Clinical trial NCT02071862: Study of the Glutaminase Inhibitor CB-839 in Solid Tumors
Official title: Ph1 Study of the Safety, PK, and PDn of Escalating Oral Doses of the Glutaminase Inhibitor CB-839, as a Single Agent and in Combination With Standard Chemotherapy in Patients With Advanced and/or Treatment-Refractory Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Solid Tumors
Triple-Negative Breast Cancer
Non Small Cell Lung Cancer
Renal Cell Carcinoma
Mesothelioma
Fumarate Hydratase (FH)-Deficient Tumors
Succinate Dehydrogenase (SDH)-Deficient Gastrointestinal Stromal Tumors (GIST)
Succinate Dehydrogenase (SDH)-Deficient Non-gastrointestinal Stromal Tumors
Tumors Harboring Isocitrate Dehydrogenase-1 (IDH1) and IDH2 Mutations
Tumors Harboring Amplifications in the cMyc Gene
Keywords: Tumor metabolism
Glutaminase
Glutamine
Tricarboxylic acid (TCA) cycle
Lead sponsor: Calithera Biosciences, Inc
Sponsor class: INDUSTRY
First posted: 2014-02-26
Enrollment: 210
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 solid tumors.

This study is an open-label Phase 1 evaluation of CB-839 in patients with advanced solid tumors. The study will be conducted in 2 parts. Part 1 is a dose escalation study enrolling patients with locally-advanced, metastatic and/or refractory solid tumors to receive CB-839 capsules orally twice or three times daily.

In Part 2, patients with each of the following diseases will be enrolled: A) Triple-Negative Breast Cancer, B) Non-Small Cell Lung Cancer (adenocarcinoma), C) Renal Cell Cancer, D) Mesothelioma, E) Fumarate hydratase (FH)-deficient tumors, F) Succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumors (GIST), G) SDH-deficient non-GIST tumors, H) tumors harboring mutations in isocitrate dehydrogenase-1 (IDH1) or IDH2, and I) cMyc mutation tumors.

As an extension of Parts 1 \& 2, patients will be treated with CB-839 in combination with standard chemotherapy. Combination groups include: Pac-CB, CBE, CB-Erl, CBD, and CB-Cabo. Pac-CB: patients with locally-advanced or metastatic TNBC will be treated with paclitaxel and CB-839. CBE: patients with advanced clear cell RCC or papillary RCC will be treated with everolimus in combination with CB-839. CB-Erl: patients with advanced NSCLC lacking the T790M EGFR mutation will be treated with erlotinib and CB-839. CBD: patients with NSCLC harboring KRAS mutation will be treated with docetaxel and CB-839. CB-Cabo: patients with histologically confirmed diagnosis of locally-advanced, inoperable or metastatic RCC treated with cabozantinib in combination with CB-839.

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

* Advanced malignancy that is relapsed and/or refractory to all available therapies that will confer clinical benefit. Newly diagnosed patients who refuse standard treatment regimens are also eligible
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1
* Life Expectancy of at least 3 months
* Adequate hepatic, renal, cardiac, and hematologic function
* Measurable disease by RECIST criteria
* Ability to provide written informed consent in accordance with federal, local, and institutional guidelines

Exclusion Criteria

* Any other current or previous malignancy
* Chemotherapy, radiation therapy, hormonal therapy, immunotherapy or biological therapy, or investigational agent within 21 days
* Unable to receive medications oral medications
* Major surgery within 28 days before Cycle 1 Day 1
* Active infection requiring within 2 weeks prior to first dose of study drug
* Patients who have HIV, Hepatitis A, B or C or CMV reactivation
* Significant neurotoxicity/neuropathy (Grade 3 or higher) within 14 days of first dose of study drug
* Conditions that could interfere with treatment or protocol-related 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 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 volume from baseline
timeFrame: Every 9 weeks until disease progression or unacceptable toxicity, assessed for an expected average of 6 months
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: UCSF Helen Diller Family Comprehensive Cancer Center
state: California
city: Stanford
country: United States
facility: Stanford University Medical Center
state: California
city: Sarasota
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Atlanta
country: United States
facility: Winship Cancer Institute of Emory School of Medicine
state: Georgia
city: Bethesda
country: United States
facility: NIH - NCI - Center for Cancer Research
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
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
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
Study officials:
affiliation: Calithera Biosciences, Inc
name: Samuel Whiting, MD, PhD
role: STUDY_DIRECTOR
References: