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Milowsky, Matthew I., M.D; Galsky, Matthew D., M.D; Morris, Michael J., M.D; Crona, Daniel J., Pharm.D., Ph.D; George, Daniel J., M.D; Dreicer, Robert, M.D; Tse, Kin, B.S; Petruck, Jesika, B.S; Webb, Iain J., M.D; Bander, Neil H., M.D; Nanus, David M., M.D; Scher, Howard I., M.D
Urologic oncology, 12/2016, Letnik: 34, Številka: 12Journal Article
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 165 mg/m2 ; 12 patients); every 2 weeks (120, 168, 236, and 330 mg/m2 ; 15 patients); every 3 weeks (330 and 426 mg/m2 ; 18 patients); and on days 1 and 15 of a 6-week schedule (6-week cycle, 330 mg/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.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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