An Open-Label, Dose-Escalation Phase I/II Study of PRI-724 for Patients with Advanced Myeloid Malignancies
The goal of Part I of this clinical research study was to learn the highest tolerable dose of PRI-724 that could be given to patients with acute advanced myeloid cancer. Acute means one of the following disease types: advanced acute myeloid leukemia, myelodysplastic syndrome, or accelerated phase chronic myeloid leukemia. Together, participants with these diseases make up the Acute Group. The goal of Part II of this clinical research study was to learn the highest tolerable dose of PRI-724 that could be given to patients with chronic myeloid leukemia. These participants make up the "Non-Acute Group.” In Part III, researchers will study the safety of PRI-724 combined with a standard drug, dasatinib or cytarabine. Part III includes participants in both the Acute and Non-Acute Groups. Researchers also want to learn if PRI-724 combined with dasatinib can help to control CML, and if PRI-724 combined with cytarabine can help control AML in patients age 65 years or older. PRI-724 is designed to keep cancer cells from sending and receiving signals that they need to grow and spread.
Disease Group: Leukemia
Treatment Agent: PRI-724
Treatment Location: Both at MD Anderson & Other Sites
Sponsor: PRISM BioLab Corporation
Primary Objectives To determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) (or maximum dose to be studied) of PRI-724 alone or in combination* when administered as a continuous 7-day intravenous (IV) infusion to patients with advanced myeloid malignancies. To determine the pharmacokinetics of PRI-724 alone or in combination* when administered as a continuous 7-day IV infusion to patients with advanced myeloid malignancies. Less extensive PK sampling will be conducted in patients receiving combination therapy (Part III). To determine the safety of PRI-724 alone or in combination* when administered as a continuous 7-day IV infusion to patients with advanced myeloid malignancies. Secondary Objectives To assess the preliminary antileukemia activity of single-agent PRI-724 when administered to patients with advanced myeloid malignancies (Part I and Part II of the study) (Part II omitted effective with Amendment 5) To assess the preliminary antileukemia activity of PRI-724 when administered in combination with low dose ara-C in patients with acute myeloid leukemia (AML) 65 years of age or older, or in combination with dasatinib in patients with chronic myeloid leukemia (CML) (Part III of the study) (combination therapy with dasatinib in patients with CML omitted effective with Amendment 5) To assess the pharmacodynamic effects of PRI-724 on leukemic cells prior to and after treatment and their correlation with antileukemia activity, if observed. Exploratory Objective To assess mRNA expression of survivin by reverse transcriptase-polymerase chain reaction (RT-PCR) in peripheral blood and/or marrow leukemic cells obtained from patients prior to and after PRI-724 therapy. *Combination Therapy: AML patients >/= 65 years of age to receive low-dose ara-C (20 mg SC BID x 10d q 28d) CML-AP or BP patients to receive dasatinib (140 mg PO daily) CML-CP patients to receive dasatinib (100 mg PO daily)
IRB Review and Approval Date: 07/17/2012
Recruitment Status: Closed
Projected Accrual: 48
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). *Amendment 5 Note: Effective with Amendment 5 of this protocol, recruitment to Part II and to Part III/Arms B and C has been discontinued; no additional patients will be entered to these portions of the study.
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). *Amendment 5 Note: Effective with Amendment 5 of this protocol, recruitment to Part II and to Part III/Arms B and C has been discontinued; no additional patients will be entered to these portions of the study.
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: a) serum creatinine </=2.0 mg/dl or calculated creatinine clearance >/=60 mL/min; b) Total bilirubin </=2xULN (</=5xULN if considered due to Gilbert’s syndrome or hemolysis); c) 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 [HCG]) within 7 days prior to the start of PRI-724.
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 heparin are allowed.
9) Patients who have demonstrated intolerance to dasatinib 100mg daily will not be eligible for Part III/Arm B or C of the study (Arms B and C omitted effective with Amendment 5).