Clinical Trial Result Information

Title of Study:
An open-label, randomized, phase III study comparing Xeloda (capecitabine) with iv bolus 5-fluorouracil in combination with low-dose leucovorin as adjuvant chemotherapy in patients who underwent surgery for Dukes C colon cancer

Fast Facts:

Protocol number:	M66001
Sponsor:	Hoffmann-La Roche AG
Company division:	Pharmaceutical
Product name:	Xeloda
Generic name:	capecitabine
Phase of development:	III
Therapeutic area, approved indication:	Colorectal Cancer
Date of report:	8/31/2004

Clinical study summary:
This was an open label, multicenter, international, randomized, parallel group, Phase III study to compare the efficacy and safety of intermittent therapy with Xeloda, and bolus iv 5-fluorouracil in combination with low dose leucovorin, as adjuvant chemotherapy in patients who had undergone surgery for Dukes stage C colon cancer.

Study center(s) :
A total of 164 centers in 25 countries, including European countries, Argentina, Australia, Brazil, Canada, Israel, Singapore, Thailand, Uruguay, and the United States.

Objectives:
Primary: To demonstrate that Xeloda is at least equivalent to intravenous (iv) bolus 5-fluorouracil (5-FU) in combination with leucovorin (LV) in terms of disease-free survival in chemotherapy-naïve patients who underwent surgery for Dukes stage C colon cancer.. Secondary: (1) To compare the overall survival of the 2 treatment arms; (2) To compare the safety profiles of the 2 treatments; (3) To evaluate and compare the 2 treatment arms with regard to changes in quality of life from baseline; and (4) To evaluate and compare medical care utilization in the 2 treatment arms.

Methodology:
Patients were randomized to one of two treatment groups, to receive either Xeloda or 5-FU/LV. Patients received study treatment for 6 months, and had tumor assessments prior to and at the end of the 6 month treatment period. Treatment was discontinued in patients who experienced a relapse or new occurrence of colon cancer during the treatment period. Patients were followed for survival.

Number of patients (planned/analyzed):
A total of 1987 patients (1004 randomized to the Xeloda treatment group and 983 to the 5-FU/LV group): 996 treated with Xeloda and 974 with 5-FU/LV.

Diagnosis and main criteria for inclusion:
Patients 18–75 years of age with histologically confirmed colon carcinoma in Dukes stage C with ≥1 positive lymph node.

Test product, dose and mode of administration or test procedure:
Xeloda oral tablets 1250 mg/m2 twice daily for 14 days followed by a 7-day resting period without treatment.

Duration of treatment:
Eight 3-week cycles (24 weeks).

Reference therapy, dose and mode of administration or reference procedure:
iv leucovorin 20 mg/m2 plus iv 5-FU 425 mg/m2, Days 1–5 of the first week in each 4-week cycle for 6 cycles (24 weeks).

Criteria for evaluation (efficacy, safety):
Primary efficacy endpoint: (1) Disease-free survival was assessed as the number of days between randomization and the first time at which relapse, a new occurrence of colon cancer, or death was recorded, or the last time a patient was known to be disease free (censoring time).

Secondary efficacy endpoints: (1) Overall survival was assessed as the number of days between randomization and death or the last time a patient was known to be alive (censoring time); (2) Relapse-free survival was assessed in the same way as disease-free survival; however, deaths unrelated to treatment or disease progression were excluded and these patients were censored at the time of the last tumor assessment; (3) Quality of life was assessed according to patients’ responses to the EORTC QLQ-C30 quality of life questionnaire.

These analyses were performed in the all-randomized population, the per-protocol population (excluding patients with major protocol violations and <12 weeks of treatment), and the extended per-protocol population (excluding patients with major protocol violations), except for quality of life, which was analyzed in the safety population.

Safety: Safety was assessed in the safety population based on adverse events, serious adverse events, deaths, dose modifications, premature withdrawals from treatment, laboratory abnormalities, and vital signs.

Statistical methods:
For the primary endpoint, disease-free survival, the hazard ratio and associated 95% confidence interval (CI) were calculated based on a proportional hazards model. Using hierarchical testing, the hypothesis of at least equivalence was tested by comparing the upper limit of the 95% CI for the hazard ratio to the noninferiority margin of 1.25 in a first step, and then of 1.20 in a second step. Equivalence hypotheses were also tested for the secondary endpoints of overall survival and relapse-free survival. Predefined treatment-related grade 3/4 adverse events or laboratory abnormalities were compared between treatment arms using the log-rank test, and a chi-squared test with Shouten correction. Change in the quality of life Global Health Status score was compared for the 2 treatment arms using a Van der Waerden test applied to the change from baseline to Week 25.

