Phase I Study of GSK461364, a Specific and Competitive Polo-like Kinase 1 Inhibitor, in Patients with Advanced Solid Malignancies

Abstract

Purpose: GSK461364 is an ATP-competitive inhibitor of polo-like kinase 1 (Plk1). A phase I study of two schedules of intravenous GSK461364 was conducted.Experimental Design: 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.Results: Forty patients received GSK461364: 23 patients in schedule A and 17 in schedule B. Doselimiting 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.Conclusions: 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.

Polo-like Kinase 1 Inhibitors and Their Potential Role in Anticancer Therapy, with a Focus on NSCLC

“…Future clinical studies should include the detection of pharmacodynamic biomarkers, such as phospho-histone H3, to validate Plk1 as the tumor target. In the first-in-humans phase I study of GSK461364 in advanced solid tumors, Plk1 inhibition in tumor cells was confirmed on the basis of the analysis of phospho-histone H3 expression in circulating tumor cells (59). Other promising biomarker assays for Plk1 inhibition in vivo have been developed, such as an immunohistochemical approach that measures serine 46-phosphorylation of the translational controlled tumor protein by Plk1 (62) and an ELISA-based assay that measures phosphorylation of the PBD-binding protein 1 (PBIP1, also known as MLF1 or CENP-U) by Plk1 (63).…”

“…The recommended phase II dose for GSK461364 was 225 mg on days 1, 8, and 15 in a 28-day cycle. Because of the high incidence (20%) of venous thromboembolism, GSK461364 should involve coadministration of prophylactic anticoagulation for further clinical evaluation (59).…”

Personalizing the Treatment of Pediatric Medulloblastoma: Polo-like Kinase 1 as a Molecular Target in High-Risk Children

“…Our study tests the PLK1 small-molecule inhibitor, BI2536, which has been evaluated in patients with cancer (33,34). Various other small molecule inhibitors to PLK1 have been designed and evaluated in phase I/II clinical trials including BI2536, BI6727, Rigosertib, and GSK461364 (35)(36)(37)(38)(39). None of these trials have specifically addressed the possibility that PLK1 inhibitors may be beneficial for the treatment of brain tumors.…”

Polo-like Kinase 1: A Potential Therapeutic Option in Combination with Conventional Chemotherapy for the Management of Patients with Triple-Negative Breast Cancer

“…These results suggest that PLK1 and PLK4 may represent attractive therapeutic targets for this subgroup of breast cancer. We then focused on PLK1 because several PLK1 inhibitors have been evaluated in clinical trials (8,27,34,35).…”