Targeting Cyclin-Dependent Kinases with Small Molecule Inhibitors

Pevarello, Paolo; Bischoff, James R.; Mercurio, Ciro

doi:10.1007/978-1-60761-178-3_15

Cited by 4 publications

(1 citation statement)

References 18 publications

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“…April 2019 Roniciclib with Platinum in ED-SCLC Pan-CDK inhibitors have been extensively studied as a promising therapeutic option to disrupt the cell cycle in highly proliferative tumors, 11,16 and three selective CDK4/6 inhibitors have recently been approved by the U.S. Food and Drug Administration for the treatment of human EGFR2-negative advanced metastatic breast cancer. [17][18][19] The toxic effects of CDK inhibitors on normal cells, particularly myeloid cells and cells in gastrointestinal linings, 20 can lead to gastrointestinal and hematologic toxicities such as nausea and vomiting as observed in this study, and similar gastrointestinal toxicities have been reported in other clinical studies. 21,22 In this study, there was a higher incidence of fatal TEAEs as well as an increase in clinically important AEs, including sepsis, acute kidney injury, and thromboembolic events, in the roniciclib plus chemotherapy group than in the placebo plus chemotherapy group.…”

Section: Discussionsupporting

confidence: 55%

Phase II Study of Roniciclib in Combination with Cisplatin/Etoposide or Carboplatin/Etoposide as First-Line Therapy in Patients with Extensive-Disease Small Cell Lung Cancer

Reck

Horn

Novello

et al. 2019

Journal of Thoracic Oncology

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Introduction: This phase II study evaluated the efficacy and safety of the pan-cyclin-dependent kinase inhibitor roniciclib with platinum-based chemotherapy in patients with extensive-disease SCLC. Methods: In this randomized, double-blind study, unselected patients with previously untreated extensivedisease SCLC received roniciclib, 5 mg, or placebo twice daily according to a 3 days-on, 4 days-off schedule in 21-day cycles, with concomitant cisplatin or carboplatin on day 1 and etoposide on days 1 to 3. The primary end point was progression-free survival. Other end points included overall survival, objective response rate, and safety. Results: A total of 140 patients received treatment: 70 with roniciclib plus chemotherapy and 70 with placebo plus chemotherapy. Median progression-free survival times was 4.9 months (95% confidence interval [CI]: 4.2-5.5) with roniciclib plus chemotherapy and 5.5 months (95% CI: 4.6-5.6) with placebo plus chemotherapy (hazard ratio

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Section: Discussionsupporting

confidence: 55%

Phase II Study of Roniciclib in Combination with Cisplatin/Etoposide or Carboplatin/Etoposide as First-Line Therapy in Patients with Extensive-Disease Small Cell Lung Cancer

Reck

Horn

Novello

et al. 2019

Journal of Thoracic Oncology

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Cancer Cell Cycle

Cerveira¹,

Bizarro²,

Teixeira³

et al. 2013

Encyclopedia of Systems Biology

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Phase I dose-escalation studies of roniciclib, a pan-cyclin-dependent kinase inhibitor, in advanced malignancies

et al. 2017

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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.

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Targeting Cyclin-Dependent Kinases with Small Molecule Inhibitors

Cited by 4 publications

References 18 publications

Phase II Study of Roniciclib in Combination with Cisplatin/Etoposide or Carboplatin/Etoposide as First-Line Therapy in Patients with Extensive-Disease Small Cell Lung Cancer

Phase II Study of Roniciclib in Combination with Cisplatin/Etoposide or Carboplatin/Etoposide as First-Line Therapy in Patients with Extensive-Disease Small Cell Lung Cancer

Cancer Cell Cycle

Phase I dose-escalation studies of roniciclib, a pan-cyclin-dependent kinase inhibitor, in advanced malignancies

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