A phase I trial of AT9283 (a selective inhibitor of Aurora kinases) in children and adolescents with solid tumours: A Cancer Research UK study
Mené sur 33 jeunes patients atteints d'une tumeur solide, cet essai de phase I évalue la dose maximale tolérée et divers paramètres d'activité clinique d'un composé appelé AT9283, un inhibiteur des kinases Aurora A et B
Purpose: A phase I trial of AT9283 (a multi-targeted inhibitor of Aurora kinases A and B) was conducted in children and adolescents with solid tumours, to identify maximum-tolerated dose (MTD), safety, efficacy, pharmacokinetics and pharmacodynamic activity. Experimental Design: AT9283 was administered as a 72-hour continuous intravenous infusion every 3 weeks. A rolling-six design, explored six dose levels (7, 9, 11.5, 14.5, 18.5 and 23 mg/m2/day). Pharmacokinetic and pharmacodynamic assessments, included inhibition of phospho-histone 3 (pHH3) in paired skin punch biopsies. Results: Thirty three patients were evaluable for toxicity. There were six dose limiting toxicities and the MTD was 18.5 mg/m2/day. Most common drug-related toxicities were haematological (neutropaenia, anaemia and thrombocytopaenia in 36.4, 18.2 and 21.2% of patients), which were Grade ≥3 in 30.3, 6.1 and 3% of patients. Non-haematological toxicities included fatigue, infections, febrile neutropaenia and ALT elevation. One patient with central nervous system primitive neuroectodermal tumour (CNS-PNET) achieved a Partial Response after 16 cycles and three cases were stable for 4 or more cycles. Plasma concentrations were comparable to those in adults at the same dose level, clearance was similar although half-life was shorter (4.9±1.5 hours, compared to 8.4±3.7 hours in adults). Inhibition of Aurora kinase B was shown by reduction in pHH3 in 17/18 patients treated at ≥11.5 mg/m2/day. Conclusions: AT9283 was well tolerated in children and adolescents with solid tumours with manageable haematologic toxicity. Target inhibition was demonstrated. Disease stabilisation was documented in intra-cranial and extra-cranial paediatric solid tumours and a phase II dose determined.