Ponatinib Hydrochloride as Second Line Therapy in Treating Patients With Chronic Myeloid Leukemia in Chronic Phase Resistant or Intolerant to Imatinib Mesylate, Dasatinib, or Nilotinib

This is an interventional treatment trial for Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive Read More

Inclusion Criteria:

• Diagnosis of Philadelphia chromosome (Ph)-positive (by cytogenetics or fluorescent in situ hybridization [FISH]) or breakpoint cluster region (BCR)-ABL-positive (by polymerase chain reaction [PCR]) CML in chronic phase
• Patients should have demonstrated to have failure to therapy to one Food and Drug Administration (FDA)-approved TKI (currently imatinib [imatinib mesylate], dasatinib, and nilotinib are approved as frontline therapy), defined as per European LeukemiaNet (ELN) recommendations: 1) less than complete hematologic response (CHR) at or beyond 3 months; 2) no cytogenetic response at or beyond 6 months; 3) less than PCyR (Ph+ > 35%) at or beyond 12 months; 4) less than CCyR at or beyond 18 months; 5) loss of response or development of mutations or other clonal chromosomal abnormalities at any time during TKI treatment; 6) intolerance to imatinib, dasatinib or nilotinib defined as grade 3 or 4 toxicity, or persistent grade 2 toxicity despite optimal management including dose adjustment, or in a patient where dose reductions are considered to be not in the patients best interest to obtain or maintain an adequate response; intolerant patients should not have achieved or have lost major cytogenetic response at the time of enrollment
• Eastern Cooperative Oncology Group (ECOG) performance of 0-2
• Total bilirubin =< 1.5 x upper limit of normal (ULN) (unless due to Gilbert syndrome, in which case it should be =< 3.0 x ULN)
• Serum glutamate pyruvate transaminase (SGPT) =< 2.5 x ULN
• Creatinine =< 1.5 x ULN
• 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
• Reliable telephone access to receive calls from an interactive voice response system (IVR) (only applicable to patients who will participate in optional symptom burden assessment)
• 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: 1) prior to study enrollment, women of childbearing potential (WOCBP) must be advised of the importance of avoiding pregnancy during trial participation & the potential risk factors for an unintentional pregnancy; 2) postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential; 3) in addition, men enrolled on this study should understand the risks to any sexual partner of childbearing potential & should practice an effective method of birth control; 4) women & men must continue birth control for the duration of the trial & at least 3 months after the last dose of study drug; 5) all WOCBP MUST have a negative pregnancy test prior to first receiving investigational product
• Patients should have discontinued therapy with imatinib, dasatinib or nilotinib or other anti-leukemia therapy (except hydroxyurea), at least 48 hours prior to start of study therapy and recovered from any toxicity due to these therapies to at least grade 1; the use of hydroxyurea is allowed immediately prior to study entry

Exclusion Criteria:

• Prior therapy with other BCR-ABL-targeted TKIs except imatinib, dasatinib or nilotinib (e.g., bosutinib)
• New York Heart Association (NYHA) cardiac class 3-4 heart disease
• 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 (QTc) interval on pre-entry electrocardiogram (> 470 msec) on both the Fridericia and Bazett's correction; congestive heart failure (NYHA class III or IV) within 3 months prior to first dose of ponatinib
• Patients with active, uncontrolled psychiatric disorders including: psychosis, major depression, and bipolar disorders
• Patients with uncontrolled hypertension (defined as sustained systolic blood pressure > 160 mmHg or diastolic > 100 mmHg)
• Pregnant or breast-feeding women are excluded
• Patients with history of pancreatitis

• Patients in accelerated or blast phase, or patients who have ever been documented to be in blast phase CML, are excluded; the definitions of excluded CML phases are as follows:

  • Blastic phase:

    • Presence of 30% blasts or more in the peripheral blood or bone marrow

  • Accelerated phase CML:

    • 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
  • 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; thus, patients with clonal evolution and no other criteria for accelerated phase will be eligible for this study, but analyzed separately
• Patients who have received more than one FDA-approved TKI for CML, or any investigational, non-FDA approved TKI