Phase I experience with an anti-glycotope monoclonal antibody, RAV12, in recurrent adenocarcinoma

Abstract

14017 Background: RAV12 is a high affinity, internalizing, chimeric IgG1 monoclonal antibody (MAb) that binds RAAG12, a novel primate-restricted N-linked carbohydrate epitope present on multiple cell-surface proteins. RAAG12 is variably expressed on normal non-keratinizing epithelia, particularly those of GI origin (cytoplasm and apical membrane), and is not expressed on human tissues from the cardiovascular, endocrine, hematolymphatic, neuromuscular, and central nervous systems. IHC studies demonstrated diffuse membrane staining on > 90% of human colorectal, gastric, and pancreatic adenocarcinoma samples. RAAG12 is distinct from previously reported mucin or Lewis blood group carcinoma-associated carbohydrates. In vitro, RAV12 kills tumor cells by oncosis and facilitates ADCC. Methods: In December 2004, a phase I dose-escalation safety and pharmacokinetics (PK) trial was begun in patients with recurrent (1 to 3 prior treatments) adenocarcinoma. RAV12 was administered weekly x 4, twenty-eight patients have received treatment in the following cohorts: 0.3 mg/kg qw (6), 1.0 mg/kg qw (8), 1.5 mg/kg qw (7), 0.5 mg/kg biw (3), 0.75 mg/kg biw (2), and 0.5 mg/kg tiw (2). Sixteen patients had colorectal, 5 gastroesophageal, 4 pancreatic, 2 lung cancer, and 1 breast cancer. Responses were evaluated on day 42. Results: Preliminary analysis demonstrated dose-dependent PK. Three clinical syndromes associated with drug administration have been observed to date: 1) abdominal cramping pain (21 patients) and diarrhea (18 patients) particularly at the higher doses, 2) asymptomatic, self-limited, generally rapidly reversible excursions of liver function tests (16 patients), and 3) asymptomatic, self-limited, rapidly reversible excursions of pancreatic enzymes (6 patients). One patient (0.3 mg/kg qw), with advanced pancreatic cancer, had a > 50% reduction in CA19–9, continued treatment, and had TTP > 5 months. One patient with colorectal cancer (1.5 mg/kg qw) experienced a durable partial remission, continued treatment, and had TTP > 8 months. Conclusions: RAV12 has activity in recurrent adenocarcinoma. Side effects uncommonly have been dose limiting. The trial continues to define dose/schedule to be recommended for phase 2 testing. No significant financial relationships to disclose.