Phase I study of DMOT4039A, an antibody-drug conjugate targeting mesothelin, in patients with unresectable pancreatic or platinum-resistant ovarian cancer

Colin D. Weekes, Laetitia E. Lamberts, Mitesh J. Borad, Johannes Voortman, Robert R. McWilliams, Jennifer R. Diamond, Elisabeth G.E. De Vries, Henk M. Verheul, Christopher H. Lieu, George P. Kim, Yulei Wang, Suzie J. Scales, Divya Samineni, Flavia Brunstein, Younjeong Choi, Daniel J. Maslyar, Gerardo Colon-Otero

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

DMOT4039A, a humanized anti-mesothelin mAb conjugated to the antimitotic agent monomethyl auristatin E (MMAE), was given to patients with pancreatic and ovarian cancer every 3 weeks (0.2-2.8 mg/kg; q3w) or weekly (0.8-1.2 mg/kg). A 3+3 design was used for dose escalation followed by expansion at the recommended phase II dose (RP2D) to evaluate safety and pharmacokinetics. Antitumor response was evaluated per RECIST 1.1 and serum CA19-9 or CA125 declines. Tumor mesothelin expression was determined by IHC. Seventyone patients (40 pancreatic cancer; 31 ovarian cancer) were treated with DMOT4039A. For the q3w schedule (n=54), the MTD and RP2D was 2.4 mg/kg, with dose-limiting toxicities of grade 3 hyperglycemia and grade 3 hypophosphatemia at 2.8 mg/kg. For the weekly schedule (n=17), the maximum assessed dose was 1.2 mg/kg, with further dose escalations deferred because of toxicities limiting scheduled retreatment in later cycles, and therefore the RP2D level for the weekly regimen was determined to be 1 mg/kg. Across both schedules, the most common toxicities were gastrointestinal and constitutional. Treatment-related serious adverse events occurred in 6 patients; 4 patients continued treatment following dose reductions. Drug exposure as measured by antibody-conjugated MMAE and total antibody was generally dose proportional over all dose levels on both schedules. A total of 6 patients had confirmed partial responses (4 ovarian; 2 pancreatic) with DMOT4039A at 2.4 to 2.8 mg/kg i.v. q3w. DMOT4039A administered at doses up to 2.4 mg/kg q3w and 1.0 mg/kg weekly has a tolerable safety profile and antitumor activity in both pancreatic and ovarian cancer.

Original languageEnglish (US)
Pages (from-to)439-447
Number of pages9
JournalMolecular cancer therapeutics
Volume15
Issue number3
DOIs
StatePublished - Mar 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Weekes, C. D., Lamberts, L. E., Borad, M. J., Voortman, J., McWilliams, R. R., Diamond, J. R., De Vries, E. G. E., Verheul, H. M., Lieu, C. H., Kim, G. P., Wang, Y., Scales, S. J., Samineni, D., Brunstein, F., Choi, Y., Maslyar, D. J., & Colon-Otero, G. (2016). Phase I study of DMOT4039A, an antibody-drug conjugate targeting mesothelin, in patients with unresectable pancreatic or platinum-resistant ovarian cancer. Molecular cancer therapeutics, 15(3), 439-447. https://doi.org/10.1158/1535-7163.MCT-15-0693