Abstract
e15034 Background: RAD001 (Afinitor, Novartis), an oral inhibitor of mammalian target of rapamycin (mTOR), and sunitinib (Sutent, Pfizer), an oral inhibitor of VEGF/PDGF receptor tyrosine kinase signaling, are both USFDA approved and provide clinical benefit in patients with advanced RCC. We sought to determine the safety and preliminary efficacy of combination therapy with these agents in patients with advanced RCC. Methods: We conducted a phase Ib dose escalation trial of sunitinib and RAD001 in patients with advanced metastatic RCC. Prior nephrectomy was required, and prior radiation or chemotherapy other than VEGF/mTOR-based therapies was permitted. The primary endpoint was to determine the MTD/recommended phase 2 dose. Secondary endpoints included safety/tolerability, pharmacokinetics, and preliminary efficacy (response rates, PFS, OS) of the combination. Results: A total of 4 out of a planned 30 subjects were enrolled on this study (M:F= 2:2; mean age 52 yrs, 50% with KPS <80). The first three patients were enrolled on a 4+2 dosing schedule of daily sunitinib 50 mg and weekly RAD001 30 mg. Mean time on drug was 99 days (all subjects), with 2 subjects completing only 1 cycle. No partial responses were seen. Toxicities included 2/4 patients with G3 mucositis, 4/4 G3-4 thrombocytopenia, 1/4 G3 anemia, 1/4 G3 fatigue, 1/4 G3 dehydration, 1/4 G4 hypoglycemia. After dose reduction to 20 mg RAD001, 37.5 mg sunitinib, the first patient experienced G3 diarrhea and thrombocytopenia and was removed due to disease progression. The second patient was also dose reduced and maintained to cycle 5 where he experienced G3 hypophosphatemia and neutropenia and was removed from study. Due to multiple grade 3-4 toxicities, the protocol was amended to 2+1 dosing of sunitinib 37.5 mg and daily RAD001 5mg. The first patient on this new dose/schedule died from multi-organ failure with septic shock after 1 cycle of treatment. Consequently, the study was closed. Conclusions: Combined use of RAD001 and sunitinib is not well tolerated when used in combination, even at doses below the individual MTDs of each agent. PK data will be presented. Further comparative studies of other well tolerated VEGF and mTOR inhibitor combinations are warranted. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis, Pfizer Novartis, Pfizer
Published Version
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