Study of CS-7017 in Combination With FOLFIRI in Subjects With Metastatic Colorectal Cancer Who Failed First-Line Therapy

Study Overview
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Brief Summary
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This phase 2, randomized, active-controlled, open-label, parallel group, multicenter study will be conducted at up to 18 study centers in the US, Central America, and South America. Adult subjects with metastatic colorectal cancer (CRC) who failed first-line chemotherapy will participate in the study, which will be conducted on an outpatient basis. It is anticipated that 100 subjects will be enrolled to obtain approximately 90 evaluable subjects.

Official Title
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Randomized, Active-Controlled, Open-Label Phase 2 Study of CS-7017 in Combination With FOLFIRI in Subjects With Metastatic Colorectal Cancer Who Failed First-Line Therapy

Conditions
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Colorectal Cancer, Neoplasms, Colorectal

Intervention / Treatment
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* Drug: CS7017
* Drug: irinotecan, leucovorin, and 5-fluorouracil (5-FU) (FOLFIRI)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Metastatic CRC that has progressed following first-line therapy. Measurable disease (Response Evaluation Criteria in Solid Tumors [RECIST], Version 1.0. Male or female ≥ 18 years of age. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. Resolution of any toxic effects of prior therapy (except alopecia) to NCI CTCAE, Version 3.0, grade ≤ 1. Adequate organ and bone marrow function as evidenced by: Hemoglobin ≥ 9 g/dL (transfusion and/or growth factor support allowed) Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L Platelet count ≥ 100 x 10^9/L Serum creatinine ≤ 1.5 x the upper limit of normal (ULN) or creatinine clearance ≥ 60 mL/min Aspartate aminotransferase (AST) and alkaline phosphatase ≤ 2.5 x ULN in participants with no liver metastasis and ≤ 5.0 x ULN in participants with liver metastasis Total bilirubin ≤ 1.5 x ULN Women of childbearing potential must be willing to consent to using effective contraception (eg, hormonal contraceptives, bilateral tubal ligation, barrier with spermicide, intrauterine device) while on treatment and for at least 3 months thereafter. Men who are the partner of a woman of childbearing potential must be willing to consent to using effective contraception (eg, vasectomy or barrier with spermicide) while on treatment and for 3 months thereafter. All female participants of childbearing potential must have a negative pregnancy test (serum or urine) result before initiating study treatment. Participants must be fully informed about their illness and the investigational nature of the study protocol (including foreseeable risks and possible side effects) and must sign and date an Independent Ethics Committee (IEC)- or Institutional Review Board (IRB)-approved informed consent form (ICF) (including HIPAA authorization, if applicable) before performance of any study-specific procedures or tests. Participants must be willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. Exclusion Criteria: First-line treatment with an irinotecan-based regimen (eg, FOLFIRI). Anticipation of need for a major surgical procedure or radiation therapy (RT) during the study. Treatment with chemotherapy, other thiazolidinediones (TZD), RT, surgery, immunotherapy, biological therapy, or any investigational anticancer agent within 4 weeks before start of study treatment. History of any of the following conditions within 6 months before initiating study treatment: Diabetes mellitus requiring treatment with insulin or TZD agents Myocardial infarction with significant impairment of cardiac function (eg, ejection fraction ≤ 50%) Severe/unstable angina pectoris Coronary/peripheral artery bypass graft New York Heart Association (NYHA) class III or IV congestive heart failure Malabsorption syndrome, chronic diarrhea (lasting > 4 weeks), inflammatory bowel disease, or partial bowel obstruction. Participants with clinically active brain metastases (defined as untreated, symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms); uncontrolled seizure disorder; spinal cord compression; or carcinomatous meningitis. Participants with treated brain metastasis will be included in the study if they have recovered from the acute, toxic effects of RT. A minimum of 15 days must have elapsed between the end of RT and enrollment into the study. History of malignancy other than CRC, unless there is an expectation that the malignancy has been cured, and tumor-specific treatment for the malignancy has not been administered within the previous 5 years. Clinically significant, severe, active infection requiring IV antibiotic or antiviral agents. Pericardial or pleural effusion (eg, requiring drainage) or pericardial involvement with the tumor. Participants with minimal pleural effusion may be eligible upon request by Investigator and approval by Sponsor. Need for concomitant use of other TZD agents during the study. Previous administration of CS-7017. Pregnant or breast feeding. Known to be homozygous for the UGT1A1*28 allele. Known history of severe hypersensitivity reactions to any of the components of CS-7017, irinotecan, leucovorin, or 5-FU. Serious intercurrent medical or psychiatric illnesses or any other conditions that in the opinion of the Investigator would impair the ability to give informed consent or unacceptably reduce protocol compliance or safety of the study treatment.

