PMID- 25320355 OWN - NLM STAT- MEDLINE DCOM- 20150921 LR - 20220311 IS - 1557-3265 (Electronic) IS - 1078-0432 (Print) IS - 1078-0432 (Linking) VI - 21 IP - 1 DP - 2015 Jan 1 TI - Combination of the mTOR inhibitor ridaforolimus and the anti-IGF1R monoclonal antibody dalotuzumab: preclinical characterization and phase I clinical trial. PG - 49-59 LID - 10.1158/1078-0432.CCR-14-0940 [doi] AB - 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 (ClinicalTrials.gov identifier: NCT00730379). CI - (c)2014 American Association for Cancer Research. FAU - Di Cosimo, Serena AU - Di Cosimo S AD - Vall d'Hebron University Hospital, Barcelona, Spain. FAU - Sathyanarayanan, Sriram AU - Sathyanarayanan S AD - Merck & Co., Inc., Whitehouse Station, New Jersey. FAU - Bendell, Johanna C AU - Bendell JC AD - Sarah Cannon Research Institute, Nashville, Tennessee. FAU - Cervantes, Andres AU - Cervantes A AD - Institute of Health Research INCLIVA, University of Valencia, Valencia, Spain. FAU - Stein, Mark N AU - Stein MN AD - The Cancer Institute of New Jersey, New Brunswick, New Jersey. FAU - Brana, Irene AU - Brana I AD - Vall d'Hebron University Hospital, Barcelona, Spain. FAU - Roda, Desamparados AU - Roda D AD - Institute of Health Research INCLIVA, University of Valencia, Valencia, Spain. FAU - Haines, Brian B AU - Haines BB AD - Merck & Co., Inc., Whitehouse Station, New Jersey. FAU - Zhang, Theresa AU - Zhang T AD - Merck & Co., Inc., Whitehouse Station, New Jersey. FAU - Winter, Christopher G AU - Winter CG AD - Merck & Co., Inc., Whitehouse Station, New Jersey. FAU - Jha, Sharda AU - Jha S AD - Merck & Co., Inc., Whitehouse Station, New Jersey. FAU - Xu, Youyuan AU - Xu Y AD - Merck & Co., Inc., Whitehouse Station, New Jersey. FAU - Frazier, Jason AU - Frazier J AD - Merck & Co., Inc., Whitehouse Station, New Jersey. FAU - Klinghoffer, Richard A AU - Klinghoffer RA AD - Merck & Co., Inc., Whitehouse Station, New Jersey. FAU - Leighton-Swayze, Ann AU - Leighton-Swayze A AD - Merck & Co., Inc., Whitehouse Station, New Jersey. FAU - Song, Yang AU - Song Y AD - Merck & Co., Inc., Whitehouse Station, New Jersey. FAU - Ebbinghaus, Scot AU - Ebbinghaus S AD - Merck & Co., Inc., Whitehouse Station, New Jersey. FAU - Baselga, Jose AU - Baselga J AD - Massachusetts General Hospital Cancer Center, Boston, Massachusetts. baselgaj@mskcc.org. LA - eng SI - ClinicalTrials.gov/NCT00730379 GR - P30 CA008748/CA/NCI NIH HHS/United States PT - Clinical Trial PT - Journal Article PT - Multicenter Study PT - Research Support, Non-U.S. Gov't DEP - 20141015 PL - United States TA - Clin Cancer Res JT - Clinical cancer research : an official journal of the American Association for Cancer Research JID - 9502500 RN - 0 (Antibodies, Monoclonal) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (IGF1R protein, human) RN - 0 (Receptors, Somatomedin) RN - 48Z35KB15K (ridaforolimus) RN - 6YI1L648RH (dalotuzumab) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.10.1 (Receptor, IGF Type 1) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Adult MH - Aged MH - Animals MH - Antibodies, Monoclonal/*administration & dosage MH - Antibodies, Monoclonal, Humanized MH - Antineoplastic Combined Chemotherapy Protocols/*administration & dosage MH - Breast Neoplasms/*drug therapy/genetics/pathology MH - Humans MH - Middle Aged MH - Receptor, IGF Type 1 MH - Receptors, Somatomedin/antagonists & inhibitors/immunology/metabolism MH - Signal Transduction/drug effects MH - Sirolimus/administration & dosage/*analogs & derivatives MH - TOR Serine-Threonine Kinases/antagonists & inhibitors MH - Xenograft Model Antitumor Assays PMC - PMC5705197 MID - NIHMS920587 COIS- Disclosure of Potential Conflicts of Interest B.B. Haines, S. Jha, Y. Song, Y. Xu, and T. Zhang are employees of Merck & Co., Inc. S. Ebbinghaus, S. Sathyanarayanan, andA. Leighton-Swayze are employees of and have ownership interest in Merck & Co., Inc. J. Frazier was an employee of and has ownership interest in Merck and Co. R.A. Klinghoffer and C.G. Winter were employees of Merck & Co., Inc. S. Ebbinghaus, R.A. Klinghoffer, S. Sathyanarayanan, and C.G. Winter are listed on a patent application for ridaforolimus owned by Merck & Co., Inc. No other potential conflicts of interest were disclosed by the other authors. EDAT- 2014/10/17 06:00 MHDA- 2015/09/22 06:00 PMCR- 2017/11/28 CRDT- 2014/10/17 06:00 PHST- 2014/10/17 06:00 [entrez] PHST- 2014/10/17 06:00 [pubmed] PHST- 2015/09/22 06:00 [medline] PHST- 2017/11/28 00:00 [pmc-release] AID - 1078-0432.CCR-14-0940 [pii] AID - 10.1158/1078-0432.CCR-14-0940 [doi] PST - ppublish SO - Clin Cancer Res. 2015 Jan 1;21(1):49-59. doi: 10.1158/1078-0432.CCR-14-0940. Epub 2014 Oct 15.