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.

Figure 1

Functional renal perfusion imaging by MAG3 nuclear scanning, performed pretreatment (A) and post-treatment on days 3 (B) and 14 (C), in a patient who experienced a reversible decline in renal function when treated with seliciclib at 1600 mg day⁻¹. Baseline pre-treatment renogram (A) shows slight asymmetry in renal function with the right kidney (dark green) slightly poorer than the left (light green). Day 3 renogram (B) shows changes consistent with bilateral parenchymal retention and delayed intrarenal transit bilaterally, which then almost completely recovers by day 14 (C).

Figure 2

Concentration–time pharmacokinetic profiles (mean±standard deviation) for all the evaluated dose levels of seliciclib (100, 200, 800 mg) on both days 1 (A) and 7 (B).

Figure 3

Seliciclib AUC_(last) values for all tested dose levels, on both days 1 (A) and 7 (B), as a function of daily administered dose.

Figure 4

Seliciclib C_max values for all tested dose levels, on both days 1 (A) and 7 (B), as a function of daily administered dose.