
             Health Organization (WHO) and chronic myelomonocytic leukemia (CMML) are eligible.

          4. Subjects with high-risk MDS (i.e. IPSS Intermediate-2 or high-risk; or R-IPSS high or
             very-high risk). Patients with Intermediate-1 risk by IPSS or Intermediate risk by
             R-IPSS and with IDH1 or IDH2, or high-risk molecular features including TP53, ASXL1,
             EZH2, and/or RUNX1 mutations are also eligible.

          5. Subjects with prior hypomethylating agent therapy exposure may be eligible based on
             discussion with the PI.

          6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.

          7. Adequate liver function, as evidenced by a serum bilirubin </= 2x the ULN (except for
             patients with Gilbert's disease) and ALT or AST </= 3x the laboratory ULN.

          8. Adequate renal function including creatinine clearance > 30 mL/min based on the
             Cockcroft-Gault equation.

          9. Able to understand and voluntarily sign a written informed consent, and willing and
             able to comply with protocol requirements

         10. Resolution of all treatment-related, non-hematological toxicities, except alopecia,
             from any previous cancer therapy to < Grade 1 prior to the first dose of study
             treatment

         11. Female patients of childbearing potential must have a negative serum or urine
             pregnancy test within 3 days of the first dose of study drug and agree to use dual
             methods of contraception during the study and for a minimum of 3 months following the
             last dose of study drug. Post-menopausal females (>/= 45 years old and without menses
             for >/= 1 year) and surgically sterilized females are exempt from these requirements.
             Male patients must use an effective barrier method of contraception during the study
             and for a minimum of 3 months following the last dose of study drug if sexually active
             with a female of childbearing potential.

        Exclusion Criteria:

          1. Any prior or coexisting medical condition that in the investigator's judgment will
             substantially increase the risk associated with the subject's participation in the
             study.

          2. Psychiatric disorders or altered mental status precluding understanding of the
             informed consent process and/or completion of the necessary study procedures

          3. Active uncontrolled infection at study enrollment including known diagnosis of human
             immunodeficiency virus or chronic active Hepatitis B or C infection.

          4. Clinically significant gastrointestinal conditions or disorders that may interfere
             with study drug absorption, including prior gastrectomy.

          5. Patients with known active CNS disease, including leptomeningeal involvement.

          6. Impaired cardiac function, uncontrolled cardiac arrhythmia, or clinically significant
             cardiac disease including the following: a) New York Heart Association Grade III or IV
             congestive heart failure, b) myocardial infarction within the last 6 months

          7. Subjects with a QTc > 480 ms (QTc > 510 msec for subjects with a bundle branch block
             at baseline).

          8. Nursing or pregnant women.

          9. Subjects with known hypersensitivity to study drugs or their excipients.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose of CB-839 in Combination with AZA
Time Frame:28 days
Safety Issue:
Description:If only 0 or 1 of 6 patients experiences a dose limiting toxicity (DLT) during Phase 1b, the dose level will be identified as the MTD.

Secondary Outcome Measures

Measure:Pharmacokinetic (PK) Testing of CB-839
Time Frame:84 days
Safety Issue:
Description:PK studies performed on plasma to assess steady-state levels of CB-839.
Measure:Pharmacodynamic (PD) Testing of CB-839
Time Frame:112 days
Safety Issue:
Description:Pharmacodynamic effects of CB-839 measured in MDS CD34+ and in bone marrow stromal cells.
Measure:Clinical activity of CB-839 + AZA assessed based on Modified IWG Response Criteria for MDS (Cheson et al, 2006).
Time Frame:4 years
Safety Issue:
Description:

Details

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

Trial Keywords

  • Myelodysplastic syndrome
  • MDS
  • Other diseases of blood and blood-forming organs
  • CB-839
  • Azacitidine
  • 5-azacytidine
  • 5-aza
  • Vidaza
  • 5-AZC
  • AZA-CR
  • Ladakamycin
  • NSC-102816
  • Azacytidine
  • Pharmacokinetic testing
  • Pharmacodynamic testing

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