Clinical trial NCT02071927: Study of the Glutaminase Inhibitor CB-839 in Leukemia
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 Relapsed and/or Treatment-Refractory Leukemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Acute Myeloid Leukemia (AML)
Acute Lymphocytic Leukemia (ALL)
Keywords: leukemia
glutaminase
glutamine
Lead sponsor: Calithera Biosciences, Inc
Sponsor class: INDUSTRY
First posted: 2014-02-26
Enrollment: 43
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 leukemia.

This study is an open-label Phase 1 evaluation of CB-839 in subjects with leukemia. Part 1 is a dose escalation study to identify the recommended Phase 2 dose as a single agent and in combination with azacitidine. Patients enrolled into Part 2 will be treated with the recommended Phase 2 dose. As an extension of Part 2, patients with relapsed/ refractory or newly diagnosed AML will be treated with CB-839 in combination with azacitidine.

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.


Eligibility criteria: Inclusion Criteria

* Diagnosis of AML or ALL, relapsed or refractory after at least 1 prior treatment regimen. Newly-diagnosed patients ≥ 60 years old who have refused or are considered unfit for standard chemotherapy regimens or stem cell transplantation are also eligible.
* Patients must have no available approved therapies that confer clinical benefit
* All patients must have bone marrow involvement of their tumor, with documented blast percentage of \> 5%.
* Peripheral blood blast count must be ≤ 30,000 cells/µL.
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2
* Adequate hepatic, renal, and cardiac function

Exclusion Criteria

* Any other current malignancy
* Patients with acute promyelocytic leukemia (APL)
* Treatment with an unapproved, investigational agent within 21 days of the first dose of study drug
* Allogeneic hematopoietic stem cell transplant or Donor Lymphocyte Infusion within 90 days prior to to the first dose of study drug
* Active GVHD
* Unable to receive medications by mouth
* Major surgery within 28 days before Cycle 1 Day 1
* 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 Day 1
* Refractory nausea and vomiting or other situation that may preclude adequate absorption
* Conditions that could interfere with treatment and procedures

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 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: % of Tumor Cells in Bone Marrow
timeFrame: Every 21 days from study start, assessed for an expected average of 6 months
Other outcomes:
Locations:
city: Denver
country: United States
facility: Colorado Blood Cancer Institute
state: Colorado
city: Chicago
country: United States
facility: Northwestern University Feinberg School of Medicine
state: Illinois
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Nashville
country: United States
facility: Tennessee Oncology, PLLC
state: Tennessee
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
Study officials:
affiliation: Calithera Biosciences
name: Keith W Orford, MD, PhD
role: STUDY_DIRECTOR
References: