BACKGROUND: Tivozanib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, -2 and -3, with a long half-life.
Tivozanib has demonstrated clinical activity and acceptable tolerability in renal cell carcinoma (RCC). This phase Ib study determined the recommended phase II dose (RP2D) and evaluated the safety and clinical activity of tivozanib plus temsirolimus, a mammalian target of rapamycin inhibitor.
PATIENTS AND METHODS: Patients with advanced RCC were administered open-label tivozanib 0.5, 1.0 or 1.5mg/d orally (3weeks on/1week off) and temsirolimus 15 or 25mg/week intravenously in a 3+3 dose-escalation design and subsequent expansion cohort.
RESULTS: Of 27 patients treated, 20 patients had received ⩾1 prior VEGF-targeted therapy. No dose-limiting toxicities occurred; the RP2D was determined to be tivozanib 1.5mg/d plus temsirolimus 25mg/week. Combination of tivozanib plus temsirolimus demonstrated acceptable tolerability and suggested no synergistic toxicity. The most common grade ⩾3 adverse events were fatigue and thrombocytopenia (15% each). One patient each required dose reduction of tivozanib or temsirolimus due to an adverse event. Confirmed partial responses and stable disease were achieved at 23% and 68%, respectively. Pharmacokinetic analyses may suggest lack of an interaction between tivozanib and temsirolimus.
CONCLUSIONS: In this small phase Ib study, tivozanib and temsirolimus were safely combined at the fully recommended dose and schedule of both agents. The observed clinical activity and manageable toxicity profile of this combination warrant further exploration in patients with RCC.
Written by:
Fishman MN, Srinivas S, Hauke RJ, Amato RJ, Esteves B, Cotreau MM, Strahs AL, Slichenmyer WJ, Bhargava P, Kabbinavar FF. Are you the author?
Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
Reference: Eur J Cancer. 2013 Sep;49(13):2841-50.
doi: 10.1016/j.ejca.2013.04.019
PubMed Abstract
PMID: 23726267
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