Skip to main content
Journal cover image

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

Publication ,  Journal Article
Milowsky, MI; Galsky, MD; Morris, MJ; Crona, DJ; George, DJ; Dreicer, R; Tse, K; Petruck, J; Webb, IJ; Bander, NH; Nanus, DM; Scher, HI
Published in: Urol Oncol
December 2016

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.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Urol Oncol

DOI

EISSN

1873-2496

Publication Date

December 2016

Volume

34

Issue

12

Start / End Page

530.e15 / 530.e21

Location

United States

Related Subject Headings

  • Urology & Nephrology
  • Prostatic Neoplasms, Castration-Resistant
  • Prostate-Specific Antigen
  • Peripheral Nervous System Diseases
  • Middle Aged
  • Maytansine
  • Maximum Tolerated Dose
  • Male
  • Immunoconjugates
  • Humans
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Milowsky, M. I., Galsky, M. D., Morris, M. J., Crona, D. J., George, D. J., Dreicer, R., … Scher, H. I. (2016). 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, 34(12), 530.e15-530.e21. https://doi.org/10.1016/j.urolonc.2016.07.005
Milowsky, Matthew I., Matthew D. Galsky, Michael J. Morris, Daniel J. Crona, Daniel J. George, Robert Dreicer, Kin Tse, et al. “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 34, no. 12 (December 2016): 530.e15-530.e21. https://doi.org/10.1016/j.urolonc.2016.07.005.
Milowsky MI, Galsky MD, Morris MJ, Crona DJ, George DJ, Dreicer R, et al. 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.
Milowsky, Matthew I., et al. “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, vol. 34, no. 12, Dec. 2016, pp. 530.e15-530.e21. Pubmed, doi:10.1016/j.urolonc.2016.07.005.
Milowsky MI, Galsky MD, Morris MJ, Crona DJ, George DJ, Dreicer R, Tse K, Petruck J, Webb IJ, Bander NH, Nanus DM, Scher HI. 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.
Journal cover image

Published In

Urol Oncol

DOI

EISSN

1873-2496

Publication Date

December 2016

Volume

34

Issue

12

Start / End Page

530.e15 / 530.e21

Location

United States

Related Subject Headings

  • Urology & Nephrology
  • Prostatic Neoplasms, Castration-Resistant
  • Prostate-Specific Antigen
  • Peripheral Nervous System Diseases
  • Middle Aged
  • Maytansine
  • Maximum Tolerated Dose
  • Male
  • Immunoconjugates
  • Humans