Study of the Glutaminase Inhibitor CB-839 in Hematological Tumors

Study Overview
=================
Brief Summary
-----------------
Many tumor cells, in contrast to normal cells, have been shown to require the amino acid glutamine to produce energy for growth and survival. To exploit the dependence of tumors on glutamine, CB-839, a potent and selective inhibitor of the first enzyme in glutamine utilization, glutaminase, will be tested in this Phase 1 study in patients with advanced hematologic malignancies. This study is an open-label Phase 1 evaluation of CB-839 in subjects with hematological tumors. Patients will receive CB-839 capsules orally two or three times daily. The study will be conducted in 2 parts. Part 1 is a dose escalation study to identify the recommended Phase 2 dose and will enroll patients with advanced and/or treatment-refractory Non-Hodgkin's Lymphoma (NHL), Multiple Myeloma (MM), or Waldenström's macroglobulinemia (WM) In Part 2, all patients will receive the recommended Phase 2 dose. This part will enroll patients with advanced and/or treatment-refractory Non-Hodgkin's Lymphoma (NHL), Multiple Myeloma (MM), or Waldenström's macroglobulinemia (WM). All patients will be assessed for safety, pharmacokinetics (plasma concentration of drug), pharmacodynamics (inhibition of glutaminase), biomarkers (biochemical markers that may predict responsiveness in later studies), and tumor response. As an extension of Part 2, a cohort of patients with relapsed and refractory MM will be enrolled to receive low dose dexamethasone and CB-839. A second cohort of patients with relapsed or refractory disease following at least 2 prior treatment regimens will be enrolled to receive CB-839 in combination with standard-dose pomalidomide and low-dose dexamethasone to further evaluate this triple combination.

Official Title
-----------------
A Phase 1 Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Escalating Oral Doses of the Glutaminase Inhibitor CB-839 in Patients With Advanced and/or Treatment-Refractory Hematological Malignancies

Conditions
-----------------
Non-Hodgkin's Lymphoma (NHL), Multiple Myeloma, Waldenstrom's Macroglobulinemia (WM), Other B-cell NHL Subtypes, Including WM, T-cell NHL

Intervention / Treatment
-----------------
* Drug: CB-839
* Drug: CB-839 and low dose dexamethasone
* Drug: CB-839, pomalidomide, and low dose dexamethasone


Participation Criteria
=================
Eligibility Criteria
-----------------
Disease-Specific Inclusion Criteria Patients must have one of the following diseases that is either relapsed or refractory to 2 or more prior treatments: NHL: At least one measurable lesion WM: Measurable IgM, with a minimum level of ≥ 2x ULN MM: Serum M-protein ≥ 0.5 g/dL and/or urine M-protein ≥ 200 mg/24 hr. In Part 2, disease that is considered measurable per the IMWG criteria Other Inclusion Criteria Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 Life Expectancy of at least 3 months Adequate hepatic, renal, cardiac and hematological function Exclusion Criteria Any other current malignancy Treatment with an unapproved, investigational therapeutic agent, immunotherapy or biological therapy within 21 days prior to the first dose of study drug Recent bone marrow transplant Unable to receive medications by mouth Major surgery within 28 days before the first dose of study drug Uncontrolled, active infection; patients who are known to have HIV infection/ seropositivity, Hepatitis A, B, or C, or CMV reactivation Significant neurotoxicity/neuropathy (Grade 3 or higher) within 14 days prior to the first dose of study drug Refractory nausea and vomiting or other situation that may preclude adequate absorption Other conditions that could interfere with treatment

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CB-839<br>CB-839 is administered as oral capsules three times daily (TID) or twice daily with food (BIDf) in 21-day cycles until disease progression or unacceptable toxicity | Drug: CB-839<br>* Glutaminase inhibitor<br>|
| Experimental: CB-839 and low dose dexamethasone<br>CB-839 is administered as oral capsules twice daily with food (BIDf) in 28 day cycles in combination with dexamethasone until disease progression or unacceptable toxicity | Drug: CB-839<br>* Glutaminase inhibitor<br>Drug: CB-839 and low dose dexamethasone<br>* CB-839 and low dose dexamethasone<br>* Other names: CBd;|
| Experimental: CB-839, pomalidomide, and low dose dexamethasone<br>CB-839 is administered as oral capsules twice daily with food (BIDf) in 28 day cycles in combination with pomalidomide and dexamethasone until disease progression or unacceptable toxicity | Drug: CB-839<br>* Glutaminase inhibitor<br>Drug: CB-839 and low dose dexamethasone<br>* CB-839 and low dose dexamethasone<br>* Other names: CBd;Drug: CB-839, pomalidomide, and low dose dexamethasone<br>* CB-839, pomalidomide, and low dose dexamethasone<br>* Other names: CBPd;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of CB-839: Incidence of adverse events |  | Every 21 days from study start until disease progression or unacceptable toxicity, assessed for an expected average of 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics: Area under the Curve (AUC) of CB-839 concentration in blood |  | Study Days 1, 15, and 22 | 
| Pharmacodynamics: % inhibition of glutaminase in blood |  | Study Days 1 and 15 | 
| Clinical activity: Change in tumor size from baseline |  | Every 9 weeks (NHL) or 3 weeks (MM and WM), assessed for an expected average of 6 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, Multiple myeloma, glutaminase, glutamine