First results from a phase I trial of AZD8055, a dual mTORC1 and mTORC2 inhibitor.

Abstract

3096 Background: AZD8055 is a dual mTORC1/mTORC2 inhibitor with properties that prevent the feedback activation of AKT seen with rapalogues. This is the first-in-man study of AZD8055 to determine the safety, PK and preliminary efficacy of two oral formulations in patients with advanced solid tumours (NCT00731263). Another dual mTORC1/mTORC2 inhibitor, AZD2014, is currently being tested in the clinic. Methods: In an open-label, ascending dose study, cohorts of 3 or 6 patients received a single dose of AZD8055 followed 1 week later by continuous, twice-daily dosing. Starting at 10 mg, each subsequent cohort received an increased dose until a non-tolerated dose was reached. The formulation was switched from oral solution to tablet when the tablet became available. Safety and PK data were collected in addition to FDG-PET and RECIST. Modulation of AKT phosphorylation on serine 473 and of 4EBP1 phosphorylation on threonine 37/46 was measured in peripheral tissue after single administration of AZD8055 to confirm proof-of-mechanism. Results: 49 patients (42 evaluable) were dosed in seven cohorts: oral solution; 10, 20, 40 mg BD, tablet; 40, 60, 90, 120 mg BD. Non-tolerated dose was 120 mg BD and so maximum tolerated dose (MTD) was 90 mg BD. Dose limiting toxicities of CTC grade 3 transaminases were reported with 40 mg BD solution (n=1), 90 mg BD tablet (n=1), 120 mg BD tablet (n=3). No cases of Hys law were observed. Onset of increased transaminases was typically between day 35 and 45 but there was no clear relationship with plasma concentration of AZD8055. AZD8055 was rapidly absorbed with median tmax of 0.5 h for both single dose (n=49) and steady state (n=36). Elimination was rapid with mean t1/2 of 2.4 h for single dose (SD=1.1, n=49) and 2.7 h for steady state (SD=0.79, n=36). AZD8055 showed a large apparent volume of distribution and high apparent clearance: mean Vss/F 2400L (SD=2062; 90 mg dose, n=11), mean Cl/F 950 L/h (SD=889; 90 mg dose, n=11). Pharmacodynamic changes in peripheral blood mononuclear cells were observed and results will be presented. Conclusions: The MTD for AZD8055 is 90 mg BD. Toxicities frequently associated with administration of rapalogues such as rash and mucositis were not dose limiting. Updated data will be presented.