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CB-839 + Azacitidine for Treatment of Myelodysplastic Syndrome (MDS)

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ClinicalTrials.gov Identifier: NCT03047993
Recruitment Status : Recruiting
First Posted : February 9, 2017
Last Update Posted : September 3, 2018
Sponsor:
Collaborators:
National Cancer Institute (NCI)
Calithera Biosciences, Inc
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Myelodysplastic Syndrome Other Diseases of Blood and Blood-forming Organs Drug: CB-839 Drug: Azacitidine Phase 1 Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase Ib/II Study of the Glutaminase Inhibitor CB-839 in Combination With Azacitidine in Patients With Advanced Myelodysplastic Syndrome
Actual Study Start Date : November 15, 2017
Estimated Primary Completion Date : November 2022
Estimated Study Completion Date : November 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Azacitidine

Arm Intervention/treatment
Experimental: CB-839 + Azacitidine

Phase 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.

Drug: CB-839

Phase 1b: CB-839 administered at Starting Dose Level 600 mg twice a day continuously.

Phase II Starting Dose Level is RPSD from Phase 1b.


Drug: Azacitidine
Phase 1b and II: Azacitidine 75 mg/m2 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.
Other Names:
  • 5-azacytidine
  • 5-aza
  • Vidaza
  • 5-AZC
  • AZA-CR
  • Ladakamycin
  • NSC-102816
  • Azacytidine




Primary Outcome Measures :
  1. Maximum Tolerated Dose of CB-839 in Combination with AZA [ Time Frame: 28 days ]
    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.

  2. Adverse Events of CB-839 in Combination with Azacitidine assessed using Common Toxicity Criteria v 4.0. [ Time Frame: 28 days ]

Secondary Outcome Measures :
  1. Pharmacokinetic (PK) Testing of CB-839 [ Time Frame: 84 days ]
    PK studies performed on plasma to assess steady-state levels of CB-839.

  2. Pharmacodynamic (PD) Testing of CB-839 [ Time Frame: 112 days ]
    Pharmacodynamic effects of CB-839 measured in MDS CD34+ and in bone marrow stromal cells.

  3. Clinical activity of CB-839 + AZA assessed based on Modified IWG Response Criteria for MDS (Cheson et al, 2006). [ Time Frame: 4 years ]


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:

  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.

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): NCT03047993


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

Locations
United States, Texas
University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact       cdinardo@mdanderson.org   
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
Calithera Biosciences, Inc
Investigators
Principal Investigator: Courtney DiNardo, MD M.D. Anderson Cancer Center

Additional Information:
Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT03047993     History of Changes
Other Study ID Numbers: 2016-0636
R01CA206210-01 ( U.S. NIH Grant/Contract )
NCI-2018-01243 ( Registry Identifier: NCI CTRP )
First Posted: February 9, 2017    Key Record Dates
Last Update Posted: September 3, 2018
Last Verified: August 2018

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

Additional relevant MeSH terms:
Syndrome
Myelodysplastic Syndromes
Preleukemia
Disease
Hematologic Diseases
Pathologic Processes
Bone Marrow Diseases
Precancerous Conditions
Neoplasms
Azacitidine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors