A phase I trial of the selective oral cyclin-dependent kinase inhibitor seliciclib (CYC202; R-Roscovitine), administered twice daily for 7 days every 21 days

Abstract

Seliciclib (CYC202; R-roscovitine) is the first selective, orally bioavailable inhibitor of cyclin-dependent kinases 1, 2, 7 and 9 to enter clinical trial. Preclinical studies showed antitumour activity in a broad range of human tumour xenografts. A phase I trial was performed with a 7-day b.i.d. p.o. schedule. Twenty-one patients (median age 62 years, range: 39 -73 years) were treated with doses of 100, 200 and 800 b.i.d. Dose-limiting toxicities were seen at 800 mg b.i.d.; grade 3 fatigue, grade 3 skin rash, grade 3 hyponatraemia and grade 4 hypokalaemia. Other toxicities included reversible raised creatinine (grade 2), reversible grade 3 abnormal liver function and grade 2 emesis. An 800 mg portion was investigated further in 12 patients, three of whom had MAG3 renograms. One patient with a rapid increase in creatinine on day 3 had a reversible fall in renal perfusion, with full recovery by day 14, and no changes suggestive of renal tubular damage. Further dose escalation was precluded by hypokalaemia. Seliciclib reached peak plasma concentrations between 1 and 4 h and elimination half-life was 2 -5 h. Inhibition of retinoblastoma protein phosphorylation was not demonstrated in peripheral blood mononuclear cells. No objective tumour responses were noted, but disease stabilisation was recorded in eight patients; this lasted for a total of six courses (18 weeks) in a patient with ovarian cancer.

R-Roscovitine simultaneously targets both the p53 and NF-κB pathways and causes potentiation of apoptosis: implications in cancer therapy

“…cases, in combination with nongenotoxic agents. 30 A model based on our study is presented in Figure 8. In this study, we have shown that R-Roscovitine inhibits TNFa-induced NF-kB pathway through inhibition of the IKK kinase activity and phosphorylation and degradation of IkBa.…”

From Roscovitine to CYC202 to Seliciclib – from bench to bedside: discovery and development

“…The absence of myelosuppression, reported in preclinical and clinical studies of roscovitine [134,137], is clinically beneficial. However, low hematotoxicity of roscovitine might in reality reflect poor distribution of roscovitine to the bone marrow.…”

“…Alzheimer's disease, viral infections, protozoal infections, and inflammatory diseases, are ongoing. The poor pharmacokinetic profile (rapid metabolism and short elimination half-life in rodents and man) and the insufficient exposure to the drug in cancer patients may explain the modest success in clinical trials [124,131,[135][136][137]. Several attempts to overcome pharmacokinetic barriers that limit the clinical use of roscovitine are ongoing.…”

“…The elimination half-life was found to be dose dependent and ranged between 2-5hr. Neither objective tumor responses nor inhibitions of retinoblastoma protein phosphorylation (PD endpoint) in mononuclear cells in peripheral blood were observed [137].…”

Cyclin-Dependent Kinases (Cdk) as Targets for Cancer Therapy and Imaging

“…Combination studies currently recruiting patients are initiated for P276-00 administered along with radiation in head and neck squamous cell carcinoma patients, and in combination with gemcitabine in patients with advanced pancreatic cancer. A phase I clinical trial of R-roscovitine has been performed in 22 patients with advanced cancer utilizing several schedules resulting in only minor therapeutical success with hypokalemia, rash and fatigue as dose limiting side-effects (Benson et al, 2007). Further evaluation of R-roscovitine in patients with non-small cell lung cancer was described: Rroscovitine in combination with cisplatin and gemcitabine in phase I showed similar adverse events, e. g., hypokalemia, liver -glutamyltranspeptidase elevation, vomiting, and a 42.9% response rate in 14 patients (Siegel-Lakhai et al, 2005).…”