Clinical Trial Result Information
Protocol number
M66016
Title of Study
An Open-Label, Phase II Study of Capecitabine in Combination with Oxaliplatin as First-Line Treatment for Patients with Advanced and/or Metastatic Colorectal Cancer
Sponsor
Hoffman-La Roche Ltd
Company division
Pharmaceutical
Product name
Xeloda
Generic name
capecitabine
Therapeutic area
Colorectal Cancer
Clinical study summary
This open-label, multicenter, multinational, single-arm study assessed the efficacy and safety of capecitabine (Xeloda) in combination with oxaliplatin as a first-line treatment for patients with advanced and/or metastatic colorectal cancer.
Study center(s)
Study sites in 8 countries: Belgium, Canada, France, Germany, Great Britain, Israel, Italy, and Spain.
Phase of development
II
Objectives
Primary: To evaluate overall response rate (complete and partial responses).
Secondary: (1) To evaluate time to progression, time to response, duration of response, and time to treatment failure; (2) to determine 1-year survival and overall survival; (3) to evaluate the safety profile of the combination of oxaliplatin and Xeloda.
Methodology
Tumor assessments were made within 14 days prior to initiation of treatment by a suitable reproducible technique (magnetic resonance imaging, computed tomography scan, or X-ray films), and the same modality was used for all assessments for an individual patient throughout the study. Tumor response was assessed after the first 9 weeks (after the first 3 cycles) and thereafter every 6 weeks (2 cycles). For those patients with no progressive disease following treatment completion, time to disease progression was evaluated on a 3-monthly basis until disease progression and post-study treatment information was collected for these patients. Survival was evaluated on a 3-monthly basis until death or lost-to-follow-up after treatment completion. Adverse events were monitored throughout the treatment period and for 28 days after the last intake/infusion of study drug. Hematology and blood chemistry were reviewed prior to treatment initiation and before starting each cycle of treatment. Urinalysis, electrocardiography, and chest X-ray were performed as clinically indicated.
Number of patients (planned/analyzed)
96
Diagnosis and main criteria for inclusion
Patients with measurable, histologically confirmed metastatic or locally advanced colorectal carcinoma, who have not received any chemotherapy (except when given as adjuvant or neoadjuvant treatment and completed >=6 months prior to initiation of study treatment).
Test product, dose and mode of administration or test procedure
Xeloda1000 mg/sqm po, twice daily as intermittent therapy (2 weeks on, 1 week off). Oxaliplatin 130mg/sqm iv (2-hour infusion), first day of each 3 week cycle for >=6 weeks.
Duration of treatment
33 weeks (Xeloda). 6 weeks (Oxaliplatin).
Reference therapy, dose and mode of administration or reference procedure
N/A
Criteria for evaluation (efficacy, safety)
Primary efficacy parameter: objective response (investigator assessment will be reviewed by an independent review committee [IRC]).
Secondary efficacy parameters: time to disease progression, time to response, duration of response, time to treatment failure, survival, and tumor marker (CEA) levels over time.
Safety parameters: deaths, serious adverse events, premature withdrawals due to adverse events, grade 3/4 toxicities (adverse events and/or laboratory abnormalities), shifts in laboratory values, vital signs, and physical measurements.
Statistical methods
A binomial test at the alpha level of 5% was used to test the activity of Xeloda and oxaliplatin on the overall response rate (primary variable). This analysis was based on the intent-to-treat (ITT) population, and the investigator assessment was based on World Health Organization (WHO) criteria.
Summary (efficacy, safety, other results)
Efficacy – Overall tumor response rates, as assessed by the investigators, were 55.2% and 62.4% in the ITT population and in the standard population, respectively. An IRC confirmed these results. Median time to disease progression was 234 days (7.7 months; ‘general’ approach) and 239 days (7.8 months; ‘on treatment’ approach). Median duration of response was 261 days (8.6 months; WHO assessment) and 184 days (6.0 months; protocol-defined assessment). Time to treatment failure was 207.5 days (6.8 months). Median survival was 594 days (19.5 months).
Safety – The following table summarizes the main safety findings of this study:
| Safety Parameter |
Capectabine (2000 mg/sqm/day) Intermittent w/Oxaliplatin 130 mg/sqm/day n(%) |
| Overall Incidence of Pts. With AEs (All grades) |
96 |
(100) |
| No. of Pts. with Treatment-Related AEs
|
95 |
(95) |
|
Frequest (>=20%)
Treatment-Related AEs |
|
Peripheral sensory neuropathy |
82 |
(85) |
|
Diarrhea |
63 |
(66) |
|
Nausea |
63 |
(66) |
|
Vomiting |
48 |
(50) |
|
Hand-foot syndrome |
35 |
(36) |
|
Asthenia |
33 |
(34) |
|
Neuropathic pain |
30 |
(31) |
|
Anorexia |
29 |
(30) |
|
Fatique |
28 |
(29) |
|
Stomatitis all |
24 |
(25) |
|
Thrombocytopenia |
23 |
(24) |
|
|
20 |
(21) |
| Treatment-Related Grade 3/4 AEs (Severer and/or Life-threatening) |
59 |
(61) |
| Treatment-Related Grade 4 AEs (Life-threatening) |
5 |
(5) |
| Treatement-Related Grade 3 AEs (Severe) |
58 |
(60) |
| Frequent (>=10%) Treatment-Related Grade 3/4 AEs |
|
Peripheral sensory neuropathy |
16 |
(17) |
|
Diarrhea |
15 |
(16) |
|
|
11 |
(11) |
|
Related Deaths on Study |
1 |
(1) |
|
Related SAEs |
20 |
(21) |
|
Patients Withdrawn Due to AEs |
17 |
(18) |
|
Patients Withdrawn Due to Treatment-Related AEs |
14 |
(15) |
|
Patients with Cllinically Relevant Laboratory Abnormalities (Grade 3/4 Shift from Baseline): |
| Hyperglycemia |
|
Grade 3/4 |
3 |
(3) |
|
Grade 4 |
0 |
| Neutrophil + Gramulocyte Cell Count |
|
Grade 3/4 |
7 |
(7.3) |
|
Grade 4 |
- |
| Thrombocytopenia |
|
Grade 3/4 |
4 |
(4.2) |
|
Grade 4 |
0 |
|
Patients Withdrawn Due to Laboratory Abnormalities |
0 |
Conclusions
The addition of Xeloda to oxaliplatin 130 mg/sqm is an effective regimen for first-line treatment of colorectal cancer with a less complicated, more convenient dosing schedule than regimens combining 5-fluorouracil/leucovorin with oxaliplatin. The efficacy achieved suggests that addition of oxaliplatin can enhance the efficacy of Xeloda in a similar fashion to that previously seen for 5-fluorouracil/leucovorin with oxaliplatin. Overall, the safety profile was predictable from the known characteristics of the 2 agents, and no unexpected adverse events were recorded.
Publications (references, if available)
Scheithauer W et al. Oral capecitabine as an alternative to iv 5-fluorouracil-based adjuvant therapy for colon cancer: safety results of a randomized phase III trial. Annals of Oncology 2003; 14 (12): 1735-1743
Date of report
2/16/2004
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