title: The Prevalence and Impact of Hyperglycemia and Hyperlipidemia in Patients With Advanced Cancer Receiving Combination Treatment With the Mammalian Target of Rapamycin Inhibitor Temsirolimus and Insulin Growth Factor-Receptor Antibody Cixutumumab.
abstract: BACKGROUND
  Cixutumumab (a humanized monoclonal antibody against insulin-like growth factor-1 receptor [IGF-1R]) and the mammalian target of rapamycin (mTOR) inhibitor temsirolimus were combined in a phase I study of patients with advanced cancer. We investigated the prevalence of metabolic toxicities, their management, and impact on outcome.
  
  
  METHODS
  The temsirolimus dose was 25 mg or 37.5 mg i.v. weekly with escalating doses of cixutumumab (3, 5, or 6 mg/kg i.v. weekly). No patients with diabetes or hyperlipidemia at baseline were eligible until the expansion cohort. We assessed metabolic derangements in our patient cohort, their management, and their association with tumor shrinkage, time to progression (TTP) and overall survival (OS).
  
  
  RESULTS
  Of the 57 patients analyzed, hyperglycemia was seen in 36 (63%) (grade 1-2: 33 [58%]; grade 3-4: 3 [5%]). The median blood sugar level (fasting and nonfasting) across cohorts was 149 mg/dL (upper limit of normal: 110 mg/dL). No patient developed diabetic ketoacidosis or nonketotic hyperosmolar coma or pancreatitis during treatment. Median maximum triglyceride, cholesterol, and low-density lipoprotein levels achieved were 247 mg/dL (range: 65-702 mg/dL), 243 mg/dL (range: 103-424 mg/dL), and 153 mg/dL (range 50-375 mg/dL), respectively. Higher glucose levels were associated with more RECIST tumor shrinkage (r = -.30 [95% confidence interval: -.52, -.03; p = .03]). There was no association between metabolic toxicities of the mTOR and IGF-1R combination and TTP or OS.
  
  
  CONCLUSIONS
  The combination of temsirolimus and cixutumumab was safe and resulted in manageable metabolic toxicities. More tumor shrinkage was seen in patients who developed these adverse events. Although perhaps limited by the small number of patients, no significant association was discerned between hyperglycemia, hypertriglyceridemia, or hypercholesterolemia and TTP or OS.
  
