Crenolanib Maintenance Following Allogeneic Stem Cell Transplantation in FLT3-positive Acute Myeloid Leukemia Patients

This is a single-arm, Phase II study of crenolanib as maintenance in AML patients with FLT3 mutations who have achieved complete remission (CR) after allogeneic stem cell transplantation. Oral crenolanib will be administered daily post-transplant for up to two years.

There are two patient subgroups: 1) those who were in complete remission (CR) at the time of transplant, and 2) those who were not in complete remission (NCR) at the time of transplant. Start of crenolanib therapy at 100 mg TID is intended at the earliest time no sooner than 42 days but no later than 90 days after allogeneic stem cell transplantation. Patients may take crenolanib continuously for up to 728 days or until one of the criteria for study discontinuation is fulfilled.

Eligibility Criteria:
Inclusion Criteria:

1. History of AML according to World Health Organization (WHO) classification
2. First allogeneic hematopoietic stem cell transplantation (HSCT) using myeloablative conditioning (MAC), non-myeloablative (NMA), or reduced-intensity conditioning (RIC) preparative regimens.
3. FLT3-ITD or FLT3-D835 positive disease at any time during disease course.
4. Hematopoietic stem cell source is either with peripheral blood, bone marrow or cord blood.
5. Donor source is matched related, unrelated, haploidentical donor or cord blood.
6. At the time of allogeneic HSCT:

   1. No more than 1 antigen mismatch at HLA-A, -B, -C, -DRB1 or -DQB1 locus for unrelated donor with peripheral blood and bone marrow as the hematopoietic stem cell source; and
   2. Bone marrow blast ≤ 10%
7. No sooner than 42 days but no later than 90 days after allogeneic HSCT.
8. Post-transplant bone marrow blast count ≤ 5% confirmed within 21 days (+4 days) prior to starting study therapy
9. Evidence of donor engraftment as defined by institutional standard T cell chimerism \> 50%.
10. Adequate engraftment within 7 days prior to starting study therapy: ANC ≥ 1.0 x 10\^9/L without daily use of myeloid growth factor; and platelet ≥ 25 x 10\^9/L without platelet transfusion within 1 week
11. Non-hematological toxicities ≤ Grade 2
12. Serum creatinine ≤ 1.5 × ULN OR creatinine clearance ≥ 50mL/min/1.73 m2 for subjects with creatinine levels above institutional normal
13. Adequate liver function with serum AST, ALT and bilirubin within the normal range at the time of crenolanib commencement
14. Acute graft-versus-host disease (GVHD) ≤ Grade 1, either no signs of chronic GVHD or mild chronic GVHD graded as limited disease
15. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
16. Age ≥ 18 years with the capacity to give written informed consent
17. Non-pregnant and non-nursing women of childbearing potential must have a negative serum or urine pregnancy test ("Women of childbearing potential" is defined as a sexually active mature woman who has not undergone a hysterectomy or who has had menses at any time in the preceding 24 consecutive months)
18. Women of childbearing potential and men must agree to use adequate contraception prior to study entry, for the duration of study participation and for 90 days following completion of therapy

Exclusion Criteria:

1. Bone marrow blast \>5% within 21 days (+4 days) of start of study drug
2. Active GVHD grade ≥ 2
3. Concurrent use of corticosteroids equivalent of prednisone at a dose \> 0.5 mg/kg
4. Active and/or untreated central nervous system (CNS) leukemia
5. Concomitant therapies for treatment or control of leukemia.
6. Use of any of the following after transplantation and prior to starting study therapy:

   1. Chemotherapeutic agents for therapy of AML (note that prophylactic use of these agents is allowed in this study, e.g., methotrexate for GVHD)
   2. Investigational agents/therapies
   3. Azacitidine, decitabine or other demethylating agents
   4. Lenalidomide, thalidomide and pomalidomide
7. Uncontrolled infection
8. Known positive for human immunodeficiency virus (HIV); active hepatitis B (HBV) or hepatitis C (HCV) infection
9. Significant cardiac disease (New York Heart Association classes III or IV) or unstable angina despite medication
10. Pregnant or breast-feeding
11. Major surgery within 4 weeks of starting study drug
12. Receipt of investigational agents within 5 half-lives of last dose of investigational agent
13. Prior treatment with crenolanib with progression on treatment