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Cytarabine

Dasatinib

Single-agent MTD (or maximum dose to be studied) of PRI-724 will be determined in escalating dose cohorts of Acute Group patients. The MTD cohort will be expanded up to 10 patients to further evaluate tolerability.

Single-agent MTD (or maximum dose to be studied) of PRI-724 will be determined in escalating dose cohorts of Non-Acute Group patients. Dosing will begin 2 dose levels below the Part I MTD. The MTD cohort will be expanded up to 10 patients to further evaluate tolerability.

Once the MTD is identified for each arm, that cohort will be expanded to a total of 10 patients each.

Escalating doses of PRI-724, beginning 2 dose levels below the Part I MTD will be administered in combination with low dose ara-C therapy (20 mg SC BID × 10d q 28d) for AML patients ≥ 65 years of age.

Once the MTD is identified for each arm, that cohort will be expanded to a total of 10 patients each.

Escalating doses of PRI-724, beginning 2 dose levels below the Part I MTD will be administered in combination with dasatinib (140 mg PO daily) to Acute Group patients with CML-AP or BC.

Once the MTD is identified for each arm, that cohort will be expanded to a total of 10 patients each.

Escalating doses of PRI-724, beginning 1 dose level below the Part II MTD will be administered in combination with dasatinib (100 mg PO daily) to Non-Acute Group patients with CML-CP.

PRI-724

PRI-724 in combination with low dose ara-C therapy

Jorge Cortes, MD

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).

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.

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

An Open-Label, Dose-Escalation Phase I/II Study of PRI-724 for Patients With Advanced Myeloid Malignancies

Observance of 1 DLT in first 3 patients during 3+3 phase will result in the enrollment of an additional 3 patients.

Observance of 2+ DLTs in 6 patients during 3+3 phase will result in the next lower dose being expanded.

Observance of DLTs in 33% of patients in 10 patient MTD expansion will result in the next lower dose being expanded.

MTD will only be established in a dose level where 0/3 pts or 1/6 pts have a DLT observed in first 2 cycles of therapy.

Two types of DLTs will be observed: non-hematologic and hematologic.

The preliminary efficacy endpoints will be changes in the response assessment according to International Working Group Response Criteria for Acute Myeloid Leukemia (AML), European LeukemiaNet Response Criteria for Chronic Myeloid Leukemia (CML), International Working Group Response Criteria for Myelodysplastic Syndromes (MDS) and International Working Group (IWG) consensus criteria for treatment response in myelofibrosis with myeloid metaplasia

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