Pilot Study of Crenolanib Combined With Standard Salvage Chemotherapy in Subjects With R/R AML

Open label, dose de-escalation, phase 1b pilot trial of crenolanib with standard salvage
chemotherapy. Subjects may receive up to 2 cycles of induction with standard salvage
chemotherapy followed by crenolanib. Each arm will enroll approximately 24 patients (72
total); stratification to each arm will be per physician's choice

Inclusion Criteria

1. Confirmed diagnosis of AML, including treatment-related secondary AML (except prior
MDS) according to World Health Organization (WHO) 2008 classification at treating
institution

2. Subjects who are refractory* or who have relapsed** following first line AML therapy
with cytarabine/anthracycline based chemotherapy, with or without a tyrosine kinase
inhibitor. *Refractory to induction therapy is defined as never achieving CR, CRi or
CRp (according to International Working Group criteria) after one line of intensive
regimen for AML (re-induction, consolidation and/or transplant allowed) including at
least one cytarabine containing induction block with a total dose no less than
700mg/m² per cycle and 3 days of an anthracycline with or without a TKI.

or

**First relapse is defined as untreated hematologic relapse (according to
International Working Group criteria) after one line of intensive regimen for AML
(re-induction, consolidation and/or transplant allowed) including at least one
cytarabine containing induction block with a total dose no less than 700mg/m² per
cycle and 3 days of an anthracycline with or without a TKI that induced a CR/CRi/CRp.
Subjects are allowed to receive induction, consolidation, transplant and/or
maintenance prior to achieving their first CR/CRi/CRp.

3. Subjects considered eligible for intensive chemotherapy

4. ECOG performance status ≤ 2

5. Age ≥ 18 years

6. Adequate liver function within 72 hours of enrollment, defined as:

- Normal total serum bilirubin

- ALT and AST ≤ 2.0 x ULN

7. Adequate renal function, defined as serum creatinine ≤ 1.5x ULN

8. Women of childbearing potential must have a negative serum or urine pregnancy test
with a sensitivity of at least 25 mIU/mL within 72 hours prior to enrollment "Woman of
childbearing potential" is defined as any woman who has not undergone a hysterectomy
and who has had menses at any time in the preceding 24 consecutive months

9. Women of child-bearing potential must either commit to continued abstinence from
heterosexual intercourse or begin one acceptable method of birth control (IUD, tubal
ligation, or partner's vasectomy) while on crenolanib and for 3 months following the
last dose of crenolanib. Hormonal contraception alone is not an acceptable method of
birth control for the purpose of this trial.

10. Men must use a latex condom during any sexual contact with women of childbearing
potential, even if they have undergone a successful vasectomy and must agree to avoid
to father a child (while on therapy and for 3 month after the last dose of
crenolanib).

11. Willing to adhere to protocol specific requirements 12. Following receipt of verbal
and written information about the study, the subject must provide signed informed
consent before any study related activity is carried out. 13. Clinically significant
toxic effects of prior therapy (expect hydroxyuria) resolved to Grade ≤ 1 before the
start of study.

Exclusion Criteria

1. < 5% blasts in blood or marrow at screening, except if measurable extramedullary AML
is confirmed

2. Acute promyelocytic leukemia (APL)

3. Known clinically active CNS leukemia

4. Clinically active or unstable graft-versus-host disease (GvHD) requiring treatment
which precludes administration of chemotherapy as defined in this protocol

5. Prior anti-leukemia therapy within 14 days of enrollment for classical cytotoxic
agents, and within 5x the half-life for other investigational agents

- Prior use of hydroxyurea or isolated doses of cytarabine for palliation (i.e.,
control of WBC) are allowed but should be discontinued at least 24 hrs prior to
enrollment.

- Other agents used strictly with palliative intent might be allowed during this
period after discussing with principal investigator

6. Pre-existing liver disease (e.g. cirrhosis, chronic hepatitis B or C, nonalcoholic
steatohepatitis, sclerosing cholangitis)

7. Known HIV infection.

8. Evidence of ongoing, uncontrolled systemic infection or an uncontrolled local
infection requiring therapy at the start of study.

9. "Currently active" second malignancy (other than non-melanoma skin cancer, carcinoma
in situ of the cervix or prostatic intraepithelial neoplasia within 1 year). Subjects
are not considered to have a "currently active" malignancy if they have completed
therapy and are considered by their physician to be at less than 30% risk of relapse
within 1 year.

10. Concurrent participation in another therapeutic clinical trial.

11. Pregnant or breastfeeding women

12. Subjects of childbearing potential not willing to use adequate contraception during
study and 3 months after last dose of crenolanib

13. Subject with uncontrolled cardiac disease including congestive heart failure class III
or IV by the NYHA, unstable angina (anginal symptoms at rest) or new onset angina
(began within the last 3 months) or myocardial infarction within the past 6 months

14. Subject with concurrent severe and/or uncontrolled medical or psychiatric conditions
that in the opinion of the investigator may impair the participation in the study or
the evaluation of safety and/or efficacy

15. Inability to give an informed consent