TY - JOUR
T1 - Phase i dose-escalation studies of roniciclib, a pan-cyclin-dependent kinase inhibitor, in advanced malignancies
AU - Bahleda, Rastislav
AU - Grilley-Olson, Juneko E.
AU - Govindan, Ramaswamy
AU - Barlesi, Fabrice
AU - Greillier, Laurent
AU - Perol, Maurice
AU - Ray-Coquard, Isabelle
AU - Strumberg, Dirk
AU - Schultheis, Beate
AU - Dy, Grace K.
AU - Zalcman, Gérard
AU - Weiss, Glen J.
AU - Walter, Annette O.
AU - Kornacker, Martin
AU - Rajagopalan, Prabhu
AU - Henderson, David
AU - Nogai, Hendrik
AU - Ocker, Matthias
AU - Soria, Jean Charles
N1 - Publisher Copyright:
© 2017 The Author(s).
PY - 2017/6/6
Y1 - 2017/6/6
N2 - Background:To evaluate safety, pharmacokinetics, and maximum tolerated dose of roniciclib in patients with advanced malignancies, with dose expansion to evaluate clinical benefit at the recommended phase II dose (RP2D).Methods:Two phase I dose-escalation studies evaluated two roniciclib dosing schedules: 3 days on/4 days off or 4 weeks on/2 weeks off. The expansion phase included patients with small-cell lung cancer (SCLC), ovarian cancer, or tumour mutations involving the CDK signalling pathway.Results:Ten patients were evaluable in the 4 weeks on/2 weeks off schedule (terminated following limited tolerability) and 47 in the 3 days on/4 days off schedule dose-escalation cohorts. On the 3 days on/4 days off schedule, RP2D was 5 mg twice daily in solid tumours (n=40); undetermined in lymphoid malignancies (n=7). Common roniciclib-related adverse events included nausea (76.6%), fatigue (65.8%), diarrhoea (63.1%), and vomiting (57.7%). Roniciclib demonstrated rapid absorption and dose-proportional increase in exposure. One partial response (1.0%) was observed. In RP2D expansion cohorts, the disease control rate (DCR) was 40.9% for patients with ovarian cancer (n=25), 17.4% for patients with SCLC (n=33), and 33.3% for patients with CDK-related tumour mutations (n=6).Conclusions:Roniciclib demonstrated an acceptable safety profile and moderate DCR in 3 days on/4 days off schedule.
AB - Background:To evaluate safety, pharmacokinetics, and maximum tolerated dose of roniciclib in patients with advanced malignancies, with dose expansion to evaluate clinical benefit at the recommended phase II dose (RP2D).Methods:Two phase I dose-escalation studies evaluated two roniciclib dosing schedules: 3 days on/4 days off or 4 weeks on/2 weeks off. The expansion phase included patients with small-cell lung cancer (SCLC), ovarian cancer, or tumour mutations involving the CDK signalling pathway.Results:Ten patients were evaluable in the 4 weeks on/2 weeks off schedule (terminated following limited tolerability) and 47 in the 3 days on/4 days off schedule dose-escalation cohorts. On the 3 days on/4 days off schedule, RP2D was 5 mg twice daily in solid tumours (n=40); undetermined in lymphoid malignancies (n=7). Common roniciclib-related adverse events included nausea (76.6%), fatigue (65.8%), diarrhoea (63.1%), and vomiting (57.7%). Roniciclib demonstrated rapid absorption and dose-proportional increase in exposure. One partial response (1.0%) was observed. In RP2D expansion cohorts, the disease control rate (DCR) was 40.9% for patients with ovarian cancer (n=25), 17.4% for patients with SCLC (n=33), and 33.3% for patients with CDK-related tumour mutations (n=6).Conclusions:Roniciclib demonstrated an acceptable safety profile and moderate DCR in 3 days on/4 days off schedule.
KW - CDK inhibitor
KW - roniciclib
KW - solid tumours
UR - http://www.scopus.com/inward/record.url?scp=85020444616&partnerID=8YFLogxK
U2 - 10.1038/bjc.2017.92
DO - 10.1038/bjc.2017.92
M3 - Article
C2 - 28463960
AN - SCOPUS:85020444616
SN - 0007-0920
VL - 116
SP - 1505
EP - 1512
JO - British Journal of Cancer
JF - British Journal of Cancer
IS - 12
ER -