Novel AKT Pathway Inhibitor, ARQ 092, Demonstrated Safety, Effective Target Inhibition

Newswise — WASHINGTON, D.C. — Researchers have confirmed that the novel oral agent ARQ 092 inhibits the AKT pathway and has a manageable safety profile in patients with a variety of advanced solid tumors, according to phase I data presented at the AACR Annual Meeting 2013, held in Washington, D.C., April 6-10.

“AKT is a signal transduction pathway crucially involved in the growth, survival and metabolism of cancer cells,” said Mansoor N. Saleh, M.D., professor of medicine at the University of Alabama Comprehensive Cancer Center in Birmingham and director of research at Georgia Cancer Specialists in Atlanta. “Many of the signaling pathways disrupted by commonly seen cancer-causing mutations merge into the AKT pathway. In addition, the AKT pathway is often amplified and mutated in patients who relapse following initial therapy.

“This means that the AKT pathway is a potential treatment target for numerous cancer types, either at diagnosis or when they become resistant to initial therapies.”

Saleh and his colleagues tested the safety and activity of ARQ 092 in patients with a broad range of advanced or metastatic solid tumors, including colorectal, endometrial and neuroendocrine cancers. They assigned patients in the first cohort to a dose of 10 mg every other day and enrolled subsequent patients into cohorts of three to six patients who were assigned to a dose escalation schedule with the drug.

“This class of agents has two common toxicities, namely skin toxicity and hyperglycemia, a rise in blood sugar levels,” Saleh said. “Based on data presented with other AKT inhibitors, skin toxicity has been the dose-limiting side effect and often resulted in drug discontinuation.”

To date, Saleh and colleagues have observed no dose-limiting skin toxicity. In addition, they have observed that with ARQ 092, blood sugar levels rise before patients experience skin toxicity, and they have been able to treat the hyperglycemia, thus allowing the patients to continue on the experimental drug.

“When we see hyperglycemia, we know that the drug is active in patients,” Saleh said. “We can ameliorate the high blood sugar, potentially allowing us to achieve drug levels that will be therapeutically active.”

Currently, the maximum tolerated dose has not been reached in this ongoing trial, but Saleh and colleagues have confirmed that the 80-mg dose once a day is not well tolerated. Seven patients have remained stable on the drug for more than four months. Four patients with advanced and refractory solid tumors have had stable disease for longer than six months, according to Saleh.

Once the maximum tolerated dose is identified, Saleh and colleagues plan to test the drug for efficacy.

“We will also explore the drug activity in patients with a high level of AKT in the tumor to identify the patient populations that can robustly benefit from our treatment,” he said.

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Abstract Number: LB-197

Presenter: Mansoor N. Saleh, M.D.

Title: First-in-human study with ARQ 092, a novel pan AKT-inhibitor: results from the advanced solid tumors cohorts

Authors: Mansoor Saleh1, Kyri Papadopoulos2, Alireza Arabnia1, Amita Patnaik2, Robin M. Stein1, Federica Cattaneo3, Giovanni Abbadessa3, Jonathan Greenberg4, Stephen Warren4, Anthony Tolcher2. 1Georgia Cancer Specialists, Atlanta, GA; 2START - South Texas Accelerated Research Therapeutics, LLC, San Antonio, TX; 3ArQule, Inc., Woburn, MA; 4Daiichi-Sankyo, Edison, NJ

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 (>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 > 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.

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