title: Phase I Study of the Investigational Anti-Guanylyl Cyclase Antibody-Drug Conjugate TAK-264 (MLN0264) in Adult Patients with Advanced Gastrointestinal Malignancies.
abstract: OBJECTIVE
  To assess the safety, tolerability, and preliminary antitumor activity of the investigational anti-guanylyl cyclase C (GCC) antibody-drug conjugate TAK-264 (formerly MLN0264) in adult patients with advanced gastrointestinal malignancies.
  
  
  METHODS
  Adult patients with GCC-expressing gastrointestinal malignancies (H-score ≥ 10) were eligible for inclusion. TAK-264 was administered as a 30-minute intravenous infusion once every 3 weeks for up to 17 cycles. Dose escalation proceeded using a Bayesian continual reassessment method. At the maximum tolerated dose (MTD), 25 patients with metastatic colorectal cancer were enrolled in a prespecified dose expansion cohort.
  
  
  RESULTS
  Forty-one patients were enrolled, including 35 (85%) with metastatic colorectal cancer. During dose escalation (0.3-2.4 mg/kg), four of 19 patients experienced dose-limiting toxicities of grade 4 neutropenia; the MTD was determined as 1.8 mg/kg. Patients received a median of two cycles of TAK-264 (range, 1-12); nine received ≥four cycles. Common drug-related adverse events (AEs) included nausea and decreased appetite (each 41%), fatigue (32%), diarrhea, anemia, alopecia, and neutropenia (each 27%); grade ≥3 AEs included neutropenia (22%), hypokalemia, and febrile neutropenia (each 7%). Peripheral neuropathy was reported in four (10%) patients. Pharmacokinetic data showed approximately dose proportional systemic exposure and a mean plasma half-life of around 4 days, supporting the dosing schedule. Overall, 39 patients were response-evaluable; three experienced durable stable disease; and one with gastric adenocarcinoma had a partial response. GCC expression did not appear to correlate with treatment duration.
  
  
  CONCLUSIONS
  These findings suggest that TAK-264 has a manageable safety profile, with preliminary evidence of potential antitumor activity in specific gastrointestinal malignancies. Further investigation is underway. Clin Cancer Res; 22(20); 5049-57. ©2016 AACR.
authors.affiliation: Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, Florida. Khaldoun.Almhanna@moffitt.org.
authors.forename: Khaldoun
authors.initials: K
authors.lastname: Almhanna
authors.affiliation: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, Massachusetts.
authors.forename: Thea
authors.initials: T
authors.lastname: Kalebic
authors.affiliation: Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital and Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Cruz
authors.affiliation: Hematology/Oncology, Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Faris
authors.affiliation: Hematology/Oncology, Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
authors.forename: David P
authors.initials: DP
authors.lastname: Ryan
authors.affiliation: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, Massachusetts.
authors.forename: JungAh
authors.initials: J
authors.lastname: Jung
authors.affiliation: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, Massachusetts.
authors.forename: Tim
authors.initials: T
authors.lastname: Wyant
authors.affiliation: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, Massachusetts.
authors.forename: Adedigbo A
authors.initials: AA
authors.lastname: Fasanmade
authors.affiliation: Division of Medical Oncology, University of Colorado Cancer Center, Aurora, Colorado.
authors.forename: Wells
authors.initials: W
authors.lastname: Messersmith
authors.affiliation: Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital and Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Rodon
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors* / Q000276:immunology; D006801:Humans; D018796:Immunoconjugates / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009842:Oligopeptides / Q000009:adverse effects / Q000627:therapeutic use
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D009842:Oligopeptides; D006162:Guanylate Cyclase; C495575:monomethyl auristatin E