Abstract LB-197: First-in-human study with ARQ 092, a novel pan AKT-inhibitor: Results from the advanced solid tumors cohorts.
Authors: Saleh Mansoor , Papadopoulos Kyri , Arabnia Alireza , Patnaik Amita , Stein Robin M. , Cattaneo Federica , Abbadessa Giovanni , Greenberg Jonathan , Warren Stephen , Tolcher Anthony 
Published: August 2014

Abstract
Background: ARQ 092 is an oral allosteric, ATP-independent, potent and selective inhibitor of AKT. Preclinical data from human cell lines and xenograft models support the exploration of anti-tumor activity of ARQ 092 across a broad range of human solid and hematological malignancies. The safety and preliminary activity of ARQ 092 in patients with advanced/metastatic solid tumors are presented.
Methods: Adults patients (pts) were enrolled into this multi-cohort phase 1 trial at the starting dose of 10 mg/QOD. Cohorts of 3 or 6 patients were based on a 3+3 dose escalation schedule. Dose was to be doubled for the first 5 cohorts, then increased according to a modified Fibonacci scheme. Treatment was continued until disease progression or unacceptable toxicity. Diabetic patients requiring insulin were excluded. Dose Limiting Toxicity (DLT) definition included grade ≥3 toxicities, grade 2 liver dysfunction, and grade 3 hyperglycemia requiring insulin (uncontrolled by metformin) during the first 28 days of treatment.
Results: As of October 20th, 2012, 22 ECOG PS1 pts (8 male; median age 63.3 yrs), with advanced/metastatic solid tumors were enrolled at doses/schedules ranging from 10 mg/QOD to 80mg/QD. Colorectal (N=4), endometrial (N=4) and neuroendocrine (N=3) were the most frequent tumors. Treatment-emergent adverse events (TEAEs) were reported in 20 (90.9%) pts. The most frequent (&gt;10%) included nausea, fatigue (both in 10 pts, 45.4%) and anorexia (7 pts, 31.8%). Grade 3 maculo-papular rash with pruritis occurred in 2 pts in the 80mg/QD cohort, triggering one DLT. Eight pts experienced 17 SAEs including diarrhea, tricuspid regurgitation, dyspnea and metabolic encephalopathy. Drug-related SAEs include: Grade 3 hyperglycemia, in 3 pts at 80mg/QD (1 constituted DLT, another was not a DLT because it was not treated with metformin, and the third, managed with insulin, occurred after 28 days). A DLT of congestive heart failure developed in a subject previously exposed to radiation and adriamycin. The MTD has not been reached, but the 80mg QD continuous dose/schedule was deemed not to be well tolerated. A cohort of 60mg QD is under evaluation. Currently, 6 pts remain stable for &gt; 4 months and 3 pts are still on therapy (1 pt on 80mg/QD, 2 pts on 20mg/QD); a 20% reduction in tumor burden was achieved in a pt with concomitant reduction of circulating pAKT expression. The study is ongoing with 7 pts on ARQ 092. PK analysis and PD results based on tumor biomarker expression and on plasma pAKT are pending.
Conclusions: A formal MTD has not yet been reached. Rash preceded by hyperglycemia and preliminary signs of activity as single agent may represent a differential feature of ARQ 092 in this class. Exploratory efficacy in a selected population over-expressing AKT will be pursued at the defined recommended phase 2 dose.
Citation Format: Mansoor Saleh, Kyri Papadopoulos, Alireza Arabnia, Amita Patnaik, Robin M. Stein, Federica Cattaneo, Giovanni Abbadessa, Jonathan Greenberg, Stephen Warren, Anthony Tolcher. First-in-human study with ARQ 092, a novel pan AKT-inhibitor: Results from the advanced solid tumors cohorts. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-197. doi:10.1158/1538-7445.AM2013-LB-197