Capecitabine and Irinotecan in Treating Patients With Locally Advanced, Recurrent, or Metastatic Colorectal Cancer

A Phase II Study of Oral Xeloda (Capecitabine) in Combination With Intravenous Irinotecan for Patients With Locally Advanced and/or Metastatic Colorectal Cancer

PURPOSE: Phase II trial to study the effectiveness of combining capecitabine and irinotecan in treating patients who have locally advanced, recurrent, or metastatic colorectal cancer.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer
• Intervention / Treatment: Drug: Capecitabine; Drug: Irinotecan

Detailed Description

OBJECTIVES:

Primary:

• Determine the overall objective response rate in patients with locally advanced, locally recurrent, or metastatic colorectal cancer treated with capecitabine and irinotecan.

Secondary:

• Determine the time to treatment failure, time to overall response, duration of overall response, duration of overall complete response, and time to progression in patients treated with this regimen.
• Determine the 1-year survival and overall survival of patients treated with this regimen.
• Determine the toxicity and safety profile of this regimen in these patients.
• Determine the feasibility of predicting responses to this regimen by the molecular profile of tumor tissue in patients treated with this regimen.

OUTLINE: This is a multicenter study.

Patients receive oral capecitabine twice daily on days 2-15 and irinotecan IV over 90 minutes on days 1 and 8. Treatment repeats every 3 weeks for 12 courses in the absence of disease progression or unacceptable toxicity. Patients maintaining a response or stable disease after 12 courses may continue treatment at the discretion of the investigator.

Patients are followed every 3 months.

PROJECTED ACCRUAL: A total of 65 patients will be accrued for this study within 9 months.

• Study Type: Interventional
• Enrollment (Actual): 67
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294-3300
      • University of Alabama at Birmingham Comprehensive Cancer Center
  • California
    • Loma Linda, California, United States, 92354
      • Loma Linda University Cancer Institute at Loma Linda University Medical Center
  • Connecticut
    • Norwich, Connecticut, United States, 06360
      • Eastern Connecticut Hematology and Oncology Associates
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Lombardi Cancer Center at Georgetown University Medical Center
    • Washington, District of Columbia, United States, 20037
      • George Washington University Medical Center
  • Florida
    • Jacksonville, Florida, United States, 32209
      • University of Florida Health Science Center - Jacksonville
  • Kentucky
    • Lexington, Kentucky, United States, 40536-0084
      • Markey Cancer Center at University of Kentucky Chandler Medical Center
  • Missouri
    • Saint Louis, Missouri, United States, 63110-0250
      • St. Louis University Hospital Cancer Center
  • New York
    • Bronx, New York, United States, 10451
      • Lincoln Medical and Mental Health Center
    • Brooklyn, New York, United States, 11235
      • HemOnCare, P.C.
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase Cancer Center
    • Philadelphia, Pennsylvania, United States, 19107-5541
      • Kimmel Cancer Center at Thomas Jefferson University - Philadelphia
  • South Carolina
    • Charleston, South Carolina, United States, 29403
      • Charleston Hematology-Oncology, P.A.
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • Cancer Center at the University of Virginia
  • Washington
    • Seattle, Washington, United States, 98104
      • Swedish Cancer Institute at Swedish Medical Center - First Hill Campus
    • Spokane, Washington, United States, 99202
      • Rockwood Clinic P.S.
  • West Virginia
    • Morgantown, West Virginia, United States, 26506-9300
      • West Virginia University Hospitals

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

DISEASE CHARACTERISTICS:

• Histologically confirmed locally advanced, locally recurrent, or metastatic colorectal adenocarcinoma

• At least 1 measurable lesion

  • At least 10 mm by spiral CT scan
  • At least 20 mm by conventional techniques
  • Bone metastases, ascites, or pleural effusions are not considered measurable disease
• No evidence of CNS metastases

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• Karnofsky 80-100%

Life expectancy:

• Not specified

Hematopoietic:

• Neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3

Hepatic:

