Pacritinib and Chemotherapy in Treating Patients With Acute Myeloid Leukemia and FLT3 Mutations

PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of pacritinib in combination with 7+3 or
decitabine (respective cohorts are independent of each other) in patients with newly
diagnosed or relapsed/refractory acute myeloid leukemia (AML) with FLT3 mutations.

II. To define the specific toxicities, maximum tolerated dose (MTD) and the dose limiting
toxicities (DLT) of these combinations.

III. To determine the recommended phase 2 dose (RP2D) of these combinations.

SECONDARY OBJECTIVES:

I. To determine the rate and duration of complete remission (CR) +/- hematologic recovery of
pacritinib and 7+3 or decitabine in AML.

II. To determine the overall response rate (ORR) and disease free survival at 1 year.

TERTIARY OBJECTIVES:

I. To conduct pharmacokinetic studies of pacritinib in combination with chemotherapy.

II. To determine the impact of pacritinib on the inhibition of Janus kinase 2 (JAK2), FLT3,
AXL receptor tyrosine kinase (AXL), signal transducer and activator of transcription 5A
(STAT5), spleen tyrosine kinase (Syk).

III. To examine the exosome, cytokine, and chemokine changes of FLT3 down-stream inhibition
by pacritinib.

IV. To examine resistance patterns associated with treatment with pacritinib. V. To examine
baseline cytogenetic, GTP binding protein overexpressed in skeletal muscle (GEM) signature,
and long non-coding (Lnc) ribonucleic acid (RNA) signature and mutational status of the AML
tumor cells to better identify subsets of patients with highest likelihood of responding to
therapy.

OUTLINE: This is a dose-escalation study of pacritinib. Patients are assigned to 1 of 2
treatment arms.

COHORT A:

INDUCTION: Patients receive pacritinib orally (PO) on days 1-21, cytarabine intravenously
(IV) every 24 hours on days 5-11, and daunorubicin hydrochloride IV every 24 hours on days
5-7. Treatment repeats every 28 days for 1-2 courses in the absence of disease progression or
unacceptable toxicity.

COHORT B:

INDUCTION: Patients receive pacritinib PO on days 1-21 and decitabine IV every 24 hours on
days 5-14. Treatment repeats every 28 days for 2-4 courses in the absence of disease
progression or unacceptable toxicity.

MAINTENANCE: Patients achieving CR will proceed with transplant evaluation (if appropriate).
Transplant-ineligible patients will receive maintenance courses of pacritinib PO on days 1-21
and decitabine IV over 1 hour daily on days 1-5. Maintenance courses repeat every 28 days in
the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for at least 30 days.

Inclusion Criteria:

- Patients with AML and the presence of FLT3 mutation

- Patients with secondary AML or therapy related disease (t-AML) are eligible

- If the patient has co-morbid medical illness, life expectancy attributed to this must
be greater than 6 months

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2

- Total bilirubin < 2.0mg/dL unless due to Gilbert's disease

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
< 2.5 X institutional upper limit of normal

- Creatinine (Cr) clearance > 50 mL/min by Cockcroft-Gault calculation

- New York Heart Association (NYHA) congestive heart failure (CHF) class II or better

- Cardiac ejection fraction >= 50% for Arm A, >= 40% for Arm B

- Female patients of child-bearing potential must agree to use dual methods of
contraception and have a negative serum pregnancy test at screening, and male patients
must use an effective barrier method of contraception if sexually active with a female
of child-bearing potential; acceptable methods of contraception are condoms with
contraceptive foam, oral, implantable or injectable contraceptives, contraceptive
patch, intrauterine device, diaphragm with spermicidal gel, or a sexual partner who is
surgically sterilized or post-menopausal; for both male and female patients, effective
methods of contraception must be used throughout the study and for three months
following the last dose

- Ability to understand and willingness to sign the written informed consent document

- Human immunodeficiency virus (HIV) infection without history of acquired immune
deficiency syndrome (AIDS) and sufficiently high cluster of differentiation (CD)4
cells (> 400/mm^3) and low HIV viral loads (< 30,000 copies/ml plasma) not requiring
anti-HIV therapy are eligible

Exclusion Criteria:

- Patients with core-binding factor AML (inv[16], t[8;21]) or t(15;17)

- Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study; treatment with hydroxyurea
is permitted during cycle 1 to maintain white blood cell (WBC) < 40,000/uL

- Patients receiving any other investigational agents or patients that have received
other investigational agents within 14 days of enrollment

- Patients with active central nervous system (CNS) malignancy

- Major surgery within 2 weeks before day 1

- Uncontrolled active infection; patients with infection requiring parenteral
antibiotics are eligible if the infection is controlled

- Patients with significantly diseased or obstructed gastrointestinal tract

- Uncontrolled intercurrent illness including, but not limited to, symptomatic
congestive heart failure (New York Heart Association [NYHA] class III or IV), unstable
angina pectoris, myocardial infarction within 6 months prior to enrollment, severe
uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute
ischemia or active conduction system abnormalities; prior to study entry, any
electrocardiogram (ECG) abnormality at screening has to be documented by the
investigator as not medically relevant

- Patients with serious medical or psychiatric illness likely to interfere with
participation in this clinical study

- Pregnant women or women who are breastfeeding are excluded from this study;
confirmation that the subject is not pregnant must be established by a negative serum
beta-human chorionic gonadotropin (beta-hCG) pregnancy test result obtained during
screening; pregnancy testing is not required for post-menopausal or surgically
sterilized women

- Patients with advanced malignant solid tumors

- Patients who are not able to swallow capsules or tablets

- Patients with baseline corrected QT (QTc) > 500 ms