Phase I study of ipilimumab in phased combination with paclitaxel and carboplatin in Japanese patients with non-small-cell lung cancer.
BACKGROUND
Ipilimumab is an antibody that targets the cytotoxic T-lymphocyte antigen-4 to potentiate an antitumor response. Adding ipilimumab 10 mg/kg to paclitaxel (PTX) and carboplatin (CBDCA) in a phased schedule improved progression-free survival in a phase II non-small-cell lung cancer (NSCLC) study.


METHODS
This dose-escalating, phase I study was designed to identify the recommended dose of ipilimumab (3 or 10 mg/kg) by evaluating dose-limiting toxicity (DLT; Cycles 3 and 4) in phased combination with PTX (175 mg/m(2)) and CBDCA (area under the curve = 6) in Japanese patients with advanced NSCLC. Treatment was administered intravenously every 3 weeks initially, followed by some eligible patients receiving maintenance ipilimumab once every 12 weeks. Additional endpoints included safety, tumor response, pharmacokinetics, and immunogenicity.


RESULTS
Fifteen patients were enrolled and 12 received ipilimumab (n = 6, 3 mg/kg; n = 6, 10 mg/kg) in combination with PTX and CBDCA. DLTs occurred in 2 patients (ipilimumab 3 mg/kg) and 1 patient (ipilimumab 10 mg/kg). The most common grade 3/4 adverse events (AEs) were decreased hemoglobin, leukopenia, and neutropenia. The most common immune-related AEs affected the skin, gastrointestinal, and nervous system. The safety profile was similar in both cohorts. Three patients in each cohort achieved a partial response. The pharmacokinetic (PK) profile of ipilimumab in Japanese patients was similar to that observed in previous studies in non-Japanese patients. Conclusions The recommended dose of ipilimumab in phased combination with PTX and CBDCA in Japanese patients with NSCLC was identified as 10 mg/kg. The safety profile was consistent with the previously defined AE profile.
Department of Thoracic Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan, hhorinou@ncc.go.jp.
Hidehito
H
Horinouchi
Noboru
N
Yamamoto
Yutaka
Y
Fujiwara
Ikuo
I
Sekine
Hiroshi
H
Nokihara
Kaoru
K
Kubota
Shintaro
S
Kanda
Shigehiro
S
Yagishita
Hiroshi
H
Wakui
Satoru
S
Kitazono
Hidenori
H
Mizugaki
Takuto
T
Tokudome
Tomohide
T
Tamura
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D044466:Asian People; D016190:Carboplatin / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D006801:Humans; D000074324:Ipilimumab; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D000074324:Ipilimumab; D016190:Carboplatin; D017239:Paclitaxel