Steve R. Ritland

Preclinical biomarkers for a cyclin-dependent kinase inhibitor translate to candidate pharmacodynamic biomarkers in phase I patients

A genomics-based approach to identify pharmacodynamic biomarkers was used for a cyclin-dependent kinase inhibitory drug. R547 is a potent cyclin-dependent kinase inhibitor with a potent antiproliferative effect at pharmacologically relevant doses and is currently in phase I clinical trials. Using preclinical data derived from microarray experiments, we identified pharmacodynamic biomarkers to test in blood samples from patients in clinical trials. These candidate biomarkers were chosen based on several criteria: relevance to the mechanism of action of R547, dose responsiveness in preclinical models, and measurable expression in blood samples. We identified 26 potential biomarkers of R547 action and tested their clinical validity in patient blood samples by quantitative real-time PCR analysis. Based on the results, eight genes (FLJ44342, CD86, EGR1, MKI67, CCNB1, JUN, HEXIM1, and PFAAP5) were selected as dose-responsive pharmacodynamic biomarkers for phase II clinical trials. [Mol Cancer Ther 2009;8(9):2517–25]

A Phase I Clinical and Pharmacokinetic Study of Ro 31-7453 Given as a 7- or 14-Day Oral Twice Daily Schedule Every 4 Weeks in Patients with Solid Tumors

Purpose: This is a dose-finding Phase I study of oral Ro 31-7453, a new class of antimitotic drug with promising preclinical activity in several chemoresistant models. Experimental Design: Two schedules of oral Ro 31-7453 (every 12 h) given for either 7 or 14 consecutive days repeated every 4 weeks were explored consecutively. Results: Thirty-seven patients with refractory cancer entered the study (14 on the 7-day schedule and 23 on the 14-day schedule). Median age was 63 years (range, 40–77 years), and median Karnofsky performance status was 80 (range, 60–100); the most frequent diagnosis was colorectal carcinoma (16 patients). Dose levels of 100, 200, 240, and 280 mg/m2 twice daily (bid) for 7 days and 70, 100, 125, and 150 mg/m2 bid for 14 days were explored. A total of 110 cycles were administered, the median number of cycles received was 3 (range, 1–7); six patients completed 6 or more cycles. Myelosuppression and mucositis were dose-limiting with both schedules. Fatigue and gastrointestinal toxicities other than mucositis were frequent but generally mild. The maximum tolerated doses were 200 mg/m2 bid and 125 mg/m2 bid for the 7- and 14-day schedules, respectively. Pharmacokinetic analysis showed rapid absorption and metabolism. The area under the concentration-time curve and trough concentrations of Ro 31-7453 and two active metabolites appeared dose proportional with a t1/2 of ∼9 h and a tmax of ∼4 h. One patient with pretreated lung cancer had a partial response. Conclusions: Both Ro 31-7453 regimens were feasible, but the 14-day schedule at the recommended dose of 125 mg/m2 bid was selected for further monotherapy Phase II evaluation because of its higher preclinical activity. This regimen is convenient, well tolerated, and has a favorable pharmacokinetic profile.

[14] Analysis of p53 mutations in human gliomas by RNA single-strand conformational polymorphism

Publisher Summary This chapter examines the leukocytes and tumor tissue of patients with brain tumors for p53 mutations. Because most mutations that occur in the p53 gene are single base pair mutations, a technique sensitive for the detection of such alteration using RNA single-strand conformational polymorphisms (rSSCP) has been developed. The determination of the genetic cause(s) and pathway(s) of oncogenesis for human cancers is important so that effective diagnosis and treatment modalities may be developed. These pathways are thought to vary from one tumor type to another, although the components are often the same negatively and positively acting gene product cell-cycle regulators. An important negative regulator of tumorigenesis is the p53 protein. The inactivation of the gene by mutation or of the p53 protein itself by oncogene products of tumor viruses is important in several tumors. Germline p53 mutations in patients from pedigree affected with Li-Fraumeni syndrome have also been shown to predispose carriers to a higher incidence of initial primary and second primary cancers, such as brain tumors, sarcomas, leukemias, breast carcinomas, and other neoplasms. Thus, the detection of somatic or germline mutations are important influences in the treatment and prognosis of these patients.