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

Inclusion Criteria:

Confirmed primary AML relapsed or refractory after prior therapy, AML secondary to antecedent chemotherapy or radiation therapy, or AML due to prior myelodysplastic syndrome (MDS)/ myeloproliferative neoplasm (MPN) as defined by WHO criteria with presence of either FLT3 ITD and/or other FLT3 activating mutations
Patients with secondary AML should have failed no more than two (2) prior regimens
Patients with antecedent MDS/MPN, defined by WHO criteria, without any prior therapy for AML, regardless of the number of therapies for MDS/ MPN
Patients with primary AML should have received no more than two (2) prior cytotoxic containing salvage regimens. Reinduction with the same regimen or stem cell transplant will not be considered a separate salvage regimen. Change of drugs will be considered a salvage regimen. Unlimited FLT3 TKI therapy (even in combination with cytotoxics/hypomethylating agents) is allowed for patients enrolled in cohort B
Patients must have tested positive for FLT3-ITD and /or other FLT3 activating mutations within 30 day screening period
Males and females age ≥18 years
ECOG PS 0-2
Adequate liver function, defined as bilirubin ≤1.5x ULN, ALT ≤3.0x ULN, and AST ≤3.0x ULN
Adequate renal function, defined as serum creatinine ≤1.5x ULN
Recovery from non-hematological toxicities of prior therapy (including HSCT) to no more than grade 1 (except alopecia)
Subjects should have received no anti-leukemic therapy (except hydroxyurea) prior to the first dose of crenolanib as follows: for 14 days for classical cytotoxic agents and for five times the t1/2 (half-life) for FLT3 inhibitors and antineoplastic agents that are neither cytotoxic nor FLT3 inhibitors (e.g. hypomethylating agent or MEK inhibitor)
Negative pregnancy test for WOCBP
Able and willing to provide written informed consent.

Exclusion Criteria:

Absence of a FLT3 activating mutation
<5% blasts in blood or marrow at screening
Concurrent chemotherapy, or targeted anti-cancer agents, other than hydroxyurea
Patient with concurrent severe and/or uncontrolled medical conditions that in the opinion of the investigator may impair the participation in the study or the evaluation of safety and/or efficacy
HIV infection or active hepatitis B (defined as hepatitis B surface antigen positive) or C (defined as hepatitis C antibody positive)
Known clinically active central nervous system (CNS) leukemia
Patients less than 30 days post HSCT
Subjects who have clinically significant graft versus host disease requiring treatment and /or have >grade 2 persistent non hematological toxicity related to transplant
Prior crenolanib treatment for a non-leukemic indication
Major surgical procedures within 14 days of Day 1 administration of crenolanib.
Unwillingness or inability to comply with protocol.