Glutaminase Inhibitor CB-839 and Capecitabine in Treating Patients with Advanced Solid Tumors or Colorectal Cancer
This phase I/II trial studies the side effects and best dose of glutaminase inhibitor CB-839 and capecitabine and to see how well they work in treating patients with solid tumors that have spread to other places in the body or colorectal cancer. Glutaminase inhibitor CB-839 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Capecitabine may kill tumor cells by inhibiting deoxyribonucleic acid and ribonucleic acid synthesis. Giving glutaminase inhibitor CB-839 and capecitabine together may work better in treating patients with solid tumors or colorectal cancer.
Inclusion Criteria
- PHASE I:
- Patients must have an advanced solid tumor malignancy with no remaining standard treatment options or for whom single agent capecitabine is an acceptable therapy; patients with colorectal cancer must have progressed on at least one line of fluoropyrimidine containing therapy; receipt of either oxaliplatin or irinotecan in combination with a fluoropyrimidine is required in the front line setting for all colorectal cancer patients unless either of these agents are otherwise contraindicated in the opinion of the treating physician; prior regorafenib or TAS-102 therapy is not required
- Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
- Hemoglobin >= 9.0 g/dl
- Leukocytes >= 3,000/mcL
- Absolute neutrophil count >= 1,500/mcL
- Platelet count >= 100,000/mcL
- Serum creatinine =< 1.5 x institutional upper limit of normal
- Total bilirubin =< 1.5 mg/dL
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) =< 2.5 x institutional upper limit of normal
- Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal
- Patients must be able to swallow pills
- Patients must have the ability to understand and the willingness to sign a written informed consent document
- Female patients of childbearing potential must have a negative serum or urine pregnancy test within 3 days prior to the first dose of study drug and agree to use dual methods of contraception during the study and for a minimum of 3 months following the last dose of study drug; post-menopausal females (> 45 years old and without menses for > 1 year) and surgically sterilized females are exempt from these requirements; male patients must use an effective barrier method of contraception during the study and for a minimum of 3 months following the last dose of study drug if sexually active with a female of childbearing potential
- PHASE II: Patients must have histologically or cytologically confirmed, PIK3CA mutant metastatic colorectal cancer; PIK3CA status must be confirmed by tumor sequencing conducted in a Clinical Laboratory Improvement Act (CLIA) certified lab
- PHASE II: Patients must have measurable disease according to RECIST 1.1 criteria that is amenable to biopsy and be willing to undergo pre- and post-treatment tumor biopsies; lesions to be biopsied do not have to be those used for measurement
- PHASE II: Patients must have received and progressed on fluoropyrimidine or fluoropyrimidine based therapy; receipt of either oxaliplatin or irinotecan in combination with a fluoropyrimidine is required in the front line setting unless either of these agents are otherwise contraindicated in the opinion of the treating physician in which case a fluoropyrimidine only may be used; prior regorafenib or TAS-102 therapy is not required
- PHASE II: Patients must have an ECOG performance status of 0-1
- PHASE II: Hemoglobin >= 9.0 g/dl
- PHASE II: Leukocytes >= 3,000/mcL
- PHASE II: Absolute neutrophil count >= 1,500/mcL
- PHASE II: Platelet count >= 100,000/mcL
- PHASE II: Serum creatinine within normal institutional limits
- PHASE II: Total bilirubin =< 1.5 mg/dL
- PHASE II: AST (SGOT) =< 2.5 x institutional upper limit of normal
- PHASE II: ALT (SGPT) =< 2.5 x institutional upper limit of normal
- PHASE II: Patients must be able to swallow pills
- PHASE II: Patients must have the ability to understand and the willingness to sign a written informed consent document
- PHASE II: Female patients of childbearing potential must have a negative serum or urine pregnancy test within 3 days prior to the first dose of study drug and agree to use dual methods of contraception during the study and for a minimum of 3 months following the last dose of study drug; post-menopausal females (> 45 years old and without menses for > 1 year) and surgically sterilized females are exempt from these requirements; male patients must use an effective barrier method of contraception during the study and for a minimum of 3 months following the last dose of study drug if sexually active with a female of childbearing potential
Exclusion Criteria
- Patients with ongoing toxicities > grade 1 according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 (excluding alopecia) due to prior anti-cancer therapy
- Patients receiving any other investigational agents or whom have received recent treatment for colorectal cancer (radiation within the previous two weeks, chemotherapy or investigational therapy within the previous four weeks)
- Patients with untreated brain metastases/central nervous system (CNS) disease will be excluded
- Patients with a history of allergic reactions attributed to or intolerance to compounds of similar chemical or biologic composition to either CB-839 or capecitabine; if capecitabine has been received previously, must have tolerated at least an equivalent dose to the dose to be administered at their assigned dose level
- Patients who are unable to swallow pills or who have undergone surgery that prohibits the absorption of pills in the stomach
- Patients with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure (i.e., New York Heart Association [NYHA] class II), unstable angina pectoris or myocardial infarction within prior 6 months, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- Patients who are pregnant or breastfeeding will be excluded from the study
- Patients known to be human immunodeficiency virus (HIV) positive who are not receiving anti-retroviral therapy will be excluded
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT02861300.
