Phase I, Open-Label Ascending Dose Trial of Anti-Ctla-4 Monoclonal Antibody AGEN1884 in Advanced Solid Malignancies, with Expansion to Patients Refractory to Recent Anti-Pd-1/pd-l1 Therapy

Background: AGEN1884 is a novel anti–cytotoxic T-lymphocyte-associated antigen (CTLA)-4 fully human immunoglobulin (IgG)-1 monoclonal antibody. Objective: Assess safety, maximum tolerated dose, and pharmacokinetics (PK)/pharmacodynamics of AGEN1884 in patients (pts) with advanced/refractory malignancies and in pts refractory to recent anti–programmed death 1 (PD-1)/PD-L1 therapy. Methods: Adult pts with relapsed/refractory lymphoma or solid tumors received AGEN1884 at 0.1, 0.3, 1, 3, or 6 mg/kg (3 + 3 design). 10 more pts each were enrolled in 1 and 3 mg/kg expansion cohorts. 10 pts with disease progression after prior treatment with approved or investigational PD-1/PD-L1 inhibitor as most recent therapy (2–5 weeks [wks] before first study drug) will be enrolled at 1 mg/kg. AGEN1884 was administered intravenously Q3 wks for 4 doses, then Q3, 6, or 12 wks at investigator’s discretion. Results: 33 pts enrolled as of 03Jan2018: 0.1 mg/kg (n = 5; 2 not evaluable [NE] for dose-limiting toxicity [DLT]); 0.3 mg/kg (n = 3); 1 mg/kg (n = 10); 3 mg/kg (n = 12; 2 NE for DLT); 6 mg/kg (n = 3). Median age: 61 y (range 26–88); baseline ECOG scores: 0 (n = 4), 1 (n = 25), unknown (n = 4); median 10 (range 3–26) prior therapies. No DLTs reported as of 31Jan2018. Immune-related adverse events (AEs) reported in 10 (30.3%) pts: 0.1 mg/kg (1, 20.0%), 0.3 mg/kg (1, 33.3%), 1 mg/kg (1, 10%), 3 mg/kg (6, 50%); included hypophysitis, colitis, diarrhea, rash, pruritus. Most were mild-moderate, consistent with other CTLA-4 inhibitors. 6 (18.2%) pts came off study due to disease progression or AEs, none treatment-related. Of 11 pts evaluable for response, 1 had complete response (angiosarcoma, 0.1 mg/kg). Stable disease (SD) in 3 pts: 1 with adenoid cystic carcinoma (0.3 mg/kg, 53 wks of SD) and 2 with breast cancer (3 mg/kg, SD at wks 6 and 12, respectively). Conclusions: AGEN1884 was well tolerated at 0.1, 0.3, 1, and 3-mg/kg dose levels. Enrollment is ongoing at 6 mg/kg. Updated safety, PK, and results for the anti–PD-1/PD-L1 refractory expansion cohort will be presented. A starting dose of 1 mg/kg is being evaluated in ongoing trials in combination with PD-1 blockade. Clinical trial identification: NCT02694822. Editorial acknowledgement: Editorial support was provided by The Medicine Group, LLC (New Hope, PA, USA) and funded by Agenus Inc. (Lexington, MA). Legal entity responsible for the study: The licensed antibody AGEN1884 was originally developed under a Collaborative Research and Development Agreement between Ludwig Cancer Research, 4-Antibody AG (now Agenus Switzerland Inc.) and Recepta Biopharma S.A. This antibody is partnered with Recepta Biopharma S.A. for certain South American rights. Funding: This analysis was funded by Agenus Inc. (Lexington, MA, USA). Disclosure: B.A. Wilky: Employment: Novartis, Janssen Oncology, Lilly; Travel, accommodations, expenses: Novartis, Lilly, Advenchen Laboratories; Research funding: Novartis, Merck Sharp & Dohmn, Daiichi Sankyo, ArQule, Agenus. R. Wesolowski: Consulting or advisory role: Novartis, Agenus, Pfizer; Research funding: Acerta Pharma. J.J. Hwang: Consulting or advisory role: Genentech/Roche, Amgen, Bayer, Taiho Pharmaceutical, Bristol-Myers Squibb, Boehringer Ingelheim, Ipsen; Speakers bureau: Genentech/Roche, Amgen, Celgene, Ipsen, Bristol-Myers Squibb. G. Yuan, M. Lim, J-M. Cuillerot, J.J. Raizer, E. Drouin, N. Wilson, A.M. Gonzalez, J.M. Goldberg, J.S. Buell, R.B. Stein, H. Youssoufian: Employee: Agenus Inc. or subsidiary there of (current or former employee), Lexington, MA. C.D. Dupont: Employee: Agenus Inc. or subsidiary there of (current or former employee), Lexington, MA; An immediate family member: Employee: Vertex; An immediate family member: Employee: Rochester Eye Associates; Travel, accommodations, expenses: Agenus; Research funding: Agenus; An immediate family member: Vertex, Pfizer, Sanofi. Stock and other ownership: Agenus; An immediate family member: Vertex. O. Shebanova: Employee: Agenus Inc. or subsidiary there of (current or former employee), Lexington, MA; Travel, accommodations, expenses: Agenus; Stock and other ownership: Agenus. E. Dow: Employee: Agenus Inc. or subsidiary there of (current or former employee), Lexington, MA; Employment: Baxalta/Shire; Foundation Medicine stock and other ownership: Baxalta/Shire, Foundation Medicine. W. Ortuzar: Full time contracted consultant: Agenus Bio, Inc. All other authors have declared no conflicts of interest.