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Front-line Treatment of Philadelphia Positive (Ph+)/BCR-ABL Positive Acute Lymphoblastic Leukemia (ALL) With AP24534 (Ponatinib), a New Potent Tyrosine Kinase Inhibitor (TKI). A Phase II Exploratory Multicentric Study in Patients More Than 60 Years Old or Unfit for a Program of Intensive Chemotherapy and Stem Cell Transplantation.

Phase 2
18 Years
Not Enrolling
Philadelphia Positive, BCR-ABL Positive, Acute Lymphoblastic Leukemia

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Trial Information

Front-line Treatment of Philadelphia Positive (Ph+)/BCR-ABL Positive Acute Lymphoblastic Leukemia (ALL) With AP24534 (Ponatinib), a New Potent Tyrosine Kinase Inhibitor (TKI). A Phase II Exploratory Multicentric Study in Patients More Than 60 Years Old or Unfit for a Program of Intensive Chemotherapy and Stem Cell Transplantation.

This is a multi-center, phase 2, single arm unblinded trial of oral Ponatinib in patients
with Ph+ Acute Lymphoblastic Leukemia. Patients will receive daily oral administration of
Ponatinib at a dose of 45 mg/day for 6 weeks (defined as one course) for 8 courses, same
dose and schedule, for a total of 48 weeks. Each patient will be followed for the subsequent
24 months, every 3 month, providing survival information and monitoring serious adverse

Each patient should be treated for a minimum of 6 weeks. Then a patient can be discontinued
in the following situation:

- at the end of first course (6 weeks), in case of lack of CHR;

- at the end of third course (18 weeks), in case of lack of CCgR;

- any time in case of loss of CHR or CCgR. If they remain on therapy after 48 weeks, they
will be able to continue treatment during the extension phase of the study, if it is of
interest of the patient, or they will be allowed to receive any treatment that is in
their interest. For all the patients remaining on trial, response, outcome and toxicity
will be followed for the subsequent 24 months.The 6-weeks periodicity must be rigidly
respected, irrespective of the temporary discontinuation of study drug (eg, if a
patient will take Ponatinib only for 4 weeks and will remain off-treatment for the
subsequent two weeks because of AE, when the 7th week begins this patient will restart
Ponatinib as a second course, as per protocol). Prednisone (P) will be administered to
all patients for 7-14 days, before Ponatinib, so as to make it possible to wait for the
results of cytogenetic and molecular tests, and to evaluate the response to P alone,
hence for another 21 days. Intrathecal therapy (IT) with MTX/AraC/DEX is mandatory,
every 28 days, in patients without clinical-cytologic evidence of meningeal
involvement. In patients with CNS disease, IT is performed twice weekly until a
complete clearance of cerebrospinal fluid blast cells is achieved, hence once weekly
for 4 weeks, hence once monthly.

Inclusion Criteria:

1. To be classified as having Ph+ ALL, patients must have >20% blasts in bone marrow at
the time of diagnosis and no prior history of CML.

2. Patients with previously untreated Ph+ and/or BCR/ABL + ALL:

- age ≥ 60 years old or

- age ≥ 18 years old, but unfit for program of intensive therapy and allogeneic

3. Signed written informed const according to ICH/EU/GCP and national local laws.

4. Effective contraception.

Exclusion Criteria:

1. Uncontrolled congestive heart failure or/and uncontrolled hypertension.

2. History of myocardial infarction within 3 months, or uncontrolled angina pectoris.

3. Significant electric heart abnormalities, including history or presence of
significant ventricular or atrial tachyarrhythmias, congenital long QT syndrome
and/or QTc > 450 msec on screening ECG (using the QTcF formula) .

4. WHO performance status ≤ 50% (Karnofsky) or ≥ 3 (ECOG).

5. Active HBV or HCV hepatitis, or AST/ALT ≥ 2.5 x ULN and bilirubine ≥ 1.5 x ULN.

6. Creatinine level > 2.5mg/dl or Glomerular Filtration Rate (GFR) < 20 ml/min or
proteinuria > 3.5 g/day.

7. History of acute pancreatitis within 1 year of study, or history of chronic
pancreatitis, history of alcohol abuse; ongoing or active infection; uncontrolled
hypertriglyceridemia (triglicerides > 450 mg/dL).

8. Impairment of gastrointestinal (GI) function, or a GI disease that may significantly
alter the absorption of study drugs (e.g., severe malabsorption syndrome, or extended
small bowel resection).

9. Patients who are currently receiving treatment with any of the medications listed in
Appendix D if the medications cannot be either discontinued or switched to a
different medication prior to starting study drug. The medications listed in Appendix
D have the potential to prolong QT.

10. Patients who have received any investigational drug ≤ 4 weeks.

11. Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or
who have not recovered from side effects of such therapy.

12. Patients who are pregnant or breast feeding and adults of reproductive potential not
employing an effective method of birth control (women of childbearing potential must
have a negative serum pregnancy test within 48 hrs prior to administration of
Ponatinib). Post menopausal women must be amenorrhoic for at least 12 months to be
considered of non-childbearing potential. Male and female patients must agree to
employ an effective barrier method of birth control throughout the study and for up
to 3 months following discontinuation of study drugs.

13. Patients with a history of another primary malignancy that is currently clinically
significant or currently requires active intervention.

14. Patients unwilling or unable to comply with the protocol.

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Proportion of patients who are in Complete Hematological Response (CHR).

Outcome Description:

The primary endpoint is the proportion of patients who are in CHR at 6 months, calculated on the total number of patients who have been enroled and have received at least one dose of the first drug (prednisone).

Outcome Time Frame:

At 6 months from study entry.

Safety Issue:


Principal Investigator

Michele Baccarani, Pr.

Investigator Role:

Principal Investigator

Investigator Affiliation:

Dpt of Hematology and Oncology "Seràgnoli", "Sant'Orsola-Malpighi" University Hospital of Bologna


Italy: The Italian Medicines Agency

Study ID:




Start Date:

April 2013

Completion Date:

March 2017

Related Keywords:

  • Philadelphia Positive
  • BCR-ABL Positive
  • Acute Lymphoblastic Leukemia
  • Ph+
  • BCR-ABL+
  • ALL
  • Ponatinib
  • stem cell transplantation
  • Leukemia
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma