Phase I clinical trial of an allosteric AKT inhibitor, MK-2206, using a once weekly (QW) dose regimen in patients with advanced solid tumors.

3037^ Background: AKT is a key regulator of cellular proliferation, apoptosis and growth. A range of cancers have genetic aberrations that involve the PI3K/AKT pathway, leading to abnormal AKT hyperactivation and tumor progression. MK-2206 is a novel potent investigational AKT inhibitor, which was initially administered orally in a QOD schedule, where the maximum tolerated dose (MTD) was established at 60mg, based on safety and biomarker studies (Yap et al, ASCO 2010). In view of a long half-life (t1/2) (60-80h), a QW schedule was subsequently pursued to explore the potential of less frequent dosing to circumvent feedback activation of alternative signaling pathways in response to sustained and uninterrupted AKT inhibition. Methods: Eligible patients with advanced solid tumors were recruited in a phase I, multi-center, dose escalation study. Patients had regular safety assessments and blood sampling for pharmacokinetic (PK) studies. Pharmacodynamic (PD) and/or predictive biomarker analyses were undertaken on paired tumor samples (mandatory biopsies at MTD), platelet-rich plasma, hair follicles and circulating nucleic acids in plasma. Results: 30 patients (17 M; median age 60 yr; ECOG PS 0/1: 11/19) received MK-2206 at 90, 135, 200, 250 and 300 mg QW. Grade 3 rash was the dose limiting toxicity (DLT) at 300mg (n=3) and 250mg (n=2). Expansion of the 200mg QW resulted in grade 3 rash DLT in 4 of 15 patients. An intermediate dose of 150mg QW is being investigated. Common reversible MK-2206-related toxicities included rash (32.3%), fatigue (9.7%) and nausea, vomiting, diarrhea, pruritus, stomatitis, dry skin and dysguesia, each occurring at 6.5%. No MK-2206-related grade 5 toxicities were observed. PK analysis showed a median Tmax of 6 hr and a mean apparent terminal t1/2 of 78.6 hr. PD analysis of platelet-rich plasma at 200mg QW (n=9) showed suppression of pAKT up to 96 hours post-dose (p<0.001). Biomarker analyses of tumor samples are ongoing. Conclusions: MK-2206 has shown an acceptable toxicology profile, significant and sustained AKT blockade and a PK-PD profile allowing for QW dosing.