Ponatinib - Frontline for Chronic Myeloid Leukemia (CML) in Accelerated Phase (AP)
Condition: Leukemia
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Intervention: Ponatinib
Intervention description: Starting dose: 45 mg by mouth once daily.
Intervention MeSH terms: Ponatinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Intervention model description: Participants enrolled before July 25, 2013 were given a starting dose of 45 mg per day. The study was amended and the dose was lowered due to tolerability. Participants enrolled after this date were given a starting dose of 30 mg per day.
Masking: None (Open Label)
Enrollment: 51.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Leukemia; Chronic Myeloid Leukemia; CML; Chronic Phase; Cytogenetic response; CCyR; Major molecular response; MMR; Complete molecular response; CMR; Ponatinib; AP24534

Summary:

      The goal of this clinical research study is to learn if ponatinib can help to control Chronic
      Myeloid Leukemia (CML) in accelerated phase. The safety of this drug will also be studied.

      Ponatinib is designed to block the function of BCR-ABL, which is the abnormal protein
      responsible for causing leukemia in certain cells.

      Ponatinib may cause a blood clot to form in an artery or in a vein. Depending on the location
      of the clot, this could cause a heart attack, a stroke, severe damage to other tissue, or
      death. A blood clot may occur within 2 weeks after you start taking the drug. About 25% (1 in
      4) of patients taking the drug form an abnormal clot. Blood clots can occur in patients that
      do not have other known risk factors for forming clots. If you develop a blood clot, you will
      need to stop taking ponatinib. In some cases, emergency surgery could be needed to remove the
      clot and restore blood flow.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Diagnosis of Ph-positive (by cytogenetics or FISH) or Bcr-ABL-positive (by PCR) CML
             with accelerated phase features at the time of diagnosis.

          2. Patients must have received no or minimal prior therapy, defined as </=1 month of
             prior IFN-α (with or without ara-C) and/or an FDA-approved tyrosine kinase inhibitor
             (e.g, dasatinib, nilotinib). Prior use of hydroxyurea or anagrelide is allowed with no
             limitations.

          3. Age >/=18 years

          4. Eastern Cooperative Oncology Group (ECOG) performance of 0-2.

          5. Adequate end organ function, defined as the following: total bilirubin <1.5x upper
             limit of normal (ULN), serum glutamate pyruvate transaminase (SGPT) <2.5x
             ULN,creatinine clearance (CrCl) >/= 30 mL/min at screening (calculation according to
             Cockcroft & Gault formula).

          6. Patients must sign an informed consent indicating they are aware of the
             investigational nature of this study, in keeping with the policies of the hospital.

          7. Women of pregnancy potential must practice an effective method of birth control during
             the course of the study, in a manner such that risk of failure is minimized. Prior to
             study enrollment, women of childbearing potential (WOCBP) must be advised of the
             importance of avoiding pregnancy during trial participation and the potential risk
             factors for an unintentional pregnancy. Postmenopausal women must be amenorrheic for
             at least 12 months to be considered of non-childbearing potential. In addition, men
             enrolled on this study should understand the risks to any sexual partner of
             childbearing potential and should practice an effective method of birth control.
             Adequate forms of contraception are barrier methods (e.g., condoms, diaphragm), oral,
             depo provera, or injectable contraceptives, intrauterine devices, spermicidal jelly or
             foam, abstinence, and tubal ligation. Women and men must continue birth control for
             the duration of the trial & at least 3 months after the last dose of study drug.

          8. **continued from above: All WOCBP MUST have a negative serum or urine pregnancy test
             within 7 days prior to first receiving investigational product. If the pregnancy test
             is positive, the patient must not receive investigational product and must not be
             enrolled in the study.

        Exclusion Criteria:

          1. NYHA cardiac class 3-4 heart disease

          2. Cardiac Symptoms: Patients meeting the following criteria are not eligible: History of
             unstable angina, myocardial infarction, transient ischemic attack (TIA), stroke,
             peripheral arterial occlusive disease, venous thromboembolism or pulmonary embolism;
             Any history of clinically significant ventricular arrhythmias (such as ventricular
             tachycardia, ventricular fibrillation, or Torsades de pointes); Prolonged corrected QT
             interval (QTc) interval on pre-entry electrocardiogram (> 470 msec) on both the
             Fridericia and Bazett's correction; Symptomatic congestive heart failure within 3
             months prior to first dose of ponatinib (NYHA class III or IV).

          3. Patients with active, uncontrolled psychiatric disorders including: psychosis, major
             depression, and bipolar disorders.

          4. Pregnant or breast-feeding women are excluded.

          5. Patients with uncontrolled hypertension (defined as sustained stage 2 hypertension,
             i.e., systolic BP >/=160 mmHg or diastolic BP >/=100 mmHg).

          6. Patients with history of pancreatitis.

          7. Patients in late chronic phase (i.e., time from diagnosis to treatment >6 months), or
             blast phase are excluded. The definitions of CML phases are as follows: A. Early
             chronic phase: time from diagnosis to therapy </= 6 months; B. Late chronic phase:
             time from diagnosis to therapy > 6 months; C. Blastic phase: presence of 30% blasts or
             more in the peripheral blood or bone marrow; D. Accelerated phase CML: presence of any
             of the following features: Peripheral or marrow blasts 15% or more; Peripheral or
             marrow basophils 20% or more; Thrombocytopenia < 100 x 10(9)/L unrelated to therapy;
             Documented extramedullary blastic disease outside liver or spleen.

          8. **continued from above: E. Clonal evolution defined as the presence of additional
             chromosomal abnormalities other than the Ph chromosome has been historically been
             included as a criterion for accelerated phase. However, patients with clonal evolution
             as the only criterion of accelerated phase have a significantly better prognosis, and
             when present at diagnosis may not impact the prognosis at all. Thus, patients with
             clonal evolution and no other criteria for accelerated phase will be eligible for this
             study.