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 (pts) with advanced solid tumors (NCT00731263).

Methods: In an open-label, ascending dose study, cohorts of 3 or 6 pts 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 study included a formulation switch from oral solution to tablet. Assessments included safety, PK, FDG-PET and RECIST. Modulation of AKT phosphorylation on serine 473 (pAKT) and of 4EBP1 phosphorylation on threonine 37/46 (p4EBP1) was measured in peripheral tissue after single administration of AZD8055 to confirm proof-of-mechanism.

Results: 49 pts (42 evaluable) were dosed in seven cohorts: oral solution; 10, 20, 40 mg BD, tablet; 40, 60, 90, 120 mg BD. The most frequent adverse events (AEs) across all cohorts, regardless of causality, were: fatigue (55%), nausea (35%), decreased appetite (33%), diarrhea (31%), constipation (27%), increased ALT (22%), increased AST (22%), dyspnea exertional (22%) and vomiting (22%). The most frequent AEs assessed by the investigator to be potentially drug-related were increased ALT (22%) and increased AST (22%). Three pts (6%) had a dose reduction due to an AE and 11 pts (22%) had a dose interruption due to an AE. Non-tolerated dose was 120 mg BD; maximum tolerated dose (MTD) was 90 mg BD. Dose limiting toxicities of CTC grade 3 transaminases were reported with the 40 mg BD solution (n=1), 90 mg BD tablet (n=1), and 120 mg BD tablet (n=3). No cases of Hy's law were observed. Onset of increased transaminases was typically between day 35 and 45. AZD8055 was orally bioavailable and rapidly absorbed following single and multiple doses with median tmax of ∼0.5 h. Elimination was rapid across all dose groups with mean t1/2 of 1.9–3.1 h. Exposure increased approximately proportionally with increasing dose although variability within cohorts was high and exposures across dose groups overlapping. At the MTD, 5 pts had data available for change in p4EBP1. A decrease was observed in 2 pts at 2 h, although there was significant variability in pre-dose marker levels. Change in pAKT was measured in 10 pts at the MTD; a decrease at 2 h was noted in all 6 pts who had a baseline pAKT value >5%, although the majority of pts had low pre-dose levels (<15%). No RECIST responses were observed but 7 pts had stable disease for ≥4 months; metabolic responses, as measured by FDG-PET, were seen at doses of 40 mg BD and above.

Conclusions: The MTD for AZD8055 is 90 mg BD. Apart from transaminitis, which occurred at most dose levels, the drug had an acceptable toxicity profile. Toxicities frequently associated with administration of rapalogues such as rash and mucositis were not dose limiting. No conclusions can be drawn from changes in p4EBP1 and pAKT because of variability in pre-dose levels and the small number of pts. The biological relevance of the decreases in pAKT is difficult to interpret due to very low pre-dose levels in the majority of pts. A more sensitive PRP assay is being pursued for future projects to mitigate against low baseline values of pAKT. No RECIST responses were observed. Clinical development of AZD8055 has been discontinued.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A168.