title: Phase 1 Study of CEP-37250/KHK2804, a Tumor-specific Anti-glycoconjugate Monoclonal Antibody, in Patients with Advanced Solid Tumors.
abstract: CEP-37250/KHK2804 is a recombinant, humanized, non-fucosylated, monoclonal antibody directed to sialic acid-containing glycoconjugates frequently found on certain tumor cell types.
  
  
  
  The objective was to determine the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, potential immunogenicity, and preliminary clinical efficacy of CEP-37250/KHK2804 monotherapy in patients with advanced cancer in a first-in-human, phase 1 study.
  
  
  
  In phase 1a, patients (n = 31) with solid tumors received increasing doses of CEP-37250/KHK2804 (0.03-1.0 mg/kg) intravenously once weekly using a standard 3 + 3 dose-escalation design. In phase 1b, two dose-expansion cohorts of patients with colorectal (n = 15) and pancreatic (n = 16) cancer, respectively, received the maximum tolerated dose (MTD).
  
  
  
  The MTD of CEP-37250/KHK2804 was 0.3 mg/kg weekly. Dose-limiting toxicities were infusion-related reactions and increased serum transaminases. In the overall population (N = 62), the most frequent treatment-related adverse event (AE) was an infusion-related reaction (45.2 %). Positive post-baseline CEP-37250/KHK2804 neutralizing antibodies were reported in 14 patients (22.6 %), almost exclusively in patients who developed infusion-related reactions. The most frequent treatment-related AE grade ≥3 was increased AST or ALT in six patients (9.7 %). Three patients experienced treatment-related serious cardiac events (grade 4 ECG abnormality, grade 4 atrial fibrillation, and grade 3 acute myocardial infarction, respectively). Pharmacokinetic exposure to CEP-37250/KHK2804 increased proportionally to dose, with accumulation up to two fold with repeated administration. Mean elimination half-life was 34.1 to 70.3 hours over the dose range from 0.03 to 1.0 mg/kg. No patient had a complete or partial best response. Thirteen of 40 (32.5 %) evaluable patients had unconfirmed stable disease, four of which were confirmed (10.0 %).
  
  
  
  The study was stopped early due to the lack of efficacy. Additionally, safety concerns (i.e., cardiac issues, hepatic toxicity, and infusion-related reactions) made the benefit-risk assessment unfavorable for continued development of CEP-37250/KHK2804, which was halted indefinitely. [Study registered at ClinicalTrials.gov #NCT01447732].
authors.affiliation: Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Suite MS31, Los Angeles, CA, 90048, USA. Monica.Mita@cshs.org.
authors.forename: Monica M
authors.initials: MM
authors.lastname: Mita
authors.affiliation: Mary Crowley Cancer Research, Dallas, TX, USA.
authors.forename: John
authors.initials: J
authors.lastname: Nemunaitis
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, and Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
authors.forename: Juneko
authors.initials: J
authors.lastname: Grilley-Olson
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA.
authors.forename: Bassil
authors.initials: B
authors.lastname: El-Rayes
authors.affiliation: Gastrointestinal Disease Research Group, The Ohio State University - James Cancer Hospital, Columbus, OH, USA.
authors.forename: Tanios
authors.initials: T
authors.lastname: Bekaii-Saab
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA.
authors.forename: R Donald
authors.initials: RD
authors.lastname: Harvey
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
authors.forename: John
authors.initials: J
authors.lastname: Marshall
authors.affiliation: Kyowa Kirin Pharmaceutical Development, Inc., Princeton, NJ, USA.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Kyowa Kirin Pharmaceutical Development, Inc., Princeton, NJ, USA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Strout
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal