PHI-101, a Novel FLT3 TKI, Shows Clinical Efficacy in Relapsed/Refractory FLT3-Mutated AML

Background: We investigated the clinical activity, PK, safety and resistance mechanisms of single-agent PHI-101 in patients (pts) with refractory/relapsed acute myeloid leukemia (R/R AML) with FLT3-ITD mutations.(NCT04842370) Study Design and Methods: PHI-101 was used in a range of once-daily (40-200 mg) regimens in a phase 1a, open label, dose-escalation expansion study in adult patients with R/R AML and in a phase 1b expansion study in adult patients with R/R FLT3 mutant AML. Study objectives were to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D), characterize the safety and tolerability and pharmacokinetic/pharmacodynamic profile, and assess the preliminary antitumor activity of PHI-101. A total of 30 pts with a median age of 64 years (range = 22-81) were enrolled in the phase 1a/1b clinical trials. Participants had received a mean of 3.9 prior therapies (range = 1-9). The most commonly observed mutations were FLT3-ITD mutations (70.0%), followed by both FLT3-ITD and FLT3-TKD mutations (13.3%). Most pts (72.0%) with known FLT3 mutations had previously received FLT3 inhibitors including gilteritinib (66.7%). Results: A total of 30 pts were enrolled in the two treatment arms of which 21 pts were evaluable, 9 pts in arm A (dose escalation) and 12 pts in arm B (dose expansion). Clinical responses with PHI-101 (composite complete remission [CRc; including complete remission (CR), complete remission with incomplete hematological recovery (CRi), and morphologic leukemia-free state (MLFS)]), were observed in 33.3% of 21 evaluable pts (FLT3-WT pts:n=3, 0%; FLT3 mutated pts:n=18, 38.9%). The Phase 1a clinical trials of PHI-101 evaluated it for safety and tolerability at five dose levels from 40 mg to 200 mg. In total, 13 R/R AML pts were enrolled in phase 1a and no DLTs were reported from daily doses of PHI-101 for the 28-day cycle. Seven pts (53.8%) had received more than 3 prior anti-leukemic treatments in Phase 1a. The target recommended dose expansion (RDE) at 160 mg was determined based on several considerations, including the PIA test achieving >85% inhibition of phospho-FLT3, all available adverse events, PK data, and recommendation by the safety monitoring committee (SMC). PHI-101 therapy in Phase 1b resulted in a 50% CRc and 25% partial remission (PR) status among 12 evaluable R/R FLT3 AML pts (11 ITD, 1 ITD+D835). 75% of these patients had received prior FLT3 inhibitors (Gilteritinib (7), Midostaurin (3), Sorafenib (1), HM43239 (1)). Notably, 4 of the R/R pts who had received previous therapy with gilteritinib had clinical responses to PHI-101, including 1 CRi, 1 MLFS and 2 PR. One responder and another patient with stable disease with under 5% BM blasts were bridged to potentially life-saving transplant (HSCT). The common hematologic adverse events included febrile neutropenia, anemia, and thrombocytopenia. The common non-hematologic adverse events were elevations of ALT and AST. The recommended phase 2 dose will be 160 mg once-daily which resulted in Cmax and AUC0-24 plasma concentrations in Phase 1b of 259 ng/ml and 3,920 ng/ml at cycle 1 day 1. Conclusion: Once-daily dosing of single-agent PHI-101 had a distinct tolerability profile and showed excellent anti-tumor activity across FLT3i-pretreated and FLT3i-naïve patients with R/R FLT3 mutant AML.