  
  CONCLUSIONS
  Results of this study show that the combination of temsirolimus and cixutumumab is safe. The most common side effects, hyperglycemia and hyperlipidemia, are tolerable and manageable. This combination of therapies should not be withheld from diabetic patients and patients with high cholesterol levels. Collaboration between oncologist and endocrinologist allows for individualized treatment and better control of these adverse events, with few dose interruptions and reductions. Supportive care and close monitoring is needed. Those patients who develop hyperglycemia or hypercholesterolemia may benefit more from the drug.
authors.affiliation: Departments of Endocrine Neoplasia and Hormonal Disorders, Head and Neck Surgery, Biostatistics, and Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, USA; Cancer Therapy Evaluation Program, National Institutes of Health/National Cancer Institute, Rockville, Maryland, USA; Center for Personalized Cancer Therapy, University of California, San Diego, Moores Cancer Center, La Jolla, California, USA anaing@mdanderson.org nbusaidy@mdanderson.org.
authors.forename: Naifa L
authors.initials: NL
authors.lastname: Busaidy
authors.affiliation: Departments of Endocrine Neoplasia and Hormonal Disorders, Head and Neck Surgery, Biostatistics, and Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, USA; Cancer Therapy Evaluation Program, National Institutes of Health/National Cancer Institute, Rockville, Maryland, USA; Center for Personalized Cancer Therapy, University of California, San Diego, Moores Cancer Center, La Jolla, California, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: LoRusso
authors.affiliation: Departments of Endocrine Neoplasia and Hormonal Disorders, Head and Neck Surgery, Biostatistics, and Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, USA; Cancer Therapy Evaluation Program, National Institutes of Health/National Cancer Institute, Rockville, Maryland, USA; Center for Personalized Cancer Therapy, University of California, San Diego, Moores Cancer Center, La Jolla, California, USA.
authors.forename: Kristie
authors.initials: K
authors.lastname: Lawhorn
authors.affiliation: Departments of Endocrine Neoplasia and Hormonal Disorders, Head and Neck Surgery, Biostatistics, and Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, USA; Cancer Therapy Evaluation Program, National Institutes of Health/National Cancer Institute, Rockville, Maryland, USA; Center for Personalized Cancer Therapy, University of California, San Diego, Moores Cancer Center, La Jolla, California, USA.
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Hess
authors.affiliation: Departments of Endocrine Neoplasia and Hormonal Disorders, Head and Neck Surgery, Biostatistics, and Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, USA; Cancer Therapy Evaluation Program, National Institutes of Health/National Cancer Institute, Rockville, Maryland, USA; Center for Personalized Cancer Therapy, University of California, San Diego, Moores Cancer Center, La Jolla, California, USA.
authors.forename: Mohammed Amir
authors.initials: MA
authors.lastname: Habra
authors.affiliation: Departments of Endocrine Neoplasia and Hormonal Disorders, Head and Neck Surgery, Biostatistics, and Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, USA; Cancer Therapy Evaluation Program, National Institutes of Health/National Cancer Institute, Rockville, Maryland, USA; Center for Personalized Cancer Therapy, University of California, San Diego, Moores Cancer Center, La Jolla, California, USA.
authors.forename: Siqing
authors.initials: S
authors.lastname: Fu
authors.affiliation: Departments of Endocrine Neoplasia and Hormonal Disorders, Head and Neck Surgery, Biostatistics, and Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, USA; Cancer Therapy Evaluation Program, National Institutes of Health/National Cancer Institute, Rockville, Maryland, USA; Center for Personalized Cancer Therapy, University of California, San Diego, Moores Cancer Center, La Jolla, California, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Hong
authors.affiliation: Departments of Endocrine Neoplasia and Hormonal Disorders, Head and Neck Surgery, Biostatistics, and Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, USA; Cancer Therapy Evaluation Program, National Institutes of Health/National Cancer Institute, Rockville, Maryland, USA; Center for Personalized Cancer Therapy, University of California, San Diego, Moores Cancer Center, La Jolla, California, USA.
authors.forename: Helen X
authors.initials: HX
authors.lastname: Chen
authors.affiliation: Departments of Endocrine Neoplasia and Hormonal Disorders, Head and Neck Surgery, Biostatistics, and Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, USA; Cancer Therapy Evaluation Program, National Institutes of Health/National Cancer Institute, Rockville, Maryland, USA; Center for Personalized Cancer Therapy, University of California, San Diego, Moores Cancer Center, La Jolla, California, USA.
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Doyle
authors.affiliation: Departments of Endocrine Neoplasia and Hormonal Disorders, Head and Neck Surgery, Biostatistics, and Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, USA; Cancer Therapy Evaluation Program, National Institutes of Health/National Cancer Institute, Rockville, Maryland, USA; Center for Personalized Cancer Therapy, University of California, San Diego, Moores Cancer Center, La Jolla, California, USA.
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
authors.affiliation: Departments of Endocrine Neoplasia and Hormonal Disorders, Head and Neck Surgery, Biostatistics, and Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, USA; Cancer Therapy Evaluation Program, National Institutes of Health/National Cancer Institute, Rockville, Maryland, USA; Center for Personalized Cancer Therapy, University of California, San Diego, Moores Cancer Center, La Jolla, California, USA anaing@mdanderson.org nbusaidy@mdanderson.org.
authors.forename: Aung
authors.initials: A
authors.lastname: Naing
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000139:chemically induced / Q000453:epidemiology; D006943:Hyperglycemia / Q000139:chemically induced* / Q000188:drug therapy / Q000453:epidemiology; D006949:Hyperlipidemias / Q000139:chemically induced* / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017526:Receptor, IGF Type 1 / Q000276:immunology; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D016019:Survival Analysis; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C557414:cixutumumab; C401859:temsirolimus; C546842:MTOR protein, human; D017526:Receptor, IGF Type 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Cixutumumab; IGF-1R pathway; Phase I clinical trials; mTOR pathway