Safety and efficacy of gilteritinib (ASP2215) in R/R AML patients - phase I/II dose-escalation, dose-expansion Chrysalis Trial

Gilteritinib was found to have a favorable safety profile and was effective in patients with Relapsed or Refractory (R/R) Acute Myeloid Leukemia (AML) with Fms Like Tyrosine Kinase 3 (FLT3) mutations according to results from a phase I/II study published in Lancet Oncology on 20^th June 2017 by Alexander E. Perl from the Abramson Comprehensive Cancer Center, University of Pennsylvania, Pennsylvania and colleagues.

In this first-in-human, open label phase I/II dose-escalation, dose-expansion Chrysalis study (NCT02014558), the safety, pharmacokinetic, pharmacodynamics and the anti-leukemic effects of gilteritinib, a potent, oral FLT3/AXL inhibitor, were assessed in patients with R/R AML.

In total, 252 R/R AML patients were enrolled in this study including patients with wild-type FLT3 (n = 58) and FLT3 mutation (n = 191). Patients were enrolled in one of seven dose-escalation (n = 23) or dose-expansion (n = 229) cohorts and were assigned to receive a once-daily oral dose of gilteritinib ranging from 20 mg – 450 mg.

The key results of the study were:

• Most common grade 3–4 Adverse Events (AEs) were febrile neutropenia (39%), anemia (24%), thrombocytopenia (13%), sepsis (11%), and pneumonia (11%)
• Death occurred in ninety-five patients, with seven or more possibly related to treatment
• At least 90% of FLT3 phosphorylation inhibition was seen by day 8 in most patients receiving a daily dose of ≥ 80 mg
• Overall Response Rate (ORR) of patients (n = 249) in the full analysis set; 40%
• ORR in FLT3^mut+(n = 191) and FLT3^wt (n = 58) patients; 49% vs 12%
• ORR was enhanced in FLT3 ^{mut +}patients at doses ≥ 80 mg/day; 52%
• Median Overall Survival (OS) in FLT3^mut+ (n = 191) and FLT3^wt (n = 58) patients; 30 vs 17 weeks

In summation, gilteritinib monotherapy was “well tolerated” and generated frequent, prolonged, clinically important responses in FLT3 mutated patients with R/R AML”. Anti-leukemic responses were enriched in FLT3^mut+ patients treated at doses that consistently and potently inhibited FLT3 phosphorylation. Alexander E Perl said that gilteritinib showed “limited efficacy in patients that did not have FLT3 mutations suggesting that this agent is highly selective in its activity against the FLT3 inhibition”.

Furthermore, in an exploratory analysis of a subpopulation of patients treated in this phase 1/2 study, the molecular response of FLT3-ITDmut+ patients to gilteritinib was assessed. It was found that FLT3-ITDmut+ patients who had a molecular response to gilteritinib had an improved clinical response. Additionally, molecular response may predict durable clinical benefit from gilteritinib therapy.  In an interview with the AGP, Professor Jessica Altman, Northwestern University, highlighted that the “median OS in patients that had achieved a molecular response to gilteritinib was significantly longer than patients that did not achieve a molecular response”.

Perl et al., highlighted that based on the findings of this phase 1/2 study, a phase 3 ADMIRAL study (NCT02421939) assessing oral gilteritinib 120 mg/day in R/R AML patients with FLT3 mutations after first-line therapy is currently underway. In an interview with the AGP, Alexander E Perl, discussed the design and plan of the phase 3 ADMIRAL study, which is assessing gilteritinib versus investigator’s choice in R/R AML patients with FLT3 mutation.

Abstract

Background

Internal tandem duplication mutations in FLT3 are common in acute myeloid leukaemia and are associated with rapid relapse and short overall survival. The clinical benefit of FLT3 inhibitors in patients with acute myeloid leukaemia has been limited by rapid generation of resistance mutations, particularly in codon Asp835 (D835). We aimed to assess the highly selective oral FLT3 inhibitor gilteritinib in patients with relapsed or refractory acute myeloid leukaemia.

