A phase 1/2 study of the oral FLT3 inhibitor pexidartinib in relapsed/refractory FLT3-ITD-mutant acute myeloid leukemia

Abstract

FMS-like tyrosine kinase 3 (FLT3) tyrosine kinase inhibitors (TKIs) have activity in acute myeloid leukemia (AML) patients with FLT3 internal tandem duplication (ITD) mutations, but efficacy is limited by resistance-conferring kinase domain mutations. This phase 1/2 study evaluated the safety, tolerability, and efficacy of the oral FLT3 inhibitor PLX3397 (pexidartinib), which has activity against the FLT3 TKI-resistant F691L gatekeeper mutation in relapsed/refractory FLT3-ITD-mutant AML. Ninety patients were treated: 34 in dose escalation (part 1) and 56 in dose expansion (part 2). Doses of 800 to 5000 mg per day in divided doses were tested. No maximally tolerated dose was reached. Plasma inhibitory assay demonstrated that patients dosed with ≥3000 mg had sufficient levels of active drug in their trough plasma samples to achieve 95% inhibition of FLT3 phosphorylation in an FLT3-ITD AML cell line. Based on a plateau in drug exposure, the 3000-mg dose was chosen as the recommended phase 2 dose. The most frequently reported treatment-emergent adverse events were diarrhea (50%), fatigue (47%), and nausea (46%). Based on modified response criteria, the overall response rate to pexidartinib among all patients was 21%. Twenty-three percent of patients treated at ≥2000 mg responded. The overall composite complete response rate for the study was 11%. Six patients were successfully bridged to transplantation. Median overall survival (OS) of patients treated in dose expansion was 112 days (90% confidence interval [CI], 77-150 days), and median OS of responders with complete remission with or without recovery of blood counts was 265 days (90% CI, 170-422 days). This trial was registered at www.clinicaltrials.gov as #NCT01349049.

Graphical abstract

Figure 1.

Patient disposition. PI, principal investigator.

Figure 2.

PKs and plasma inhibitory activity (PIA). (A) Dose proportionality in the steady-state plasma exposures of PLX3397 (pexidartinib) in AML patients. (B-C) In part 1 of the study, plasma samples from 29 patients across 8 dosing cohorts were collected and evaluated for PIA in the FLT3-ITD–containing human AML cell line Molm14. Predose samples were collected on day 1, day 2, and at steady state (day 15 or 29). (B) Inhibition of pFLT3 by PIA is concentration dependent with an EC95 of 6530 ng/mL. (C) Inhibition of phosphorylated (phospho) FLT3 by PIA increases with dose and is ≥95% at ≥3000 mg for both day 2 and steady-state samples.

Figure 3.

Best clinical response, treatment duration, and survival. (A) Number and proportion of best response (modified criteria) per patient by cohort. Includes all patients with a best response of at least PR. Bars are overlaid with the geometric mean of steady-state AUC_0-6 (ng × h/mL) for each cohort. The ORR for the study was 19 (21%) of 90 and CRc rate is 10 (11%) of 90. (B) Best percentage change in blasts is shown for individual patients, and bars are blue gradient–filled with steady-state AUC_0-6. Gray-filled bars indicate that AUC_0-6 was not determined. Patients who were successfully bridged to transplantation are shown with solid triangles. Best response by modified criteria is indicated at the top of each bar. (C) Treatment duration is represented by a gray line drawn from C1D1 to the day of last known dose. If last dose day is unknown, gray line extends to the day of study discontinuation or database lock. Response assessments by modified criteria are shown with color-coded boxes. Empty boxes indicate that a patient was not assessable (NA). The day of disease progression or death (end PFS), whichever came first, is marked with a red "×." In part 1 of the study, 2 patients were successfully bridged to transplantation (07_002 [2000 mg] and 07_004 [5000 mg]), discontinued the study drug to undergo HSCT, and did not resume pexidartinib treatment. In part 2, 4 patients were successfully bridged to transplantation. Of these, 2 patients (03_009 and 06_013) resumed maintenance treatment with pexidartinib, as provided for by protocol amendment 7, but later discontinued treatment because of an AE or voluntary withdrawal from the study. One patient (05_017) resumed treatment with pexidartinib and was still on treatment at database lock, and 1 patient (06_022) did not resume study treatment. (D) OS stratified by response (≥PR). PD, progressive disease; SD, stable disease.