A Safety and Tolerability Study of Crenolanib in Combination With Chemotherapy in Newly Diagnosed Acute Myeloid Leukemia Patients With FLT3 Mutations

Inclusion Criteria:

1. Unequivocal diagnosis of AML based on the WHO classification, excluding acute
promyelocytic leukemia

2. No prior therapy for AML, except for hydroxyurea, in this setting is allowed.

3. Subjects with AML evolving from MDS may have received prior MDS therapy with
demethylating agents

4. Subjects must have tested positive for FLT3-ITD and/or other FLT3 activating mutations

5. Age ≥18 years

6. ECOG PS 0 - 2

7. Adequate liver function, defined as normal total bilirubin, ALT ≤2.0x ULN, and AST
≤2.0x ULN measured within 24 hours prior to crenolanib commencement

8. Adequate renal function, defined as serum creatinine ≤1.5x ULN or GFR >50 mL/min

9. Negative pregnancy test (serum or urine) for women of childbearing potential (WOCBP)

• Women considered not of childbearing potential include any of the following: no
menses for at least 2 years or menses within 2 years but amenorrheic for at least 2
months and luteinizing hormone (LH) and follicular stimulating hormone (FSH) values
within normal range (according to definition of postmenopausal for laboratory used) or
bilateral oophorectomy or radiation castration and amenorrheic for at least 3 months
or with bilateral tubal ligation

10. WOCBP must practice contraception. Acceptable methods of contraception are double
barrier methods (condoms with spermicidal jelly or foam and diaphragm with spermicidal
jelly or foam), oral, depo provera, or injectable contraceptives, intrauterine
devices, tubal ligations, and abstention

11. Male patients (except those with prior surgical contraceptive procedures) with female
partners who are of childbearing potential: Recommendation is for male and partner to
use effective contraceptive methods, such as latex condoms, during the study

12. Able and willing to provide written informed consent

Exclusion Criteria:

1. Pre-existing liver diseases (i.e., cirrhosis, chronic hepatitis B or C, nonalcoholic
steatohepatitis, and sclerosing cholangitis, etc.)

2. Active CNS leukemia

3. Subject 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

4. NYHA Class III-IV heart failure, myocardial infarction <6 months prior to study entry,
and/or serious arrhythmia requiring anti-arrhythmic therapy

5. Unable to swallow pills

6. Major surgical procedures within 14 days of administration of crenolanib (does not
include line placement as needed for chemotherapy administration).

7. Unwillingness or inability to comply with protocol.

8. Concurrent use of other investigational agents.

9. Subjects who are not eligible for standard chemotherapy