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

ByoungChul Cho, Grace K. Dy, Ramaswamy Govindan, Dong Wan Kim, Nathan A. Pennell, Gerard Zalcman, Benjamin Besse, Joo Hang Kim, Goekben Koca, Prabhu Rajagopalan, Simon Langer, Matthias Ocker, Hendrik Nogai, Fabrice Barlesi

Research output: Contribution to journalArticle

5 Citations (Scopus)

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/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.

Original languageEnglish
Pages (from-to)14-21
Number of pages8
JournalLung Cancer
Volume123
DOIs
Publication statusPublished - 2018 Sep 1

Fingerprint

Cyclin-Dependent Kinases
Small Cell Lung Carcinoma
Etoposide
Combination Drug Therapy
Carboplatin
Cisplatin
Maximum Tolerated Dose
Pharmacokinetics
Safety
Platinum
Nausea
Vomiting
Oral Administration
Appointments and Schedules

All Science Journal Classification (ASJC) codes

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research

Cite this

Cho, ByoungChul ; Dy, Grace K. ; Govindan, Ramaswamy ; Kim, Dong Wan ; Pennell, Nathan A. ; Zalcman, Gerard ; Besse, Benjamin ; Kim, Joo Hang ; Koca, Goekben ; Rajagopalan, Prabhu ; Langer, Simon ; Ocker, Matthias ; Nogai, Hendrik ; Barlesi, Fabrice. / 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. In: Lung Cancer. 2018 ; Vol. 123. pp. 14-21.
@article{1e739f536f754460828c666a2c1a2d6b,
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",
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/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.",
author = "ByoungChul Cho and Dy, {Grace K.} and Ramaswamy Govindan and Kim, {Dong Wan} and Pennell, {Nathan A.} and Gerard Zalcman and Benjamin Besse and Kim, {Joo Hang} and Goekben Koca and Prabhu Rajagopalan and Simon Langer and Matthias Ocker and Hendrik Nogai and Fabrice Barlesi",
year = "2018",
month = "9",
day = "1",
doi = "10.1016/j.lungcan.2018.04.022",
language = "English",
volume = "123",
pages = "14--21",
journal = "Lung Cancer",
issn = "0169-5002",
publisher = "Elsevier Ireland Ltd",

}

Cho, B, 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 2018, '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', Lung Cancer, vol. 123, pp. 14-21. https://doi.org/10.1016/j.lungcan.2018.04.022

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. / Cho, ByoungChul; Dy, Grace K.; Govindan, Ramaswamy; Kim, Dong Wan; Pennell, Nathan A.; Zalcman, Gerard; Besse, Benjamin; Kim, Joo Hang; Koca, Goekben; Rajagopalan, Prabhu; Langer, Simon; Ocker, Matthias; Nogai, Hendrik; Barlesi, Fabrice.

In: Lung Cancer, Vol. 123, 01.09.2018, p. 14-21.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 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

AU - Cho, ByoungChul

AU - Dy, Grace K.

AU - Govindan, Ramaswamy

AU - Kim, Dong Wan

AU - Pennell, Nathan A.

AU - Zalcman, Gerard

AU - Besse, Benjamin

AU - Kim, Joo Hang

AU - Koca, Goekben

AU - Rajagopalan, Prabhu

AU - Langer, Simon

AU - Ocker, Matthias

AU - Nogai, Hendrik

AU - Barlesi, Fabrice

PY - 2018/9/1

Y1 - 2018/9/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85049104249&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85049104249&partnerID=8YFLogxK

U2 - 10.1016/j.lungcan.2018.04.022

DO - 10.1016/j.lungcan.2018.04.022

M3 - Article

VL - 123

SP - 14

EP - 21

JO - Lung Cancer

JF - Lung Cancer

SN - 0169-5002

ER -