Combination of the mTOR inhibitor ridaforolimus and the anti-IGF1R monoclonal antibody dalotuzumab: Preclinical characterization and phase I clinical trial Journal Article
| Authors: | Di Cosimo, S.; Sathyanarayanan, S.; Bendell, J. C.; Cervantes, A.; Stein, M. N.; Braña, I.; Roda, D.; Haines, B. B.; Zhang, T.; Winter, C. G.; Jha, S.; Xu, Y.; Frazier, J.; Klinghoffer, R. A.; Leighton-Swayze, A.; Song, Y.; Ebbinghaus, S.; Baselga, J. |
| Article Title: | Combination of the mTOR inhibitor ridaforolimus and the anti-IGF1R monoclonal antibody dalotuzumab: Preclinical characterization and phase I clinical trial |
| Abstract: | 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). |
| Keywords: | immunohistochemistry; osteosarcoma; protein kinase b; controlled study; treatment response; antibiotic agent; human cell; major clinical study; drug tolerability; fatigue; histopathology; neutropenia; advanced cancer; cancer combination chemotherapy; diarrhea; drug efficacy; drug potentiation; drug safety; drug withdrawal; monotherapy; nonhuman; recommended drug dose; solid tumor; treatment duration; endometrium cancer; colorectal cancer; melanoma; progression free survival; infection; ovary cancer; pharmacodynamics; breast cancer; anemia; mucosa inflammation; nausea; stomatitis; thrombocytopenia; vomiting; animal experiment; animal model; body weight; in vivo study; antineoplastic activity; enzyme activation; in vitro study; drug screening; asthenia; drug dose escalation; ewing sarcoma; fever; hyperglycemia; rash; sarcoma; skin; cancer inhibition; hospitalization; lung adenocarcinoma; health status; dosage schedule comparison; colon cancer; mammalian target of rapamycin; fluorodeoxyglucose f 18; computer assisted emission tomography; lentivirus vector; cell cycle arrest; insulin; antidiabetic agent; phase 1 clinical trial; salivary gland cancer; hypercholesterolemia; leiomyosarcoma; synovial sarcoma; rectum cancer; drug sensitivity; chondrosarcoma; epistaxis; electrocardiography; short hairpin rna; cell cycle g1 phase; hypertriglyceridemia; hematologic disease; liposarcoma; electrolyte disturbance; vital sign; non small cell lung cancer; decreased appetite; dalotuzumab; ridaforolimus; desmoplastic round cell tumor; human; female; article; cancer cell line |
| Journal Title: | Clinical Cancer Research |
| Volume: | 21 |
| Issue: | 1 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2015-01-01 |
| Start Page: | 49 |
| End Page: | 59 |
| Language: | English |
| DOI: | 10.1158/1078-0432.ccr-14-0940 |
| PROVIDER: | scopus |
| PUBMED: | 25320355 |
| PMCID: | PMC5705197 |
| DOI/URL: | |
| Notes: | Export Date: 2 February 2015 -- Source: Scopus |
