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: Glutaminase Inhibitor CB-839 and Azacitidine in Treating Patients With Advanced Myelodysplastic Syndrome
  • 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: NCI-2018-01243
  • SECONDARY ID: 2016-0636
  • SECONDARY ID: P30CA016672
  • SECONDARY ID: R01CA206210
  • NCT ID: NCT03047993

Conditions

  • Acute Myeloid Leukemia With Multilineage Dysplasia
  • Blasts 20-30 Percent of Bone Marrow Nucleated Cells
  • Blasts 20-30 Percent of Peripheral Blood White Cells
  • Chronic Myelomonocytic Leukemia
  • High Risk Myelodysplastic Syndrome
  • IPSS Risk Category Intermediate-2
  • Myelodysplastic Syndrome

Interventions

DrugSynonymsArms
Azacitidine5 AZC, 5-AC, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, U-18496, VidazaTreatment (glutaminase inhibitor CB-839, azacitidine)
Glutaminase Inhibitor CB-839CB-839Treatment (glutaminase inhibitor CB-839, azacitidine)

Purpose

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.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the safety, tolerability and clinical activity of glutaminase inhibitor
      CB-839 (CB-839) in combination with azacitidine (AZA) for patients with advanced
      myelodysplastic syndrome (MDS).

      SECONDARY OBJECTIVES:

      I. To explore the pharmacokinetics (PK) of CB-839 in combination with AZA. II. To explore the
      pharmacodynamics (PDn) of CB-839 in combination with AZA. III. To assess overall survival,
      event-free survival and duration of response of CB-839 in combination with AZA.

      OUTLINE:

      Patients receive glutaminase inhibitor CB-839 orally (PO) twice daily (BID) on days 1-28 and
      azacitidine subcutaneously (SC) or intravenously (IV) over 10-40 minutes on days 1-7.

      After completion of study treatment, patients are followed up at 28 days.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (glutaminase inhibitor CB-839, azacitidine)ExperimentalPatients receive glutaminase inhibitor CB-839 PO BID on days 1-28 and azacitidine SC or IV over 10-40 minutes on days 1-7.
  • Azacitidine
  • Glutaminase Inhibitor CB-839

Eligibility Criteria

        Inclusion Criteria:

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

          -  Subjects with a histologically confirmed diagnosis of MDS, including both MDS and
             refractory anemia with excess blasts (RAEB)-T (acute myeloid leukemia [AML] with
             20-30% blasts and multilineage dysplasia by French-American-British [FAB] criteria) by
             World Health Organization (WHO) and chronic myelomonocytic leukemia (CMML) are
             eligible

          -  Subjects with high-risk MDS (i.e. International Prognostic Scoring System [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

          -  Subjects with prior hypomethylating agent therapy exposure may be eligible based on
             discussion with the principal investigator (PI)

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

          -  Serum bilirubin =< 2 x the upper limit of normal (ULN) (except for patients with
             Gilbert's disease)

          -  Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) =< 3 x the
             laboratory ULN

          -  Creatinine clearance > 30 mL/min based on the Cockcroft-Gault equation

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

          -  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

          -  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:

          -  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

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

          -  Active uncontrolled infection at study enrollment including known diagnosis of human
             immunodeficiency virus or chronic active hepatitis B or C infection

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

          -  Patients with known active central nervous system (CNS) disease, including
             leptomeningeal involvement

          -  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

          -  Subjects with a corrected QT (QTc) > 480 ms (QTc > 510 msec for subjects with a bundle
             branch block at baseline)

          -  Nursing or pregnant women

          -  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:Incidence of adverse events Common Toxicity Criteria version 4.0
Time Frame:Up to 4 years
Safety Issue:
Description:Safety data will be summarized using frequency and percentage, by category and severity.

Secondary Outcome Measures

Measure:Rates of response (complete response + partial response) to therapy
Time Frame:Up to 4 years
Safety Issue:
Description:Will be estimated along with the 95% confidence interval.
Measure:Event-free survival
Time Frame:Up to 4 years
Safety Issue:
Description:The Kaplan-Meier method will be used to estimate the probabilities. Log-rank tests will be used to compare among subgroups of patients.
Measure:Overall survival
Time Frame:Up to 4 years
Safety Issue:
Description:The Kaplan-Meier method will be used to estimate the probabilities. Log-rank tests will be used to compare among subgroups of patients.
Measure:Duration of response
Time Frame:Up to 4 years
Safety Issue:
Description:The Kaplan-Meier method will be used to estimate the probabilities. Log-rank tests will be used to compare among subgroups of patients.
Measure:Anti-tumor activity
Time Frame:Up to 4 years
Safety Issue:
Description:Will be summarized graphically and with descriptive statistics.
Measure:Pharmacodynamic markers
Time Frame:Up to 4 years
Safety Issue:
Description:Will be summarized graphically and with descriptive statistics.
Measure:Exploratory biomarkers
Time Frame:Up to 4 years
Safety Issue:
Description:Will be summarized graphically and with descriptive statistics.
Measure:Drug exposure levels
Time Frame:Up to 4 years
Safety Issue:
Description:Will be summarized graphically and with descriptive statistics.

Details

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

Last Updated

June 22, 2020