Premium
Combination testing (Stage 2) of the Anti‐IGF‐1 receptor antibody IMC‐A12 with rapamycin by the pediatric preclinical testing program
Author(s) -
Kolb E. Anders,
Gorlick Richard,
Maris John M.,
Keir Stephen T.,
Morton Christopher L.,
Wu Jianrong,
Wozniak Amy W.,
Smith Malcolm A.,
Houghton Peter J.
Publication year - 2012
Publication title -
pediatric blood and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.116
H-Index - 105
eISSN - 1545-5017
pISSN - 1545-5009
DOI - 10.1002/pbc.23157
Subject(s) - medicine , sarcoma , antibody , combination therapy , cancer , pharmacology , oncology , cancer research , immunology , pathology
Background IMC‐A12, a fully human antibody that blocks ligand binding to the Type 1 insulin‐like growth factor receptor, and rapamycin, a selective inhibitor of mTORC1 signaling, have both demonstrated significant antitumor activity against PPTP solid tumor models. Here we have evaluated antitumor activity of each agent individually and in combination against nine tumor models. Procedures IMC‐A12 was administered twice weekly and rapamycin was administered daily for 5 days per week for a planned 4 weeks. The impact of combining IMC‐A12 with rapamycin was evaluated using two measures: (1) the “therapeutic enhancement” measure, and (2) a linear regression model for time‐to‐event to formally evaluate for sub‐ and supra‐additivity for the combination compared to the agents used alone. Results Two osteosarcomas, and one Ewing sarcoma of the nine xenografts tested showed therapeutic enhancement. The combination effect was most dramatic for EW‐5 for which PD2 responses of short duration were observed for both single agents and a prolonged PR response was observed for the combination. Both OS‐2 and OS‐9 showed significantly longer times to progression with the combination compared to either of the single agents, although objective response criteria were not met. Conclusions The combination of IMC‐A12 with rapamycin was well tolerated, and induced tumor responses that were superior to either single agent alone in several models. These studies confirm reports using other antibodies that inhibit IGF‐1 receptor‐mediated signaling that indicate enhanced therapeutic effect for this combination, and extend the range of histotypes to encompass additional tumors expressing IGF‐1R where this approach may be effective. Pediatr Blood Cancer 2012; 58: 729–735. © 2011 Wiley Periodicals, Inc.