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|Ref Type||Journal Article|
|Authors||Cho BC, Dy GK, Govindan R, Kim DW, Pennell NA, Zalcman G, Besse B, Kim JH, Koca G, Rajagopalan P, Langer S, Ocker M, Nogai H, Barlesi F|
|Title||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.|
|Journal||Lung cancer (Amsterdam, Netherlands)|
|Abstract Text||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).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/m2 or carboplatin (AUC5) dose was administered on day 1, and etoposide 100 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.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 tmax 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).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.|
|Molecular Profile||Treatment Approach|
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|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
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|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
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|Unknown unknown||lung small cell carcinoma||not applicable||Carboplatin + Etoposide + Roniciclib||Phase Ib/II||Actionable||In a Phase Ib/II trial, first-line treatment with the combination of Roniciclib (BAY1000394) and either carboplatin plus etoposide or cisplatin plus etoposide demonstrated tolerability and resulted in a response rate of 81.4% (35/43; all partial responses), median OS of 12.6 mo, and median PFS of 7.3 mo in extensive disease small cell lung cancer patients; however due to a safety signal in a related trial further development of Roniciclib (BAY1000394) was discontinued (PMID: 30089585; NCT01573338).||30089585|