Safety, tolerability, pharmacokinetics and pharmacodynamics of the oral cyclin-dependent kinase inhibitor AZD5438 when administered at intermittent and continuous dosing schedules in patients with advanced solid tumours - PubMed (original) (raw)

Clinical Trial

. 2010 Apr;21(4):884-894.

doi: 10.1093/annonc/mdp377. Epub 2009 Oct 13.

G K Schwartz 2, M R Middleton 3, D D Amakye 4, H Swaisland 4, R S Midgley 3, M Ranson 5, S Danson 6, H Calvert 7, R Plummer 7, C Morris 4, R D Carvajal 2, L R Chirieac 8, J H M Schellens 9, G I Shapiro 10

Affiliations

Clinical Trial

Safety, tolerability, pharmacokinetics and pharmacodynamics of the oral cyclin-dependent kinase inhibitor AZD5438 when administered at intermittent and continuous dosing schedules in patients with advanced solid tumours

D S Boss et al. Ann Oncol. 2010 Apr.

Abstract

Background: AZD5438 is an orally bioavailable inhibitor of cyclin E-cdk2, cyclin A-cdk2 and cyclin B-cdk1 complexes. Three phase I studies assessed the clinical safety, tolerability, pharmacokinetics and pharmacodynamics of AZD5438 when administered in different dosing schedules.

Patients and methods: AZD5438 was administered four times daily, once every 7 days (study 1), for 14 consecutive days followed by 7 days of rest (study 2), or continuously (study 3), to patients with advanced solid tumours. Dose escalation proceeded until the emergence of dose-limiting toxic effects.

Results: Sixty-four patients were included across the three studies (19, 17 and 28, respectively). Nausea and vomiting were the most common adverse events. When dosed continuously, 40 mg four times daily was considered intolerable, and due to safety issues, all studies were terminated prematurely. Consequently, no intolerable dose was identified during the weekly schedule. Pharmacokinetics demonstrated dose-proportional exposure, high interpatient variability and accumulation after multiple doses. Skin biopsies indicated reduced retinoblastoma protein phosphorylation at cdk2 phospho-sites; other pharmacodynamic assessments did not reveal consistent trends.

Conclusions: AZD5438 was generally well tolerated in a weekly dosing schedule, but not in continuous schedules. The clinical development programme for AZD5438 was discontinued owing to tolerability and exposure data from these studies.

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Figures

Figure 1.

Figure 1.

Exposure [area under the curve (AUC)] versus AZD5438 dose. This figure shows the AUC as a function of AZD5438 dose. The AUCs were calculated after a single dose of AZD5438, on day 1 of treatment. There is a dose-proportional increase in exposure, but a high interpatient variability in exposure to AZD5438.

Figure 2.

Figure 2.

Total and phospho-Rb staining in skin biopsies. (A) Skin biopsies were obtained pre-treatment (pre) and 2 h after the first dose on day 22 of continuous ADZ5438 dosing. Five-micrometer sections from formalin-fixed, paraffin-embedded samples were subjected to immunohistochemistry with the indicated antibodies. Results from patient 23 are shown (treated at the 40-mg dose level), demonstrating reduced Rb staining at the S249/T252 and S780 phospho-sites in the keratinocyte layers, suggestive of reduced cyclin-dependent kinase activity after treatment. Total Rb staining is maintained in the post-treatment sample. (B) Immunohistochemical data were quantified by scoring the nuclei of 100–200 keratinocytes as 0, 1+ or 2+. The percentage of positive nuclei was considered as 100 for each pre-treatment sample. Bars indicate the percent positive staining (1+, 2+) in each post-treatment sample, relative to the pre-treatment sample. The _x_-axis designations indicate the patient number and the dose of AZD5438 administered. In these samples, reductions in phospho-Rb staining were noted, while total Rb staining was maintained after treatment.

Figure 3.

Figure 3.

Post hoc analysis: exposure to AZD5438 and tolerability outcome in continuous dosing studies. Owing to the lack of multiple-dose data for many of the patients, the total daily area under the curve was calculated from day 1 pharmacokinetic measurements. Tolerability categories were (1) patients who completed at least the initial safety assessment period (21 or 28 days) or withdrew after 1 week due to disease progression; (2) patients who withdrew within 1 week of starting treatment due to poor tolerability or for disease-related reasons and (3) patients who discontinued due to fatality and/or dose-limiting toxicity.

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