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: FOLFIRI<br>Participants who received irinotecan, leucovorin, and 5-fluorouracil (5-FU) (FOLFIRI). FOLFIRI was administered by intravenous (IV) injection once every 2 weeks. The FOLFIRI regimen consisted of: Irinotecan, 180 mg/m^2 IV infusion over 30 to 120 minutes Leucovorin, 400 mg/m^2 IV infusion to match the duration of the irinotecan infusion 5-FU, 1200 mg/m^2/day x 2 days (total 2400 mg/m^2 over 46 to 48 hours continuous infusion) | Drug: irinotecan, leucovorin, and 5-fluorouracil (5-FU) (FOLFIRI)<br>* FOLFIRI will be administered IV once every 2 weeks. The FOLFIRI regimen consists of: Irinotecan, 180 mg/m^2 IV infusion over 30 to 120 minutes Leucovorin, 400 mg/m^2 IV infusion to match the duration of the irinotecan infusion 5-FU, 1200 mg/m^2/day x 2 days (total 2400 mg/m^2 over 46 to 48 hours continuous infusion)<br>* Other names: 5-fluorouracil;|
| Experimental: CS7017+FOLFIRI<br>Participants who received CS7017 plus irinotecan, leucovorin, and 5-fluorouracil (5-FU) (FOLFIRI). Two CS-7017 tablets were administered by mouth (PO) twice a day (BID) every 12 hours. FOLFIRI was administered IV once every 2 weeks. The FOLFIRI regimen consisted of: Irinotecan, 180 mg/m^2 IV infusion over 30 to 120 minutes Leucovorin, 400 mg/m^2 IV infusion to match the duration of the irinotecan infusion 5-FU, 1200 mg/m^2/day x 2 days (total 2400 mg/m^2 over 46 to 48 hours continuous infusion) | Drug: CS7017<br>* CS-7017 (0.25mg tablet) Two CS-7017 tablets will be administered by mouth (PO) BID every 12 hours. FOLFIRI will be administered IV once every 2 weeks.<br>Drug: irinotecan, leucovorin, and 5-fluorouracil (5-FU) (FOLFIRI)<br>* FOLFIRI will be administered IV once every 2 weeks. The FOLFIRI regimen consists of: Irinotecan, 180 mg/m^2 IV infusion over 30 to 120 minutes Leucovorin, 400 mg/m^2 IV infusion to match the duration of the irinotecan infusion 5-FU, 1200 mg/m^2/day x 2 days (total 2400 mg/m^2 over 46 to 48 hours continuous infusion)<br>* Other names: 5-fluorouracil;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Progression-Free Survival at 16 Weeks After Administration of CS-7017 Combined With Irinotecan, Leucovorin, and 5-Fluorouracil (5-FU) After Failure of First-line Therapy in Treatment of Metastatic Colorectal Cancer | Progression-free survival (PFS) was defined as the time from randomization until the first objective evidence of disease progression or death from any cause. | Baseline to 16 weeks postdose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Overall Progression-Free Survival Following Administration of CS-7017 in Combination With Irinotecan, Leucovorin, and 5-Fluorouracil (5-FU) (FOLFIRI) After Failure of First-line Therapy in Treatment of Metastatic Colorectal Cancer | Progression-free survival (PFS) was defined as the time from randomization until the first objective evidence of disease progression or death from any cause. | Baseline to approximately 3 years postdose | 
| Median Overall Progression-Free Survival: Sensitivity Analysis Including Clinical Progression After Administration of CS-7017 and Irinotecan, Leucovorin, and 5-Fluorouracil After Failure of First-line Therapy of Metastatic Colorectal Cancer | Progression-free survival (PFS) was defined as the time from randomization to the date of the first objective documentation of progressive disease (PD) or death resulting from any cause, whichever came first. The sensitivity analysis included clinical progression as an event. | Baseline to approximately 3 years postdose | 
| Best Overall Response and Objective Response Rate Following Administration of CS-7017 in Combination With Irinotecan, Leucovorin, and 5-Fluorouracil (FOLFIRI) After Failure of First-line Therapy in Treatment of Metastatic Colorectal Cancer | As per Response Evaluation Criteria for Solid Tumors v1.0, best overall response was characterized as confirmed complete response (CR) defined as disappearance of all target lesions, confirmed partial response (PR) defined as ≥30% decrease from baseline, stable disease (SD) defined as neither progressive disease (PD) nor PR, and PD defined as ≥20% increase from smallest sum of longest diameter recorded since treatment started. Objective response rate (ORR) was defined as CR + PR. If there is no tumor assessment after the first dose of study drug, the best overall response is classified as Inevaluable. | Baseline to approximately 3 years postdose | 
| Treatment-Emergent Adverse Events Occurring in ≥10% of Participants Following Administration of CS-7017 Combined With Irinotecan, Leucovorin, and 5-Fluorouracil (FOLFIRI) After Failure of First-line Therapy in Treatment of Metastatic Colorectal Cancer | An adverse event (AE) >30 days after last dose of study drug was not included as a treatment-emergent adverse events (TEAE) unless considered related to treatment. | Baseline to 30 days post last dose, up to approximately 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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metastatic, colon, rectum, combination, chemotherapy