Clinical Trials /

Study of the Glutaminase Inhibitor CB-839 in Solid Tumors

NCT02071862

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.

Related Conditions:
  • Breast Carcinoma
  • Clear Cell Renal Cell Carcinoma
  • Gastrointestinal Stromal Tumor
  • Malignant Solid Tumor
  • Non-Small Cell Lung Carcinoma
  • Papillary Renal Cell Carcinoma
  • Peritoneal Mesothelioma
  • Pleural Mesothelioma
  • Renal Cell Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

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

DrugSynonymsArms
CB-839Glutaminase InhibitorCB-839
Pac-CBcombo CB-839 and PaclitaxelPac-CB
CBEcombo CB-839 and everolimusCBE
CB-Erlcombo CB-839 and erlotnibCB-Erl
CBDcombo CB-839 and docetaxelCBD
CB-Cabocombo CB-839 and cabozantinibCB-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

NameTypeDescriptionInterventions
CB-839ExperimentalCB-839 administered as oral capsules two (BID) or three times daily (TID) in 21-day cycles until disease progression or unacceptable toxicity
  • CB-839
Pac-CBExperimentalCB-839 administered as oral capsules twice daily (BID) in combination with standard dose paclitaxel in 28-day cycles until disease progression or unacceptable toxicity
  • CB-839
  • Pac-CB
CBEExperimentalCB-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-839
  • CBE
CB-ErlExperimentalCB-839 administered as oral capsules twice daily (BID) in combination with standard dose erlotnib in 28-day cycles until disease progression or unacceptable toxicity
  • CB-839
  • CB-Erl
CBDExperimentalCB-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-839
  • CBD
CB-CaboExperimentalCB-839 administered as oral capsules twice daily (BID) in combination with standard dose cabozantinib in 28-day cycles until disease progression or unacceptable toxicity
  • CB-Cabo

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:Recruiting
Lead Sponsor:Calithera Biosciences, Inc

Trial Keywords

  • Tumor metabolism
  • Glutaminase
  • Glutamine
  • Tricarboxylic acid (TCA) cycle

Last Updated

August 18, 2016