Phase 1/2 multiple ascending dose trial of the prostate-specific membrane antigen-targeted antibody drug conjugate MLN2704 in metastatic castration-resistant prostate cancer

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 165 mg/m(2); 12 patients); every 2 weeks (120, 168, 236, and 330 mg/m(2); 15 patients); every 3 weeks (330 and 426 mg/m(2); 18 patients); and on days 1 and 15 of a 6-week schedule (6-week cycle, 330 mg/m(2); 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. (C) 2016 Published by Elsevier Inc.