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

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

  • Urol Oncol. 2016 Dec;34(12):530.e15-530.e21. doi: 10.1016/j.urolonc.2016.07.005.
Matthew I Milowsky 1,  Matthew D Galsky 1,  Michael J Morris 1,  Daniel J Crona 2,  Daniel J George 3,  Robert Dreicer 4,  Kin Tse 5,  Jesika Petruck 6,  Iain J Webb 6,  Neil H Bander 7,  David M Nanus 8,  Howard I Scher 9
Affiliations

Affiliations

  • 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.
PMID: 27765518 DOI: 10.1016/j.urolonc.2016.07.005
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.

Keywords

Castration-resistant prostate cancer; DM1; MLN2704; Maytansinoid; Multiple ascending dose; PSMA.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-P991360
    抗PSMA单克隆抗体
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