Summary (efficacy, safety, other results):
Efficacy – The primary objective of the study was met. Xeloda was at least equivalent to iv 5-FU/LV in terms of disease-free survival in the all-randomized, per-protocol, and extended per-protocol populations, based on the pre-specified margins of 1.25 and 1.20 for the hazard ratio, corresponding to the hierarchical testing strategy specified in the protocol. The upper limit of the 95% CI of the hazard ratio was well below 1.20 for all 3 populations, as shown in the following

Xeloda retained >=75% of the benefit that 5-FU/LV has shown over surgery alone (P<0.001) regarding disease survival. In this calculation, the benefit of 5-FU/LV over surgery alone was assumed to be given by a hazard ratio of 1.90 (surgery vs 5-FU/LV) with a 95% CI of 1.53–2.35.

In all 3 populations, Xeloda was at least equivalent to 5-FU/LV in terms of overall survival, based on the protocol-specified noninferiority margin of 1.25. The upper limits of the 95% CIs of the hazard ratios for the 3 populations were >=1.10.

For Xeloda vs 5 FU/LV, there was a strong trend toward superiority with respect to disease-free survival, a trend toward superiority with respect to overall survival, and superiority in relapse-free survival in the all-randomized population.

The quality of life scores for Global Health Status (EORTC QLQ-C30 items 29 and 30) over time were similar for the 2 treatment arms. A statistically significant difference between treatment arms in the change from baseline to Week 25 could not be shown. Other quality of life results were generally similar for the 2 treatment arms.

Safety – The overall occurrence of predefined treatment-related grade 3/4 adverse events and laboratory abnormalities (diarrhea, stomatitis, nausea, vomiting, alopecia, palmar-plantar erythrodysesthesia, neutropenia, neutropenic fever, sepsis, dehydration) was lower in the Xeloda treatment arm (29%) than in the 5 FU/LV treatment arm (44%) (P<0.0001). The time to the first onset of those events was significantly longer in the Xeloda treatment arm than in the 5-FU/LV treatment arm (P<0.0001).

Gastrointestinal (GI) adverse events (all grades) were among the most common adverse events in both treatment arms. The most common GI adverse events (diarrhea, nausea, stomatitis, vomiting) were less frequent with Xeloda than with 5-FU/LV. Among other frequent adverse events (reported by >=5% of patients in >=1 treatment arm), alopecia and neutropenia were less frequent with Xeloda than with 5 FU/LV, whereas palmar-plantar erythrodysesthesia was more frequent with Xeloda (60% of patients) than with 5-FU/LV (9%).

Among treatment-related grade 3/4 adverse events reported by >=1% of patients in >=1 treatment arm, neutropenia, febrile neutropenia/sepsis, and stomatitis were less frequent with Xeloda than with 5 FU/LV. Grade 3/4 diarrhea occurred with similar frequency in the 2 treatment arms; however, hospitalizations due to diarrhea occurred more frequently with Xeloda. Grade 3 palmar-plantar erythrodysesthesia was more frequent with Xeloda than with 5-FU/LV (17% vs <1%). In the Xeloda arm, median time to onset of treatment-related grade 3 palmar-plantar erythrodysesthesia was 79 days, and median duration was 13 days. Most patients with grade 3 treatment-related palmar-plantar erythrodysesthesia had only 1 episode at that intensity. This adverse event rarely became serious (4 patients) or was a single reason for hospitalization (2 patients).

Mortality within 60 days of treatment initiation was low (<1%) in both treatment arms. More treatment withdrawals for adverse events occurred with Xeloda than with 5-FU/LV (11% vs 8%). The difference was attributable to the greater percentage of Xeloda treated patients withdrawn for palmar-plantar erythrodysesthesia (Xeloda: 3%, representing 29% of withdrawals due to adverse events; 5-FU/LV, <1%, representing 5% of withdrawals due to adverse events).

Patients treated with Xeloda experienced more hyperbilirubinemia of all grades (50%), more grade 3/4 hyperbilirubinemia (20%), and more grade 4 hyperbilirubinemia (1.4%) than did those treated with 5 FU/LV (19% all grades, 6% grade 3/4, 0.3% grade 4). However, hyperbilirubinemia had no major clinical significance, rarely being associated with clinical signs or symptoms related to hepatobiliary dysfunction or to other biochemical abnormalities indicative of liver dysfunction.

The improved safety profile of Xeloda compared with 5-FU/LV was maintained in older patients (>=65 years and >=70 years).

Conclusions:
The results of this Phase III study demonstrate that, when compared to iv 5-FU/LV (Mayo Clinic regimen) in adjuvant treatment of patients with Dukes C colon cancer, orally administered Xeloda provided at least equivalent efficacy, with a trend toward superior efficacy, as well as significant safety advantages. Overall, the results indicate a favorable risk–benefit ratio for Xeloda in this treatment setting.

Publications (references, if available):
Scheithauer W et al. Oral capecitabine as an alternative to iv 5-fluorouracil/leucovorin-based adjuvant therapy for colon cancer:safety results of a randomized phase III trial. Annals of Oncology 2003; 14: 1735-1743

Twelves C, Wong A, Nowacki MP et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 2005; 352 (26): 2696-2704

Click here for the protocol registry listing of this trial.