gpNMB is an internalizable transmembrane glycoprotein expressed in multiple tumor types including melanoma. The ADC GV (CDX-011) delivers the potent cytotoxin MMAE to gpNMB+ cells. GV has shown promising activity in advanced melanoma and breast cancer (Ott JCO 2014; Yardley JCO 2015).
In this Phase 2 single-arm study (CDX011-05), efficacy and safety of GV (1.9 mg/kg q3w) is assessed in advanced melanoma patients (pts) with disease progression after ≤1 chemotherapy, ≥1 checkpoint inhibitor, and if BRAF mutation ≥1 BRAF or MEK + BRAF inhibitor. gpNMB expression is determined retrospectively by central IHC on archival tumor and/or pre-treatment tumor biopsy. Primary endpoint is objective response rate (ORR) (RECIST 1.1) with ≥6 responders out of 52 evaluable pts as threshold for determining statistical positive outcome. Additional endpoints include progression free survival and overall survival (PFS, OS) (95% CI), duration of response (DOR), safety, pharmacodynamics, pharmacokinetics, and correlation of outcome with gpNMB expression.
Enrollment (n = 62) completed in April 2016: median age = 67 years; 55% male; 21% BRAF mutation; 53% >2 lines prior therapy. Preliminary tumor response data (n = 57 evaluable; 5 pts pending 1st response assessment): 1 complete response (CR) and 7 partial response (PR [current confirmed ORR = 14%]); 1 single time-point PR; 26 stable disease (SD) (duration 6-51+ weeks, 11 ongoing). Thus far, 50/51 evaluable pts had gpNMB+ tumors, and 38/51 had 100% of epithelial cells gpNMB+. Toxicities include rash, alopecia, fatigue, neuropathy, nausea, neutropenia, decreased appetite and diarrhea; rash may correlate with efficacy.
GV has shown promising activity including induction of partial and complete responses in patients with heavily pre-treated melanoma. The safety profile is manageable and consistent with cytotoxic treatment. DOR, PFS, OS, and correlation of biomarkers with outcome will be analyzed on the mature dataset. An additional cohort will be treated with GV in combination with varlilumab, an activating anti-CD27 monoclonal antibody, in order to evaluate safety and efficacy of the combination.
Clinical trial identification
Legal entity responsible for the study
Celldex Therapeutics, Inc.
Celldex Therapeutics, Inc.
P.A. Ott: Grants and personal fees from Bristol-Myers Squibb, personal fees from Amgen and Alexion, and grants from Merck and AztraZeneca/MedImmune outside of the submitted work. D.B. Johnson: Advisory board for Genoptix and BMS. L.L. Hart: My only COI is research funding to my institution nothing to me personally. J.J. Luke: Ad board - amgen, array Research support to institution: –Novartis, MedImmune, Bristol-Myers Squibb, Pharmacyclics, Merck, BBI Therapeutics, Five Prime Therapeutics, Genentech, Corvus Pharmaceuticals, Delcath,Abbvie, Celldex, EMD Serono, Incyte. A. Salama: research funding (paid to institution) BMS, merck, genentech, immunocore, reata advisory board: BMS. Y. He, R.G. Bagley, J. Zhang: Full time employee of and stock ownership in Celldex Therapeutics, Inc. All other authors have declared no conflicts of interest.