Faculty Collaboration Database

Phase I trial of cixutumumab combined with temsirolimus in patients with advanced cancer. Clin Cancer Res 2011 Sep 15;17(18):6052-60

Date

07/14/2011

Pubmed ID

21750201

Pubmed Central ID

PMC3176947

DOI

10.1158/1078-0432.CCR-10-2979

Scopus ID

2-s2.0-80052831572 (requires institutional sign-in at Scopus site)   105 Citations

Abstract

PURPOSE: Mammalian target of rapamycin (mTOR) inhibitors mediate AKT activation through a type 1 insulin-like growth factor receptor (IGF-1R)-dependent mechanism. Combining the mTOR inhibitor temsirolimus with cixutumumab, a fully human immunoglobulin G1 monoclonal antibody directed against IGF-1R, was expected to enhance mTOR-targeted anticancer activity by modulating resistance to mTOR inhibition. The objectives of this phase I study were to evaluate the tolerability and activity of temsirolimus and cixutumumab.

EXPERIMENTAL DESIGN: Patients in sequential cohorts ("3 + 3" design) received escalating doses of temsirolimus with cixutumumab weekly for 28 days. At the maximum tolerated dose (MTD), 21 patients were randomized into three separate drug sequence treatment groups for serial blood draws and 2[18F]fluoro-2-deoxy-d-glucose positron emission tomography combined with X-ray computed tomography (FDG-PET/CT) scans for pharmacodynamic analyses (PD).

RESULTS: Forty-two patients with advanced cancer (19 male/23 female, median age = 53, median number of prior therapies = 4) were enrolled. MTD was reached at cixutumumab, 6 mg/kg IV and temsirolimus, 25 mg IV. Dose-limiting toxicities included grade 3 mucositis, febrile neutropenia, and grade 4 thrombocytopenia. The most frequent toxicities were hypercholesterolemia, hypertriglyceridemia, hyperglycemia, thrombocytopenia, and mucositis. Tumor reduction was observed in 2 of 3 patients with Ewing's sarcoma and in 4 of 10 patients with adrenocortical carcinoma. PD data suggest that cixutumumab alone or combined with temsirolimus increased plasma IGF-1 and IGF binding protein 3. FDG-PET/CT showed the odds of achieving stable disease decreased by 58% (P = 0.1213) with a one-unit increase in absolute change of standard uptake value from baseline to day 3.

CONCLUSIONS: Temsirolimus combined with cixutumumab was well tolerated. We are currently enrolling expansion cohorts at the MTD for Ewing's sarcoma and adrenocortical carcinoma.

Author List

Naing A, Kurzrock R, Burger A, Gupta S, Lei X, Busaidy N, Hong D, Chen HX, Doyle LA, Heilbrun LK, Rohren E, Ng C, Chandhasin C, LoRusso P

Author

Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Antineoplastic Combined Chemotherapy Protocols
Female
Humans
Insulin-Like Growth Factor Binding Protein 3
Insulin-Like Growth Factor I
Male
Middle Aged
Multimodal Imaging
Neoplasm Staging
Neoplasms
Positron-Emission Tomography
Protein Kinase Inhibitors
Sirolimus
Tomography, X-Ray Computed
Treatment Outcome
Young Adult