PRIMARY OBJECTIVES:
I. To determine the safety, tolerability and recommended phase II dose (RP2D) of combination glutaminase inhibitor CB-839 (CB-839) and capecitabine chemotherapy in patients with advanced solid tumors for whom there are no remaining treatment options or for whom single agent capecitabine is an acceptable therapy. (Phase I)
II. To determine the disease control rate of combination CB-839 and capecitabine chemotherapy in patients with metastatic PIK3CA mutant colorectal cancers who are refractory to fluoropyrimidine based therapy. (Phase II)
SECONDARY OBJECTIVES:
I. To determine the dose-limiting toxicities and maximum tolerated dose of combination therapy with CB-839 and capecitabine in patients with advanced solid tumors for whom there are no remaining treatment options or for whom single agent capecitabine is an acceptable therapy. (Phase I)
II. To determine the antitumor response as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria of combination therapy with CB-839 and capecitabine in patients with advanced solid tumors for whom there are no remaining treatment options or for whom single agent capecitabine is an acceptable therapy. (Phase I)
III. To determine the progression free survival following treatment with CB-839 and capecitabine chemotherapy in patients with metastatic PIK3CA mutant colorectal cancer and are refractory to fluoropyrimidine based therapy. (Phase II)
IV. To determine the overall survival following treatment with CB-839 and capecitabine chemotherapy in patients who have metastatic PIK3CA mutant colorectal cancer and are refractory to fluoropyrimidine based therapy. (Phase II)
CORRELATIVE OBJECTIVES:
I. To determine the change in glutaminase activity level in tumor specimens and platelets following treatment with CB-839 and capecitabine chemotherapy in patients with metastatic PIK3CA mutant colorectal cancer who are refractory to fluoropyrimidine based therapy. (Phase II)
II. To determine the reduction in nucleotide levels in tumor specimens following treatment with CB-839 and capecitabine chemotherapy in patients with metastatic PIK3CA mutant colorectal cancer who are refractory to fluoropyrimidine based therapy. (Phase II)
III. To determine genomic changes in both deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) in tumor specimens following treatment with CB-839 and capecitabine chemotherapy in patients with metastatic PIK3CA mutant colorectal cancer who are refractory to fluoropyrimidine based therapy. (Phase II)
IV. To determine the correlation between plasma trough levels of CB-839 and biomarkers of interest in patients with metastatic PIK3CA mutant colorectal cancer who are refractory to fluoropyrimidine based therapy and who have received treatment with CB-839 and capecitabine chemotherapy. (Phase II)
V. To determine the correlation between clinical response to treatment and biomarkers of interest in patients with metastatic PIK3CA mutant colorectal cancer who are refractory to fluoropyrimidine based therapy and who have received treatment with CB-839 and capecitabine chemotherapy. (Phase II)
VI. To generate organoids from patient tissue biopsies obtained prior to and following treatment in patients treated with CB-839 and capecitabine chemotherapy in patients with metastatic PIK3CA mutant colorectal cancer who are refractory of fluoropyrimidine based therapy. (Phase II)
OUTLINE: This is a phase I, dose escalation followed by a phase II study.
Patients receive glutaminase inhibitor CB-839 orally (PO) twice daily (BID) on days 1-21 and capecitabine PO BID on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days, then every 3 months for up to 2 years.
Trial PhasePhase I/II
Trial Typetreatment
Lead OrganizationCase Comprehensive Cancer Center
Principal InvestigatorDavid Lawrence Bajor
- Primary IDCASE1216
- Secondary IDsNCI-2016-01647
- ClinicalTrials.gov IDNCT02861300