title: Phase I study of Nivolumab, an anti-PD-1 antibody, in patients with malignant solid tumors.
abstract: Background This study evaluated the safety, tolerability, pharmacokinetics, immunogenicity and antitumor activity of single and multiple doses of nivolumab in Japanese patients with malignant solid tumors. Subjects and Methods This was an open-label, dose-escalation study in 17 patients with advanced solid tumors with a life expectancy of ≥3 months. Patients were observed for 3 weeks after a single dose of nivolumab at 1, 3, 10 or 20 mg/kg, then received the same dose of nivolumab every 2 weeks until unacceptable toxicity or disease progression occurred. This study included a maximum dose of 20 mg/kg, which is the highest dose of nivolumab evaluated to date. The maximum dose was 10 mg/kg in previous studies. Results The commonest adverse drug reaction was lymphopenia, which occurred in 10 (58.8%) patients, including two (11.8%) with Grade ≥3 events. No dose-limiting toxicities (DLTs) were observed up to the maximum dose of 20 mg/kg. The area under the concentration-time curve from time 0 to the last measurable concentration was linear up to 20 mg/kg. The maximum concentration showed dose-dependency up to 10 mg/kg, but not between 10 and 20 mg/kg. One durable complete response and two partial responses were observed. Conclusions Nivolumab at doses of 1-20 mg/kg was not associated with DLTs, and it was generally well tolerated at doses of up to 20 mg/kg in Japanese patients with advanced solid tumors.
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji Chuo-ku, Tokyo, 104-0045, Japan. nbryamam@ncc.go.jp.
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamamoto
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nokihara
authors.affiliation: Department of Gastrointestinal Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Shibata
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Tamura
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Seki
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Honda
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tanabe
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Wakui
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tamura
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D000077594:Nivolumab; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D000077594:Nivolumab
keywords: Immune checkpoint inhibitor; Nivolumab; Pharmacokinetics; Phase I study