Clinical Trial Result Information

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

Fast Facts:

Protocol number:	M66016
Sponsor:	Hoffman-La Roche Ltd
Company division:	Pharmaceutical
Product name:	Xeloda
Generic name:	capecitabine
Phase of development:	II
Therapeutic area, approved indication:	Colorectal Cancer
Date of report:	2/16/2004

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.

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)
Neutropenia	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)
Vomiting Nos	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