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Tumor growth profiles were simulated for 2 years using the Wang and Claret models under a phase 3 clinical trial design. Profiles were censored when tumor size increased >20% from nadir similar to clinical practice. The percent of patients censored varied from 0% (perfect case) to 100% (real-life case). The model used to generate the data was then fit to the censored data using FOCE in NONMEM. The percent bias in the estimated model parameters determined with censored data was compared to the true values. A total of 100 simulation replicates was used. For the Wang model, under clinical conditions (100% censoring), the parameter related to tumor reduction SR was underpredicted by 30% and the parameter related to tumor growth PR was underpredicted by ∼45%. Most of the variance components in the model were within ±20% of the true values. However, biased parameter estimates in the Wang model did not translate to biased tumor size predictions as the mean percent prediction error between true and model predicted tumor size never exceeded 10%. For the Claret model, at 100% censoring, the tumor growth parameter KL was unaffected by censoring. Both tumor shrinkage parameters, KD and λ, were overestimated by ∼20% in both cases. Future research needs to be directed to develop less empirically based models and to use simulation as a way to improve clinical oncology trials designs.

2593 Background: P is a tyrosine kinase inhibitor of PDGFR, VEGFR and KIT. This study aimed to determine the recommended phase II dose (RP2D) of P combined with I. To assess the impact of scheduling on tolerability, two I schedules were explored. Methods: Pts with progressive ST, no standard therapy available, PS 0-1 and good organ function were eligible. Pts received daily P with 3-weekly I, 9 g/m2/cycle, either continuously (Iciv) or as 3 hrs boluses (Ibolus) for 3 days. P was escalated in serial cohorts of 3-9 pts per I-schedule. If in 3-6 pts dose-limiting toxicity (DLT) of 33.3% within 1st cycle was seen 3 more pts at that dose level (DL) were enrolled. RP2D was exceeded if in > 1/3 pts, > 2/6 pts or ≥ 3/9 pts DLT occurred. P was maximized at 1000 mg/day. At RP2D, an expansion cohort of 6-9 pts was studied to confirm safety. PK samples of P and I were collected in all pts. Sampling allowed intra-individual comparison of I-PK with or without P and vice versa. Results: 47 pts were studied. For Iciv (25 pts), RP2D was the maximum dose of P (1000 mg), higher than the single agent RP2D. At RP2D 2 DLTs in 15 pts occurred: 1 febrile neutropenia (FN); 1 encephalopathy. With Ibolus (22 pts), P 400 mg with or without GCSF was not tolerated (5 DLTs in 10 pts: 3*FN, 1 encephalopathy; 1 proteinuria). At RP2D (P 200 mg + Ibolus + GCSF) 3 DLTs in 12 pts (FN; encephalopathy, renal insufficiency) were observed. Toxicity occurring in >30% of pts in Iciv (all grades/grade 3-4,%) were neutropenia (92/92) anemia (92/8); thrombocytopenia (35/12), elevated ASAT, ALAT, alkaline phosphatase (73/4; 73/0; 62/2), nausea (58/0), vomiting (73/0), diarrhea (54/0) and hypertension (31/12). 4/25 pts in Iciv evaluable for response had PR (2 sarcoma, 2 ovary) and 10 prolonged (≥3 mths) SD. In Ibolus, 6/20 pts had PR (2 urothelial, 1 sarcoma, 1 ovary, 1 CUP, 1 mesothelioma) and 3/20 prolonged SD. Preliminary PK analysis showed no effect of P on I-exposure, neither of Ibolus or Iciv on P. Conclusions: P is tolerated at a higher dose combined with Iciv compared to Ibolus (1000 vs 200 mg). PK cannot explain this difference. This study underlines the impact of scheduling on the tolerability of VEGFR-TKI and cytotoxic drug combinations.