Abstract B147: A phase 1 PK/PD study of ASN003, a novel, highly selective BRAF and PI3K dual inhibitor, in patients with advanced solid tumors

Abstract

Abstract Background: RAS-RAF-MEK and PI3K-AKT-mTOR are two major pathways involved in tumor cell signaling and growth. Components of these pathways are frequently mutated in a broad range of tumors. ASN003 is a highly selective and potent (low nM IC50) inhibitor of BRAF and PI3K-α and -δ (low affinity for PI3K-β). ASN003 shows strong antitumor activity in tumor models harboring BRAF and PIK3CA or PTEN mutations, and also in patient-derived xenograft (PDX) models that are resistant to selective BRAF and MEK inhibitors. Patients and Methods: Oral once-daily ASN003 is being evaluated for safety/tolerability and preliminary efficacy in eligible patients with advanced solid tumors using an accelerated dose titration design (Part A) and enrolling cohorts of patients diagnosed with melanoma, CRC, NSCLC, and other solid tumors with a BRAF, PIK3CA, or PTEN mutation at MTD (Part B). Pharmacokinetic (PK) profile and the pharmacodynamic (PD) effects of ASN003 on tumor tissue biomarkers such as pERK and pS6 are investigated in both parts of the study. Results: Patient accrual in Part A is ongoing. As of June 2017, nine eligible patients are enrolled in dose levels ranging from 10 - 240 mg QD. ASN003 has been well tolerated. Treatment-related adverse events (TRAEs) were mild (G1) to moderate (G2). TRAEs include diarrhea (G2) (n=1), nausea/vomiting (G1), blurred vision (G1), and dry mouth/lips/skin (G1). Transient G1 elevation of glucose and insulin c-peptide levels has been noted in 1 pt. No G3/4 or serious TRAEs have been observed to date. The PK profile showed dose-dependent, systemic exposure with Cmax ranging from 74 to 1055 ng/mL, AUCT from 912 to 20100 ng.h/mL. Conclusions: ASN003 is a novel small molecule, with uniquely selective and potent inhibition of BRAF, PI3K-α and -δ kinases. To date, ASN003 was well tolerated at doses up to 240 mg QD and achieved good systemic exposure. Updated and detailed clinical safety/efficacy and PK/PD results will be presented. Citation Format: Drew Rasco, Nehal Lakhani, Ryan Sullivan, Monica Mita, Jaimini Shah, Helena Usansky, Sanjeeva Reddy, Niranjan Rao, Louis J. Denis, Anthony Tolcher, Keith Flaherty. A phase 1 PK/PD study of ASN003, a novel, highly selective BRAF and PI3K dual inhibitor, in patients with advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B147.