Clinical Trial Result Information

Title of Study:
An open-label randomized phase III study of intermittent oral capcitabine in combination with intravenous oxaliplatin (Q3W) ("XELOX") versus bolus and continuous infusion fluorouracil/intravenous leucovorin with intravenous oxaliplatin (Q2W) ("FOLFOX4") as treatment for patients with metastatic colorectal cancer who have received prior treatment with irinotecan in combination with 5-FU/LV as first line therapy.

Fast Facts:

Protocol number:	NO16967
Sponsor:	Hoffmann-La Roche Ltd
Company division:	Pharmaceutical
Product name:	Xeloda
Generic name:	capecitabine
Phase of development:	III
Therapeutic area, approved indication:	Metastatic Colorectal Cancer
Date of report:	2/1/2007

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

Study center(s) :
87 centers in Belgium, Canada, Croatia, Finland, France, Germany, Greece, Israel, Italy, Korea, Poland, Serbia, Slovakia, Slovenia, South Africa, Spain, Taiwan, UK and United States.

Objectives:
Primary: To demonstrate that the combination of Xeloda (capecitabine) plus oxaliplatin (XELOX) is non-inferior to the combination of 5-fluorouracil/leucovorin (5-FU/LV) plus oxaliplatin (FOLFOX-4) in terms of progression-free survival (PFS) in patients with metastatic colorectal carcinoma who have received prior treatment with irinotecan in combination with 5-FU/LV as first-line therapy.
Secondary: To evaluate and compare efficacy (overall survival, overall response rate according to Response Evaluation Criteria in Solid Tumors [RECIST], time to response, duration of response, and time to treatment failure) in the two treatment groups; to evaluate and compare the safety profiles of the treatment groups using the National Cancer Institute Common Toxicity Criteria (NCI CTCAE, version 3.0).

Methodology:
After screening, patients were randomized to receive either XELOX or FOLFOX-4 and underwent treatment for up to 24 weeks (8 cycles of XELOX or 12 cycles of FOLFOX-4). Imaging and tumor measurements (CT, MRI, X-ray) were conducted every 6 weeks. Vital signs were recorded and clinical laboratory tests were conducted on the first day of each cycle and at the end of the primary study treatment phase. Adverse events were recorded throughout the primary study treatment phase. After completing the primary study treatment phase, patients without disease progression were qualified to enter an optional post study treatment phase to continue treatment phase to continue treatment until progression. After completing or withdrawing from the primary (or post) study treatment phase, patients were evaluated every 3 months for disease progression (unless already documented) and survival during the optional post-study treatment phase and a treatment-free follow-up phase.

Number of patients (planned/analyzed):
A total of 627 patients were randomized; 619 were treated.

Diagnosis and main criteria for inclusion:
Male and female outpatients ≥18 years of age, ECOG performance status ≤2, with histologically confirmed adenocarcinoma of the colon or rectum with metastatic disease, whose disease had recurred or progressed during or within 6 months after completion of first-line therapy with irinotecan + 5-FU/LV, or who stopped first line irinotecan + 5-FU/LV due to excessive toxicity within the first 8 weeks.

Test product, dose and mode of administration or test procedure:
Oxaliplatin 130mg/m² intravenous (IV) infusion over 2 hours (on day 1) in combination with Xeloda (capecitabine) orally, 1000mg/m² twice daily (total daily dose of 2000mg/m²), with first dose the evening of day 1 and last dose the morning of day 15, given as intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) for up to 8 cycles (24 weeks).

Duration of treatment:
24 weeks

Reference therapy, dose and mode of administration or reference procedure:
Oxaliplatin 85mg/m² IV infusion over 2 hours (on day 1) concomitantly with LV 200mg/m² infusion over 2 hours, followed by 5-FU 400mg/m² bolus injection and then 600mg/m² continuous infusion over 22 hours; on day 2, LV 200mg/m² followed by 5-FU 400mg/m² bolus injection and 5-FU 600mg/m² continuous infusion (2-week cycles comprising 48 hours of infusion and 12 days of rest) for up to 12 cycles (24 weeks).

Criteria for evaluation (efficacy, safety):
Efficacy: The primary efficacy parameter, PFS, was measured as the time from randomization to the date of first documented disease progression or death, whichever occurred first. The secondary efficacy parameters were overall survival, best overall response, time to response, duration of response, and time to treatment failure. The parameters were determined from tumor assessments made by the investigators throughout the study. In addition, PFS and best overall response were determined from tumor assessments by an independent review committee (IRC), who reviewed blinded radiological images and assessed tumor response. All tumor assessments were performed according to RECIST. Information was collected on third line anti-cancer treatment.

Safety: Safety parameters were exposure to study drug, concomitant medications, adverse events, deaths, laboratory values, vital signs and ECG.

Statistical methods:
A non-inferiority hypothesis was applied to the primary efficacy parameter, PFS. The pre-specified non-inferiority margin (1.30) was compared with the upper limit of the 95% confidence interval (CI) of the hazard ratio (HR, XELOX vs. FOLFOX-4) in the per-protocol population (PPP). The analyses were repeated in the intent-to-treat (ITT) population and using tumor assessments from the IRC in the PPP. PFS was also analyzed using an on-treatment approach that comprised only disease progression and death occurring no later than 28 days after the last dose of study medication in the primary treatment phase.
The 2 treatment groups were compared with respect to overall survival, best overall response, time to response, duration of response, and time to treatment failure using descriptive statistics.

Summary (efficacy, safety, other results):
Efficacy: The primary objective of this study was met. Non-inferiority of XELOX compared with FOLFOX-4 in terms of PFS in the PPP was demonstrated: HR = 1.03, 95% CI = 0.87 to 1.24. The upper limit of the 95% CI was below the pre-specified non inferiority margin of 1.30. Results in the ITT population were consistent with those in the PPP, as shown in the following table.

XELOX retained at least 50% of the benefit of FOLFOX-4 over 5 FU/LV; in pre-specified effect retention tests, p = 0.00486 for arithmetic definition, 0.00628 for geometric definition.
The analysis of overall survival was supportive of the primary analysis: HR = 1.07, 95% CI = 0.88 to 1.31 in the PPP; HR = 1.03, 95% CI = 0.87 to 1.23 in the ITT population.
A non-inferiority analysis using tumor assessments by the IRC was supportive of the primary non-inferiority analysis: HR = 0.93, 95% CI = 0.74 to 1.17 in the PPP. The concordance rates of PFS in investigators’ assessments vs. IRC assessments were similar for the FOLFOX-4 and XELOX groups.
Best overall response was similar for the 2 treatment groups: FOLFOX-4 = 20.2%, XELOX = 23.1% in the PPP; FOLFOX-4 = 17.5%, XELOX = 20.1% in the ITT population. The 2 treatment groups were also similar in time to response and time to treatment failure.

Safety: The overall incidence of adverse events was similar between treatment groups. Most adverse events were gastrointestinal disorders or nervous system disorders, the most commonly occurring of which were nausea (60% XELOX and 56% FOLFOX-4) and paresthesia (33% XELOX and 32% FOLFOX-4). The incidences of adverse events were similar between the treatment groups, with the following exceptions: diarrhea, vomiting, pharynx dysesthesia and palmar-plantar erythrodysesthesia (PPE) occurred with a higher incidence in the XELOX group; and neutropenia, stomatitis, constipation and cough occurred with a higher incidence in the FOLFOX-4 group.
Severe (grade 3/4) adverse events had a lower incidence in the XELOX treatment group (60%) than the FOLFOX-4 treatment group (72%). The most commonly occurring severe adverse events were neutropenia (5% XELOX vs. 35% FOLFOX-4) and diarrhea (20% XELOX vs. 5% FOLFOX-4). In the XELOX treatment group, the incidence of grade 3 and grade 4 diarrhea was 19% and <1%, respectively.
The percentages of patients who died during the study were similar between the 2 treatment groups (80% XELOX and 78% FOLFOX-4). A total of 4% of patients in each treatment group died within 28 days of the last dose of study medication, and 4% of patients in each treatment group died within 60 days of treatment start. Most deaths were due to disease progression.
Serious adverse events occurred in a similar percentage of patients in the XELOX group (30%) and the FOLFOX-4 group (31%). The highest percentage of serious adverse events were gastrointestinal disorders (17% XELOX and 8% FOLFOX-4) or infections and infestations (4% XELOX and 7% FOLFOX-4), the most commonly occurring of which were diarrhea (6% XELOX and <1% FOLFOX-4) and neutropenia (2% FOLFOX-4 patients only).
Predefined adverse events of special interest to chemotherapy included grade 3/4 neutropenia/granulocytopenia, neurosensory toxicity, nausea/vomiting, stomatitis, diarrhea, and grade 3 PPE. Overall, a lower percentage of patients in the XELOX group compared with the FOLFOX-4 group reported treatment-related adverse events of special interest to chemotherapy (35.7% XELOX and 46.4% FOLFOX 4). Of the individual events, the incidences of grade 3/4 neurosensory toxicity, nausea/vomiting, and stomatitis were similar between the XELOX and FOLFOX treatment groups. The incidence of grade 3/4 neutropenia/granulocytopenia was higher in the FOLFOX-4 group (35.1%) compared with the XELOX group (4.5%), grade 3/4 diarrhea was higher in the XELOX group (19.9%) compared with the FOLFOX-4 group (4.9%); and grade 3 PPE, although higher in the XELOX treatment group, was low overall-- XELOX (3.5%) vs. FOLFOX-4 (0.6%). In addition, the incidences of grade 3/4 elevation of liver function tests and cardiac disorders were low and similar between treatment groups.
Adverse events requiring dose modification occurred in a lower percentage of patients in the XELOX treatment group (67%) compared with the FOLFOX-4 treatment group (74%). The most frequently reported adverse events leading to dose modification were neutropenia (18% XELOX vs. 46% FOLFOX-4) and diarrhea (24% XELOX vs. 6% FOLFOX-4). Adverse events leading to discontinuation occurred in a higher percentage of patients in the XELOX treatment group (20%) compared with the FOLFOX-4 treatment group (13%). The most commonly occurring events leading to discontinuation were diarrhea (4% XELOX vs. <1% FOLFOX) and nausea (2% of XELOX patients only).
Grade 3/4 or 4 abnormalities in laboratory values of WBCs, neutrophils, and neutrophils/granulocytes, were more common in the FOLFOX-4 treatment group than in the XELOX group.

Conclusions:
The primary objective of this study was met. As second-line treatment for patients with metastatic colorectal cancer, XELOX was non-inferior to FOLFOX-4 in terms of progression-free survival. Other efficacy results, including overall survival and best overall response, supported the non-inferiority of XELOX.
There was no excess of toxicity of XELOX compared with FOLFOX-4.
Considering the efficacy and safety results, and the advantage of oral administration of Xeloda compared with an intravenous 48-hour 5-FU infusion requiring an indwelling catheter, this study has established a positive benefit/risk ratio for XELOX.

Click here for the protocol registry listing of this trial.