Clinical Trial Result Information

Protocol number
ML16987

Title of Study
Randomized, open-label, comparative phase III study of capecitabine plus oxaliplatin (XELOX) versus infusional 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX 6) as first-line combination chemotherapy in patients with metastatic colorectal cancer.

Sponsor
Roche SAS

Company division
Pharmaceutical

Product name
Xeloda

Generic name
capecitabine

Therapeutic area
Colorectal cancer

Clinical study summary
This was a randomized, open-label, parallel group, efficacy and safety study to evaluate the effect of Xeloda + oxaliplatin, versus 5-fluorouracil/leucovorin + oxaliplatin as first-line therapy in patients with metastatic colorectal cancer.

Study center(s)
33 centers in France.

Phase of development
III

Objectives
Primary: To demonstrate the non-inferiority in terms of efficacy of capecitabine/oxaliplatin combination (XELOX) versus a standard chemotherapy combination with 5 Fluorouracil (5 FU)/leucovorin/oxaliplatin (FOLFOX-6).
Secondary: To compare between arms the safety profile, patients' quality of life using the Cancer Quality of life Questionnaire-C30 (QLQ-C30) of the European Organization for Research and Treatment of Cancer (EORTC) and "Chemotherapy convenience and satisfaction questionnaire on therapy" from Functional Assessment of Chronic Illness Therapy (FACIT) scales, pharmaco-economic parameters and relative dose intensity of oxaliplatin.

Methodology
After screening, patients were randomized to receive either XELOX or FOLFOX-6 and underwent treatment for up to 24 weeks (8 cycles of XELOX or 12 cycles of FOLFOX-6). Imaging and tumor measurements (CT, MRI) were conducted at baseline, cycle 3, cycle 6 and at the end of study treatment for the XELOX arm and at baseline, cycle 4, cycle 8 and at the end of treatment for the FOLFOX-6 arm. Health related quality of life was recorded at screening, cycle 3/cycle 4, cycle 6/cycle 8 and at the final visit in both treatment arms.
Pharmacoeconomic parameters (need for central venous catheter, hospitalizations, concomitant treatments, were recorded at each visit throughout the study. Adverse events were recorded throughout the study treatment phase until the final visit. Vital signs and laboratory tests were assessed at each study visit until the final visit. After completing the treatment phase, patients were evaluated every 3 months for disease progression until 18 months after the last patient’s inclusion.

Number of patients (planned/analyzed)
304 planned; 306 included

Diagnosis and main criteria for inclusion
Male or female patient having given their written inform consent, at least 18 years of age, with histologically proven metastatic colorectal carcinoma (MCRC) and at least one measurable target lesion using Response Evaluation Criteria In Solid Tumors (RECIST), and Eastern Cooperative Oncology Group (ECOG) performance status 0-2.

Test product, dose and mode of administration or test procedure
XELOX: Oxaliplatin 130 mg/m² intravenous (IV) infusion over 2 hours (on day 1 of each 21 day cycle) in combination with Xeloda (capecitabine) orally, 1000 mg/m² twice daily (total dose of 2000 mg/m²), from day 1 to day 15 of each 21 day cycle for up to 8 cycles (24 weeks).

Duration of treatment
24 weeks

Reference therapy, dose and mode of administration or reference procedure
FOLFOX-6: Oxaliplatin 130 mg/m² intravenous (IV) infusion over 2 hours (on day 1 of each 14 day cycle) in combination with leucovorin 400 mg/m² as a 2-hour IV infusion on day 1 of each 14 day cycle and 5-FU 400 mg/m2 as an IV bolus on day 1 (immediately after leucovorin) followed by 2400 mg/m² as a 46-hour IV infusion (3000 mg/m² from cycle 3 in the absence of grade 3-4 toxicity) for up to 12 cycles (24 weeks).

