Criteria for participation in trial (Source of data: BASEC)
erwachsene Patienten die an myeloischer Leukämie in der chronischen Phase erkrankt sind und die mindestens zwei Tyrosinkinase-Inhibitoren (TKI) erhalten haben und nachweislich resistant gegen die Behandlung sind oder die eine bestimmte Mutation in der CML-Erbsubstanz haben;
Blutwerte liegen innerhalb bestimmter Bereiche
Exclusion criteria (Source of data: BASEC)
medikamentöse Behandlung der myeloischen Leukämie innerhalb von vorhergehenden 14 Tagen, Stammzellentranslplantation innherhalb der 60 vorangegangenen Tage, Einnahme bestimmter Medikamente, bestimmte Erkrankungen (u.a. Herz-Kreislauf, Zentrales Nervensystem, unkontrollierter Diabetes), Schwangerschaft
Inclusion/Exclusion Criteria (Source of data: WHO)
1. Have CP-CML and have received at least two prior TKI therapies and have demonstrated
resistance to treatment OR have documented history of presence of T315I mutation after
receiving any number of prior TKI.
o The diagnosis of chronic myeloid leukemia (CML) will be made using standard
hematopathologic and cytogenetic criteria; CP-CML will be defined by all of the
following: i <15% blasts in bone marrow ii <30% blasts plus promyelocytes in bone
marrow iii <20% basophils in peripheral blood. iv >= 100*10^9/liter (L) platelets
(>=100,000/mm^3). v No evidence of extramedullary disease except hepatosplenomegaly vi
No prior diagnosis of AP-CML, and BP-CML
o Cytogenetic assessment at screening must demonstrate the BCR-ABL1 fusion by presence
of the t(9;22) Philadelphia chromosome.
i Variant translocations are only allowed provided they meet inclusion criterion 1d.
o Resistance to prior TKI therapy is defined as follows (participants must meet at
least 1 criterion): i Three months after the initiation of prior TKI therapy: No
cytogenetic response (>95% Ph+) or failure to achieve CHR or new mutation ii Six
months after the initiation of prior TKI therapy: BCR-ABL1IS >10% and/or Ph+ >65% or
new mutation iii Twelve months after the initiation of prior TKI therapy: BCR ABL1IS
>10% and/or Ph+ >35% or new mutation iv At any time after the initiation of prior TKI
therapy, the development of a new BCR-ABL1 kinase domain mutation(s) v At any time
after the initiation of prior TKI therapy, the development of new clonal evolution vi
At any time after the initiation of prior TKI therapy, the loss of CHR, or CCyR, or
the confirmed loss of MMR in 2 consecutive tests, one of which has a BCR-ABL1IS
transcript level of >=1% or new mutation
o >1% of BCR-ABL1IS as shown by real-time polymerase chain reaction
2. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
3. Have adequate renal function as defined by the following criterion:
- Serum creatinine <=1.5*ULN for institution
- Estimated creatinine clearance >=30 milliliter per minute (mL/min)
4. Have adequate hepatic function as defined by the following criteria:
- Total serum bilirubin <=1.5*ULN, unless due to Gilbert's syndrome
- Alanine transaminase (ALT) <=2.5*ULN, or <=5*ULN if leukemic infiltration of the
liver is present
- Aspartate transaminase (AST) <=2.5*ULN, or <=5*ULN if leukemic infiltration of
the liver is present
5. Have normal pancreatic status as defined by the following criterion:
o Serum lipase and amylase <=1.5*ULN
6. Have normal QT interval corrected (Frederica) (QTcF) interval on screening
electrocardiogram (ECG) evaluation, defined as QTcF of <=450 milliseconds (ms) in
males or <=470 ms in females.
7. Have a negative pregnancy test documented prior to enrollment (for females of
8. Agree to use a highly effective form of contraception with sexual partners from
randomization through at least 4 months after the end of treatment (for female and
male participants who are fertile).
9. Provide written informed consent.
10. Be willing and able to comply with scheduled visits and study procedures.
11. Have recovered from toxicities related to prior anticancer therapy to National Cancer
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v 4.0 grade
1. Have used any approved TKIs or investigational agents within 2 weeks or 6 half-lives
of the agent, whichever is longer, prior to receiving study drug.
2. Received interferon, cytarabine, or immunotherapy within 14 days, or any other
cytotoxic chemotherapy, radiotherapy, or investigational therapy within 28 days prior
to receiving the first dose of ponatinib, or have not recovered (>grade 1 by NCI
CTCAE, version 4.0) from AEs (except alopecia), due to agents previously administered.
3. Have undergone autologous or allogeneic stem cell transplant <60 days prior to
receiving the first dose of ponatinib; have any evidence of ongoing graft-versus-host
disease (GVHD) or GVHD requiring immunosuppressive therapy.
4. Are being considered for hematopoietic stem cell transplant (HSCT) within 6-12 months
of enrollment (note: ponatinib is not to be used as a bridge to HSCT in this trial).
5. Are taking medications with a known risk of Torsades de Pointes.
6. Have previously been treated with ponatinib.
7. Have active CNS disease as evidenced by cytology or pathology; in the absence of
clinical CNS disease, lumbar puncture is not required. History itself of CNS
involvement is not exclusionary if CNS has been cleared with a documented negative
8. Have clinically significant, uncontrolled, or active cardiovascular disease,
specifically including, but not restricted to:
- Any history of myocardial infarction (MI), unstable angina, cerebrovascular
accident, or Transient Ischemic Attack (TIA)
- Any history of peripheral vascular infarction, including visceral infarction
- Any revascularization procedure, including the placement of a stent
- Congestive heart failure (CHF) (New York Heart Association [NYHA] class III or
IV) within 6 months prior to enrollment, or left ventricular ejection fraction
(LVEF) less than lower limit of normal, per local institutional standards, within
6 months prior to enrollment
- History of clinically significant (as determined by the treating physician)
atrial arrhythmia or any history of ventricular arrhythmia
- Venous thromboembolism, including deep venous thrombosis or pulmonary embolism,
within 6 months prior to enrollment
9. Have uncontrolled hypertension (that is, >150 and >90 for systolic blood pressure
(SBP) and diastolic blood pressure (DBP) respectively). Participants with hypertension
should be under treatment at study entry to ensure blood pressure control. Those
requiring 3 or more antihypertensive medications should be discussed with the medical
10. Have poorly controlled diabetes defined as HbA1c values of >7.5%. Participants with
preexisting, well-controlled diabetes are not excluded.
11. Have a significant bleeding disorder unrelated to CML.
12. Have a history of alcohol abuse.
13. Have a history of either acute pancre