423PD - Phase I, open-label, dose-escalation study of SNX-5422 plus everolimus in neuroendocrine tumors (NETs)

Date 10 October 2016
Event ESMO 2016 Congress
Session Endocrine and neuroendocrine tumours
Topics Cytotoxic agents
Clinical research
Neuroendocrine Cancers
Basic Scientific Principles
Therapy
Biological therapy
Presenter Martin Gutierrez
Citation Annals of Oncology (2016) 27 (6): 136-148. 10.1093/annonc/mdw369
Authors M.E. Gutierrez1, G. Giaccone2, S.V. Liu2, A. Rajan3, U. Guha3, T.R. Halfdanarson4, K.K. Curtis5, P.L. Kunz6, N. Gabrail7, J.M. Hinson8, E.O. Orlemans9
  • 1Hematology & Oncology, The John Theurer Cancer Center, 07601 - Hackensack/US
  • 2Hematology & Oncology, Lombardi Cancer Center Georgetown University, Washington/US
  • 3Thoracic And Gastrointestinal Oncology, Center for Cancer Research-National Cancer Institute, Bethesda/US
  • 4Medicine, Mayo Clinic, Rochester/US
  • 5Internal Medicine, Mayo Clinic, Scottsdale/US
  • 6Medicine-oncology, Stanford University School of Medicine, Palo Alto/US
  • 7Hematology, Gabrail Cancer Center, Canton/US
  • 8Clinical Research, Unicorn Pharma Consulting, Nashville/US
  • 9Clinical Research, Esanex, Inc., Indianapolis/US

Abstract

Background

SNX-5422 is an orally bioavailable pro-drug of SNX-2112, a highly potent and selective heat shock protein 90 (Hsp90) inhibitor. In preclinical studies, the effects of SNX-2112 and EVR appear at least additive. Previously, at doses of 42-100 mg/m2 of SNX-5422 taken every other day (qod), 2 of 3 patients (pts) with refractory NETs achieved stable disease for >8 cycles. EVR, a mammalian target of rapamycin (mTOR) inhibitor, now has FDA approval for pancreatic NETs and nonfunctional gastrointestinal and pulmonary NETs.

Methods

Eligible pts had unresectable gastro-entero-pancreatic or pulmonary NETs and

Results

We enrolled 17 pts (10 male, 7 female; median age 59 years) with NETs. The MTD of SNX-5422 was determined to be 75 mg/m2 in combination with EVR. Dose limiting toxicity was 1 case of G3 diarrhea. Other adverse events in ≥2 pts possibly related to either or both agents included anemia, anorexia, blurred vision (3 pts, all mild, all continued SNX-5422), diarrhea, fatigue, hyponatremia, mucositis, nausea, increased creatinine (EVR), dehydration (EVR), maculopapular rash (EVR), thrombocytopenia (EVR), and weight loss (EVR). All events were G1/G2, except for G3 diarrhea (1 SNX, 1 EVR, 1 both), increased creatinine (1, EVR), hyponatremia (2, EVR). There was also 1 pt who developed possibly related G4 hyponatremia with combination therapy. Six pts with NETs are continuing therapy at this time. Of 14 NET pts evaluable for efficacy, 2 had partial responses (14%; both ongoing, 1 >25 cycles), 8 stable disease (57%), and 4 (29%) progressive disease as best response. Of 8 pts with stable disease, 2 ongoing (1 >23 cycles), 3 study withdrawal (1 personal reasons [minor response], 2 for tolerability) and 3 progressed.

Conclusions

The addition of SNX-5422 75 mg/m2 to EVR in pts with advanced NETs warrants further study.

Clinical trial identification

ClinicalTrials.gov identifier: NCT02063958

Legal entity responsible for the study

Esanex, Inc.

Funding

Esanex, Inc.

Disclosure

S.V. Liu: Advisory boards for Genentech/Roche, Boehringer Ingelheim, Ariad, Caris Life Sciences and Biodesix.

P.L. Kunz: Research funding to institution: Advanced Accelerator Applications, Esanex, Genentech, Lexicon, Merck, Oxigene. Advisor/Consultant: Ipsen, Novartis, Lexicon.

J.M. Hinson: Paid consultant to Esanex, Inc.

E.O. Orlemans: Employee and stockholder Esanex, Inx.

All other authors have declared no conflicts of interest.