Combination of the mTOR Inhibitor Ridaforolimus and the Anti-IGF1R Monoclonal Antibody Dalotuzumab: Preclinical Characterization and Phase I Clinical Trial
| Autor: | Di Cosimo S, Sathyanarayanan S, Bendell JC, Cervantes A, Stein MN, Braña I, Roda D, Haines BB, Zhang T, Winter CG, Jha S, Xu Y, Frazier J, Klinghoffer RA, Leighton-Swayze A, Song Y, Ebbinghaus S, Baselga J |
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| Rok vydání: | 2015 |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA instname |
| ISSN: | 1557-3265 |
| Popis: | Purpose: Mammalian target of rapamycin (mTOR) inhibition activates compensatory insulin-like growth factor receptor (IGFR) signaling. We evaluated the ridaforolimus (mTOR inhibitor) and dalotuzumab (anti-IGF1R antibody) combination. Experimental Design: In vitro and in vivo models, and a phase I study in which patients with advanced cancer received ridaforolimus (10-40 mg/day every day x 5/week) and dalotuzumab (10 mg/kg/week or 7.5 mg/kg/every other week) were explored. Results: Preclinical studies demonstrated enhanced pathway inhibition with ridaforolimus and dalotuzumab. With 87 patients treated in the phase I study, main dose-limiting toxicities (DLT) of the combination were primarily mTOR-related stomatitis and asthenia at doses of ridaforolimus lower than expected, suggesting blockade of compensatory pathways in normal tissues. Six confirmed partial responses were reported (3 patients with breast cancer); 10 of 23 patients with breast cancer and 6 of 11 patients with ER+/high-proliferative breast cancer showed antitumor activity. Conclusions: Our study provides proof-of-concept that inhibiting the IGF1R compensatory response to mTOR inhibition is feasible with promising clinical activity in heavily pretreated advanced cancer, particularly in ER+/high-proliferative breast cancer. (C) 2014 AACR. |
| Databáze: | OpenAIRE |
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