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

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).

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia; Chronic Myeloid Leukemia
• Intervention / Treatment: Drug: PRI-724; Drug: PRI-724; Drug: PRI-724

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 49
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University / Winship Cancer Institute
  • Massachusetts
    • Worcester, Massachusetts, United States, 01655
      • University of Massachusetts Medical Center
  • New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • New Mexico Cancer Care Alliance
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Columbus, Ohio, United States, 43210-1267
      • Ohio State University
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas M.D. Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part I; 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.	Drug: PRI-724; PRI-724; Drug: PRI-724; PRI-724 in combination with dasatinib; Drug: PRI-724; PRI-724 in combination with low dose ara-C therapy
Experimental: Part II; 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.	Drug: PRI-724; PRI-724; Drug: PRI-724; PRI-724 in combination with dasatinib; Drug: PRI-724; PRI-724 in combination with low dose ara-C therapy
Experimental: Part III Arm A; 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.	Drug: PRI-724; PRI-724; Drug: PRI-724; PRI-724 in combination with dasatinib; Drug: PRI-724; PRI-724 in combination with low dose ara-C therapy
Experimental: Part III Arm B; 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.	Drug: PRI-724; PRI-724; Drug: PRI-724; PRI-724 in combination with dasatinib; Drug: PRI-724; PRI-724 in combination with low dose ara-C therapy
Experimental: Part III Arm C; 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.	Drug: PRI-724; PRI-724; Drug: PRI-724; PRI-724 in combination with dasatinib; Drug: PRI-724; PRI-724 in combination with low dose ara-C therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DLT (Dose Limiting Toxicity)	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.	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Preliminary Efficacy Endpoints	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	1 year

Collaborators and Investigators

• Sponsor: Prism Pharma Co., Ltd.
• Collaborators: inVentiv Health Clinical

Study record dates

Study Major Dates

• Study Start: July 1, 2012
• Primary Completion (Actual): December 30, 2016
• Study Completion (Actual): December 30, 2016

Study Registration Dates

• First Submitted: May 16, 2012
• First Submitted That Met QC Criteria: May 23, 2012
• First Posted (Estimate): May 25, 2012

Study Record Updates

• Last Update Posted (Actual): August 17, 2017
• Last Update Submitted That Met QC Criteria: August 16, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: MPN; AML; Leukemia; MDS; CML; acute myeloid leukemia; myelodysplastic syndrome; chronic myeloid leukemia; myeloproliferative neoplasia
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Other Study ID Numbers: PRI-724-201

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No