title: Phase 1 Dose Escalation Study of MEDI-565, a Bispecific T-Cell Engager that Targets Human Carcinoembryonic Antigen, in Patients With Advanced Gastrointestinal Adenocarcinomas.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors: Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC. Electronic address: pishvaim@georgetown.edu.
authors: Michael
authors: M
authors: Pishvaian
authors: Division of Hematology/Oncology, Duke Cancer Institute, Duke University Medical Center, Durham, NC.
authors: Michael A
authors: MA
authors: Morse
authors: MedImmune, Gaithersburg, MD.
authors: Jennifer
authors: J
authors: McDevitt
authors: MedImmune, Gaithersburg, MD.
authors: Jonathan D
authors: JD
authors: Norton
authors: MedImmune, Gaithersburg, MD.
authors: Song
authors: S
authors: Ren
authors: MedImmune, Gaithersburg, MD.
authors: Gabriel J
authors: GJ
authors: Robbie
authors: MedImmune, Gaithersburg, MD.
authors: Patricia C
authors: PC
authors: Ryan
authors: MedImmune, Gaithersburg, MD.
authors: Serguei
authors: S
authors: Soukharev
authors: MedImmune, Gaithersburg, MD.
authors: Haifeng
authors: H
authors: Bao
authors: Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA.
authors: Crystal S
authors: CS
authors: Denlinger
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy*; D000328:Adult; D000368:Aged; D018033:Antibodies, Bispecific / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D017252:CD3 Complex / Q000276:immunology; D002272:Carcinoembryonic Antigen / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D057127:Single-Chain Antibodies / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
chemical_list: D018033:Antibodies, Bispecific; D000970:Antineoplastic Agents; D017252:CD3 Complex; D002272:Carcinoembryonic Antigen; D057127:Single-Chain Antibodies
keywords: Bispecific antibodies; Clinical trial; Gastrointestinal cancer; Pancreatic cancer; Pharmacokinetics