title: Phase I trial of cixutumumab combined with temsirolimus in patients with advanced cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), MD Anderson Cancer Center, University of Texas, Houston, Texas, USA. anaing@mdanderson.org
authors.forename: Aung
authors.initials: A
authors.lastname: Naing
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
authors.forename: Angelika
authors.initials: A
authors.lastname: Burger
authors.forename: Sachin
authors.initials: S
authors.lastname: Gupta
authors.forename: Xiudong
authors.initials: X
authors.lastname: Lei
authors.forename: Naifa
authors.initials: N
authors.lastname: Busaidy
authors.forename: David
authors.initials: D
authors.lastname: Hong
authors.forename: Helen X
authors.initials: HX
authors.lastname: Chen
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Doyle
authors.forename: Lance K
authors.initials: LK
authors.lastname: Heilbrun
authors.forename: Eric
authors.initials: E
authors.lastname: Rohren
authors.forename: Chaan
authors.initials: C
authors.lastname: Ng
authors.forename: Chandtip
authors.initials: C
authors.lastname: Chandhasin
authors.forename: Patricia
authors.initials: P
authors.lastname: LoRusso
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D064847:Multimodal Imaging; D009367:Neoplasm Staging; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049268:Positron-Emission Tomography; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D047428:Protein Kinase Inhibitors; C401859:temsirolimus; D007334:Insulin-Like Growth Factor I; D020123:Sirolimus