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Phase 1 trial of everolimus plus sunitinib in patients with metastatic renal cell carcinoma
Author(s) -
Molina Ana M.,
Feldman Darren R.,
Voss Martin H.,
Ginsberg Michelle S.,
Baum Michael S.,
Brocks Dion R.,
Fischer Patricia M.,
Trinos Michael J.,
Patil Sujata,
Motzer Robert J.
Publication year - 2011
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.26429
Subject(s) - sunitinib , everolimus , medicine , renal cell carcinoma , tyrosine kinase inhibitor , urology , oncology , pharmacology , gastroenterology , cancer
BACKGROUND: Simultaneous inhibition of the vascular epithelial growth factor (VEGF) and the mammalian target of rapamycin (mTOR) pathway may improve treatment response in advanced renal cell carcinoma (RCC). Everolimus, an oral mTOR inhibitor, and sunitinib, an oral tyrosine kinase inhibitor targeting VEGF, are standard agents in the management of metastatic RCC. METHODS: Sequential cohorts of 3 to 6 patients with advanced RCC received dose‐escalated combinations of sunitinib (37.5 or 50 mg daily, 4 weeks on/2 weeks off) with everolimus (2.5‐5 mg daily or 20‐30 mg weekly). Dose‐limiting toxicities (DLTs) were assessed in the first 6‐week cycle to determine maximum tolerated dose (MTD). Pharmacokinetic profiles were obtained. RESULTS: Twenty patients (13 clear cell and 7 nonclear cell RCC) were enrolled in 5 cohorts. Daily everolimus was not tolerated when combined with sunitinib; the first 2 patients on the second cohort suffered DLTs. With weekly everolimus, the MTD was 30 mg everolimus on days 7, 14, 21, and 28, plus 37.5 mg sunitinib on days 1 to 28 of a 42‐day cycle; however, chronic treatment was associated with grade 3 and 4 toxicities. A schedule of 20 mg everolimus weekly/37.5 mg sunitinib was tolerated as chronic therapy. Five patients (25%) had confirmed partial responses, and 3 had nonclear cell RCC. No unexpected accumulation of everolimus, sunitinib, or N‐desethyl sunitinib was observed. CONCLUSIONS: The combination of everolimus and sunitinib is associated with significant acute and chronic toxicities and is only tolerated at attenuated doses. Responses were observed in nonclear cell and clear cell RCC. Cancer 2012. © 2011 American Cancer Society.