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 max 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.
Bibliographical noteFunding Information:
This study was supported by Bayer AG. The study sponsor played a role in the design of the study, data interpretation, writing of the manuscript, and the decision to submit for publication. At each study center, the principal investigator was responsible for the study. Medical writing support for the manuscript was funded by the study sponsor, based on detailed direction and feedback from all authors.
This work was supported by Bayer AG.
Byoung Chul Cho, MD, PhD reports grants from Novartis, AstraZeneca, Yuhan, Dong-A, Ono/Bristol-Myers Squibb, and Merck Sharp and Dohme; and personal fees from Novartis, AstraZeneca, Yuhan, Ono/Bristol-Myers Squibb, Merck Sharp and Dohme, Boehringer Ingelheim, Roche, and Ignyta outside the submitted work. Grace K. Dy, MD reports research fees to Roswell Park Cancer Institute from Bayer, Roche, GlaxoSmithKline, Boehringer Ingelheim, AbbVie, Merck, Genentech, Novartis, ARIAD, Bristol-Myers Squibb, Pfizer, Celgene, and AstraZeneca; and consultant fees from Novartis and Astra Zeneca outside the submitted work. Nathan A. Pennell, MD, PhD reports personal fees from Eli Lilly, AstraZeneca, and Regeneron outside the submitted work. Gerard Zalcman, MD, PhD reports personal fees from Roche, Bristol-Myers Squibb, Merck Sharp and Dohme, and Boehringer Ingelheim; and meeting attendance for AstraZeneca outside the submitted work. Simon Langer, MSc reports personal fees from Bayer outside the submitted work. Fabrice Barlesi, MD, PhD reports personal fees from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Clovis Oncology, Eli Lilly Oncology, F. Hoffmann-La Roche, Novartis, Merck, Merck Sharp and Dohme, Pierre Fabre, and Pfizer outside the submitted work. Goekben Koca, MD, Prabhu Rajagopalan, PhD, Matthias Ocker, MD, and Hendrik Nogai, MD are employees of Bayer. Prabhu Rajagopalan, PhD and Matthias Ocker, MD report stocks in Bayer. The remaining authors declare no conflict of interest.
Medical writing assistance was provided by Laura Badtke, PhD, at Complete HealthVizion, Chicago, IL, based on detailed discussion and feedback from all authors. Medical writing assistance was funded by Bayer AG.
All Science Journal Classification (ASJC) codes
- Pulmonary and Respiratory Medicine
- Cancer Research