Colorectal Cancer
Conditions
Keywords
stage III colon cancer, stage IV colon cancer, stage III rectal cancer, stage IV rectal cancer, recurrent colon cancer, recurrent rectal cancer, adenocarcinoma of the colon, adenocarcinoma of the rectum
Brief summary
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.
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.
Interventions
DRUGCapecitabine
DRUGIrinotecan
Sponsors
Hoffmann-La Roche
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Tumor Response Rate Based on Tumor Measurement as Per Response Evaluation Criteria In Solid Tumors Version 1.0 (RECIST 1.0) | Approximately 43 Months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Treatment Failure | Approximately 43 Months | 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. |
| Percentage of Participants With One-year Survival | Up to Month 12 | Survival was measured as the time from start of treatment to the date of death or till one year whichever occurred first. |
| Duration of Overall Complete Response | Approximately 43 Months | 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. |
| Time to Disease Progression | Approximately 43 Months | 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. |
| Time To Objective Response | Approximately 43 Months | 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. |
| Duration of Overall Response | Approximately 43 Months | 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. |
| Number of Participants With Any Adverse Events, Serious Adverse Events and Deaths | Approximately 43 Months | 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. |
| Overall Survival | Approximately 43 Months | 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. |
Countries
United States
Participant flow
Recruitment details
A total of 67 participants were enrolled in the study, which was conducted from 18 May 2001 to 9 December 2004 at 18 study centers in the United States.
Pre-assignment details
Data for participants who completed 12 cycles of the study treatment is presented.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1, Initial Regimen: (Capecitabine + Irinotecan) Participants received capecitabine 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 IV infusion on Day 1 and Day 8, every 3 weeks. A total of 12 cycles of treatment was administered. At the discretion of the investigator, participants who were responding or whose disease was stable were permitted to continue capecitabine/irinotecan combination therapy until progressive disease was documented in the post-study treatment phase. Participants not receiving post-study treatment were followed every 3 months until time of death, loss to follow-up, or until median survival had been reached (whichever occurred first). | 15 |
| Cohort 2, Amended Regimen: (Capecitabine + Irinotecan) Participants received 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 IV infusion on Day 1 and 8, every 3 weeks. A total of 12 cycles of treatment was administered. At the discretion of the investigator, participants who were responding or whose disease was stable were permitted to continue capecitabine/irinotecan combination therapy until progressive disease was documented in the post-study treatment phase. Participants not receiving post-study treatment were followed every 3 months until time of death, loss to follow-up, or until median survival had been reached (whichever occurred first). | 52 |
| Total | 67 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative /other | 1 | 7 |
| Overall Study | Adverse Event | 5 | 9 |
| Overall Study | Death | 0 | 2 |
| Overall Study | Failure to return | 0 | 1 |
| Overall Study | Insufficient therapeutic response | 2 | 14 |
| Overall Study | Refused treatment | 0 | 2 |
Baseline characteristics
| Characteristic | Cohort 1, Initial Regimen: (Capecitabine + Irinotecan) | Cohort 2, Amended Regimen: (Capecitabine + Irinotecan) | Total |
|---|---|---|---|
| Age, Continuous | 63.1 years STANDARD_DEVIATION 8.3 | 61.4 years STANDARD_DEVIATION 11.1 | 61.8 years STANDARD_DEVIATION 10.5 |
| Sex: Female, Male Female | 9 Participants | 21 Participants | 30 Participants |
| Sex: Female, Male Male | 6 Participants | 31 Participants | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 15 / 15 | 52 / 52 |
| serious Total, serious adverse events | 10 / 15 | 25 / 52 |
Outcome results
Primary
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.
Time frame: Approximately 43 Months
Population: The All Patients Population included participants who received at least one dose of study drug in Cohort 1 or Cohort 2.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1, Initial Regimen:(Capecitabine + Irinotecan) | Tumor Response Rate Based on Tumor Measurement as Per Response Evaluation Criteria In Solid Tumors Version 1.0 (RECIST 1.0) | CR | 7 percentage of participants |
| Cohort 1, Initial Regimen:(Capecitabine + Irinotecan) | Tumor Response Rate Based on Tumor Measurement as Per Response Evaluation Criteria In Solid Tumors Version 1.0 (RECIST 1.0) | PR | 40 percentage of participants |
| Cohort 2, Amended Regimen: (Capecitabine + Irinotecan) | Tumor Response Rate Based on Tumor Measurement as Per Response Evaluation Criteria In Solid Tumors Version 1.0 (RECIST 1.0) | CR | 2 percentage of participants |
| Cohort 2, Amended Regimen: (Capecitabine + Irinotecan) | Tumor Response Rate Based on Tumor Measurement as Per Response Evaluation Criteria In Solid Tumors Version 1.0 (RECIST 1.0) | PR | 42 percentage of participants |
Secondary
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.
Time frame: Approximately 43 Months
Population: The All Patients Population included participants who received at least one dose of study drug in Cohort 1 or Cohort 2. Data for participants present at the time of assessment was used for analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1, Initial Regimen:(Capecitabine + Irinotecan) | Duration of Overall Complete Response | 12.45 months |
| Cohort 2, Amended Regimen: (Capecitabine + Irinotecan) | Duration of Overall Complete Response | 12.68 months |
Secondary
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.