• Bilirubin no greater than 1.25 times upper limit of normal (ULN)
• ALT and AST no greater than 2.5 times ULN (5 times ULN if liver metastases present)
• Alkaline phosphatase no greater than 2.5 times ULN (5 times ULN if liver metastases present or 10 times ULN if bone metastases present)
• No known Gilbert's disease

Renal:

• Creatinine no greater than 1.5 times ULN
• Creatinine clearance at least 50 mL/min

Cardiovascular:

• No clinically significant cardiac disease
• No congestive heart failure
• No symptomatic coronary artery disease
• No cardiac arrhythmias uncontrolled with medication
• No myocardial infarction within the past 12 months

Gastrointestinal:

• Able to swallow tablets
• No lack of physical integrity of the upper gastrointestinal tract
• No malabsorption syndrome

Other:

• No prior unanticipated severe reaction to fluoropyrimidine therapy
• No hypersensitivity to fluorouracil
• No history of uncontrolled seizures or CNS disorders
• No psychological illness or condition that would preclude study entry
• No other malignancy within the past 5 years except curatively treated basal cell skin cancer or carcinoma in situ of the cervix
• No serious infection
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• At least 12 months since prior neoadjuvant or adjuvant, active or passive immunotherapy
• No concurrent active or passive immunotherapy (e.g., 17-1A antibody) for colon cancer
• No concurrent prophylactic hematopoietic growth factors

Chemotherapy:

• At least 12 months since prior neoadjuvant or adjuvant cytotoxic chemotherapy
• No prior chemotherapy for metastatic colorectal cancer
• No prior therapy with irinotecan or capecitabine
• No other concurrent cytotoxic agents

Endocrine therapy:

• Not specified

Radiotherapy:

• At least 4 weeks since prior radiotherapy
• No prior radiotherapy to measurable lesion (newly arising lesions in a previously irradiated area allowed)
• No concurrent radiotherapy

Surgery:

• At least 4 weeks since prior major surgery and recovered
• No prior organ allograft

Other:

• At least 4 weeks since prior participation in an investigational drug study
• No other concurrent investigational drugs

