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

Michael Pishvaian, Michael A. Morse, Jennifer McDevitt, Jonathan D. Norton, Song Ren, Gabriel J. Robbie, Patricia C. Ryan, Serguei Soukharev, Haifeng Bao, Crystal S. Denlinger

Research output: Contribution to journalArticlepeer-review

Abstract

This phase I, multicenter, open-label study evaluated MEDI-565 (0.75-20 μg to 7.5 mg on days 1-5, 28-day cycles) in 39 adults with gastrointestinal adenocarcinoma. The maximum tolerated dose was 5 mg on days 1 through 5 every 28 days with dexamethasone. No objective responses were observed. A study of MEDI-565 as a continuous infusion in patients with gastrointestinal adenocarcinomas is ongoing. 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.

Original languageEnglish (US)
Pages (from-to)345-351
Number of pages7
JournalClinical colorectal cancer
Volume15
Issue number4
DOIs
StatePublished - Dec 1 2016
Externally publishedYes

Keywords

  • Bispecific antibodies
  • Clinical trial
  • Gastrointestinal cancer
  • Pancreatic cancer
  • Pharmacokinetics

ASJC Scopus subject areas

  • Oncology
  • Gastroenterology

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