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Phase 1 Dose Escalation Study of MEDI-565, a Bispecific T-Cell Engager that Targets Human Carcinoembryonic Antigen, in Patients With Advanced Gastrointestinal Adenocarcinomas.

Publication ,  Journal Article
Pishvaian, M; Morse, MA; McDevitt, J; Norton, JD; Ren, S; Robbie, GJ; Ryan, PC; Soukharev, S; Bao, H; Denlinger, CS
Published in: Clin Colorectal Cancer
December 2016

INTRODUCTION: MEDI-565, a bispecific, single-chain antibody targeting human carcinoembryonic antigen on tumor cells and the CD3 epsilon subunit of the human T-cell receptor complex, showed antitumor activity in carcinoembryonic antigen-expressing tumors in murine models. PATIENTS AND METHODS: This phase I, multicenter, open-label dose escalation study enrolled adults with gastrointestinal adenocarcinomas. MEDI-565 was given intravenously over 3 hours on days 1 through 5 in 28-day cycles, with 4 single-patient (0.75-20 μg) and 5 standard 3 + 3 escalation (60 μg-3 mg; 1.5-7.5 mg with dexamethasone) cohorts. Primary objective was determining maximum tolerated dose; secondary objectives were evaluating pharmacokinetics, antidrug antibodies, and antitumor activity. RESULTS: Thirty-nine patients were enrolled (mean age, 59 years; 56% male; 72% colorectal cancer). Four patients experienced dose-limiting toxicities (2 at 3 mg; 2 at 7.5 mg + dexamethasone): hypoxia (n = 2), diarrhea, and cytokine release syndrome (CRS). Five patients reported grade 3 treatment-related adverse events: diarrhea, CRS, increased alanine aminotransferase, hypertension (all, n = 1), and hypoxia (n = 2); 6 experienced treatment-related serious adverse events: diarrhea, vomiting, pyrexia, CRS (all, n = 1), and hypoxia (n = 2). MEDI-565 pharmacokinetics was linear and dose-proportional, with fast clearance and short half-life. Nineteen patients (48.7%) had antidrug antibodies; 5 (12.8%) had high titers, 2 with decreased MEDI-565 concentrations. No objective responses occurred; 11 (28%) had stable disease as best response. CONCLUSIONS: The maximum tolerated dose of MEDI-565 in this patient population was 5 mg administered over 3 hours on days 1 through 5 every 28 days, with dexamethasone. Pharmacokinetics were linear. No objective responses were observed.

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Published In

Clin Colorectal Cancer

DOI

EISSN

1938-0674

Publication Date

December 2016

Volume

15

Issue

4

Start / End Page

345 / 351

Location

United States

Related Subject Headings

  • T-Lymphocytes
  • Single-Chain Antibodies
  • Oncology & Carcinogenesis
  • Middle Aged
  • Maximum Tolerated Dose
  • Male
  • Immunotherapy
  • Humans
  • Gastrointestinal Neoplasms
  • Female
 

Citation

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Pishvaian, M., Morse, M. A., McDevitt, J., Norton, J. D., Ren, S., Robbie, G. J., … Denlinger, C. S. (2016). Phase 1 Dose Escalation Study of MEDI-565, a Bispecific T-Cell Engager that Targets Human Carcinoembryonic Antigen, in Patients With Advanced Gastrointestinal Adenocarcinomas. Clin Colorectal Cancer, 15(4), 345–351. https://doi.org/10.1016/j.clcc.2016.07.009
Pishvaian, Michael, Michael A. Morse, Jennifer McDevitt, Jonathan D. Norton, Song Ren, Gabriel J. Robbie, Patricia C. Ryan, Serguei Soukharev, Haifeng Bao, and Crystal S. Denlinger. “Phase 1 Dose Escalation Study of MEDI-565, a Bispecific T-Cell Engager that Targets Human Carcinoembryonic Antigen, in Patients With Advanced Gastrointestinal Adenocarcinomas.Clin Colorectal Cancer 15, no. 4 (December 2016): 345–51. https://doi.org/10.1016/j.clcc.2016.07.009.
Pishvaian M, Morse MA, McDevitt J, Norton JD, Ren S, Robbie GJ, et al. Phase 1 Dose Escalation Study of MEDI-565, a Bispecific T-Cell Engager that Targets Human Carcinoembryonic Antigen, in Patients With Advanced Gastrointestinal Adenocarcinomas. Clin Colorectal Cancer. 2016 Dec;15(4):345–51.
Pishvaian, Michael, et al. “Phase 1 Dose Escalation Study of MEDI-565, a Bispecific T-Cell Engager that Targets Human Carcinoembryonic Antigen, in Patients With Advanced Gastrointestinal Adenocarcinomas.Clin Colorectal Cancer, vol. 15, no. 4, Dec. 2016, pp. 345–51. Pubmed, doi:10.1016/j.clcc.2016.07.009.
Pishvaian M, Morse MA, McDevitt J, Norton JD, Ren S, Robbie GJ, Ryan PC, Soukharev S, Bao H, Denlinger CS. Phase 1 Dose Escalation Study of MEDI-565, a Bispecific T-Cell Engager that Targets Human Carcinoembryonic Antigen, in Patients With Advanced Gastrointestinal Adenocarcinomas. Clin Colorectal Cancer. 2016 Dec;15(4):345–351.
Journal cover image

Published In

Clin Colorectal Cancer

DOI

EISSN

1938-0674

Publication Date

December 2016

Volume

15

Issue

4

Start / End Page

345 / 351

Location

United States

Related Subject Headings

  • T-Lymphocytes
  • Single-Chain Antibodies
  • Oncology & Carcinogenesis
  • Middle Aged
  • Maximum Tolerated Dose
  • Male
  • Immunotherapy
  • Humans
  • Gastrointestinal Neoplasms
  • Female