Methods

In this phase 1–2 trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia who either were refractory to induction therapy or had relapsed after achieving remission with previous treatment. Patients were enrolled into one of seven dose-escalation or dose-expansion cohorts assigned to receive once-daily doses of oral gilteritinib (20 mg, 40 mg, 80 mg, 120 mg, 200 mg, 300 mg, or 450 mg). Cohort expansion was based on safety and tolerability, FLT3 inhibition in correlative assays, and antileukaemic activity. Although the presence of an FLT3 mutation was not an inclusion criterion, we required ten or more patients with locally confirmed FLT3 mutations (FLT3mut+) to be enrolled in expansion cohorts at each dose level. On the basis of emerging findings, we further expanded the 120 mg and 200 mg dose cohorts to include FLT3mut+ patients only. The primary endpoints were the safety, tolerability, and pharmacokinetics of gilteritinib. Safety and tolerability were assessed in the safety analysis set (all patients who received at least one dose of gilteritinib). Responses were assessed in the full analysis set (all patients who received at least one dose of study drug and who had at least one datapoint post-treatment). Pharmacokinetics were assessed in a subset of the safety analysis set for which sufficient data for concentrations of gilteritinib in plasma were available to enable derivation of one or more pharmacokinetic variables. This study is registered with ClinicalTrials.gov, number NCT02014558, and is ongoing.

Findings

Between Oct 15, 2013, and Aug 27, 2015, 252 adults with relapsed or refractory acute myeloid leukaemia received oral gilteritinib once daily in one of seven dose-escalation (n=23) or dose-expansion (n=229) cohorts. Gilteritinib was well tolerated; the maximum tolerated dose was established as 300 mg/day when two of three patients enrolled in the 450 mg dose-escalation cohort had two dose-limiting toxicities (grade 3 diarrhoea and grade 3 elevated aspartate aminotransferase). The most common grade 3–4 adverse events irrespective of relation to treatment were febrile neutropenia (97 [39%] of 252), anaemia (61 [24%]), thrombocytopenia (33 [13%]), sepsis (28 [11%]), and pneumonia (27 [11%]). Commonly reported treatment-related adverse events were diarrhoea (92 [37%] of 252]), anaemia (86 [34%]), fatigue (83 [33%]), elevated aspartate aminotransferase (65 [26%]), and increased alanine aminotransferase (47 [19%]). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (98 [39%] of 252; five related to treatment), progressive disease (43 [17%]), sepsis (36 [14%]; two related to treatment), pneumonia (27 [11%]), acute renal failure (25 [10%]; five related to treatment), pyrexia (21 [8%]; three related to treatment), bacteraemia (14 [6%]; one related to treatment), and respiratory failure (14 [6%]). 95 people died in the safety analysis set, of which seven deaths were judged possibly or probably related to treatment (pulmonary embolism [200 mg/day], respiratory failure [120 mg/day], haemoptysis [80 mg/day], intracranial haemorrhage [20 mg/day], ventricular fibrillation [120 mg/day], septic shock [80 mg/day], and neutropenia [120 mg/day]). An exposure-related increase in inhibition of FLT3 phosphorylation was noted with increasing concentrations in plasma of gilteritinib. In-vivo inhibition of FLT3 phosphorylation occurred at all dose levels. At least 90% of FLT3 phosphorylation inhibition was seen by day 8 in most patients receiving a daily dose of 80 mg or higher. 100 (40%) of 249 patients in the full analysis set achieved a response, with 19 (8%) achieving complete remission, ten (4%) complete remission with incomplete platelet recovery, 46 (18%) complete remission with incomplete haematological recovery, and 25 (10%) partial remission

Interpretation

Gilteritinib had a favourable safety profile and showed consistent FLT3 inhibition in patients with relapsed or refractory acute myeloid leukaemia. These findings confirm that FLT3 is a high-value target for treatment of relapsed or refractory acute myeloid leukaemia; based on activity data, gilteritinib at 120 mg/day is being tested in phase 3 trials.