Phase i study of the anti-IGF1R antibody cixutumumab with everolimus and octreotide in advanced well-differentiated neuroendocrine tumors

Arvind Dasari, Alexandria Phan, Sanjay Gupta, Asif Rashid, Sai Ching Jim Yeung, Kenneth Hess, Helen Chen, Emily Tarco, Huiqin Chen, Caimiao Wei, Kim Anh-Do, Daniel Halperin, Funda Meric-Bernstam, James Yao

Research output: Contribution to journalArticle

16 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)431-441
Number of pages11
JournalEndocrine-Related Cancer
Volume22
Issue number3
DOIs
StatePublished - Jun 1 2015

Keywords

  • Carcinoids
  • IGF
  • Intracellular signaling
  • Neuroendocrine tumors

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Oncology
  • Endocrinology
  • Cancer Research

Fingerprint Dive into the research topics of 'Phase i study of the anti-IGF1R antibody cixutumumab with everolimus and octreotide in advanced well-differentiated neuroendocrine tumors'. Together they form a unique fingerprint.

Cite this