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

Study Overview
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Brief Summary
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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
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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.

Official Title
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Phase Ib/II Study of the Glutaminase Inhibitor CB-839 in Combination With Azacitidine in Patients With Advanced Myelodysplastic Syndrome

Conditions
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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

Intervention / Treatment
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* Drug: Azacitidine
* Drug: Glutaminase Inhibitor CB-839


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (glutaminase inhibitor CB-839, azacitidine)<br>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<br>* Given IV or SC<br>* Other names: Vidaza;Drug: Glutaminase Inhibitor CB-839<br>* Given PO<br>* Other names: CB-839;|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

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