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Lung Cancer. 2018 Sep;123:14-21. doi: 10.1016/j.lungcan.2018.04.022. Epub 2018 Apr 27.

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.

Author information

1
Yonsei Cancer Center, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea. Electronic address: cbc1971@yuhs.ac.
2
Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA. Electronic address: grace.dy@roswellpark.org.
3
Washington University in St. Louis, 1 Brookings Dr, St. Louis, MO 63130, USA. Electronic address: rgovindan@wustl.edu.
4
Seoul National University Hospital, 101, Daehak-ro, Jongno-gu, Seoul 03080, Korea. Electronic address: kimdw@snu.ac.kr.
5
Cleveland Clinic Taussig Cancer Institute, 10201 Carnegie Ave, Cleveland, OH 4419, USA. Electronic address: penneln@ccf.org.
6
University Hospital, Clinical Research Center, Avenue de la Côte de Nacre, 14033 Caen, France. Electronic address: zalcman-g@chu-caen.fr.
7
Gustave Roussy, 114 Rue Edouard Vaillant, 94800 Villejuif, France. Electronic address: benjamin.besse@gustaveroussy.fr.
8
CHA Bundang Medical Center, CHA University, 222 Yatap-dong, Bundang-gu, Seongnam-shi, Gyeongghi-do, Korea. Electronic address: kim123@cha.ac.kr.
9
Bayer AG, Müllerstraße 178, 13353 Berlin, Germany. Electronic address: goekben.koca@bayer.com.
10
Bayer HealthCare Pharmaceuticals, Inc., 100 Bayer Boulevard, PO Box 915, Whippany, NJ 07981, USA. Electronic address: prabhu.rajagopalan@bayer.com.
11
Chrestos Concept GmbH & Co. KG, Girardetstraße 1-5, 45131 Essen, Germany. Electronic address: simon.langer.ext@bayer.com.
12
Bayer AG, Müllerstraße 178, 13353 Berlin, Germany. Electronic address: matthias.ocker@bayer.com.
13
Bayer AG, Müllerstraße 178, 13353 Berlin, Germany. Electronic address: hendrik.nogai@bayer.com.
14
Aix Marseille University, Jardin du Pharo, 58, bd Charles Livon, 13284 Marseille, France; Assistance Publique Hôpitaux de Marseille, 80, rue Brochier, 13005 Marseille, France; Centre d'Essais Précoces en Cancérologie de Marseille (CLIP(2)), Hôpital La Timone - Basement F, 1st Floor, 264, rue St Pierre, 13885 Marseille, France. Electronic address: fabrice.barlesi@ap-hm.fr.

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).

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/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.

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 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).

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.

KEYWORDS:

Extensive-disease small-cell lung cancer; Platinum chemotherapy; Roniciclib

PMID:
30089585
DOI:
10.1016/j.lungcan.2018.04.022
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