Abstract CT024: Results of a phase I dose escalation study of ARQ 751 in adult subjects with advanced solid tumors with AKT1, 2, 3 genetic alterations, activating PI3K mutations, PTEN-null, or other known actionable PTEN mutations
Authors: Shubham Pant, Vivek Subbiah, Jordi Rodon, Filip Janku, David Hong, Daniel Karp, Sarina Piha-Paul, Apostolia M. Tsimberidou, Aung Naing, Siqing Fu, Ron E. Savage, Feng Chai, Yi Yu, Brian Schwartz, Funda Meric-Bernstam, Tim Yap
Journal: Cancer Research (2018)

Abstract Background: Dysregulation of the PI3K-AKT signaling pathway is associated with a number of cancers. and plays a critical role in cancer initiation and progression. AKT can be activated through activated receptor tyrosine kinases, gain-of-function mutations of PIK3CA, PTEN deficiency, and AKT amplification or activating mutations such as AKT1E17K. As the second generation of allosteric AKT inhibitor, ARQ 751 potently inhibits AKT1, 2 and 3 with biochemical IC50 values of 0.55 nM, 0.81 nM and 1.31 nM receptively. In addition, ARQ 751 is very selective; it does not inhibit any other kinase (out of the 245 tested) by greater than 50% at 5 µM. The objective of this study is to determine maximum tolerated dose in patients with advanced solid tumors. Material and Methods: This is Phase 1 Dose Escalation Study to assess the safety and tolerability of ARQ 751 in subjects with advanced solid tumors with AKT1, 2, 3 genetic alterations, activating PI3K mutations, PTEN-null, or other known actionable PTEN mutations. Treatment emerging adverse events (TEAE) were assessed per NCI CTCAE v. 4.03. Tumor response were evaluated per RECIST 1.1. Blood samples were collected for PK. Results: A total of 15 pts have been enrolled [73% female; median age 61 years; 5 Breast (5), endometrial (2), and others (9); activating PI3K mutation (9), PTEN null/other known actionable PTEN mutations (5), AKT 1 mutation (1)] and treated at dose levels of 5 mg QD, 10 mg QD, 20 mg QD, 25 mg QOD and 25 mg QD. There have been no DLTs reported so far. ARQ 751 related TEAEs included nausea (27%), stomatitis, vomiting, fatigue, mucosal inflammation, white blood cell count decreased, hyperkalaemia, cough, oropharyngeal pain, sinus congestion, pain of skin, puritus and hot flushes (7% each). All these TEAEs were grade 1 or 2. There was no ≥ Grade 3 drug related TEAEs or any grade drug-related SAEs. Four pts achieved a best response of stable disease (SD) including 1 with breast cancer treated at 25 mg QOD for 42+ weeks, 1 with head and neck cancer treated at 20 mg QD for 16 weeks, 1 with breast cancer treated at 25 mg QD for 12+, and 1 with endometrial cancer treated at 25 mg QD for 10+ weeks. 3 of 4 SD pts are currently on therapy. Conclusions: ARQ 751 demonstrated a manageable safety profile at Dose level up to 25 mg QD. The dose escalation is ongoing. PK and updated safety, efficacy data will be presented. Citation Format: Shubham Pant, Vivek Subbiah, Jordi Rodon, Filip Janku, David Hong, Daniel Karp, Sarina Piha-Paul, Apostolia M. Tsimberidou, Aung Naing, Siqing Fu, Ron E. Savage, Feng Chai, Yi Yu, Brian Schwartz, Funda Meric-Bernstam, Tim Yap. Results of a phase I dose escalation study of ARQ 751 in adult subjects with advanced solid tumors with AKT1, 2, 3 genetic alterations, activating PI3K mutations, PTEN-null, or other known actionable PTEN mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT024.