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: 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.
  
  
  
  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.
  
  
  
  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%.
  
  
  
  MLN2704 has limited activity in metastatic castration-resistant prostate cancer. Disulfide linker lability and rapid deconjugation lead to neurotoxicity and a narrow therapeutic window.
authors.affiliation: Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Medicine, Weill Cornell Medical College, New York, NY.
authors.forename: Matthew I
authors.initials: MI
authors.lastname: Milowsky
authors.affiliation: Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Medicine, Weill Cornell Medical College, New York, NY.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Galsky
authors.affiliation: Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Medicine, Weill Cornell Medical College, New York, NY.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Morris
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Crona
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: George
authors.affiliation: Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH.
authors.forename: Robert
authors.initials: R
authors.lastname: Dreicer
authors.affiliation: Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Kin
authors.initials: K
authors.lastname: Tse
authors.affiliation: Millennium Pharmaceuticals, Inc., Takeda Pharmaceuticals Company Inc., Cambridge, MA.
authors.forename: Jesika
authors.initials: J
authors.lastname: Petruck
authors.affiliation: Millennium Pharmaceuticals, Inc., Takeda Pharmaceuticals Company Inc., Cambridge, MA.
authors.forename: Iain J
authors.initials: IJ
authors.lastname: Webb
authors.affiliation: Department of Urology, Weill Cornell Medical College, New York, NY; Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Neil H
authors.initials: NH
authors.lastname: Bander
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, NY.
authors.forename: David M
authors.initials: DM
authors.lastname: Nanus
authors.affiliation: 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.
authors.forename: Howard I
authors.initials: HI
authors.lastname: Scher
mesh_terms: D000230:Adenocarcinoma / Q000097:blood / Q000188:drug therapy / Q000556:secondary*; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D000074322:Antineoplastic Agents, Immunological / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018572:Disease-Free Survival; D004306:Dose-Response Relationship, Immunologic; D016903:Drug Monitoring; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D020714:Maximum Tolerated Dose; D008453:Maytansine / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D008875:Middle Aged; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced; D017430:Prostate-Specific Antigen / Q000097:blood; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood / Q000188:drug therapy*
chemical_list: D000911:Antibodies, Monoclonal; D000074322:Antineoplastic Agents, Immunological; D018796:Immunoconjugates; C528898:MLN2704 antibody; D008453:Maytansine; D017430:Prostate-Specific Antigen
keywords: Castration-resistant prostate cancer; DM1; MLN2704; Maytansinoid; Multiple ascending dose; PSMA