Phase II Study of Crenolanib in Subjects With Relapsed/Refractory AML With FLT3 Activating Mutations

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

This is a Phase II open label study of crenolanib besylate. This study will enroll subjects with relapsed or refractory AML with FLT3 activating mutations. Prior treatment with other FLT3 TKIs is allowed. Subjects will take crenolanib 200mg/m2/day divided in three doses daily (preferably every eight hours), taken orally at least 30 minutes pre or post meal until disease progression, death, or the patient discontinues treatment for adverse events, investigator's judgment, or other reasons. Patients who are able to proceed to allogeneic stem cell transplant will be able to resume crenolanib therapy post-transplant in an attempt to maintain remission.

Inclusion Criteria:

• Relapsed/refractory primary AML or AML secondary to antecedent hematologic disorder with an expected survival of 3 months or greater
• Patients must have tested positive for FLT3-ITD and /or other FLT3 activating mutations within < 60 days of the screening period.
• Age ≥18 years
• ECOG PS 0 - 2
• Adequate liver function, defined as total or direct bilirubin ≤1.5x ULN, ALT ≤3.0x ULN,AST ≤3.0x ULN. Exceptions for ALT and AST restrictions will be made in the setting of documented liver involvement with leukemia
• 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 women of childbearing potential
• Able and willing to provide written informed consent
• Subjects who received crenolanib prior to and are within 30-90 days of an allogeneic stem cell transplant (HSCT) and have either no active GVHD where therapy has been initiated or GVHD where therapy has not been escalated within 14 days prior to start of study drug

Exclusion Criteria:

• Absence of FLT3 activating mutation
• <5% blasts in blood or marrow at screening
• Concurrent chemotherapy, systemic immunosuppressants, 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 manifested as hepatitis surface antigen positive (HepBsAg) or hepatitis C manifested as hepatitis C antibody positive
• For post HSCT, subjects who are within 29 days of an allogeneic transplant, and/or are on an unstable dose of immunosuppressive drugs for management or prophylaxis of GVHD or have escalated therapy for GVHD within 14 days of starting study drug and/or have >/=Grade 2 persistent non hematological toxicity related to the transplant or did not receive crenolanib prior to HSCT
• Evidence of lack of engraftment if post allogeneic transplant
• Unable to swallow pills
• Major surgical procedures within 14 days of Cycle 1 Day 1 administration of crenolanib
• Unwillingness or inability to comply with protocol.