RESUMO
OBJECTIVES: This phase Ib/II study evaluated safety, pharmacokinetics, maximum tolerated dose (MTD), and efficacy of the pan-cyclin-dependent kinase inhibitor roniciclib with cisplatin-etoposide (CIS-ETOP) or carboplatin-etoposide (CARBO-ETOP) in patients with extensive-disease small-cell lung cancer (ED-SCLC). PATIENTS AND METHODS: In this open-label, non-randomized study, patients with previously untreated ED-SCLC received roniciclib twice daily (BID) in a 3â¯days on/4â¯days off schedule. Cisplatin 75 mg/m2 or carboplatin (AUC5) dose was administered on day 1, and etoposide 100â¯mg/m2 on days 1-3, of 21-day cycles. Phase Ib used a dose-escalation design to define the MTD for phase II. Pharmacokinetics were assessed. RESULTS: Forty-three patients received treatment (roniciclib 2.5â¯mg BID [+â¯CARBO-ETOP, nâ¯=â¯4;â¯+â¯CIS-ETOP, nâ¯=â¯3] and roniciclib 5â¯mg BID [+â¯CARBO-ETOP, nâ¯=â¯24;â¯+â¯CIS-ETOP, nâ¯=â¯12]). The MTD of roniciclib was 5â¯mg BID with CARBO-ETOP or CIS-ETOP. Common adverse events were nausea (90.7%) and vomiting (69.8%). Roniciclib was readily absorbed following oral administration at the MTD (median tmax 0.5-1â¯h), with a 30-40% reduction in exposure when co-administered with CARBO-ETOP or CIS-ETOP; administration of roniciclib had no effect on etoposide or platinum pharmacokinetics. The response rate was 81.4% (35/43) overall and 86.1% (31/36) in the pooled roniciclib 5â¯mg BID population (all partial responses). CONCLUSION: Roniciclib co-administered with chemotherapy in patients with ED-SCLC demonstrated tolerability, acceptable pharmacokinetics, and promising efficacy. An observed safety signal in a related phase II study resulted in discontinuation of the present study and termination of further roniciclib development.