A Phase 1a/1b First in Human Study of PHI-101, a Potent Small Molecule Inhibitor of FLT3 in Relapsed and Refractory Acute Myeloid Leukemia
Authors: Yoon Sung-Soo , Shin Dong-Yeop , Lee Je-Hwan , Jang Jun Ho , Cheong June-Won , Shin Ho-Jin , Lee Jeong-Ok , Choi Yunsuk , Puliyayil Anish , Clarey Joseph , Im Jeejin , Nam Ky-Youb , Kim Kyu-Tae , Han June H-J. , Yoon Jeong-Hyeok , Nguyen Bao , Li Li , Small Donald 
Published: November 2021

Abstract
Background: The FMS-like tyrosine kinase 3 (FLT3) is mutated in approximately 30% of acute myeloid leukemia (AML) patients either by internal tandem duplication (ITD) or by point mutations in the tyrosine kinase domain (TKD). PHI-101 is a Type I FLT3 inhibitor developed to overcome resistance in AML. PHI-101 showed potent cellular activity in vitro and in vivo for both FLT3 ITD mutations and a wide variety of FLT3 point mutations in TKD. In preclinical studies utilizing primary human FLT3-ITD leukemia cells, PHI-101 showed increased anti-leukemic activity compared to gilteritinib based on increased survival in mice transplanted with these samples.
The Phase 1a and Phase 1b global clinical trial with PHI-101 (NCT04842370) is currently underway to assess the overall safety and efficacy of PHI-101 in refractory and relapsed AML.
Study Design and Methods: The overall design of the AML clinical trial consists of two parts, phase 1a, the dose-escalation, and phase 1b, the dose-expansion trial utilizing oral PHI-101 tablets. Up to 5 dose levels are planned for phase 1a and a single subject enrolled per dose level until the occurrence of at least one subject with more than Grade 2 toxicity according to CTCAE5.0 criteria during the 28-day evaluation period. The dose escalation will then convert to a standard 3+3 scheme, with 3 to 6 subjects per dose level cohort over the 28-day cycle. If there are no dose-limiting toxicities (DLT), dose escalation to the next higher dose levels will proceed upon the recommendation of the Safety Monitoring Committee. Subjects with FLT3 mutations or FLT3 wild-type will be enrolled in the dose-escalation cohort, and blood samples are collected for the primary endpoint pharmacokinetics (PK) and for the exploratory pharmacodynamic (PD) endpoint evaluation, including plasma inhibitory assay and biomarker analysis.
Results: The Phase 1a clinical trial of PHI-101 was initiated in June 2020 at a daily dose of 40mg for level 1. As of July 31, 2021, 8 patients with relapsed or refractory AML have been enrolled in the trial, all of whom had prior anti-leukemic treatments with intensive chemotherapy, hypomethylating agents and/or other FLT3 inhibitors. To date, 5 enrolled patients were available for safety assessment at three dose levels and have not experienced any dose-limiting toxicities (DLTs) from repeating doses of the 28-day DLT-assessment window. The leukemic blasts in marrow or peripheral blood were dramatically reduced by up to 98% with one cycle (28 days). The pharmacokinetic data of plasma PHI-101 varied in a dose-proportional manner and peak plasma concentrations (Cmax) were reached between 4 and 6 hours after once-daily dosing. The pharmacodynamic evaluation by plasma inhibitory assay showed that plasma from patients receiving at daily doses of PHI-101 inhibited more than 90% of the phosphorylation of the FLT3-ITD receptor. PHI-101 was well tolerated with these dose levels. This study is currently recruiting FLT3 mutation or wild-type AML patients at multiple sites in Korea and Australia.
Conclusion: PHI-101 is a next-generation FLT3 inhibitor that showed a potent anti-leukemic activity and improved efficacy in primary AML samples harboring FLT3/ITD and FLT3/TKD mutations in preclinical studies. The current analysis of this trial indicated that PHI-101 is a very effective FLT3 inhibitor for both refractory and relapsed AML patients, including those that have relapsed on other FLT3 TKI. The assessments of safety, tolerability, and PK of PHI-101 to determine the recommended dose for expansion are ongoing in the Phase 1a clinical trial.

Disclosures
Lee: Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board; AbbVie: Honoraria, Other: Advisory board; Korean Society of Hematology: Membership on an entity's Board of Directors or advisory committees. Im: Pharos iBio Co., Ltd.: Current Employment. Nam: Pharos iBio Co., Ltd.: Current holder of individual stocks in a privately-held company. Kim: Pharos iBio Co., Ltd.: Current holder of individual stocks in a privately-held company. Han: Pharos iBio Co., Ltd.: Current holder of individual stocks in a privately-held company. Yoon: Pharos iBio Co., Ltd.: Current holder of individual stocks in a privately-held company. Small: Pharos iBio Co., Ltd.: Consultancy, Other: Scientific Advisory Board. The arrangement has been reviewed and approved by Johns Hopkins University in accordance with its conflict-of-interest policies, Research Funding; InSilico Medicine: Other: Scientific Advisory Board.