Clinical Trial Result Information

Title of Study:
An open-label phase II study of continuous oral capecitabine in combination with weekly irinotecan in patients with advanced and/or metastatic colorectal cancer.

Fast Facts:

Protocol number:	MO16460
Sponsor:	Hoffmann-La Roche Inc
Company division:	Pharmaceutical
Product name:	Xeloda
Generic name:	capecitabine
Phase of development:	II
Therapeutic area, approved indication:	Colorectal Cancer
Date of report:	9/3/2007

Clinical study summary:
This was an open-label, single arm, multicenter study to evaluate the efficacy and safety of continuous oral Xeloda (capecitabine) in combination with cycles of irinotecan treatment in untreated patients with advanced and/or metastatic colorectal cancer.

Study center(s) :
8 centers in the USA.

Objectives:
Primary: To evaluate overall response rate (ORR; complete and partial response) according to the Response Evaluation Criteria in Solid Tumors (RECIST) of Xeloda (capecitabine) and irinotecan as first-line treatment of patients with advanced/metastatic colorectal cancer.
Secondary: To evaluate time to progression or death, time to response, duration of response and time to treatment failure; to determine one-year survival and overall survival; to evaluate the tumor marker carcinoembryonic antigen (CEA) over time in patients with increased values at baseline; to evaluate the safety profile of the combination of Xeloda and irinotecan.

Methodology:
Patients received up to a planned total of 6 x 6 week irinotecan cycles. During the Study Treatment Phase, tumor assessments and tumor marker measurements (in applicable patients) took place during week 6 of cycles 1, 2, 4 and 6 or at the time of coming off treatment. Tumor assessments were done every 12 weeks in applicable patients during the Post-Study Treatment Phase. Patients with clearly documented progressive disease were taken off treatment at time of progression. Adverse events were monitored continuously during the Study Treatment Phase and for a further 28 days. Only serious adverse events were reported during the Post-Study Treatment Phase.

Number of patients (planned/analyzed):
57 patients

Diagnosis and main criteria for inclusion:
Male and female outpatients with histologically confirmed colorectal adenocarcinoma with locally advanced and/or metastatic disease.

Test product, dose and mode of administration or test procedure:
Patients <65 years of age: Xeloda (capecitabine) 1000mg/m² po bid every day for 6 weeks, and irinotecan 75mg/m² i.v. on days 1, 8, 15 and 22 of each 6 week cycle.
Patients ≥65 years of age and/or with creatinine clearance 30-50mL/min: Xeloda (capecitabine) 500mg/m² po morning and 1000mg/m² po evening every day for 6 weeks, and irinotecan 60mg/m² i.v. on days 1, 8, 15, and 22 of each 6 week cycle.

Duration of treatment:
36 week (+ 4 weeks follow-up)

Reference therapy, dose and mode of administration or reference procedure:
N/A.

Criteria for evaluation (efficacy, safety):
Efficacy: The primary efficacy parameter was ORR based on the investigators' tumor assessments. The secondary efficacy parameters were time to tumor progression (TTP) or death, time to response, duration of response, time to treatment failure (TTF), one-year survival, overall survival (OS), and CEA levels over time (in patients with elevated baseline values).
Safety: Exposure to study drug, adverse events, deaths, laboratory values, and vital signs.

Statistical methods:
The null hypothesis (H₀) was that the ORR was 30% or lower (equating to a low activity profile). The alternative hypothesis (H₁) was that the overall response rate was superior to 30% (yielding an encouraging activity profile). The primary efficacy analysis was a binomial test (using exact distribution) for activity of Xeloda and irinotecan and included the 95% confidence interval (Pearson-Clopper). The analysis of efficacy was based on the intent-to-treat population and the investigators' assessment of patient response utilizing the RECIST criteria. The best overall response achieved within the time from drug administration to progressive disease or end of study was reported. Patients without tumor assessment after baseline were classified as non-responders.
TTP or death, time to response, duration of response, TTF and survival are summarized by medians and CIs.

Summary (efficacy, safety, other results):
The main efficacy results are summarized below:

Efficacy Parameter	Xeloda 2000 (mg/m2/day) +Irinotecan 75 (mg/m2 weekly)
Median overall response rate: Investigator ITT (9 responders)	17.3% (CI: 8.23-30.33)
Median time to disease progression General approach (48 events)	161 days (5.3 months) (CI: 82-168)
Median duration of response Standard (8 events)	325 days (10.7 months) (CI: 267-387)
Time to treatment failure ITT (50 events)	101.5 days (3.3 months) (CI: 58-162)
Median overall survival ITT (33 events)	420.5 days (13.7 months) (CI: 314-503)
1-year survival rate	58%

Safety: The most frequently occurring adverse events were gastrointestinal disorders (93% of patients) of which diarrhea and nausea/vomiting were the most common, and general disorders and administration site conditions (67%), of which fatigue/asthenia was the most common.
The most frequently reported adverse events leading to dose modification were diarrhea (60% of patients), nausea/vomiting (16%), neutropenia (12%) and hand-foot syndrome (11%).
A total of 19% of the patients experienced AEs leading to treatment discontinuation. The organ system affected most was the gastrointestinal system.
A total of 37 patients (65%) died during the study with the majority of deaths (33 patients, 58%) due to progressive disease. Three deaths occurred within 28 days after the last dose of study drug, of which 2 (respiratory failure and septic shock) were considered by the investigator to be related to study treatment.
Eighteen patients (32%) experienced serious adverse events, the most frequent being gastrointestinal disorders (12%) and infections and infestations (9%).
The most common grade 3/4 hematologic abnormality considered to be clinically relevant was neutropenia/granulocytopenia (5%).

Conclusions:
In the ITT population, the ORR based on the investigators' tumor assessments was 17.3%. Therefore, based on this study, the Xeloda/irinotecan combination regimen evaluated is not considered sufficiently active in this patient population.
The safety profile of Xeloda plus irinotecan was predictable from the known characteristics of the two agents, and no unexpected AEs were recorded. The most common treatment-related AEs and grade 3/4 AEs were diarrhea and nausea/vomiting. Notably, only one patient experienced grade 3 hand-foot syndrome.
Based on the results of this phase II study, the regimen of continuous Xeloda plus weekly irinotecan cannot be recommended for further evaluation.

Click here for the protocol registry listing of this trial.