Safety Analysis of Intra-Patient Dose- Study of Crenolanib Maintenance Therapy in Patients with FLT3 Mutant AML Following Allogeneic Hematopoietic Stem Cell Transplant
Authors: Oran Betul , Ciurea Stefan O. , Marin David , McCarty Jessica M , Bashir Qaiser , Ahmed Sairah , Olson Amanda L. , Popat Uday , Nieto Yago , Kebriaei Partow , Shpall Elizabeth J. , Agrawal Trishala , Champlin Richard E 
Published: October 2019

Abstract
Background: FLT3 inhibitors (like sorafenib and midostaurin) have been administered as maintenance therapy post allogeneic stem cell transplantation (SCT) to reduce persistent relapse risks in FLT3-mutant AML patients. Reduced doses of both sorafenib and midostaurin have been found to be tolerable in the post-HSCT setting. Crenolanib is a highly potent and selective FLT3-targeted TKI that has activity as a single-agent and combined with chemotherapy in patients with FLT3-ITD and/or FLT3-TKD mutations. We here report the outcomes of safety and tolerability of crenolanib maintenance in FLT3 mutant AML patients after allo-HSCT (NCT02400255).
Methods: To assess the tolerability of crenolanib maintenance in post-SCT AML patients and evaluate the appropriate dose for such patient population, a clinical trial of crenolanib maintenance therapy was performed in patients (age ≥ 18) with FLT3 mutant AML who had undergone SCT. Enrollment criteria included patients with FLT3-ITD, or FLT3-TKD positive disease at any point prior to SCT, having first SCT, with ≥ 50% T cell donor chimerism, adequate engraftment with complete remission (CR) at post-SCT evaluations. Patients needed to enroll between 42 and 90 days post-transplant without uncontrolled infection and graft versus host disease (GvHD).
Initially, the study was designed for patients to be treated with crenolanib 80 mg TID (240 mg daily. Due to initial tolerability in the first patients (n=4), the design was changed to an intra-patient dose-escalation, in which patients received crenolanib starting at a dose of 60 mg BID for a month and then escalated to 80 mg BID and finally 80 mg TID as tolerated.
As of July 2018, 24 patients, median age 53.5 years (range 31-74) have been enrolled and received crenolanib maintenance therapy. Disease status at SCT was CR (n=10, 42%), CR without count recovery (CRi, n=12, 50%), and active disease (n=2, 8%). The minimal residual disease (MRD) by multicolor flow cytometry was evaluable in 22 CR/CRi patients at SCT and was deemed to positive in 5 (23%). Conditioning regimen was myeloablative (20, 83%) or reduced intensity (4, 17%). Donors were matched related (n=11, 46%), matched unrelated (n=11, 46%) or haploidentical (n=2, 8%).
After 4 patients enrolled, the trial design was altered to allow for intra-patient dose escalation. Ten patients were never able to escalate above 60mg BID, one patient stayed at 60 mg TID, 12 patients escalated to 80 mg BID, of those 12, 7 were able to escalate to 80 mg TID.
The median days on crenolanib was 474 days (4-728 days) and median number of cycles was 17.5 cycles (1-26 cycles). Of the 21 patients no longer on study, 6 were due to relapse with median time to progression of 17 days (7-76 days) after first dose of crenolanib. Of the 6 relapses, four patients were positive for MRD prior to transplant and two had active disease. Two patients came off study due to noncompliance with study procedures, two were due to withdrawal of consent, 7 were patient decision due to side effects, one was due to suicidal ideation, and one was for insurance non-payment. Only one patient completed the planned 24 cycles of treatment with crenolanib 60 mg BID. Currently, four patients remain on study.
Observed side effects were predominantly grade 1 and 2 with the most common (regardless of attribution) being nausea (62%), vomiting (38%), and diarrhea (33%), 13 adverse events that were grade 3 were reported likely attributable to crenolanib, no grade 4 side effects reported. There were two grade 2 GVHD-AEs, one grade 1 and one ungraded GVHD-AEs reported. One patient had a grade 3 rash that was confirmed as GVHD.
Conclusion: These interim results suggest that crenolanib can be safely given at a dose of 160 mg to 240 mg total daily in the post-SCT setting. Two randomized phase III trials have been initiated to investigate the efficacy of crenolanib with chemotherapy vs chemotherapy alone in R/R FLT3 mutated AML as well as crenolanib vs midostaurin following chemotherapy in newly diagnosed FLT3 mutated AML (NCT03250338, EudraCT 2017-001600-29; NCT03258931). Post HSCT crenolanib maintenance will be offered at 100 mg BID (200 mg daily) in both trials.

Disclosures
Oran: AROG pharmaceuticals: Research Funding; ASTEX: Research Funding; Celgene: Consultancy, Research Funding. Shpall:Affirmed GmbH: Research Funding. Agrawal:Arog: Employment. Champlin:Sanofi: Research Funding; Otsuka: Research Funding.