Phase 1 Study of Monotherapy with KHK2866, an Anti-Heparin-Binding Epidermal Growth Factor-Like Growth Factor Monoclonal Antibody, in Patients with Advanced Cancer.
KHK2866 is a recombinant, humanized, non-fucosylated, monoclonal antibody directed at heparin-binding epidermal growth factor-like growth factor (HB-EGF).



To determine the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, potential immunogenicity, and preliminary clinical efficacy of KHK2866 monotherapy in patients with advanced and refractory cancer in a first-in-human, phase 1 study.



Using a standard 3 + 3 dose-escalation design, 20 patients received KHK2866 (0.3, 1, and 3 mg/kg) intravenously once weekly. Two additional patients received 0.1 mg/kg in a cohort which was subsequently added following protocol amendment.



The first three patients enrolled experienced grade 2 hypersensitivity (acute infusion reactions) after the first dose of KHK2866. After prophylactic treatment with an H1-blocker and corticosteroids in subsequently recruited patients, two grade 2 hypersensitivity reactions were observed in the remaining 19 patients. Grade 2/3 neurotoxicity appeared to be dose-limiting at 3 mg/kg in the original dose-escalation cohorts (n = 2), at 1 mg/kg in the MTD dose expansion cohort (n = 1), and at 0.1 mg/kg (n = 1). Neurotoxicity was manifested as complex partial seizure activity, aphasia, and confusion after first-dose administration. Pharmacokinetic exposure to KHK2866 increased proportionally to dose. Mean elimination half-life was 71.9-118 h over the dose range from 0.3 to 3 mg/kg. All KHK2866 doses decreased serum free HB-EGF levels, generally below the lower limit of quantification.



The study was terminated because of neuropsychiatric toxicity. The only predictive factor for neuropsychiatric toxicity was administration of KHK2866. These effects were reversible, but were not predictable. Their etiology is not presently understood. [Study registered at ClinicalTrials.gov #NCT0179291].
Institute for Drug Development, Cancer Therapy and Research Center at University of Texas Health Science Center San Antonio, 4th Floor, Zeller Building, 7979 Wurzbach Road, San Antonio, TX, 78229, USA. sarantopoulo@uthscsa.edu.
John
J
Sarantopoulos
Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Monica M
MM
Mita
Gillette Center of Gynecologic Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Michael J
MJ
Birrer
University of Arizona Cancer Center, Tuscon, AZ, USA.
Lee D
LD
Cranmer
Oncology Consultants, Houston, TX, USA.
Luis T
LT
Campos
Kyowa Hakko Kirin Pharma, Inc., Princeton, NJ, USA.
Xiaoping
X
Zhang
Kyowa Hakko Kirin Pharma, Inc., Princeton, NJ, USA.
Penelope
P
Bristow
Kyowa Hakko Kirin Pharma, Inc., Princeton, NJ, USA.
Hidekuni
H
Kaito
Kyowa Hakko Kirin Pharma, Inc., Princeton, NJ, USA.
Vincent
V
Strout
Oncology Consultants, Houston, TX, USA.
Luis H
LH
Camacho
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D066255:EGF Family of Proteins / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*
D000911:Antibodies, Monoclonal; D066255:EGF Family of Proteins