Phase II randomised discontinuation trial of brivanib in patients with advanced solid tumours.

BACKGROUND: Brivanib is a selective inhibitor of vascular endothelial growth factor and fibroblast growth factor (FGF) signalling. We performed a phase II randomised discontinuation trial of brivanib in 7 tumour types (soft-tissue sarcomas [STS], ovarian cancer, breast cancer, pancreatic cancer, non-small-cell lung cancer [NSCLC], gastric/esophageal cancer and transitional cell carcinoma [TCC]). PATIENTS AND METHODS: During a 12-week open-label lead-in period, patients received brivanib 800 mg daily and were evaluated for FGF2 status by immunohistochemistry. Patients with stable disease at week 12 were randomised to brivanib or placebo. A study steering committee evaluated week 12 response to determine if enrolment in a tumour type would continue. The primary objective was progression-free survival (PFS) for brivanib versus placebo in patients with FGF2-positive tumours. RESULTS: A total of 595 patients were treated, and stable disease was observed at the week 12 randomisation point in all tumour types. Closure decisions were made for breast cancer, pancreatic cancer, NSCLC, gastric cancer and TCC. Criteria for expansion were met for STS and ovarian cancer. In 53 randomised patients with STS and FGF2-positive tumours, the median PFS was 2.8 months for brivanib and 1.4 months for placebo (hazard ratio [HR]: 0.58, p = 0.08). For all randomised patients with sarcomas, the median PFS was 2.8 months (95% confidence interval [CI]: 1.4-4.0) for those treated with brivanib compared with 1.4 months (95% CI: 1.3-1.6) for placebo (HR = 0.64, 95% CI: 0.38-1.07; p = 0.09). In the 36 randomised patients with ovarian cancer and FGF2-positive tumours, the median PFS was 4.0 (95% CI: 2.6-4.2) months for brivanib and 2.0 months (95% CI: 1.2-2.7) for placebo (HR: 0.56, 95% CI: 0.26-1.22). For all randomised patients with ovarian cancer, the median PFS in those randomised to brivanib was 4.0 months (95% CI: 2.6-4.2) and was 2.0 months (95% CI: 1.2-2.7) in those randomised to placebo (HR = 0.54, 95% CI: 0.25-1.17; p = 0.11). CONCLUSION: Brivanib demonstrated activity in STS and ovarian cancer with an acceptable safety profile. FGF2 expression, as defined in the protocol, is not a predictive biomarker of the efficacy of brivanib.

Phase I and pharmacokinetic study of oral irinotecan given once daily for 5 days every 3 weeks in combination with capecitabine in patients with solid tumors.

PURPOSE: To assess the maximum tolerated dose, dose-limiting toxicity, pharmacokinetics, and preliminary antitumor activity of oral irinotecan given in combination with capecitabine to patients with advanced, refractory solid tumors. PATIENTS AND METHODS: Patients were treated from day 1 with irinotecan capsules given once daily for 5 consecutive days (50 to 60 mg/m2/d) concomitantly with capecitabine given twice daily for 14 consecutive days (800 to 1,000 mg/m2); cycles were repeated every 21 days. RESULTS: Twenty-eight patients were enrolled and received 155 cycles of therapy (median, five cycles; range, one to 18 cycles). With irinotecan 60 mg/m2/d and capecitabine 2 x 800 mg/m2/d, grade 3 delayed diarrhea in combination with grade 2 nausea (despite maximal antiemetic support) and grade 3 anorexia and colitis, were the first-cycle dose-limiting toxicities in two of six patients, respectively. At the recommended doses (irinotecan 50 mg/m2/d; capecitabine 2 x 1,000 mg/m2/d), side effects were mostly mild to moderate and uniformly reversible. Pharmacokinetic analysis showed that there was no interaction between oral irinotecan and capecitabine, and that body-surface area was not significantly contributing to the observed pharmacokinetic variability. Confirmed partial responses were observed in two patients with gallbladder carcinoma and in one patient with melanoma. Disease stabilization was noted in 16 patients. CONCLUSION: The recommended phase II doses for oral irinotecan and capecitabine are 50 mg/m2/d for 5 consecutive days, and 2 x 1,000 mg/m2/d for 14 consecutive days repeated every 3 weeks, respectively.