Abstract 3660: Crenolanib: A next generation FLT3 inhibitor
Authors: Galanis Allison , Rajkhowa Trivikram , Muralidhara Chaitanya , Ramachandran Abhijit , Levis Mark 
Published: August 2012

Abstract
Every year in the US there are approximately 12,000 new cases of acute myeloid leukemia (AML). Amongst these patients, 25% have internal tandem duplications (ITDs) of the type III receptor tyrosine kinase, FLT3, causing constitutive activation of the receptor. This mutation has been associated with a poor survival rate, thus making the FLT3/ITD an important target in the treatment of AML. Treatment with small molecule tyrosine kinase inhibitors (TKIs) has shown high response rates in AML patients.1 However, this response is often temporary due to the development of resistance-conferring point mutations.2 Furthermore, QTc prolongation has proven to be a dose-limiting toxicity with some FLT3 TKIs.1 Crenolanib is a TKI with activity against PDGFR and FLT3 and is currently being tested in trials involving patients with a variety of solid tumors. We have determined that crenolanib has potent activity in vitro against FLT3. Crenolanib is cytotoxic to the FLT3/ITD-expressing leukemia cell lines Molm14 and MV411, with an IC50 of 7 nM and 8 nM, respectively. In immunoblots, crenolanib inhibited phosphorylation of both the wild type FLT3 receptor (in SEMK2 cells) and the FLT3/ITD receptor (in Molm14 cells) in culture medium with an IC50 of 1-3 nM. Importantly, the IC50 of crenolanib against the D835Y mutated form of FLT3 was 8.8 nM in culture medium. Using primary AML patient samples, we determined that crenolanib was cytotoxic to FLT3/ITD-expressing samples in a manner comparable to agents such as sorafenib and AC220. Furthermore, crenolanib had cytotoxic activity against primary samples that were obtained from patients who had developed D835 resistance mutations while receiving FLT3 TKIs. In vitro, the IC50 of crenolanib for inhibition of FLT3/ITD in plasma was found to be 34 nM, indicating a relatively low degree of plasma protein binding. From pharmacokinetic studies of crenolanib in solid tumor patients, steady state trough plasma levels of roughly 500 nM were found to be safe and tolerable, suggesting that crenolanib could potentially inhibit the target in vivo as effectively as AC220. Unlike AC220, crenolanib has no significant activity against c-KIT, which may be an advantage in that myelosuppression can be avoided. Furthermore, there was no evidence of QTc prolongation in patients treated with crenolanib. In summary, crenolanib offers a number of advantages over other FLT3 TKIs. Clinical trials of crenolanib in AML patients with FLT3 activating mutations are planned. References: 1) Cortes et al. (2011) A Phase II Open-Label, AC220 Monotherapy Efficacy Study in Patients with Refractory/Relapsed Flt3-Itd Positive Acute Myeloid Leukemia: Updated Interim Results. American Society of Hematology Abstract no. 2576. 2) Smith et al (2011) Validation of FLT3-ITD As a Therapeutic Target in Human Acute Myeloid Leukemia. American Society of Hematology Abstract no. 937.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3660. doi:1538-7445.AM2012-3660