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

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 30
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.

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 45 days but no later than 90 days after allogeneic HSCT.

8. Post-transplant bone marrow blast count ≤ 5% confirmed by standard of care bone marrow
biopsy performed post-transplant (at least 30 days post-transplant).

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 109/L
without daily use of myeloid growth factor; and platelet ≥ 25 x 109/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. Active GVHD grade ≥ 2

2. Concurrent use of corticosteroids equivalent of prednisone at a dose > 0.5 mg/kg

3. Active and/or untreated central nervous system (CNS) leukemia

4. Concomitant therapies for treatment or control of leukemia.

5. 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

6. Uncontrolled infection

7. Known positive for human immunodeficiency virus (HIV); active hepatitis B (HBV) or
hepatitis C (HCV) infection

8. Significant cardiac disease (New York Heart Association classes III or IV) or unstable
angina despite medication

9. Pregnant or breast-feeding

10. Receipt of investigational agents within 5 half-lives of last dose of investigational
agent

11. Prior treatment with crenolanib with progression on treatment