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

   

Authors:	Milowsky, M. I.; Galsky, M. D.; Morris, M. J.; Crona, D. J.; George, D. J.; Dreicer, R.; Tse, K.; Petruck, J.; Webb, I. J.; Bander, N. H.; Nanus, D. M.; Scher, H. I.
Article Title:	Phase 1/2 multiple ascending dose trial of the prostate-specific membrane antigen-targeted antibody drug conjugate MLN2704 in metastatic castration-resistant prostate cancer
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. © 2016
Keywords:	dm1; psma; castration-resistant prostate cancer; maytansinoid; mln2704; multiple ascending dose
Journal Title:	Urologic Oncology: Seminars and Original Investigations
Volume:	34
Issue:	12
ISSN:	1078-1439
Publisher:	Elsevier Inc.
Date Published:	2016-12-01
Start Page:	530.e15
End Page:	530.e21
Language:	English
DOI:	10.1016/j.urolonc.2016.07.005
PROVIDER:	scopus
PUBMED:	27765518
PMCID:	PMC5464417
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-84997076993&doi=10.1016%2fj.urolonc.2016.07.005&partnerID=40&md5=f76938055f381cbc8f0fb2fe66bc2d90
Notes:	Article -- Export Date: 3 January 2017 -- Source: Scopus

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