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

Sponsor

M.D. Anderson Cancer Center (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT03047993

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Location

Arm

64.5

Anticipated Duration (Months)

0.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
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	Drug: Azacitidine Drug: Glutaminase Inhibitor CB-839	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

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:

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

40 participants

Allocation:

N/A

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 :

Nov 15, 2017

Anticipated Primary Completion Date :

Apr 1, 2022

Anticipated Study Completion Date :

Apr 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (glutaminase inhibitor CB-839, azacitidine) Patients receive glutaminase inhibitor CB-839 PO BID on days 1-28 and azacitidine SC or IV over 10-40 minutes on days 1-7.	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: Glutaminase Inhibitor CB-839 Given PO Other Names: CB-839

Arm

Intervention/Treatment

Experimental: Treatment (glutaminase inhibitor CB-839, azacitidine)

Patients receive glutaminase inhibitor CB-839 PO BID on days 1-28 and azacitidine SC or IV over 10-40 minutes on days 1-7.

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: Glutaminase Inhibitor CB-839

Given PO

Other Names:

CB-839

Outcome Measures

Primary Outcome Measures

Incidence of adverse events Common Toxicity Criteria version 4.0 [Up to 4 years]
Safety data will be summarized using frequency and percentage, by category and severity.

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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