Phase I Clinical Trial of the Chimeric Anti-Mesothelin Monoclonal Antibody MORAb-009 in Patients with Mesothelin-Expressing Cancers

• Published in: Clinical cancer research Vol. 16; no. 24; pp. 6132 - 6138
• Main Authors: Hassan, Raffit, Cohen, Steven J., Phillips, Martin, Pastan, Ira, Sharon, Elad, Kelly, Ronan J., Schweizer, Charles, Weil, Susan, Laheru, Daniel
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.12.2010
• Subjects: Aged; Aged, 80 and over; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - adverse effects; Antibodies, Monoclonal - therapeutic use; Antineoplastic agents; Biological and medical sciences; Dose-Response Relationship, Drug; Female; GPI-Linked Proteins - antagonists & inhibitors; GPI-Linked Proteins - immunology; GPI-Linked Proteins - metabolism; Humans; Male; Maximum Tolerated Dose; Medical sciences; Membrane Glycoproteins - antagonists & inhibitors; Membrane Glycoproteins - immunology; Membrane Glycoproteins - metabolism; Mesothelin; Middle Aged; Neoplasms - drug therapy; Neoplasms - metabolism; Pharmacology. Drug treatments; Recombinant Fusion Proteins - administration & dosage; Recombinant Fusion Proteins - adverse effects; Recombinant Fusion Proteins - therapeutic use; Treatment Outcome; Human; Phase I trial; Mesothelin; Patient; Monoclonal antibody; Chimerism; Malignant tumor; Gene expression; Cancer
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-10-2275

Purpose: MORAb-009 is a chimeric monoclonal antibody that targets mesothelin, a tumor differentiation antigen overexpressed in pancreatic cancer, ovarian cancer, mesothelioma, and other malignancies. We conducted a phase I clinical trial of MORAb-009 in patients with advanced mesothelin-expressing cancers to determine its safety, dose-limiting toxicity (DLT), and maximum tolerated dose (MTD). Methods: Cohorts consisting of 3 to 6 subjects each received MORAb-009 intravenously on days 1, 8, 15, and 22 at progressively increasing doses ranging from 12.5 to 400 mg/m2. Disease evaluation with computed tomography occurred on day 35. Subjects with responding or stable disease could receive additional cycles of MORAb-009. Results: A total of 24 subjects were treated including 13 mesothelioma, 7 pancreatic cancer, and 4 ovarian cancer patients. The median number of MORAb-009 infusions was 4 (range 1–24 infusions). At the 400 mg/m2 dose level, 2 subjects experienced DLT (grade 4 transaminitis and a grade 3 serum sickness). Thus, although there were other contributing causes of these adverse events, 200 mg/m2 was considered the MTD. Other adverse events at least possibly related to MORAb-009 included 7 drug hypersensitivity events (all grade 1 or 2) and a thromboembolic event (grade 4). Eleven subjects had stable disease. There was a dose-dependent increase in serum MORAb-009 concentration. Conclusion: MORAb-009 is well tolerated and the MTD when administered weekly is conservatively set at 200 mg/m2. In this group of previously treated patients, 11 subjects had stable disease. Phase II studies of MORAb-009 in different mesothelin-expressing cancers are ongoing.