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

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

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.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer; Neoplasms, Colorectal
• Intervention / Treatment: Drug: irinotecan, leucovorin, and 5-fluorouracil (5-FU) (FOLFIRI); Drug: CS7017

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, B1900BAJ
    • Instituto FIDES Oncologia y Especialidades Medicas
  • Tucuman, Argentina, T4000GTB
    • CAIPO Centro para la Atencion Integral del Paciente Oncologico
• Brazil
  • Porto Alegre, Brazil, 90610-000
    • Hospital Sao Lucas da Pontificia Universidade Catolica do Rio Grande do Sul - PUC-RS
  • Rio de Janeiro, Brazil, 20231-050
    • Instituto Nacional de Cancer INCA
  • Sao Paulo, Brazil, 01209-000
    • ICAVC
• Chile
  • Santiago, Chile, 8380455
    • Instituto Nacional del Cancer
  • Santiago, Chile, 8320000
    • Fundacion Arturo Lopez Perez
  • Vina del Mar, Chile, 2540364
    • Instituto Oncologico Clinica Renaca
• Peru
  • Callao, Peru
    • Hospital Nacional Alberto Sabogai Sologuren
  • Lima, Peru
    • Hospital Nacional Dos de Mayo
  • Lima, Peru, 01
    • Hospital Nacional Dos de Mayo
  • Lima, Peru, 41
    • Oncosalud Sac
• United States
  • California
    • Beverly Hills, California, United States, 90211
      • Beverly Hills Cancer Center
    • Fullerton, California, United States, 92835
      • St. Jude Heritage Medical Group
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • John Marshall
  • Georgia
    • Atlanta, Georgia, United States, 30341
      • Georgia Cancer Specialists
  • Maryland
    • Bethesda, Maryland, United States, 20817
      • Victor Priego
  • Ohio
    • Canton, Ohio, United States, 44718
      • Gabrail Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: FOLFIRI; 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); 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); Other Names: 5-FU; 5-fluorouracil; Leucovorin; Irinotecan
Experimental: CS7017+FOLFIRI; 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: irinotecan, leucovorin, and 5-fluorouracil (5-FU) (FOLFIRI); 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); Other Names: 5-FU; 5-fluorouracil; Leucovorin; Irinotecan; Drug: CS7017; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Daiichi Sankyo, Inc.

Study record dates

Study Major Dates

• Study Start: September 1, 2009
• Primary Completion (Actual): April 1, 2013
• Study Completion (Actual): April 1, 2013

Study Registration Dates

• First Submitted: August 27, 2009
• First Submitted That Met QC Criteria: August 27, 2009
• First Posted (Estimate): August 28, 2009

Study Record Updates

• Last Update Posted (Actual): May 4, 2020
• Last Update Submitted That Met QC Criteria: April 22, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: chemotherapy; metastatic; colon; rectum; combination
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Topoisomerase Inhibitors; Micronutrients; Vitamins; Topoisomerase I Inhibitors; Antidotes; Vitamin B Complex; Fluorouracil; Leucovorin; Irinotecan; Levoleucovorin; Efatutazone
• Other Study ID Numbers: CS7017-A-U203

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/
• IPD Sharing Time Frame: Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.
• IPD Sharing Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR