Abstract
3543 Background: SU is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET and FLT3, approved multinationally for the treatment of advanced RCC and imatinib-resistant or -intolerant GIST. In mouse xenograft models of breast cancer, SU enhanced the antitumor activity of D. This study was designed to assess the safety/maximum tolerated doses (MTDs), PK profile and preliminary efficacy of SU+D in pts with advanced STs. Methods: This is a phase I, dose-finding study in pts with advanced STs. The primary objective is to determine the MTD and safety of SU and D administered in combination. Successive cohorts of pts with advanced STs were to receive oral SU at 25, 37.5 or 50 mg daily for 4 wks of a 6-wk cycle (4/2 schedule) or for 2 wks of a 3-wk cycle (2/1 schedule) in combination with IV D at 60 or 75 mg/m2 every 21 days (q21d). The MTD was defined as the highest dose at which 0 of 3 or 1 of 6 pts encountered dose-limiting toxicities (DLTs) during cycle 1. Antitumor activity was assessed by CT or MRI scan. Results: 37 pts (most common primary tumor types: mRCC [n=10], NSCLC [n=13]) have been enrolled as of Nov. 2006: 10 pts on the 4/2 schedule and 27 pts on the 2/1 schedule (see table ). The most commonly observed DLT was neutropenia (with or without fever; maximum grade 4), which occurred in 5 pts and was manageable/reversible. There was 1 grade 5 event on the 2/1 schedule (C1D3), of pulseless electrical activity and pulmonary hemorrhage. The MTDs on the 4/2 schedule were SU 25 mg and D 60 mg/m2. The MTDs on the 2/1 schedule were SU 37.5 mg and D 75 mg/m2; PK analysis at this dose level is ongoing. Stable disease has been observed in 5 of 9 evaluable pts (56%) on the 4/2 schedule and 20 of 25 evaluable pts (80%) on the 2/1 schedule at the MTD. Conclusions: The combination of oral SU 37.5 mg/day on the 2/1 schedule with D 75 mg/m2 IV q21d has a manageable safety profile in pts with advanced STs. PK and preliminary efficacy analyses are ongoing to support these dosing combinations for further study. [Table: see text] No significant financial relationships to disclose.
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