A Potent Small Molecule Inhibitor of FLT3, PHI-101 Overcomes Resistance in Acute Myeloid Leukemia: Efficacy and PK/PD Profile in Phase 1 First in Human Study

Background: Mutations in FMS-like tyrosine kinase 3 (FLT3) are found in approximately 25-35% of acute myeloid leukemia (AML) patients and are often associated with relapse and poor prognosis. PHI-101 is an orally active, potent small molecule Type I FLT3 tyrosine kinase inhibitor (TKI) developed to overcome resistance in AML. It selectively inhibits both FLT3-ITD mutations and a wide variety of FLT3 point mutations in TKD in preclinical AML models. PHI-101 showed increased anti-leukemic activity compared to gilteritinib in both in vitro and in vivo studies with AML patient-derived primary leukemic cells. Phase 1 global clinical trials for PHI-101 (NCT04842370) against refractory and relapsed (R/R) AML are currently ongoing to assess the overall safety and efficacy.

Study Design and Methods: Eligible subjects, regardless of FLT3 mutation status, were enrolled at each dose level in phase 1a to evaluate dose-limiting toxicities (DLTs) during the 28-day daily dosing period according to an accelerated 3+3 design. A dose escalation to the next dose level proceeds upon the recommendation of the safety monitoring committee. Blood samples from patients were collected to evaluate the concentration of PHI-101 in plasma during the 24-h observation period after the initial dose (cycle1, day1) and after multiple doses (cycle1, day15). A pharmacodynamic evaluation of serial plasma samples via a plasma inhibitory assay (PIA) was used to assess the FLT3-inhibitory activity of PHI-101 in FLT3-mutant cell lines. The variant allele frequency (VAF) analysis for FLT3-ITD, FLT3-TKD and other AML-related mutant in the population was performed using next-generation sequencing (NGS) technology in accordance with instructions for HEMEaccuTest^TM IVD kit, with bone marrow aspirate samples collected from the patients before and after PHI-101 treatment.

Results: To date, 10 enrolled patients with R/R AML have been evaluated for safety assessment at four dose levels in the dose-escalation phase 1a clinical trial of PHI-101, and they have not experienced any DLTs from daily doses of the 28-day cycle. Seventy percent of enrolled patients had more than 3 prior anti-leukemic treatment attempts, and four patients had relapsed or refractory disease after treatment with other FLT3 inhibitors including gilteritinib, quizartinib, or HM43239. The median percentage of blasts at the time of enrollment was 71%, and the median duration on study with PHI-101 was 83 days. After 1 cycle of PHI-101 treatment, bone marrow blasts were reduced by up to 98%, and the responses extended to patients who had relapsed after treatment with other FLT3 targeted therapeutics. Clinical benefits, including improvement of hematological parameters, were observed in five patients who harbored FLT3 mutations. PHI-101 exhibits a dose-proportional pharmacokinetic profile in patients. The median maximum concentration was reached 4-6h following dosing of PHI-101, and the accumulated concentration of PHI-101 in plasma on day 15 of treatment was 3-5 times higher than on day 1. Estimated T_1/2 and T_max did not appear to be dose dependent. The concomitant plasma inhibitory assay (PIA) and PK data demonstrated that exposure-related inhibition of FLT3 phosphorylation of at least 90% by plasma PHI-101 was seen within 6 hours after a single dose as long as the plasma concentration of PHI-101 reached at least 70 ng/mL. The patients with FLT3-ITD or TKD mutations showed clinical reductions of FLT3 mutation VAF of up to 77% and leukemic blast reductions of up to 87% during the same period. Notably, PHI-101 treatment significantly cleared the FLT3-N676K mutation by 96% in addition to FLT3-D835Y mutations.

Conclusion: A dose-escalating phase 1a clinical data of PHI-101, which reflects up to cohort 4 of the study, indicates that PHI-101 generated potent FLT3 inhibition leading to encouraging anti-leukemic responses in R/R AML patients, including in those with prior FLT3 TKI therapeutic failure. PHI-101 showed good tolerance and favorable safety profile and reduced leukemic blasts significantly with 28-day dosing. PHI-101 sustained its activity to clear FLT3-ITD and/or FLT3-TKD mutations including D835Y or N676K identified in AML patients. Oral PHI-101 treatment results in a dose-dependent PK profile and clinically relevant efficacy of FLT3 phosphorylation inhibition. This trial indicates that PHI-101 is a next generation of FLT3 inhibitor effective for R/R AML patients.

Yoon:Amgen: Consultancy; Roche-Genetech: Research Funding; Takeda: Consultancy; Janssen Pharmaceutical: Consultancy; Astellas Pharma: Consultancy; Celgene: Consultancy; Kyowa Kirin: Research Funding; Chugai Pharmaceutical: Consultancy; Novartis: Consultancy; Yuhan Pharmaceutical: Research Funding; Tikaros: Consultancy. Im:Pharos iBio Co., Ltd.: Current equity holder in private company. Kim:Pharos iBio Co., Ltd.: Current Employment. Nam:Pharos iBio CO., Ltd.: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Kim:Pharos iBio Co., Ltd.: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Han:Pharos iBio Co., Ltd.: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Yoon:Pharos iBio Co., Ltd.: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Small:Pharos iBio Co., Ltd.: Consultancy, Other: Scientific Advisory Board, Research Funding; InSilico Medicine: Other: Scientific Advisory Board.