Matthew I Milowsky1, Matthew D Galsky1, Michael J Morris1, Daniel J Crona2, Daniel J George3, Robert Dreicer4, Kin Tse5, Jesika Petruck6, Iain J Webb6, Neil H Bander7, David M Nanus8, Howard I Scher9. 1. Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Medicine, Weill Cornell Medical College, New York, NY. 2. Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC. 3. Department of Medicine, Duke University Medical Center, Durham, NC. 4. Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH. 5. Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY. 6. Millennium Pharmaceuticals, Inc., Takeda Pharmaceuticals Company Inc., Cambridge, MA. 7. Department of Urology, Weill Cornell Medical College, New York, NY; Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY. 8. Department of Medicine, Weill Cornell Medical College, New York, NY. 9. Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Medicine, Weill Cornell Medical College, New York, NY. Electronic address: scherh@mskcc.org.
Abstract
BACKGROUND: This phase 1/2 study evaluated the dose-limiting toxicity and maximum tolerated dose of MLN2704, a humanized monoclonal antibody MLN591 targeting prostate-specific membrane antigen, linked to the maytansinoid DM1 in patients with progressive metastatic castration-resistant prostate cancer. PATIENTS AND METHODS: A total of 62 patients received MLN2704 at ascending doses on 4 schedules: weekly (60, 84, 118, and 165mg/m2; 12 patients); every 2 weeks (120, 168, 236, and 330mg/m2; 15 patients); every 3 weeks (330 and 426mg/m2; 18 patients); and on days 1 and 15 of a 6-week schedule (6-week cycle, 330mg/m2; 17 patients). The primary efficacy endpoint was a sustained ≥50% decline from baseline prostate-specific antigen (PSA) without evidence of disease progression. Toxicity, pharmacokinetics, immunogenicity, and antitumor activity were assessed. RESULTS: Neurotoxicity was dose-limiting. Overall, 44 patients (71%) exhibited peripheral neuropathy: 6 (10%) had grade 3/4. Neurotoxicity rates remained high despite increasing the dosing interval to 3 (13 of 14; one grade 3) and 6 weeks (16 of 17; three grade 3). MLN2704 pharmacokinetics were dose-linear. Rapid deconjugation of DM1 from the conjugated antibody was seen. In all, 5 patients (8%) experienced ≥50% decline in PSA; 5 (8%) had PSA stabilization lasting≥90 days. Only 2 of 35 patients on the 3- and 6-week schedules achieved a PSA decline of >50%. CONCLUSIONS: MLN2704 has limited activity in metastatic castration-resistant prostate cancer. Disulfide linker lability and rapid deconjugation lead to neurotoxicity and a narrow therapeutic window. Copyright Â
BACKGROUND: This phase 1/2 study evaluated the dose-limiting toxicity and maximum tolerated dose of MLN2704, a humanized monoclonal antibody MLN591 targeting prostate-specific membrane antigen, linked to the maytansinoidDM1 in patients with progressive metastatic castration-resistant prostate cancer. PATIENTS AND METHODS: A total of 62 patients received MLN2704 at ascending doses on 4 schedules: weekly (60, 84, 118, and 165mg/m2; 12 patients); every 2 weeks (120, 168, 236, and 330mg/m2; 15 patients); every 3 weeks (330 and 426mg/m2; 18 patients); and on days 1 and 15 of a 6-week schedule (6-week cycle, 330mg/m2; 17 patients). The primary efficacy endpoint was a sustained ≥50% decline from baseline prostate-specific antigen (PSA) without evidence of disease progression. Toxicity, pharmacokinetics, immunogenicity, and antitumor activity were assessed. RESULTS:Neurotoxicity was dose-limiting. Overall, 44 patients (71%) exhibited peripheral neuropathy: 6 (10%) had grade 3/4. Neurotoxicity rates remained high despite increasing the dosing interval to 3 (13 of 14; one grade 3) and 6 weeks (16 of 17; three grade 3). MLN2704 pharmacokinetics were dose-linear. Rapid deconjugation of DM1 from the conjugated antibody was seen. In all, 5 patients (8%) experienced ≥50% decline in PSA; 5 (8%) had PSA stabilization lasting≥90 days. Only 2 of 35 patients on the 3- and 6-week schedules achieved a PSA decline of >50%. CONCLUSIONS:MLN2704 has limited activity in metastatic castration-resistant prostate cancer. Disulfide linker lability and rapid deconjugation lead to neurotoxicity and a narrow therapeutic window. Copyright Â
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