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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.
- Source :
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Lung cancer (Amsterdam, Netherlands) [Lung Cancer] 2018 Sep; Vol. 123, pp. 14-21. Date of Electronic Publication: 2018 Apr 27. - Publication Year :
- 2018
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Abstract
- 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).<br />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 <superscript>2</superscript> or carboplatin (AUC5) dose was administered on day 1, and etoposide 100 mg/m <superscript>2</superscript> 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.<br />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 <subscript>max</subscript> 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).<br />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.<br /> (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)
- Subjects :
- Aged
Antineoplastic Combined Chemotherapy Protocols adverse effects
Female
Humans
Lung Neoplasms mortality
Male
Middle Aged
Protein Kinase Inhibitors administration & dosage
Protein Kinase Inhibitors pharmacokinetics
Pyrimidines administration & dosage
Pyrimidines pharmacokinetics
Small Cell Lung Carcinoma mortality
Sulfoxides administration & dosage
Sulfoxides pharmacokinetics
Treatment Outcome
Antineoplastic Combined Chemotherapy Protocols therapeutic use
Lung Neoplasms drug therapy
Lung Neoplasms pathology
Small Cell Lung Carcinoma drug therapy
Small Cell Lung Carcinoma pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1872-8332
- Volume :
- 123
- Database :
- MEDLINE
- Journal :
- Lung cancer (Amsterdam, Netherlands)
- Publication Type :
- Academic Journal
- Accession number :
- 30089585
- Full Text :
- https://doi.org/10.1016/j.lungcan.2018.04.022