title: Phase I study of the anti-IGF1R antibody cixutumumab with everolimus and octreotide in advanced well-differentiated neuroendocrine tumors.
abstract: Preclinical data suggest multiple roles for the IGF1 receptor (IGF1R) in neuroendocrine tumors (NETs), including mediating resistance to mammalian target of rapamycin (mTOR) inhibitors. Everolimus, an oral mTOR inhibitor, and octreotide long-acting repeatable (LAR) are approved for subgroups of well-differentiated NET. The primary objective of the present study was to establish the safety and recommended phase II dose (RP2D) of cixutumumab, a monoclonal antibody (MAB) against IGF1R, with everolimus and octreotide LAR. Patients with well-differentiated NET were treated with 10  mg everolimus p.o. daily, 20  mg octreotide LAR i.m. every 21 days, and escalating doses of cixutumumab. An expansion cohort was enrolled at RP2D. Correlative studies included the evaluation of mTOR pathway inhibition in paired tumor biopsies and the effects of this combination on metabolism via indirect calorimetry. Nineteen patients with progressive disease were enrolled, including nine to the expansion portion. Two patients had dose-limiting toxicities of grade 3 mucositis at 15  mg/kg cixutumumab. Long-term tolerance at RP2D was problematic, and the most common ≥grade 3 adverse event was fatigue. One patient with metastatic insulinoma had a confirmed partial response, whereas 17 had stable disease. The median progression-free survival was 43.6 weeks, and the median overall survival was 25.5 months. The RP2D of this combination per the predefined study protocol of 10  mg/kg cixutumumab i.v., 20  mg octreotide LAR i.m. every 21 days plus 10  mg everolimus p.o. daily is associated with non-dose-limiting toxicities that limit long-term tolerance. Although a signal of activity was noted in the present study, this will need to be reconciled with limited tolerance of the combination and data from larger studies of anti-IGF1R MABs in NET that have been disappointing.
authors.affiliation: Department of Gastrointestinal Medical OncologyThe University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Street, Unit 426, Houston, Texas 77030, USANational Cancer InstituteRockville, Maryland, USA.
authors.forename: Arvind
authors.initials: A
authors.lastname: Dasari
authors.affiliation: Department of Gastrointestinal Medical OncologyThe University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Street, Unit 426, Houston, Texas 77030, USANational Cancer InstituteRockville, Maryland, USA.
authors.forename: Alexandria
authors.initials: A
authors.lastname: Phan
authors.affiliation: Department of Gastrointestinal Medical OncologyThe University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Street, Unit 426, Houston, Texas 77030, USANational Cancer InstituteRockville, Maryland, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Department of Gastrointestinal Medical OncologyThe University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Street, Unit 426, Houston, Texas 77030, USANational Cancer InstituteRockville, Maryland, USA.
authors.forename: Asif
authors.initials: A
authors.lastname: Rashid
authors.affiliation: Department of Gastrointestinal Medical OncologyThe University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Street, Unit 426, Houston, Texas 77030, USANational Cancer InstituteRockville, Maryland, USA.
authors.forename: Sai-Ching Jim
authors.initials: SC
authors.lastname: Yeung
authors.affiliation: Department of Gastrointestinal Medical OncologyThe University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Street, Unit 426, Houston, Texas 77030, USANational Cancer InstituteRockville, Maryland, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Hess
authors.affiliation: Department of Gastrointestinal Medical OncologyThe University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Street, Unit 426, Houston, Texas 77030, USANational Cancer InstituteRockville, Maryland, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Gastrointestinal Medical OncologyThe University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Street, Unit 426, Houston, Texas 77030, USANational Cancer InstituteRockville, Maryland, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Tarco
authors.affiliation: Department of Gastrointestinal Medical OncologyThe University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Street, Unit 426, Houston, Texas 77030, USANational Cancer InstituteRockville, Maryland, USA.
authors.forename: Huiqin
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Gastrointestinal Medical OncologyThe University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Street, Unit 426, Houston, Texas 77030, USANational Cancer InstituteRockville, Maryland, USA.
authors.forename: Caimiao
authors.initials: C
authors.lastname: Wei
authors.affiliation: Department of Gastrointestinal Medical OncologyThe University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Street, Unit 426, Houston, Texas 77030, USANational Cancer InstituteRockville, Maryland, USA.
authors.forename: Kim
authors.initials: K
authors.lastname: Anh-Do
authors.affiliation: Department of Gastrointestinal Medical OncologyThe University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Street, Unit 426, Houston, Texas 77030, USANational Cancer InstituteRockville, Maryland, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Halperin
authors.affiliation: Department of Gastrointestinal Medical OncologyThe University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Street, Unit 426, Houston, Texas 77030, USANational Cancer InstituteRockville, Maryland, USA.
authors.forename: Funda
authors.initials: F
authors.lastname: Meric-Bernstam
authors.affiliation: Department of Gastrointestinal Medical OncologyThe University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Street, Unit 426, Houston, Texas 77030, USANational Cancer InstituteRockville, Maryland, USA jyao@mdanderson.org.
authors.forename: James
authors.initials: J
authors.lastname: Yao
mesh_terms: 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*; D004305:Dose-Response Relationship, Drug; D000068338:Everolimus / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000188:drug therapy* / Q000473:pathology; D015282:Octreotide / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C557414:cixutumumab; D000068338:Everolimus; D015282:Octreotide
keywords: IGF; carcinoids; intracellular signaling; neuroendocrine tumors