S-Space College of Medicine/School of Medicine (의과대학/대학원) Cancer Research Institute (암연구소) Journal Papers (저널논문_암연구소)
Phase Ib/II study of the pan-cyclin-dependent kinase inhibitor roniciclib in combination with chemotherapy in patients with extensive-disease small-cell lung cancer
- Cho, Byoung Chul; Dy, Grace K.; Govindan, Ramaswamy; Kim, Dong-Wan; Pennell, Nathan A.; Zalcman, Gerard; Besse, Benjamin; Kim, Joo-Hang; Koca, Goekben; Rajagopalan, Prabhu; Langer, Simon; Ocker, Matthias; Nogai, Hendrik; Barlesi, Fabrice
- Issue Date
- Lung Cancer, Vol.123, pp.14-21
- 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 3 days on/4 days off schedule. Cisplatin 75 mg/m(2) or carboplatin (AUC5) dose was administered on day 1, and etoposide 100 mg/m(2) 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 2.5 mg BID [+ CARBO-ETOP, n = 4; + CIS-ETOP, n = 3] and roniciclib 5 mg BID [+ CARBO-ETOP, n = 24; + CIS-ETOP, n = 12]). The MTD of roniciclib was 5 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 t,,, 0.5-1 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 5 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.
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