Time frame: Approximately 43 Months
Population: The All Patients Population included participants who received at least one dose of study drug in Cohort 1 or Cohort 2. Data for participants present at the time of assessment was used for analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1, Initial Regimen:(Capecitabine + Irinotecan) | Duration of Overall Response | 7.0 months |
| Cohort 2, Amended Regimen: (Capecitabine + Irinotecan) | Duration of Overall Response | 7.7 months |
Secondary
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.
Time frame: Approximately 43 Months
Population: The Safety Population consisted of all participants who received at least 1 dose of any study drug and had at least one post-baseline safety assessment. This included participants in Cohort 1 and Cohort 2.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1, Initial Regimen:(Capecitabine + Irinotecan) | Number of Participants With Any Adverse Events, Serious Adverse Events and Deaths | Any AEs | 15 Number of participants |
| Cohort 1, Initial Regimen:(Capecitabine + Irinotecan) | Number of Participants With Any Adverse Events, Serious Adverse Events and Deaths | SAEs | 10 Number of participants |
| Cohort 1, Initial Regimen:(Capecitabine + Irinotecan) | Number of Participants With Any Adverse Events, Serious Adverse Events and Deaths | Deaths During Study | 0 Number of participants |
| Cohort 1, Initial Regimen:(Capecitabine + Irinotecan) | Number of Participants With Any Adverse Events, Serious Adverse Events and Deaths | Deaths During Follow-up | 13 Number of participants |
| Cohort 2, Amended Regimen: (Capecitabine + Irinotecan) | Number of Participants With Any Adverse Events, Serious Adverse Events and Deaths | Deaths During Follow-up | 23 Number of participants |
| Cohort 2, Amended Regimen: (Capecitabine + Irinotecan) | Number of Participants With Any Adverse Events, Serious Adverse Events and Deaths | Any AEs | 52 Number of participants |
| Cohort 2, Amended Regimen: (Capecitabine + Irinotecan) | Number of Participants With Any Adverse Events, Serious Adverse Events and Deaths | Deaths During Study | 3 Number of participants |
| Cohort 2, Amended Regimen: (Capecitabine + Irinotecan) | Number of Participants With Any Adverse Events, Serious Adverse Events and Deaths | SAEs | 25 Number of participants |
| Total Participants (Cohort 1 + Cohort 2) | Number of Participants With Any Adverse Events, Serious Adverse Events and Deaths | Deaths During Follow-up | 36 Number of participants |
| Total Participants (Cohort 1 + Cohort 2) | Number of Participants With Any Adverse Events, Serious Adverse Events and Deaths | SAEs | 35 Number of participants |
| Total Participants (Cohort 1 + Cohort 2) | Number of Participants With Any Adverse Events, Serious Adverse Events and Deaths | Deaths During Study | 3 Number of participants |
| Total Participants (Cohort 1 + Cohort 2) | Number of Participants With Any Adverse Events, Serious Adverse Events and Deaths | Any AEs | 67 Number of participants |
Secondary
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.
Time frame: Approximately 43 Months
Population: The All Patients Population included participants who received at least one dose of study drug in Cohort 1 or Cohort 2.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1, Initial Regimen:(Capecitabine + Irinotecan) | Overall Survival | 22.9 months |
| Cohort 2, Amended Regimen: (Capecitabine + Irinotecan) | Overall Survival | 20.5 months |
Secondary
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.
Time frame: Up to Month 12
Population: The All Patients Population included participants who received at least one dose of study drug in Cohort 1 or Cohort 2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1, Initial Regimen:(Capecitabine + Irinotecan) | Percentage of Participants With One-year Survival | 67 percentage of participants |
| Cohort 2, Amended Regimen: (Capecitabine + Irinotecan) | Percentage of Participants With One-year Survival | 71 percentage of participants |
Secondary
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.
Time frame: Approximately 43 Months
Population: The All Patients Population included participants who received at least one dose of study drug in Cohort 1 or Cohort 2.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1, Initial Regimen:(Capecitabine + Irinotecan) | Time to Disease Progression | 6.1 months |
| Cohort 2, Amended Regimen: (Capecitabine + Irinotecan) | Time to Disease Progression | 7.6 months |
Secondary
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.
Time frame: Approximately 43 Months
Population: The All Patients Population included participants who received at least one dose of study drug in Cohort 1 or Cohort 2.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1, Initial Regimen:(Capecitabine + Irinotecan) | Time To Objective Response | 5.5 months |
| Cohort 2, Amended Regimen: (Capecitabine + Irinotecan) | Time To Objective Response | 4.3 months |
Secondary
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.
Time frame: Approximately 43 Months
Population: The All Patients Population included participants who received at least one dose of study drug in Cohort 1 or Cohort 2.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1, Initial Regimen:(Capecitabine + Irinotecan) | Time to Treatment Failure | 5.8 months |
| Cohort 2, Amended Regimen: (Capecitabine + Irinotecan) | Time to Treatment Failure | 7.3 months |