Patient case: 4-year-old female with leukemia; genetic feature: ABL1

Clinical trial: Ponatinib as Second Line Therapy for Patients With Chronic Myeloid Leukemia in Chronic Phase Resistant or Intolerant to Imatinib, Dasatinib or Nilotinib

Summary: The goal of this clinical research study is to learn if ponatinib can help to control CML in chronic 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 CML. This may cause the cancer cells to die.
  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.

Detailed description: Study Drug Administration:
  You will take ponatinib by mouth 1 time every day while you are on study with about a cup (8 ounces) of water. You may take ponatinib with or without food. If you vomit a dose, you should not take ponatinib again to make up for that dose. You should wait until your next scheduled dose. You will complete a study diary in which you will record the date and time that you take the study drug each time. If you miss any doses, you will also note this in the study diary. You will bring this diary to every study visit.
  Study Visits:
  The study staff will help you schedule your study visits. The following tests and procedures will be performed:
  -  Blood (about 1/2 tablespoon each time) will be drawn for routine tests every 1-2 weeks for the first 4 weeks, every 4-6 weeks for the first year, every 3-4 months for second year, then every 4-6 months after that. These tests can be done by your home doctor and sent to your study doctor.
  -  You will have an EKG every 3 months for the first year.
  -  You will have a physical exam and you will be asked about any drugs you may be taking and any side effects you may be having every 3 months for the first year, then every 6-12 months after that.
  -  Blood (about 2 teaspoons) will be drawn to check the status of the disease every 3-4 months for the first year, then every 6-12 after that.
  -  You will have a bone marrow aspirate for genetic testing and to check the status of the disease every 3-4 months for the first year, then every 6-12 months for the next 2 years, then every 2-3 years after that.
  Length of Study:
  You may take the study drug for up to 5 years. You will be taken off study early if intolerable side effects occur, if the disease gets worse, or if you are unable to follow study directions.
  Your participation on the study will be over when you have completed the follow-up visit/call (described below).
  If the disease gets worse or the disease never responds to treatment with ponatinib, blood (about 1 tablespoon) will be drawn about 30 days after your last dose of ponatinib to check for changes in the BCR-ABL protein which may explain why there was no response to the study drug.
  Follow-Up:
  Within 30 days after you leave the study, you will be called or you will come to the clinic to learn about any side effects or symptoms you may be having. If you are called, this call will last about 2-3 minutes.
  This is an investigational study. Ponatinib is FDA approved to treat patients with certain types of leukemia. Its use in this study is investigational.
  Up to 50 participants will be enrolled in this study. All will be enrolled at MD Anderson.

Eligibility: Inclusion Criteria:
  1. Diagnosis of Ph-positive (by cytogenetics or FISH) or BCR-ABL-positive (by PCR) CML in chronic phase.
  2. Patients should have demonstrated to have failure to therapy to one FDA-approved TKI (currently imatinib, 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.
  3. Age >/= 18 years.
  4. ECOG performance of 0-2.
  5. Adequate end organ function, defined as the following: total bilirubin </= 1.5x ULN (unless due to Gilbert syndrome, in which case it should be </= 3.0x ULN), SGPT </= 2.5x ULN, creatinine </=1.5x ULN.
  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. 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).
  8. 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;
  9. **continued from above: 5. All WOCBP MUST have a negative pregnancy test prior to first receiving investigational product.
  10. 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:
  1. Prior therapy with other BCR-ABL-targeted TKIs except imatinib, dasatinib or nilotinib (e.g., bosutinib).
  2. NYHA cardiac class 3-4 heart disease.
  3. Cardiac Symptoms: Patients meeting the following criteria are not eligible: History of unstable angina, myocardial infarction, 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 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.
  4. Patients with active, uncontrolled psychiatric disorders including: psychosis, major depression, and bipolar disorders.
  5. Patients with uncontrolled hypertension (defined as sustained systolic blood pressure > 160 mmHg or diastolic > 100 mmHg).
  6. Pregnant or breast-feeding women are excluded.
  7. Patients with history of pancreatitis.
  8. 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: a. Blastic phase: presence of 30% blasts or more in the peripheral blood or bone marrow; b. 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; c. 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.
  9. **continued from above: 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.
  10. Patients who have received more than one FDA-approved TKI for CML, or any investigational, non-FDA approved TKI.

Relevance to patient case: not relevant