CB-839 + Capecitabine in Solid Tumors and Fluoropyrimidine Resistant PIK3CA Mutant Colorectal Cancer

Study Overview
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Brief Summary
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This study has two portions. The main goal of the Phase I portion of this research study is to see what doses of CB-839 and capecitabine can safely be given to patients without having too many side effects. Other purposes of this research study will be to determine what side effects are seen with this combination of medicines. The Phase II portion of the study will test how many patients show shrinkage in their tumor with this combination of medicines and what changes occur inside the cancer cells and blood cells after treatment.

Detailed Description
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Phase I Primary Objective: To determine the safety, tolerability and recommended phase II dose (RP2D) of combination 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 II Primary Objective: 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 I Secondary Objectives: 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. To determine the disease control rate as assessed by 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 II Secondary Objectives: 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 therapy. 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 therapy.

Official Title
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Phase I/II Study of CB-839 and Capecitabine in Patients With Advanced Solid Tumors and Fluoropyrimidine Resistant PIK3CA Mutant Colorectal Cancer

Conditions
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Colorectal Cancer, Colon Cancer, Rectal Cancer, Solid Tumor

Intervention / Treatment
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* Drug: CB-839
* Drug: Capecitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Phase I Patients must have an advanced solid tumors for whom there are no remaining treatment options or colorectal patients who have progressed on front-line fluoropyrimidine containing 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 Patients must have normal organ and marrow function as defined below: 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 ≤ 1.5mg/dL Aspartate Aminotransferase (AST) serum glutamic oxaloacetic transaminase (SGOT) ≤ 2.5 X institutional upper limit of normal Alanine Aminotransferase (ALT) serum glutamic pyruvic 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, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutant metastatic colorectal cancer. PIK3CA status must be confirmed by tumor sequencing in a CLIA certified lab. Patients must have measurable disease according to Response Evaluation Criteria In Solid Tumors (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. 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. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Patients must have normal organ and marrow function as defined below: Hemoglobin ≥ 9.0 g/dl Leukocytes ≥ 3,000/mcL Absolute neutrophil count ≥ 1,500/mcL Platelet count ≥ 100,000/mcL Serum creatinine within normal institutional limits Total bilirubin ≤ 1.5 mg/dL AST (SGOT) ≤ 2.5 X institutional upper limit of normal ALT (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. Exclusion Criteria: Both Phase I and Phase II Patients with ongoing toxicities > grade 1 according to National Cancer Institute (NCI) Common Terminology Criteria For Adverse Events (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 disease will be excluded due to their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. 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, 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 HIV positive who are not receiving anti-retroviral therapy will be excluded due to the marrow suppressive therapy involved in administration of the study treatment.

Ages Eligible for Study
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Minimum Age: 19 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CB-839 + capecitabine<br>Patients will receive CB-839 orally twice daily for 21 days (continuous administration) and capecitabine orally twice daily for 14/21 days. In the phase I portion of the study, patients will receive escalating doses of CB-839 and capecitabine and will have day 15 blood samples drawn and archived for as needed assessment of CB-839 pharmacokinetics. In the phase II portion of the study, patients will receiving 800mg CB-839 and 1000mg/m^2 capecitabine as were determined to be safe doses during the phase I portion of the study. They will also undergo pre-treatment and post-treatment blood samples and tissue biopsies for evaluation of pharmacodynamic biomarkers. | Drug: CB-839<br>* Patients will receive CB-839 orally twice daily during each cycle. Each cycle will be 21 days long. Disease assessment will occur after cycle 3.<br>Drug: Capecitabine<br>* capecitabine will be given orally twice daily for 14-21 days of cycles. Each cycle will be 21 days long. Disease assessment will occur after cycle 3.<br>* Other names: Xeloda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PHASE 1: Recommended dose for phase II study | The Phase I study has been designed to define the recommended phase II dose of CB-839 and capecitabine. A traditional 3+3 dose escalation design will be adopted. Nine to twenty-four patients are expected to be enrolled, depending on the number of dose escalations and assuming that a total of 6 patients will be treated at the final recommended phase II dose level. Patients who complete the first 21 day treatment cycle of CB-839 and capecitabine chemotherapy will be included in the analysis. | At least 21 days of treatment | 
| PHASE 2: Number of patients with response to treatment | In the phase II component of this study, the primary endpoint is response rate. Disease control rate will be determined using RECIST criteria. RECIST response categories: Progressive disease (PD): >=20% increase in sum of longest diameter (LD) of target lesion(s), taking as reference smallest sum LD recorded since treatment started. Complete response (CR): disappearance of all target lesions. Partial response (PR): >=30% decrease in sum of LD of target lesion(s), taking as reference baseline sum LD. Stable disease (SD): neither sufficient shrinkage to qualify as PR nor sufficient increase to qualify as PD. | Up to 18 months after beginning treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PHASE 1: proportion of patient who respond to treatment | Disease control rate will be determined using RECIST criteria. RECIST response categories: Progressive disease (PD): >=20% increase in sum of longest diameter (LD) of target lesion(s), taking as reference smallest sum LD recorded since treatment started. Complete response (CR): disappearance of all target lesions. Partial response (PR): >=30% decrease in sum of LD of target lesion(s), taking as reference baseline sum LD. Stable disease (SD): neither sufficient shrinkage to qualify as PR nor sufficient increase to qualify as PD. | At least 21 days of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CB-839, PIK3CA, capecitabine