On November 16, 2018 ArQule, Inc. (Nasdaq: ARQL) reported the presentation of clinical and preclinical data on ARQ 751 in three poster presentations at the 30th EORTC/AACR/NCI Symposium held from November 13 to 16, 2018 in Dublin, Ireland (Press release, ArQule, NOV 16, 2018, View Source [SID1234531401]). The data presented highlight clinical data from ARQ 751-101, a Phase 1 study in adult patients with refractory and/or metastatic tumors that harbor AKT, PI3K or PTEN genetic alterations, and preclinical data on ARQ 751 in combination with other agents.
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Clinical data highlights and key conclusions include:
1. A Phase 1 Dose Escalation Study of ARQ 751 in Adult Patients with Advanced Solid Tumors with AKT1, 2, 3 Genetic Alterations, Activating PI3K Mutations, PTEN-null, or Other Known Actionable PTEN Mutations
ARQ 751 demonstrated manageable toxicity at doses from 5 mg QD to 75 mg QD, and the recommended Phase 2 dose was determined to be 75 mg QD
Evidence of clinical activity was observed with two partial responses in ER+/PR+/HER2- stage IV breast cancer patients, one with PTEN C296fs*2 mutation, one with PIK3CA H1047R mutation, 11 patients had stable disease
The data support continued development of ARQ 751 as a monotherapy or in combination with other anti-cancer agents due to its manageable safety profile and preliminary evidence of biological activity
"ARQ 751, as a highly specific allosteric AKT inhibitor, holds great potential in treating patients with solid tumors harboring mutations in the AKT/PI3K/PTEN pathways," said Brian Schwartz, M.D., Chief Medical Officer of ArQule. "The presented data are very encouraging and demonstrate both preliminary signs of clinical activity and a favorable safety profile while also determining the recommended Phase 2 dose. At ArQule, we are committed to developing genetically targeted cancer treatments to provide effective new treatment options for patients, particularly those with advanced or relapsed disease, and look forward to advancing the ARQ 751 clinical program."
Preclinical data highlights include:
2. Combination of the AKT inhibitor ARQ 751 with Immune Checkpoint Inhibitor and Other Therapeutic Agents
In preclinical cellular models, ARQ 751 exerted greater anti-proliferative and biochemical effects when in combination with multiple therapeutic agents including an ER antagonist, aromatase inhibitor, androgen receptor antagonist and a BTK inhibitor
In an in vivo colon cancer animal model, ARQ 751 in combination with an anti-PD-1 antibody exhibited superior anti-tumor activity compared to single agents
3. Miransertib and ARQ 751 exhibit superior cell-death-inducing properties compared to other AKT inhibitors and can overcome resistance to other allosteric AKT inhibitors
ArQule’s AKT inhibitors, miransertib and ARQ 751 showed superior activity in comparison to other allosteric and ATP-competitive AKT inhibitors currently in clinical development
Miransertib and ARQ 751 have the potential to overcome some mechanisms of resistance to AKT inhibitors
Miransertib and ARQ 751 in combination with ATM inhibition demonstrated synergistic effects
Dr. Shubham Pant, MD, Associate Professor in the Department of Investigational Cancer Therapeutics at MD Anderson Cancer Center, said "AKT inhibitors have significant potential to treat a broad range of solid tumors in molecularly defined patient populations. The presented data show that ARQ 751 exhibits unique properties that differentiate it from other AKT inhibitors. It is our hope that by combining ARQ 751 with a broad spectrum of therapeutic agents, including hormonal agents, we could provide new opportunities for combinatorial interventions in oncology."
All posters presented by ArQule at the EORTC/AACR/NCI Symposium are available on the company’s website at View Source
About ARQ 751
ARQ 751 is an orally bioavailable, selective small molecule inhibitor of the AKT serine/threonine kinase. The AKT pathway when abnormally activated is implicated in multiple oncogenic processes such as cell proliferation and apoptosis. This pathway has emerged as a target of potential therapeutic relevance for compounds that inhibit its activity, which has been linked to a variety of cancers as well as to select non-oncology indications. ARQ 751 is currently in a Phase 1 study in adult patients with refractory and/or metastatic tumors that harbor genetic alterations along the AKT pathway.
About Miransertib
Miransertib (ARQ 092) is an orally bioavailable, selective, pan-AKT (protein kinase B) inhibitor that potently inhibits AKT1, 2 and 3 isoforms. Dysregulation of AKT has been implicated in a variety of rare overgrowth diseases and cancers; however, there are currently no approved inhibitors of AKT. AKT inhibitors, either as single agent or combination therapy, show significant promise in molecularly defined patient populations. Miransertib is currently in a Phase 1/2 company-sponsored study for PIK3CA-Related Overgrowth Spectrum (PROS), a Phase 1 study for ultra-rare Proteus syndrome conducted by the National Institutes of Health (NIH/NHGRI), and a Phase 1b study in combination with the hormonal therapy, anastrozole, in patients with advanced endometrial cancer with AKT and PI3K mutations. Miransertib has been granted Rare Pediatric Disease Designation and Fast Track Designation by the U.S. Food and Drug Administration (FDA), as well as Orphan Designation by the FDA and European Medicines Agency in the rare overgrowth disease, Proteus syndrome.