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1,Initial Regimen:(Capecitabine + Irinotecan ); Participants will receive capecitabine (Xeloda) 1000 mg/m^2, orally, twice daily, for 14 days (Day 2 through Day 15) every 3 weeks, along with irinotecan 125 mg/m^2 as a 90-minute intravenous (IV) infusion on Day 1 and Day 8, every 3 weeks. A total of 12 cycles of treatment will be administered. At the discretion of the investigator, participants who are responding or whose disease is stable will be permitted to continue capecitabine/irinotecan combination therapy until progressive disease is documented in the post-study treatment phase. Participants not participating in post-study treatment will be followed every 3 months until time of death, loss to follow-up, or until median survival had been reached (whichever occurred first).	Drug: Capecitabine; Drug: Irinotecan
Experimental: Cohort 2,Amended Regimen:(Capecitabine + Irinotecan); Participants will receive capecitabine 900 mg/m^2, orally, twice daily, for 14 days (Day 2 through Day 15) every 3 weeks, along with irinotecan 100 mg/m^2 as a 90-minute intravenous (IV) infusion on Day 1 and Day 8, every 3 weeks. A total of 12 cycles of treatment will be administered. At the discretion of the investigator, participants who will be responding or whose disease is stable will be permitted to continue capecitabine/irinotecan combination therapy until progressive disease is documented in the post-study treatment phase. Participants not participating in post-study treatment will be followed every 3 months until time of death, loss to follow-up, or until median survival had been reached (whichever occurred first).	Drug: Capecitabine; Drug: Irinotecan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tumor Response Rate Based on Tumor Measurement as Per Response Evaluation Criteria In Solid Tumors Version 1.0 (RECIST 1.0)	Objective Response Rate (ORR) is defined as the percentage of participants with complete response (CR) or partial response (PR) according to response evaluation criteria in solid tumors (RECIST 1.0). CR is defined as the disappearance of all target and non-target lesions and normalization of tumor marker level. PR is defined as a greater than or equal to (>/=) 30% decrease in the sum of the longest diameter (LD) of the target lesions, taking as reference the baseline sum of LD. Participants who did not have a post-baseline tumor measurement were considered non-responders in the assessment of ORR.	Approximately 43 Months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Disease Progression	Time to disease progression was assessed as the time from start of treatment to the time the participant was first recorded as having disease progression or died due to causes other than disease progression. If a participant never progressed while being followed, he/she was censored at the date of the last tumor assessment or the date of the last dose if no post-baseline tumor measurement was available.	Approximately 43 Months
Time to Treatment Failure	Time to treatment failure was assessed as the time from start of treatment to the time the participant was withdrawn due to any of the reasons such as adverse events, progressive disease, insufficient therapeutic response, death, failure to return, or refused treatment, did not cooperate or withdrew consent.	Approximately 43 Months
Percentage of Participants With One-year Survival	Survival was measured as the time from start of treatment to the date of death or till one year whichever occurred first.	Up to Month 12
Overall Survival	Overall Survival is defined as the time from start of treatment to the date of death. Participants who did not die were censored at the last date the participant was known to be alive.	Approximately 43 Months
Time To Objective Response	The time to objective response is defined as the time from start of treatment to the date of first objective response. Participants who never responded during study were censored at the last tumor assessment or the date of last dose, whichever was later, or at the date of death if occurring prior to response.	Approximately 43 Months
Duration of Overall Response	Duration of overall response was assessed from the time that measurement criteria were first met for CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease was documented. It was analyzed for responders only. Participants without observed progressive disease after an objective response were censored at the date of the last tumor assessment.	Approximately 43 Months
Duration of Overall Complete Response	The duration of overall complete response was assessed from the time that measurement criteria were met for complete response until the first date that recurrent or progressive disease was objectively documented. Participants without observed progressive disease after an objective complete response were censored at the date of the last tumor assessment.	Approximately 43 Months
Number of Participants With Any Adverse Events, Serious Adverse Events and Deaths	An adverse event (AEs) is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. A serious adverse event is defined as any event which was fatal (resulted in death), life-threatening (with immediate risk of death), resulted in a new or prolongation of a current hospitalization, resulted in persistent or significant disability or incapacity, was a congenital anomaly or birth defect, considered medically significant by the investigator, required intervention to prevent one or more of the outcomes listed above.	Approximately 43 Months

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Publications and helpful links

General Publications

• Meropol NJ, Gold PJ, Diasio RB, Andria M, Dhami M, Godfrey T, Kovatich AJ, Lund KA, Mitchell E, Schwarting R. Thymidine phosphorylase expression is associated with response to capecitabine plus irinotecan in patients with metastatic colorectal cancer. J Clin Oncol. 2006 Sep 1;24(25):4069-77. doi: 10.1200/JCO.2005.05.2084.
• Carlini LE, Meropol NJ, Bever J, Andria ML, Hill T, Gold P, Rogatko A, Wang H, Blanchard RL. UGT1A7 and UGT1A9 polymorphisms predict response and toxicity in colorectal cancer patients treated with capecitabine/irinotecan. Clin Cancer Res. 2005 Feb 1;11(3):1226-36.

Study record dates

Study Major Dates

• Study Start: May 1, 2001
• Primary Completion (Actual): December 1, 2004
• Study Completion (Actual): December 1, 2004

Study Registration Dates

• First Submitted: August 10, 2001
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimate): January 27, 2003

Study Record Updates

• Last Update Posted (Estimate): April 15, 2016
• Last Update Submitted That Met QC Criteria: March 16, 2016
• Last Verified: February 1, 2005

More Information

Terms related to this study

• Keywords: adenocarcinoma of the rectum; stage IV rectal cancer; stage IV colon cancer; adenocarcinoma of the colon; recurrent colon cancer; recurrent rectal cancer; stage III colon cancer; stage III rectal cancer
• 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; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Topoisomerase Inhibitors; Topoisomerase I Inhibitors; Capecitabine; Irinotecan
• Other Study ID Numbers: ML16323