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Phase 1 Study of Monotherapy with KHK2866, an Anti-Heparin-Binding Epidermal Growth Factor-Like Growth Factor Monoclonal Antibody, in Patients with Advanced Cancer

Abstract

Background

KHK2866 is a recombinant, humanized, non-fucosylated, monoclonal antibody directed at heparin-binding epidermal growth factor-like growth factor (HB-EGF).

Objective

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.

Materials and Methods

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.

Results

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.

Conclusions

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]

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Acknowledgments

Medical writing assistance provided by Peter Todd of Tajut Ltd. (Kaiapoi, New Zealand) was supported financially by Kyowa Hakko Kirin Inc. during the preparation of this manuscript. The Institute for Drug Development, Cancer Therapy, and Research Center at University of Texas Health Science Center San Antonio (San Antonio, TX, USA) received support from Cancer Center Support Grant P30CA054174.

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Correspondence to John Sarantopoulos.

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Funding

Kyowa Hakko Kirin, Inc.

Conflict of Interest

XZ, HK, and VS are employees of Kyowa Hakko Kirin. PB was an employee of Kyowa Hakko Kirin until 29 August 2014. JS, MMM, MJB, LDC, LTC, and LHC declare that they have no conflict of interest

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Sarantopoulos, J., Mita, M.M., Birrer, M.J. et al. Phase 1 Study of Monotherapy with KHK2866, an Anti-Heparin-Binding Epidermal Growth Factor-Like Growth Factor Monoclonal Antibody, in Patients with Advanced Cancer. Targ Oncol 11, 317–327 (2016). https://doi.org/10.1007/s11523-015-0394-5

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Keywords

  • Epithelial Ovarian Cancer
  • Maximum Tolerate Dose
  • Cynomolgus Monkey
  • Eastern Cooperative Oncology Group Score
  • Premedication Regimen