Clinical pharmacodynamic/exposure characterisation of the multikinase inhibitor ilorasertib (ABT-348) in a phase 1 dose-escalation trial
Mené sur 58 patients atteints d'une tumeur de stade avancé, cet essai de phase I évalue les caractéristiques pharmacodynamiques, l'activité antitumorale et la dose maximale tolérée de l'ilorasertib, un inhibiteur multikinase (Aurora et VEGFR) dispensé par voie intraveineuse en monothérapie
Background : Ilorasertib (ABT-348) inhibits Aurora and VEGF receptor (VEGFR) kinases. Patients with advanced solid tumours participated in a phase 1 dose-escalation trial to profile the safety, tolerability, and pharmacokinetics of ilorasertib. Methods : Ilorasertib monotherapy was administered at 10–180 mg orally once daily (Arm I, n = 23), 40–340 mg orally twice daily (Arm II, n = 28), or 8–32 mg intravenously once daily (Arm III, n = 7), on days 1, 8, and 15 of each 28-day cycle. Results : Dose-limiting toxicities were predominantly related to VEGFR inhibition. The most frequent treatment-emergent adverse events ( > 30%) were: fatigue (48%), anorexia (34%), and hypertension (34%). Pharmacodynamic markers suggested that ilorasertib engaged VEGFR2 and Aurora B kinase, with the VEGFR2 effects reached at lower doses and exposures than Aurora inhibition effects. In Arm II, one basal cell carcinoma patient (40 mg twice daily (BID)) and one patient with adenocarcinoma of unknown primary site (230 mg BID) had partial responses. Conclusions : In patients with advanced solid tumours, ilorasertib treatment resulted in evidence of engagement of the intended targets and antitumour activity, but with maximum inhibition of VEGFR family kinases occurring at lower exposures than typically required for inhibition of Aurora B in tissue.