Combination mTOR and IGF-1R inhibition: phase I trial of everolimus and figitumumab in patients with advanced sarcomas and other solid tumors.

Abstract

PURPOSE:

Preclinical models demonstrate synergistic antitumor activity with combination blockade of mTOR and IGF-1R signaling. We aimed to determine the safety, tolerability, and recommended phase II dose (RP2D) of the combination of figitumumab, a fully human IgG(2) anti-insulin-like growth factor-1 receptor (IGF-1R) monoclonal antibody (Pfizer) and the mTOR inhibitor, everolimus (Novartis). Pharmacokinetics and preliminary antitumor effects of the combination were evaluated.

EXPERIMENTAL DESIGN:

Phase I trial in patients with advanced sarcomas and other solid tumors. Initial cohort combined full phase 2 dose figitumumab (20 mg/kg IV every 21 days) with full dose everolimus (10 mg orally once daily). Intercohort dose de-escalation was planned for unacceptable toxicities. Dose modifications were allowed beyond cycle 1.

RESULTS:

No DLTs were observed in the initial cohort during cycle one, therefore full dose figitumumab and everolimus was declared the RP2D. In total, 21 patients were enrolled on study. Most toxicities were grade 1 or 2, and were similar to reported toxicities of the single agents. Mucositis was the most frequently observed grade 3 toxicity. Median time on study was 104 days (range 17-300). Of 18 patients evaluable for response, best response was partial response in 1 patient with malignant solitary fibrous tumor and, stable disease in 15 patients. There were no apparent pharmacokinetic interactions between everolimus and figitumumab.

CONCLUSIONS:

Combination figitumumab plus everolimus at full doses appears safe and well tolerated with no unexpected toxicities. Dose reductions in everolimus may be required after prolonged drug administration. This regimen exhibits interesting antitumor activity warranting further investigation.

• Authors: Richard Quek, Qian Wang, Jeffrey A Morgan, Geoffrey I Shapiro, James E Butrynski, Nikhil Ramaiya, Tarsha Huftalen, Nicole Jederlinic, Judith Manola, Andrew J Wagner, George D Demetri, Suzanne George
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 4 Pg. 871-9 (Feb 15 2011) ISSN: 1557-3265 [Electronic] United States
• PMID: 21177764 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2010 AACR.

Chemical References

• Antibodies, Monoclonal
• Immunoglobulins, Intravenous
• Everolimus
• MTOR protein, human
• Receptor, IGF Type 1
• TOR Serine-Threonine Kinases
• figitumumab
• Sirolimus

Topics

• Adult
• Aged
• Antibodies, Monoclonal (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, pharmacokinetics, therapeutic use)
• Everolimus
• Female
• Humans
• Immunoglobulins, Intravenous
• Male
• Middle Aged
• Neoplasms (drug therapy, pathology)
• Receptor, IGF Type 1 (antagonists & inhibitors)
• Sarcoma (drug therapy, pathology)
• Sirolimus (administration & dosage, analogs & derivatives)
• TOR Serine-Threonine Kinases (antagonists & inhibitors)
• Treatment Outcome
• Tumor Burden (drug effects)
• Young Adult