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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 × min/mL) and paclitaxel (200 mg/m2). 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 (≥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 γ‐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. (Cancer Sci 2009)