Phase I Trial Using a Time-to-Event Continual Reassessment Strategy for Dose Escalation of Cisplatin Combined With Gemcitabine and Radiation Therapy in Pancreatic Cancer

Abstract

Purpose The primary objective of this study was to determine the maximum-tolerated dose of cisplatin that could be added to full-dose gemcitabine and radiation therapy (RT) in patients with pancreatic cancer. Patients and Methods Nineteen patients were treated. Gemcitabine 1,000 mg/m2 was administered over 30 minutes on days 1, 8, and 15 of a 28-day cycle. Cisplatin followed gemcitabine on days 1 and 15. The initial dose level of cisplatin was 30 mg/m2, escalated to a targeted dose of 50 mg/m2 using Time-to-Event Continual Reassessment Method. RT was initiated on cycle 1, day 1, in 2.4 Gy fractions to a total dose of 36 Gy. A second cycle of chemotherapy was planned following a 1-week rest. Results Four of eight patients experienced acute dose limiting toxicity at the 50 mg/m2 cisplatin dose level. Patients treated at 30 and 40 mg/m2 cisplatin dose level tolerated therapy without dose-limiting toxicity. Median survival was 10.7 months (95% CI, 5.4 to 18.2) for all patients, and 12.9 months (95% CI, 7.4 to 21.2) for those without metastasis. Conclusion Cisplatin at doses up to 40 mg/m2 may be safely added to full-dose gemcitabine and conformal RT. The Time-to-Event Continual Reassessment Method trial design allowed rapid completion of the study and confidence in the conclusion about the maximum tolerated dose, but accrued more patients to a dose level above the maximum tolerated dose than the typical phase I design. Local and systemic disease control and survival in this study cohort supports further investigation of gemcitabine-based RT and combination chemotherapy in this disease.