PONAZA : A COMBINATION OF PONATINIB AND 5-AZACITIDINE IN CHRONIC MYELOGENOUS LEUKAEMIA IN ACCELERATED PHASE OR IN MYELOID BLAST CRISIS

Prior treatment

• Participation in another clinical trial with any investigative drug within 30 days prior to study enrolment,
• Prior history of hematopoietic stem cell transplantation
• Cardiovascular disease:
  • Stage II to IV congestive heart failure (CHF) as determined by the New York Heart Association (NYHA) classification system for heart failure.
  • Myocardial infarction within the previous 6 months
  • Symptomatic cardiac arrhythmia requiring treatment
• Previous treatment with azacitidine,
• Diagnosis of malignant disease within the previous 12 months (excluding base cell carcinoma, "in-situ" carcinoma of the cervix or breast or other local malignancy excised or irradiated with a high probability of cure)

Other illness

• Individuals with another active malignancy
• Patients at high risk or very high risk of arterio-veinous occlusive disease defined by European CVD score
• Known active viral infection with Human Immunodeficiency Virus (HIV) or Hepatitis type B or C

Other

• Pregnant or lactating women,

• Patient aged 18 years or more
• Signed informed consent
• Patient with Philadelphia chromosome positive CML in first blast crisis or first accelerated phase:
  • AP-CML is defined by the presence of any of the following features:
  • 15-29% blasts in peripheral blood (PB) or bone marrow (BM)
  • ≥ 20% basophils in PB
  • ≥ 30% blasts plus promyelocytes (with blasts \<30%) in PB or BM,
  • \<100 x10(9)/L platelets unrelated to therapy, or by clonal cytogenetics evolution (i.e., the presence of cytogenetic abnormalities other than the Philadelphia chromosome);
  • MBC-CML is defined by the presence of ≥ 30% blasts in the bone marrow and/or peripheral blood or the presence of extramedullary disease.
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, 2 or 3
• Have adequate renal function as defined by the following criterion: Serum creatinine ≤ 1.5 × upper limit of normal (ULN) for institution
• Have adequate hepatic function as defined by the following criteria:
  • Total serum bilirubin ≤ 1.5 × ULN, unless due to Gilbert's syndrome or CML
  • Alanine aminotransferase (ALT) ≤ 2.5 × ULN, or ≤ 5 × ULN if leukemic infiltration of the liver is present
  • Aspartate aminotransferase (AST) ≤ 2.5 × ULN, or ≤ 5 × ULN if leukemic infiltration of the liver is present
• Have normal pancreatic status as defined by the following criterion: Serum lipase and amylase ≤ 1.5 × ULN
• Have normal QTcF interval on screening electrocardiogram (ECG) evaluation, defined as QTcF of ≤ 450 ms in males or ≤ 470 ms in females.
• Have a negative pregnancy test documented prior to enrollment (for females of childbearing potential).
• Agree to use an effective form of contraception with sexual partners throughout study participation (for female and male patients who are fertile).
• Have fully recovered (≤ grade 1, returned to baseline, or deemed irreversible) from the acute effects of prior cancer therapy before initiation of study drug