Safety and Efficacy Study of PRI-724 in Subjects With Advanced Myeloid Malignancies

PRI-724 is a new investigational drug being studied to treat subjects with cancer who have
advanced myeloid malignancies. PRI-724 is thought to work by blocking the Wnt signaling
pathway that cancer cells need to grow and spread (metastasize).

Purpose:

- To test the safety of PRI-724 when taken intravenously (through the vein).

- To observe whether PRI-724 can slow or stop the progression of leukemia.

- To find the Maximum Tolerated Dose (highest safe dose) in the first two parts of the
study.

- To find the dose of PRI-724 that should be used in the third part of the study and
possible future clinical trials that will study effectiveness and additional safety.

- To test the safety of combining PRI-724 with an approved cancer drug called dasatinib in
treating chronic myeloid leukemia (CML).

- To evaluate whether the combination of PRI-724 with the approved cancer drug dasatinib
slows or stops the progression of chronic myeloid leukemia (CML).

- To test the safety of combining PRI-724 with an approved cancer drug called Cytarabine
in treating acute myelogenous leukemia (AML).

- To evaluate whether the combination of PRI-724 with the approved cancer drug Cytarabine
slows or stops the progression of acute myelogenous leukemia (AML).

- To measure how much PRI-724 appears and remains in the blood after infusion.

- To measure several signals called biomarkers associated with cancer in the blood to see
if PRI-724 affects those signals.

Study Design:

This will be a single center, open-label escalating-dose cohort study with 3 parts: Part I
during which the MTD will be determined in acute group patients; Part II during which the MTD
will be determined in non-acute group patients; and Part III during which safety and
tolerability of escalating doses of PRI-724 will be assessed in combination with dasatinib
for CML patients or low dose ara-C therapy for AML patients ≥ 65 years of age.

Inclusion Criteria

1. Patients 18 years or older

2. Part I: Patients with one of the following histologically- or cytologically-proven
conditions: relapsed/refractory AML, relapsed/refractory MDS, or advanced CML in AP or
BP (i.e., Acute Group patients).

3. Part II: Patients with one of the following documented conditions: CML in CP that is
Philadelphia chromosome (Ph)-positive (by cytogenetics) or BCR-ABL1-positive by
fluorescent in situ hybridization [FISH], or PCR), as well as resistant to at least 2
FDA-approved tyrosine kinase inhibitors (TKIs); or a myeloproliferative neoplasia
which includes: PMF and myelofibrosis secondary to polycythemia vera (PV) and
essential thrombocythemia (ET) myelofibrosis (MF) (with intermediate-1, intermediate-2
or high risk disease according to the International Working Group [IWG] prognostic
scoring system) (i.e., Non-Acute Group patients).

4. Part III:

- Arm A: Patients with AML who are 65 years of age or older with refractory or
relapsed disease, or who have not received prior therapy but are not eligible to
receive intensive frontline chemotherapy (i.e., Acute Group patients);

- Arm B: Patients with CML in AP or BP, either newly diagnosed or failing TKI
therapy (i.e., Acute Group patients);

- Arm C: Patients with CML in CP after failure of 2 FDA-approved TKIs (i.e.,
Non-Acute group patients)

5. Performance status 0-2 of the Eastern Cooperative Oncology Group (ECOG) scale

6. Patients must have been off all prior therapy for leukemia except hydroxyurea for 1
week prior to entering this study and recovered from the toxic effects of that therapy

7. Adequate organ function as defined by:

- Serum creatinine ≤ 2.0 mg/dL or calculated creatinine clearance ≥60 mL/min

- Total bilirubin ≤2 x ULN (≤5 x ULN if considered due to Gilbert's syndrome or
hemolysis)

- Alanine aminotransferase (ALT) ≤3xULN

8. Patients must sign an informed consent indicating that they are aware of the
investigational nature of this study.

9. Women of childbearing potential and men should practice effective methods of
contraception. Women of childbearing potential should have a negative urine or serum
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic
gonadotropin within 7 days prior to the start of PRI 724.

Exclusion Criteria

1. Patients receiving any other investigational agents

2. Patients who are pregnant or breast-feeding

3. Known hypersensitivity to any of the components of PRI-724

4. Pretreatment QTcF interval >470 msec (females) or >450 msec (males)

5. Known active hepatitis B, hepatitis C

6. Serious uncontrolled medical disorder or active systemic infection or current unstable
or decompensated medical condition, which makes it undesirable or unsafe for the
patient to participate in the study including: New York Heart Association (NYHA) Class
3 or 4, myocardial infarction within 3 months, uncontrolled angina within 3 months,
history of clinically significant ventricular arrhythmia, diabetes mellitus with
ketoacidosis, or chronic obstructive pulmonary disease (COPD) requiring
hospitalization in 6 months prior to the start of treatment with PRI-724.

7. Any other condition, including mental illness or substance abuse deemed by the
Investigator to be likely to interfere with a patient's ability to sign informed
consent, cooperate, and participate in the study

8. Patients on full dose anticoagulants or any dose of warfarin; patients on prophylactic
dose of low-molecular weight or unfractionated heparin are allowed.

9. Patients who have demonstrated intolerance to dasatinib 100 mg daily will not be
eligible for Part III/Arm B or C of the study.