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 ⁹⁰Y-clivatuzumab tetraxetan (⁹⁰Y-labeled hPAM4) in patients with advanced pancreatic cancer. Experimental Design: Twenty-one patients (4 stage III; 17 stage IV) received ¹¹¹In-hPAM4 for imaging and serum sampling before ⁹⁰Y-hPAM4. Study procedures evaluated adverse events, safety laboratories, computed tomography (CT) scans, biomarkers, pharmacokinetics, radiation dosimetry, and immunogenicity (HAHA). Results: ¹¹¹In-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 ⁹⁰Y-hPAM4; otherwise, 20 patients received ⁹⁰Y doses of 15 (n = 7), 20 (n = 9), and 25 mCi/m² (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 ⁹⁰Y dose. There were no bleeding events or serious infections, and most cytopenias recovered to grade 1 within 12 weeks. Three patients at 25 mCi/m² encountered dose-limiting toxicity with grade 4 cytopenias more than 7 days, establishing 20 mCi/m² as the maximal tolerated ⁹⁰Y 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: ⁹⁰Y-Clivatuzumab tetraxetan was well tolerated with manageable hematologic toxicity at the maximal tolerated ⁹⁰Y dose, and is a potential new therapeutic for advanced pancreatic cancer.