Preliminary clinical activity of TP-0903 in relapsed or refractory acute myeloid leukemia with FLT3-ITD mutations

Bhavana Bhatnagar ^1* Daelynn R Buelow ² Kaitlyn M Dvorak-Kornaus ³ Shelley J Orwick ² Jae Yoon Jeon ² Zahra Talebi ² Amy S Ruppert ³ James S Blachly ^3,4 Uma Borate ^3,4 Sharyn D Baker ^2*

• ¹ Cancer Institute, West Virginia University, Morgantown, United States
• ² Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio, United States
• ³ Division of General Internal Medicine, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio, United States
• ⁴ The James Cancer Hospital and Solove Research Institute, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States

AML patients with FLT3-ITD experience shorter disease-free survival and high relapse rates even with FLT3inhibitor therapy. One of the main mechanisms for loss of response is the acquisition of molecular mutations that confer drug resistance to FLT3 inhibitors. TP-0903 is an oral multi-kinase inhibitor with activity against FLT3 and several other kinases known to mediate drug resistance. Three heavily treated relapsed/refractory acute myeloid leukemia (AML) patients with FLT3-ITD were treated with TP-0903 50 mg daily, on a phase 1b/2 clinical trial, for as long as disease response or clinical benefit was observed. One patient was dose reduced to 37 mg daily mid-cycle after developing grade 3 nausea which improved to grade 2 within 24 hours of holding the drug. All patients achieved stable disease, however significant reduction in bone marrow blast percentage after 1-2 cycles of treatment was observed in two patients, which correlated with a decrease in FLT3-ITD allelic ratio and variant allele frequency of co-occurring mutations (e.g., NPM1 and DNMT3A). TP-0903 was feasible with no unusual toxicity signals. Additional pre-clinical and clinical studies are needed in order to determine a role for TP-0903 in AML.