Criteria for evaluation (efficacy, safety)
Efficacy: The primary efficacy parameter was the overall response (complete response and partial response) rate.
Secondary efficacy parameters were progression-free survival, overall survival, time to response, duration of response, time to treatment failure, Quality of Life.
Pharmacoeconomic parameters were need for catheterization, number of hospitalizations, concomitant treatments.
Safety: Safety parameters were adverse events, laboratory tests and vital signs

Statistical methods
Primary endpoint: A one sided 95% confidence interval (CI = ]-∞ ,(P_b-P_a+z_0.05 x s_d )] with Z_0.05 = 1.6445) was considered in the per protocol population; if CI < ]-∞,15%], the inferiority hypothesis was rejected in favor of the non inferiority hypothesis with a type I error fixed at 5%, with P_b the success rate in Arm B and P_a in Arm A and s²_d estimated variance of the difference.
Secondary endpoints: The same analyses as for the primary endpoint were performed. In addition, Cox regression analyses were used to determine hazard ratios and its one sided 95% CI (upper margin being compared with the 1.75 non-inferiority margin). Between group comparisons of tumor response were assessed using a Fisher exact test.
Safety: Descriptive statistics and between arm comparisons (if relevant)
Compliance, HRQoL and pharmaco-economic analyses: descriptive statistics; between-arm differences were provided using a Chi square test (or Fisher exact test) for qualitative parameters and a Wilcoxon test or (Fisher exact test) for quantitative parameters.

Summary (efficacy, safety, other results)
Efficacy: In the Per Protocol Set (N = 284), the overall response (CR and PR) rate was 41.7% in the XELOX group (60 patients) and 46.4% in the FOLFOX-6 group (65 patients). The difference between both groups was 4.7% and the upper limit of the 95% unilateral CI (14.44%) was below the non inferiority margin of 15%. Median PFS in the ITT population was similar in both groups; 8.8 months in the XELOX group and 9.3 months in the FOLFOX-6 group [HR=1.000 (90% CI 0.819 to 1.221)]; the upper limit of the 90% CI was below the predefined non-inferiority limit of 1.75. The non-inferiority of the tested regimen (XELOX) to the reference regimen (FOLFOX-6) in terms of PFS was confirmed in the Per-Protocol Set, [HR=0.982 (90%CI 0.798 ; 1.207)]. Median OS in the ITT population was 19.9 months in the XELOX group and 20.5 months in the FOLFOX-6 group [HR=1.021 (90% CI 0.805 to 1.295)]; the upper limit of the 90% CI was below the predefined non-inferiority limit of 1.75. A similar outcome was reported in the PP population [HR=1.015 (90% CI 0.793 to 1.299)]. Median time to response in the Intention To Treat Set was not reached in the XELOX group and was equal to 3.7 months in the FOLFOX-6 group. The non-inferiority of the tested regimen (XELOX) to the reference regimen (FOLFOX-6) in terms of time to objective response was confirmed in the Intention To Treat Set as hazard ratio and its 90% CI was 0.859 [0.643 ; 1.149]. A similar outcome was reported in the PP population. Tumor response was not statistically different between groups, whatever the study assessment taken into consideration in the ITT and PP sets. Median response duration in the Intention To Treat Set was 9.9 months in the XELOX group and 8.8 months in the FOLFOX-6 group. The non-inferiority of the tested regimen (XELOX) to the reference regimen (FOLFOX-6) in terms of response duration was confirmed in the Intention To Treat Set as hazard ratio and its 90% CI was 0.911 [0.667 ; 1.244]. A similar outcome was reported in the PP population. Median time to treatment failure in the Intention To Treat Set, tended to be shorter in the XELOX group (5.8 months) than in the FOLFOX-6 group (6.8 months). The non-inferiority of the tested regimen (XELOX) to the reference regimen (FOLFOX-6) in terms of time to treatment failure was confirmed in the Intention To Treat Set as hazard ratio and its 90% CI was 1.290 [0.965; 1.725]. Results were different in the Per Protocol Set, the inferiority hypothesis of the tested regimen (XELOX) to the reference regimen (FOLFOX-6) could not be rejected for this efficacy criterion.

