Data presented at AACR Annual Meeting
WOBURN, MA, USA I April 9, 2013 I Researchers presented data today on ARQ 092, an AKT inhibitor in Phase 1 clinical development by ArQule, Inc. (ARQL) at the AACR (American Association for Cancer Research) Annual Meeting held in Washington, D.C., April 6-10, showing that this novel, oral agent inhibits the AKT pathway and has a manageable safety profile in an ongoing Phase 1 clinical trial.
“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 declared in this ongoing trial. Of twenty evaluable patients, seven patients have remained stable on the drug for more than four months. Four of these seven 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’s 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.
ArQule recently regained worldwide rights to its AKT program, including ARQ 092, from Daiichi Sankyo Co., Ltd. ARQ 092 is a selective AKT inhibitor that was discovered through technology from the ArQule Kinase Inhibitor Platform (AKIP™) and optimized through a structure-based drug design methodology. The AKT signaling pathway, which plays a role in regulating cell growth, survival, migration and angiogenesis, is frequently dysregulated in cancer.
About ArQule
ArQule is a biotechnology company engaged in the research and development of next-generation, small-molecule cancer therapeutics. The Company’s targeted, broad-spectrum products and research programs are focused on key biological processes that are central to human cancers. ArQule’s lead product, in Phase 2 and Phase 3 clinical development, is tivantinib (ARQ 197), an oral, selective inhibitor of the c-MET receptor tyrosine kinase. The Company’s pipeline consists of ARQ 092, designed to inhibit AKT, ARQ 087, designed to inhibit fibroblast growth factor receptor (FGFR), ARQ 621, designed to inhibit the Eg5 kinesin motor protein, and ARQ 736, designed to inhibit the RAF kinases. ArQule’s current discovery efforts, which are based on the ArQule Kinase Inhibitor Platform (AKIP™), are focused on the identification of novel kinase inhibitors that are potent, selective and do not compete with ATP (adenosine triphosphate) for binding to the kinase.
SOURCE: ArQule
Post Views: 86
Data presented at AACR Annual Meeting
WOBURN, MA, USA I April 9, 2013 I Researchers presented data today on ARQ 092, an AKT inhibitor in Phase 1 clinical development by ArQule, Inc. (ARQL) at the AACR (American Association for Cancer Research) Annual Meeting held in Washington, D.C., April 6-10, showing that this novel, oral agent inhibits the AKT pathway and has a manageable safety profile in an ongoing Phase 1 clinical trial.
“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 declared in this ongoing trial. Of twenty evaluable patients, seven patients have remained stable on the drug for more than four months. Four of these seven 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’s 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.
ArQule recently regained worldwide rights to its AKT program, including ARQ 092, from Daiichi Sankyo Co., Ltd. ARQ 092 is a selective AKT inhibitor that was discovered through technology from the ArQule Kinase Inhibitor Platform (AKIP™) and optimized through a structure-based drug design methodology. The AKT signaling pathway, which plays a role in regulating cell growth, survival, migration and angiogenesis, is frequently dysregulated in cancer.
About ArQule
ArQule is a biotechnology company engaged in the research and development of next-generation, small-molecule cancer therapeutics. The Company’s targeted, broad-spectrum products and research programs are focused on key biological processes that are central to human cancers. ArQule’s lead product, in Phase 2 and Phase 3 clinical development, is tivantinib (ARQ 197), an oral, selective inhibitor of the c-MET receptor tyrosine kinase. The Company’s pipeline consists of ARQ 092, designed to inhibit AKT, ARQ 087, designed to inhibit fibroblast growth factor receptor (FGFR), ARQ 621, designed to inhibit the Eg5 kinesin motor protein, and ARQ 736, designed to inhibit the RAF kinases. ArQule’s current discovery efforts, which are based on the ArQule Kinase Inhibitor Platform (AKIP™), are focused on the identification of novel kinase inhibitors that are potent, selective and do not compete with ATP (adenosine triphosphate) for binding to the kinase.
SOURCE: ArQule
Post Views: 86
