PHI-101 As a Potent Next-Generation FLT3 Inhibitor, Overcome Resistances in Previously Treated Patients with FLT3-ITD or TKD Acute Myeloid Leukemia: Results of a Phase Ia/Ib Clinical Trial
Authors: Yoon Sung-Soo , Shin Dongyeop , Lee Je-Hwan , Jang Jun Ho , Cheong June-Won , Shin Ho-Jin , Lee Jeong-Ok , Lee Yoo Jin , Clarey Joseph , Sung Gi-Jun , Kim Kyung-Ah , Nam Ky-Youb , Kim Kyu-Tae , Han June , Yoon JeongHyeok , Nguyen Bao , Li Li , Small Donald 
Published: December 2023

Background:
The FLT3 receptor is mutated in about 30% of acute myeloid leukemia (AML) patients (pts) and has proven to be an attractive therapeutic target. The most prevalent alteration is internal tandem duplication (ITD) of the juxtamembrane domain, and several FLT3 inhibitors (e.g. gilteritinib, quizartinib, midostaurin) succeddfully target this mutation. However, patients frequently relapse due to resistance to these FLT3 inhibitors after initial clinical responses, often caused by the secondary mutations observed in the kinase domain (TKD) region. PHI-101, an orally bioavailable novel small molecule, is a next-generation FLT3 inhibitor that shows a potent anti-leukemic activity in primary AML samples harboring several FLT3-resistance mutations in preclinical studies. Global Phase I clinical trials with PHI-101 (NCT04842370) are currently underway in refractory or relapsed (R/R) AML pts.
Study Design and Methods:
The open-label, multicenter AML clinical trial consists of phase Ia, dose-escalation, and phase Ib, dose-expansion, utilizing oral PHI-101 tablets as a single-agent with R/R AML pts. If dose-escalation concludes with no dose-limiting toxicities (DLT), dose-expansion proceeds upon recommendation from the Safety Monitoring Committee (SMC). Response assessments with PHI-101 were reported according to 2017 ELN guidelines. The variant allelic frequency of mutations of FLT3 and other AML-related mutations was analyzed using NGS with bone marrow aspirates collected from pts before and after PHI-101 treatment. Blood samples were collected to evaluate pharmacokinetics (PK) and the plasma inhibitory assay (PIA) using FLT3-mutant cell lines. Together, these assessments were considered to determine the recommended dose for expansion (RDE) in phase Ib trials.
Results:
Phase Ia clinical trials of PHI-101 was designed to evaluate for safety and tolerability at five dose levels ranging from 40 mg to 200 mg. A total of 13 R/R AML pts were enrolled in the phase Ia and no DLTs were reported from daily doses of PHI-101 during the 28-day cycle.
The target RDE at 160 mg was determined based on several considerations, including the PIA test achieving &gt;85% inhibition of phosphor-FLT3, all available adverse events, PK data, and recommendation by the SMC.
As of May 2023, with 6 pts enrolled in phase Ib, a total of 19 pts (5 FLT3-wild type (26.3%) and 14 FLT3 mutated (73.7%)), have been treated with PHI-101. Thirteen pts (68.4%) had more than 3 prior anti-leukemic treatments. Twelve of 13 pts (92%) assessed for the leukemic blast evaluation achieved clinical responses-4 pts with composite complete remissions [CRc, including complete remission with incomplete hematological recovery (CRi) and morphological leukemia free state (MLFS)] within 1 cycle of PHI-101 treatment. Ten pts were R/R following previous treatment with other FLT3 inhibitors (gilteritinib, quizartinib, midostaurin, or HM43239). 88 % of these pts achieved clinical responses including 3 CRc and 1 partial response (PR). Notably, all 5 R/R pts after gilteritinib treatment had clinical responses that included 2 with CRc. In addition, a patient with both FLT3-ITD and TKD (D835E and N676K) mutations who was resistant to 3 different FLT3 inhibitor treatments achieved PR and continued PHI-101 treatment for 6 cycles. Among pts who received 160 mg of PHI-101, 4 pts (57.1%) responded: 2 (28.6%) achieved CRi, 1(14.3%) achieved MLFS, and 1 (14.3%) achieved PR.
Conclusion:
In dose-escalating phase Ia clinical trials, PHI-101 was well tolerated at all dose levels with no DLTs. Phase Ib dose-expansion trials with 160 mg daily dosing are currently ongoing. PHI-101 has delivered CRcs at 120 mg and 160 mg. In this first-in-human, phase Ia/Ib trial of PHI-101, 92% of FLT3-wild or -mutated AML pts showed clinical responses even after having previously been treated with otherFLT3 inhibitors. More notably, 100% of pts who had relapsed after prior gilteritinib treatment showed clinical responses. The data from the clinical study of PHI-101to date demonstrates significant efficacy, particularly in R/R FLT3 mutant AML pts.