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