Phase I study of TLR9 agonist PF-3512676 in combination with carboplatin and paclitaxel in patients with advanced non-small-cell lung cancer.
This phase I, open-label study investigated the Toll-like receptor 9 agonist, PF-3512676, in combination with carboplatin and paclitaxel in Japanese patients with advanced, non-small-cell lung cancer (NSCLC). Patients (n = 12) with treatment-naive stage IIIB or IV NSCLC received single-agent PF-3512676 subcutaneously once during the first 7 days (monotherapy phase) in three escalating dose levels (0.1, 0.2, and 0.4 mg/kg) followed by a combination phase during which patients received 0.1 or 0.2 mg/kg PF-3512676 subcutaneously on days 8 and 15 of each 3-week cycle of carboplatin (area under the curve, 6 mg x min/mL) and paclitaxel (200 mg/m(2)). Safety and pharmacokinetics of PF-3512676 were assessed during monotherapy and combination therapy phases. PF-3512676 was tolerable as monotherapy or in combination with chemotherapy in patients with NSCLC. Most common treatment-related, non-hematologic adverse events (AEs) throughout the study were injection-site reactions (n = 12, 100%) and flu-like symptoms (n = 11, 91.7%) that were each grade 1 or 2 in all but one patient. All patients experienced neutropenia and leukopenia (>or=grade 3 in 11 [91.7%] and seven [58.3%] patients, respectively). One patient in dose level 2 had a dose-limiting toxicity: grade 3 rash and grade 3 increase in gamma-glutamyltransferase during combination therapy. Mean PF-3512676 half-life ranged from 4.8 to 21.6 h (longer with higher doses). Four (33%) patients had objective responses (one complete response, three partial responses), and seven (58%) patients achieved stable disease. PF-3512676 as monotherapy and in combination with chemotherapy had an acceptable safety profile in Japanese patients with treatment-naive NSCLC.
Yamada
Kazuhiko
K
Department of Internal Medicine, National Cancer Center Hospital, Tokyo, Japan.
Nakao
Masao
M
Fukuyama
Chikara
C
Nokihara
Hiroshi
H
Yamamoto
Noboru
N
Sekine
Ikuo
I
Kunitoh
Hideo
H
Ohe
Yuichiro
Y
Ohki
Emiko
E
Hashimoto
Junichi
J
Tamura
Tomohide
T
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D017239:Paclitaxel / Q000008:administration & dosage; D051217:Toll-Like Receptor 9 / Q000037:antagonists & inhibitors*
D009838:Oligodeoxyribonucleotides; C483020:ProMune; D051217:Toll-Like Receptor 9; D016190:Carboplatin; D017239:Paclitaxel