Combination of the mTOR inhibitor ridaforolimus and the anti-IGF1R monoclonal antibody dalotuzumab: preclinical characterization and phase I clinical trial
| Autor: | Andrés Cervantes, Ann Leighton-Swayze, Richard A. Klinghoffer, José Baselga, Scot Ebbinghaus, Sriram Sathyanarayanan, Christopher Winter, Theresa Zhang, Irene Brana, Sharda Jha, Yang Song, Serena Di Cosimo, Johanna C. Bendell, Brian B. Haines, Desamparados Roda, Jason Frazier, Mark N. Stein, Youyuan Xu |
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| Rok vydání: | 2014 |
| Předmět: |
Adult
Cancer Research Phases of clinical research Breast Neoplasms Pharmacology Antibodies Monoclonal Humanized Article Receptor IGF Type 1 Ridaforolimus chemistry.chemical_compound Breast cancer In vivo Antineoplastic Combined Chemotherapy Protocols Medicine Animals Humans PI3K/AKT/mTOR pathway Insulin-like growth factor 1 receptor Aged Sirolimus Dalotuzumab business.industry TOR Serine-Threonine Kinases Antibodies Monoclonal Receptors Somatomedin Middle Aged medicine.disease Xenograft Model Antitumor Assays Oncology chemistry Monoclonal business Signal Transduction |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research. 21(1) |
| 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 × 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 (ClinicalTrials.gov identifier: NCT00730379). Clin Cancer Res; 21(1); 49–59. ©2014 AACR. |
| Databáze: | OpenAIRE |
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