Abstract A034: The use of biomarkers and ctDNA in a phase 1 trial of ARQ 751
MOLECULAR CANCER THERAPEUTICS(2019)
摘要
Background: AKT, a critical node in the PI3K/AKT/mTOR pathway, is one of the most frequently activated protein kinases in human cancers. ARQ 751 is a potent and highly selective pan-AKT inhibitor against AKT1, AKT2, and AKT3, and is currently in a phase 1b clinical trial as a single agent, or combination with paclitaxel or fluvestrant. Inhibition of the PI3K/AKT pathway is known to cause increases in serum glucose and insulin in patients. Recent advances in next generation sequencing technologies are providing physicians and researchers with access to tumor genomic data, including circulating tumor DNA (ctDNA), to support and evaluate treatment strategies. Methods: Samples were collected for pharmacokinetic, pharmacodynamic, and genetic analysis. PK samples were collected on Days 1 and 22 to generate PK profiles. Samples were analyzed, and PK parameters generated, including Cmax, AUC, and t1/2 (where possible). Biomarkers evaluated for target engagement were serum glucose and insulin. Finally, whole blood was collected and mutational status of ctDNA was analyzed using Guardant360. Results: The Recommended Phase 2 Dose (RP2D) of ARQ 751 was determined to be 75 mg QD, with a mean Cmax of 263 ng/mL and an AUClast 2240 h*ng/mL on Day 22. Changes in both serum insulin and glucose were observed, and these increases correlated with ARQ 751 exposure. In patients with detectable levels of ctDNA (matching tumor); 6 (1PR, 4SD, 1PD) showed a decrease between Cycle 1, Day 1 and Cycle, 2 Day 1, and 3 showed an increase (1PR, 1SD, 1 PD). Conclusions: Preliminary PK, PD, and ctDNA data support the selection of 75 mg QD as the RP2D for ARQ 751. ARQ 751 plasma levels at this dose produced increases in both serum insulin and glucose, confirming target engagement. Additionally, an evaluation of a limited set of pre and post treatment ctDNA data provides interesting new insights on patient’s responses to therapy. Additional data to be presented at the meeting. Citation Format: Shubham Pant, Maria Lamar, Julia Kazakin, Ronald Savage, Brian Schwartz, terence hall. The use of biomarkers and ctDNA in a phase 1 trial of ARQ 751 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A034. doi:10.1158/1535-7163.TARG-19-A034
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Cancer Genomics
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