Safety: During the treatment period (from date of randomization), all 304 patients (100%) experienced at least one adverse event for a total of 6647 adverse events. Among them, 549/6647 adverse events were of grade 3-4 (70.1% of patients), 5253/6647 were treatment related (98.7% of patients). The most common AEs were diarrhea, nausea, asthenia, vomiting, hand-foot syndrome, neuropathy, fever, alopecia and stomatitis. Overall, 403 adverse events were both of grade 3-4 and considered treatment related (59.9%). A total of 76/304 patients (25%) experienced at least one SAE during the treatment period for a total of 113 serious adverse events and 38/304 patients (12.5%) discontinued the treatment for adverse events during the treatment period (from date of randomization). During the follow-up period, 79/304 patients (26.0%) experienced at least one adverse event. A total of 40/150 adverse events (11.8% of patients) were of grade 3-4 and 75/150 were treatment related (14.1 % of patients). Among them, 14 adverse events were both of grade 3-4 and considered treatment related. Moreover, 21/304 patients (6.9%) experienced at least one SAE and 24/304 patients (7.9%) withdrew from the study for adverse events during the follow up period.

Quality of Life: No statistically significant between group differences were shown for changes from baseline in the EORTC QLQ-C30 questionnaire. For the FACIT CCSQ, patients in the XELOX group reported statistically significantly better chemotherapy convenience compared with the FOLFOX-6 group as well as better chemotherapy satisfaction, fewer days spent on hospital visits and less hours of work or usual daily activities were lost. No other statistically significant between group differences were shown for this questionnaire.

Pharmacoeconomic results: The number of hospitalizations was statistically significantly higher in the FOLFOX-6 group compared with the XELOX group, as were hospital stays and the total cost of chemotherapy.

Conclusions
The primary objective of the study was met. XELOX was non-inferior to FOLFOX-6 in terms of overall response rate according to independent review in the PP population.
In the Per Protocol Set, the analysis of secondary efficacy criteria confirmed the non-inferiority of XELOX to FOLFOX-6 for PFS and OS with a non-inferiority upper margin fixed at 1.75 for hazard ratios with a one-sided risk of 5% and for time to objective response and response duration. Non-inferiority was not proven for the median time to treatment failure.
In the ITT population, non-inferiority in terms of the primary objective (overall response rate) was not reached. Non-inferiority of the tested regimen (XELOX) to the reference regimen (FOLFOX-6) in term of PFS and OS as well as time to objective response, response duration and time to treatment failure, was confirmed in the Intention To Treat Set.
A better safety profile of XELOX was shown in terms of neutropenia (all grades and grade 3-4), febrile neutropenia, nausea, fatigue, neuropathies and alopecia, whereas a trend of higher frequency of patients with hand foot syndrome, grade 3-4 diarrhea and grade 3-4 thrombocytopenia was observed in comparison with FOLFOX-6.
Patients of the XELOX group reported statistically significantly better chemotherapy convenience and satisfaction at C3/C4 as well as better chemotherapy convenience at C6/C8, less days spent on hospital visits and less hours of work or usual daily activities were lost at the final visit, using FACIT questionnaire. No between group differences were shown using the QLQ C30 questionnaire.
Mean total cost (chemotherapy and adverse event management) per patient for the whole treatment period was statistically significantly lower in the XELOX group than in the FOLFOX-6 group.

Publications (references, if available)
Ducreux et al., J. Clin. Oncol., 2005 ASCO Annual Meeting Proceedings. Vol 23, No. 16S, Part I of II (June 1 Supplement), 2005: 3596.
Ducreux et al., Société nationale française de gastroentérologie 2005: Abstract No 49.
Bennouna et al., Proc ECCO 2005; Abstract 636.
Bennouna et al., Gastrointestinal Cancers Symposium: Abstract No 272.
Bennouna et al., Gastrointestinal Cancers Symposium: Abstract No 273.
Ducreux et al., J. Clin. Oncol., 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 4029.
Hebbar et al., J. Clin. Oncol., 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 4099.
Ducreux et al., Journées Francophones de Pathologie Digestive. Paris, March 2008.

Date of report
12/12/2007

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