Treatment of Advanced Pancreatic Carcinoma with 90Y-Clivatuzumab Tetraxetan: A Phase I Single-Dose Escalation Trial

Purpose: Humanized antibody hPAM4 specifically binds a mucin glycoprotein expressed in pancreatic adenocarcinomas. This phase I study evaluated a single dose of Y-90-clivatuzumab tetraxetan (Y-90-labeled hPAM4) in patients with advanced pancreatic cancer. Experimental Design: Twenty-one patients (4 stage III; 17 stage IV) received In-111-hPAM4 for imaging and serum sampling before Y-90-hPAM4. Study procedures evaluated adverse events, safety laboratories, computed tomography (CT) scans, biomarkers, pharmacokinetics, radiation dosimetry, and immunogenicity (HAHA). Results: In-111-hPAM4 showed normal biodistribution with radiation dose estimates to red marrow and solid organs acceptable for radioimmunotherapy and with tumor targeting in 12 patients. One patient withdrew before Y-90-hPAM4; otherwise, 20 patients received Y-90 doses of 15 (n = 7), 20 (n = 9), and 25 mCi/m(2) (n = 4). Treatment was well tolerated; the only significant drug-related toxicities were (NCI CTC v. 3) grade 3 to 4 neutropenia and thrombocytopenia increasing with Y-90 dose. There were no bleeding events or serious infections, and most cytopenias recovered to grade 1 within 12 weeks. Three patients at 25 mCi/m(2) encountered dose-limiting toxicity with grade 4 cytopenias more than 7 days, establishing 20 mCi/m(2) as the maximal tolerated Y-90 dose. Two patients developed HAHA of uncertain clinical significance. Most patients progressed rapidly and with CA19-9 levels increasing within 1 month of therapy, but 7 remained progression-free by CT for 1.5 to 5.6 months, including 3 achieving transient partial responses (32%-52% tumor diameter shrinkage). Conclusion: Y-90-Clivatuzumab tetraxetan was well tolerated with manageable hematologic toxicity at the maximal tolerated Y-90 dose, and is a potential new therapeutic for advanced pancreatic cancer. Clin Cancer Res; 17(12); 4091-100. (C) 2011 AACR.