A population-based clinical trial of irinotecan and carboplatin
Lau D et al. – Study demonstrates that the population-based design of phase I trial allows optimization of dose intensity and derivation of a population-based maximum tolerated dose (pMTD). The pMTD has been applied in phase II trial of irinotecan and carboplatin in patients with small-cell lung cancer. Methods- Study describes a population-based design for phase I trials of combining anticancer drugs such as irinotecan and carboplatin
- Intrapatient dose escalation of irinotecan and carboplatin was performed to reach individual dose-limiting toxicity (DLT)
- 50 pts with solid tumors refractory to previous chemotherapy
- The individual toxicity-limiting dose levels were analyzed for normal distribution using the method of Ryan-Joiner
- This was subsequently used to determine a pMTD
- For comparison, a simulation study was performed using the method of modified Fibonacci
Results- Most common DLTs: neutropenia (58%), thrombocytopenia (16%), and diarrhea (8%)
- Fequency of individual toxicity-limiting dose levels of 50 pts approximated a normal distribution
- Dose levels associated with individual limiting toxicities ranged from level 1 to level 8
- pMTD was determined to be dose level 3 (150mg/m2 for irinotecan and AUC=5 for carboplatin)
- In contrast, the MTD was determined to be dose level 4 (200mg/m2 for irinotecan and AUC 5 for carboplatin) by modified-Fibonacci simulation
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