Clinical trial NCT02071888: Study of the Glutaminase Inhibitor CB-839 in Hematological Tumors
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Non-Hodgkin's Lymphoma (NHL)
Multiple Myeloma
Waldenstrom's Macroglobulinemia (WM)
Other B-cell NHL Subtypes, Including WM
T-cell NHL
Keywords: Non-Hodgkin's lymphoma
Waldenstrom's macroglobulinemia
Multiple myeloma
glutaminase
glutamine
Lead sponsor: Calithera Biosciences, Inc
Sponsor class: INDUSTRY
First posted: 2014-02-26
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Safety and tolerability of CB-839: Incidence of adverse events
timeFrame: Every 21 days from study start until disease progression or unacceptable toxicity, assessed for an expected average of 6 months
Secondary outcomes:
measure: Pharmacokinetics: Area under the Curve (AUC) of CB-839 concentration in blood
timeFrame: Study Days 1, 15, and 22
measure: Pharmacodynamics: % inhibition of glutaminase in blood
timeFrame: Study Days 1 and 15
measure: Clinical activity: Change in tumor size from baseline
timeFrame: Every 9 weeks (NHL) or 3 weeks (MM and WM), assessed for an expected average of 6 months
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic
state: Arizona
city: Denver
country: United States
facility: Colorado Blood Cancer Institute
state: Colorado
city: Atlanta
country: United States
facility: Winship Cancer Institute of Emory School of Medicine
state: Georgia
city: Hackensack
country: United States
facility: John Theruer Cancer Center at Hackensack University Medical Center
state: New Jersey
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: Philadelphia
country: United States
facility: University of Pennsylvania, Abramson Cancer Center
state: Pennsylvania
city: Nashville
country: United States
facility: Tennessee Oncology, PLLC
state: Tennessee
Study officials:
affiliation: Calithera Biosciences
name: Keith W Orford, MD, PhD
role: STUDY_DIRECTOR
References: