Phase II study of irinotecan and cetuximab given every 2 weeks as second-line therapy for advanced colorectal cancer.

BACKGROUND: Irinotecan and weekly cetuximab (I+C) is a standard second-line regimen for metastatic colorectal cancer (mCRC). This study investigated the safety and efficacy of every 2 weeks I+C in patients with mCRC. PATIENTS AND METHODS: Patients with mCRC refractory to first-line fluoropyrimidine/oxaliplatin regimens and not previously treated with I+C were eligible. Response rate (RR) was the primary endpoint. Cetuximab 500 mg/m(2) and irinotecan 180 mg/m(2) were administered intravenously (I.V.) on day 1 every 2 weeks. RESULTS: Patient characteristics (n = 31): male (n = 17), median age 62; Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤1 (n = 30), and PS = 2 (n = 1). Median number of cycles = 3 (range, 1-22). I+C doses were modified in 18 and 12 patients, respectively. Grade 3/4 adverse events: acneiform rash (n = 6); neutropenia (n = 6); and diarrhea (n = 5); there was one grade 5 respiratory failure, possibly related to therapy. Two patients had a partial response, 11 had stable disease, and 18 had progressive disease resulting in an overall RR of 6% and disease control rate of 41.9%. Median overall survival (OS) was 9.3 months (95% CI, 5.1-15), and time to progression (TTP) was 2.4 months (95% CI, 1.3-4.6). K-ras and BRAF mutations were detected in 39% and 9%, respectively, of the patients tested. There was a trend toward longer TTP among patients with wild-type K-ras and BRAF (2.6 vs. 1.7 months; P = 0.16), and OS was significantly longer in those patients (14.1 vs. 5.5 months; P = 0.04). CONCLUSIONS: The RR and TTP were lower than expected and may reflect the reduced dose intensity due to toxicities. While the OS was consistent with previous publications, the efficacy of this combination was not demonstrated.

A phase I/II study of capecitabine given on a week on/week off schedule combined with bevacizumab and oxaliplatin for patients with untreated advanced colorectal cancer.

BACKGROUND: A week on/week off capecitabine schedule with oxaliplatin/bevacizumab was evaluated in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Forty patients were required. The projected median progression-free survival (PFS) was 12 months (81% power, 1-sided level 0.1 log-rank test). Capecitabine dose was 2500 mg/m(2)/day on days 1-7 (n = 11) and was increased to 3000 mg/m(2)/day (n = 29) in combination with oxaliplatin (85 mg/m(2)) and bevacizumab (5 mg/kg). Cycles were repeated every 2 weeks. RESULTS: Patient characteristics included Eastern Cooperative Oncology Group (ECOG) performance status 0 (n = 24) or 1 (n = 15); median age of 62 years (range, 38-81 years). Median cycles administered were 7 (range, 125), corresponding to 3.5 months' treatment duration. Pertinent grade 3/4 toxicities seen were diarrhea (18%), hand-foot syndrome (10%), and peripheral neuropathy (10%). Bowel perforation in 1 patient (3%) and 1 death due to a cerebral hemorrhage (3%) were noted. Response rate (RR) was 38% (1 complete and 14 partial responses). Median PFS was 8.6 months (95% confidence interval [CI], 4.7-10.2 months). Median overall survival was 17.2 months (95% CI, 10.4-24.2 months). CONCLUSION: The first US experience of capecitabine to our knowledge (3000 mg/m(2) on days 1-7) in combination with oxaliplatin/bevacizumab in mCRC does not appear to have advantages compared with current standard first-line mCRC treatment regimens.

A phase I/II study of trimetrexate and capecitabine in patients with advanced refractory colorectal cancer.

OBJECTIVE: We tested the hypothesis that the combination of trimetrexate (TMTX) and capecitabine (CAP) would be active in patients with previously treated metastatic colorectal cancer (CRC). Because the optimum dose of this combination was unknown, we used a phase I/II design. METHODS: In the phase I cohort, patients received 110 mg/m2 TMTX intravenously weekly x6 and CAP starting at 750 mg/m2 orally twice daily from days 2 to 15 and 23 to 36 (one cycle). Cycles were repeated every 8 weeks. The phase II doses were 110 mg/m2 TMTX and 1000 mg/m2 CAP orally twice daily. RESULTS: Thirty-two patients were entered. All patients had prior 5-fluorouracil therapy and 94% had prior exposure to irinotecan. Grade 3/4 toxicities included abdominal pain in 4 patients (12.5%) and vomiting in 3 patients (9.4%). Twenty-seven patients were evaluable for response: one patient each had a complete response and a partial response for an overall response rate of 7.4%. The median time to progression was 3.3 months (95% confidence interval [CI], 1.6-3.7 months) and the median overall survival was 5.9 months (95% CI, 5.2-10.2 months). CONCLUSIONS: The combination of TMTX and CAP is well tolerated. However, recent studies have shown more active regimens in the second- and third-line metastatic setting.