Description:
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.
Title
- Brief Title: 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
Clinical Trial IDs
- ORG STUDY ID:
CX-839-001
- NCT ID:
NCT02071862
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
Interventions
Drug | Synonyms | Arms |
---|
CB-839 | Glutaminase Inhibitor | CB-839 |
Pac-CB | combo CB-839 and Paclitaxel | Pac-CB |
CBE | combo CB-839 and everolimus | CBE |
CB-Erl | combo CB-839 and erlotnib | CB-Erl |
CBD | combo CB-839 and docetaxel | CBD |
CB-Cabo | combo CB-839 and cabozantinib | CB-Cabo |
Purpose
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.
Trial Arms
Name | Type | Description | Interventions |
---|
CB-839 | Experimental | CB-839 administered as oral capsules two (BID) or three times daily (TID) in 21-day cycles until disease progression or unacceptable toxicity | |
Pac-CB | Experimental | CB-839 administered as oral capsules twice daily (BID) in combination with standard dose paclitaxel in 28-day cycles until disease progression or unacceptable toxicity | |
CBE | Experimental | CB-839 administered as oral capsules twice daily (BID) in combination with standard dose everolimus in 28-day cycles until disease progression or unacceptable toxicity | |
CB-Erl | Experimental | CB-839 administered as oral capsules twice daily (BID) in combination with standard dose erlotnib in 28-day cycles until disease progression or unacceptable toxicity | |
CBD | Experimental | CB-839 administered as oral capsules twice daily (BID) in combination with standard dose docetaxel in 21-day cycles until disease progression or unacceptable toxicity | |
CB-Cabo | Experimental | CB-839 administered as oral capsules twice daily (BID) in combination with standard dose cabozantinib in 28-day cycles until disease progression or unacceptable toxicity | |
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
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Safety and tolerability of CB-839: Incidence of adverse events |
Time Frame: | Every 21 days from study start until disease progression or unacceptable toxicity, assessed for an expected average of 6 months |
Safety Issue: | |
Description: | |
Secondary Outcome Measures
Measure: | Pharmacokinetics: Area under the Curve (AUC) of CB-839 concentration in blood |
Time Frame: | Study Days 1, 15, and 22 |
Safety Issue: | |
Description: | |
Measure: | Pharmacodynamics: % inhibition of glutaminase in blood |
Time Frame: | Study Days 1 and 15 |
Safety Issue: | |
Description: | |
Measure: | Clinical activity: Change in tumor volume from baseline |
Time Frame: | Every 9 weeks until disease progression or unacceptable toxicity, assessed for an expected average of 6 months |
Safety Issue: | |
Description: | |
Details
Phase: | Phase 1 |
Primary Purpose: | Interventional |
Overall Status: | Completed |
Lead Sponsor: | Calithera Biosciences, Inc |
Trial Keywords
- Tumor metabolism
- Glutaminase
- Glutamine
- Tricarboxylic acid (TCA) cycle
Last Updated
February 17, 2020