ABSTRACT
BACKGROUND: AT9283 is an inhibitor of aurora kinases A and B with antitumor activity in preclinical models. This a First in Human phase I study assessed the safety, tolerability, pharmacokinetic and pharmacodynamic properties and preliminary efficacy of AT9283. PATIENTS AND METHODS: Patients with advanced tumors received AT9283 as a continuous central venous infusion over 3 days in cohorts of three to six patients starting at 1.5 mg/m(2)/day (equivalent to 4.5 mg/m(2)/72 h). The oral bioavailability of AT9283 was assessed in a cohort of seven patients. Pharmacodynamic analysis of biomarkers included phosphorylation of histone H3 on serine 10, proliferating cell nuclear antigen, Ki67, M30 and M65 in skin and plasma. RESULTS: Forty patients were included in all analyses. AT9283 was generally well tolerated with main toxic effects of reversible dose-related myelosuppression, gastrointestinal disturbance, fatigue and alopecia. The dose-limiting toxicity of AT9283 was grade 3 febrile neutropenia in two patients at 36 mg/m(2)/72 h and the maximum tolerated dose (MTD) was established at 27 mg/m(2)/72 h. Systemic exposure was dose proportional. The mean oral bioavailability of a 0.9 mg/m(2) dose was 29.4% (range 11.2%-36.7%). Pharmacodynamic analyses indicated antiproliferative and apoptotic activity of AT9283. Four patients with esophageal, non-small-cell lung cancer (n = 2) and colorectal cancer demonstrated RECIST stable disease ≥ 6 months. CONCLUSION: AT9283 was well tolerated up to the MTD of 27 mg/m(2)/72 h. AT9283 is currently assessed in phase II trials.
Subject(s)
Benzimidazoles/administration & dosage , Neoplasms/drug therapy , Urea/analogs & derivatives , Adult , Aged , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/blood , Antineoplastic Agents/pharmacokinetics , Aurora Kinases , Benzimidazoles/adverse effects , Benzimidazoles/blood , Benzimidazoles/pharmacokinetics , Cohort Studies , Disease Progression , Dose-Response Relationship, Drug , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/adverse effects , Enzyme Inhibitors/blood , Enzyme Inhibitors/pharmacokinetics , Female , Humans , Male , Maximum Tolerated Dose , Middle Aged , Neoplasms/blood , Neoplasms/metabolism , Neoplasms/pathology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Urea/administration & dosage , Urea/adverse effects , Urea/blood , Urea/pharmacokineticsABSTRACT
BACKGROUND: AT7519 is an inhibitor of multiple cyclin-dependent kinases (CDKs). Based on potent antitumor activity in preclinical models, a first-in-human clinical trial in refractory solid tumors investigated its safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD). PATIENTS AND METHODS: AT7519 was administered in a '3 + 3' dose- escalation scheme on 5 consecutive days every 3 weeks to patients with advanced, refractory solid tumors. Samples to monitor AT7519 PK and PD were obtained. RESULTS: Twenty-eight patients were treated at seven dose levels (1.8-40 mg/m(2)/day). At 40 mg/m(2)/day, one patient developed hypotension and ST segment elevation. At 34 mg/m(2)/day, dose-limiting toxic effects (DLTs) were QTc prolongation with one death (grade 5), fatigue (grade 4) and mucositis (grade 3). Electrocardiogram review suggested a dose-dependent increase in QTc and recruitment was discontinued without establishing a maximum tolerated dose. Four patients exhibited stable disease for >6 months and one had a prolonged partial response. PK profile revealed modest interpatient variation with linear exposure at increasing doses. Inhibition of markers of CDK activity was observed across the dose range and manifested in antiproliferative activity at a dose of 28 mg/m(2). CONCLUSION: AT7519 elicited clinical and PD activity resulting from CDK inhibition at doses below the appearance of DLT of QTc prolongation.
Subject(s)
Neoplasms/drug therapy , Neoplasms/metabolism , Piperidines/administration & dosage , Piperidines/pharmacokinetics , Pyrazoles/administration & dosage , Pyrazoles/pharmacokinetics , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Cyclin-Dependent Kinases/antagonists & inhibitors , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Humans , Infusions, Intravenous , Male , Middle Aged , Neoplasms/enzymology , Piperidines/adverse effects , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/pharmacokinetics , Pyrazoles/adverse effectsABSTRACT
A 12-month study of emergency medical admissions at one trust suggests most readmissions could not be avoided. The re-admission rate within 28 days was 10 per cent, of which 5 per cent were found to be preventable. Readmissions were higher among smokers, men and people living in hostels. The study found no evidence of increased readmissions in winter.
