Not Just for GIST: A New FLT3 Inhibitor Active in Kinase Domain Mutated AML

A Phase II Study of Crenolanib in Relapsed/Refractory Acute Myeloid Leukemia Patients With FLT3 Activating Mutations

NCT01657682

Arog Pharmaceuticals LLC

MD Anderson Cancer Center

41

This is a phase II study of a new Fmslike tyrosine kinase 3 (FLT3) inhibitor (crenolanib) in relapsed or refractory acute myeloid leukemia (AML). The study includes two cohorts: one with relapsed/refractory AML without prior FLT3 tyrosine kinase inhibitor (TKI) treatment, and one with relapsed/refractory AML with prior FLT3 TKI treatment. The primary endpoints are response rate after the first 28-day cycle and at best response and safety. There is a stopping rule that will be applied if there is more than a 95 percent chance that the toxicity rate exceeds 30 percent, with toxicity defined as a grade 4 or greater non-hematologic adverse event. The secondary endpoints are duration of clinical response and progression-free and overall survival. Pharmacodynamic markers, including phospho-FLT3, will be assayed in blood and marrow blast samples, and pharmacokinetic studies will be performed to determine the relationship of drug concentration to response and toxicity. Patients in each cohort receive the same dose of crenolanib besylate (200 mg/m²/day) divided into three daily doses, preferably every eight hours, taken orally at least 30 minutes before or after a meal. Concurrent hydroxyurea (maximum 5g total daily dose for 14 days) is permitted during the first 28 days of study therapy.

AML patients with FLT3 internal tandem duplications (ITD) have a poor prognosis. Several FLT3 TKIs have been studied in clinical trials, and the results have been disappointing to date because of lack of efficacy and treatment-related toxicity (Serve H et al. J Clin Oncol. 2013;31:3110-3118). Crenolanib was initially found to have activity against the imatinib-resistant PDGFRA-mutant kinases that drive gastrointestinal stromal tumors (GIST) (Heinrich MC at al. Clin Cancer Res. 2012;18:4375-4384). In addition, it is not only a potent inhibitor of FLT-ITD, but it is also active against FLT3 with gain-of-function mutations in the tyrosine kinase domain (TKD), including D835H/Y.

About 30 percent of AML patients have FLT3- ITD mutations, and another 8 percent have FLT3-TKD mutations. Studies of sorafenib, one of the early TKIs tried in AML patients with FLT3-ITD, did not show appreciable benefit despite early reduction in blasts (Serve H et al. J Clin Oncol. 2013;31:3110-3118). This ultimate lack of efficacy was explained by near uniform development of drug resistance, by 72 days on average, attributed to emergence of a clone with the D835 mutation in the kinase domain of FLT3 (Man CH et al. Blood. 2012;119:5133-5143). Subsequent trials were conducted with midostaurin (Stone RM et al. Leukemia. 2012;26:2061-2068) and quizartinib (Cortes JE et al. J Clin Oncol. 2013;31:3681-3687). The latter is believed to be one of the most active clinical agents. However, these drugs are not active against cells with FLT3-TKD activating mutations. A recent publication showed efficacy of crenolanib in laboratory studies of drug-resistant FLT-TKD-mutated leukemia cells (Zimmerman EI et al. Blood. 2013;122:3607-3615). The current clinical trial will assess the efficacy of crenolanib in two groups of patients: those without prior treatment with TKIs and those who developed resistance after TKI therapy. The two-cohort design should provide data about whether the activity against FLT3-TKD mutants observed in pre-clinical studies translates to the clinic and whether use of the inhibitor in naïve patients prevents development of drug resistance.