Abstract
GSK461364 is an ATP-competitive inhibitor of polo-like kinase 1 (Plk1). A phase I study of two schedules of intravenous GSK461364 was conducted. GSK461364 was administered in escalating doses to patients with solid malignancies by two schedules, either on days 1, 8, and 15 of 28-day cycles (schedule A) or on days 1, 2, 8, 9, 15, and 16 of 28-day cycles (schedule B). Assessments included pharmacokinetic and pharmacodynamic profiles, as well as marker expression studies in pretreatment tumor biopsies. Forty patients received GSK461364: 23 patients in schedule A and 17 in schedule B. Dose-limiting toxicities (DLT) in schedule A at 300 mg (2 of 7 patients) and 225 mg (1 of 8 patients) cohorts included grade 4 neutropenia and/or grade 3-4 thrombocytopenia. In schedule B, DLTs of grade 4 pulmonary emboli and grade 4 neutropenia occurred at 7 or more days at 100 mg dose level. Venous thrombotic emboli (VTE) and myelosuppression were the most common grade 3-4, drug-related events. Pharmacokinetic data indicated that AUC (area under the curve) and C(max) (maximum concentration) were proportional across doses, with a half-life of 9 to 13 hours. Pharmacodynamic studies in circulating tumor cells revealed an increase in phosphorylated histone H3 (pHH3) following drug administration. A best response of prolonged stable disease of more than 16 weeks occurred in 6 (15%) patients, including 4 esophageal cancer patients. Those with prolonged stable disease had greater expression of Ki-67, pHH3, and Plk1 in archived tumor biopsies. The final recommended phase II dose for GSK461364 was 225 mg administered intravenously in schedule A. Because of the high incidence (20%) of VTE, for further clinical evaluation, GSK461364 should involve coadministration of prophylactic anticoagulation.
Highlights
The polo-like kinase (Plk) family comprises 4 members (Plk1–4), of which Plk[1] has a prominent mitotic role: It is required for centrosome maturation, chromosome condensation, and cytokinesis (1), as well as other functions including cell polarity, DNA damage response, and p53 pathways (2–4)
Pharmacokinetic data indicated that elimination t1/2 (AUC) and Cmax were proportional across doses, with a half-life of 9 to 13 hours
Pharmacodynamic studies in circulating tumor cells revealed an increase in phosphorylated histone H3 following drug administration
Summary
The polo-like kinase (Plk) family comprises 4 members (Plk1–4), of which Plk[1] has a prominent mitotic role: It is required for centrosome maturation, chromosome condensation, and cytokinesis (1), as well as other functions including cell polarity, DNA damage response, and p53 pathways (2–4). The constitutive expression of PLK1 in NIH3T3 fibroblasts drives malignant transformation and results in tumor formation in nude mice (8) It is an attractive target for cancer treatment, and a number of Plk inhibitors (Plki), with varying specificity for Plk isoforms, are currently in clinical trials (9, 10). A strategy of Plk[1] inhibition is based on the finding that PLK1 has been shown to be amplified in esophageal cancer and the protein is overexpressed in a number of hematologic and solid malignancies. This phase I study was conducted to determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetics of GSK461364 given in 2 competing IV schedules. This trial shows the effectiveness of PLK1 inhibition in the treatment of solid tumors but recommends the use of GSK461364 alongside prophylactic anticoagulants in future trials
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