Primary Objective:
To evaluate the percentage of complete molecular responses (CMR) after two cycles of
remission induction therapy composed of two cycles of chemotherapy plus ponatinib. CMR is
defined as BCR-ABL1 below the Limit of Quantification by Droplet Digital Polymerase Chain
Reaction (ddPCR).
Outline:
Pre-phase:
dexamethasone 10 mg/m2 PO (day -5 till -1), cyclophosphamide IV 200 mg/m2 (day -3 till -1),
methotrexate 15 mg IT.
Induction I:
ponatinib 30 mg/day PO once daily (QD) continuously since day 1, rituximab 375 mg/m2 IV (day
1), dexamethasone 10 mg/m2 PO (day 1-2, 8-11), vincristine 2 mg IV (day 1, 8, 15),
Granulocyte-Colony Stimulating Factor (G-CSF) until recovery.
Induction II:
ponatinib 30 mg/day PO QD continuously, rituximab 375 mg/m2 IV (day 23), cyclophosphamide
1000 mg/m2 IV (day 24), cytarabine 75 mg/m2 IV (day 26-29, 33-36), Granulocyte StimuG-CSF
until recovery, methotrexate 15 mg IT (day 26, 33) methotrexate 15 mg + cytarabine 40 mg +
dexamethasone 4 mg IT (day 40). Week 11: Primary endpoint assessment.
Consolidation I (week 12):
ponatinib 30 mg/day PO QD continuously, rituximab 375 mg/m2 IV (day 1), dexamethasone 10
mg/m2 PO (day 1-4), vindesine 3 mg/m2 IV (day 2), methotrexate 1.5 g/m2 IV (day 2),
cytarabine 2x 2 g/m2 IV (day 5), G-CSF until recovery, methotrexate 15 mg + cytarabine 40 mg
+ dexamethasone 4 mg IT (day 8). Patients in complete molecular response at week 11 will be
treated with 5 additional blocks of chemotherapy followed by maintenance therapy; patients
with molecular failure at week 11 will end the study and be directed to alloSCT.
Consolidation II (week 18):
ponatinib 15 mg/day PO QD continuously, rituximab 375 mg/m2 IV (day 1), cyclophosphamide 500
mg/m2 IV (day 2,3), etoposide (VP-16) 75 mg/m2 IV (day 2,3), methotrexate 15 mg + cytarabine
40 mg + dexamethasone 4 mg IT (day 1).
Consolidation III+V (weeks 24 and 36):
ponatinib 15 mg/day PO QD continuously, rituximab 375 mg/m2 IV (day 1), methotrexate 1.5 g/m2
IV (day 2), vincristine 1 mg IV (day 2), 6-mercaptopurine 60 mg/m2 PO (day 2-8), methotrexate
15 mg + cytarabine 40 mg + dexamethasone 4 mg IT at day 1.
Consolidation IV+VI (weeks 30+40):
ponatinib 15 mg/day PO QD continuously, rituximab 375 mg/m2 IV (day 1), dexamethasone 10
mg/m2 PO (day 1-4), cytarabine 1.5 g/m2 IV (day 1+3+5), methotrexate 15 mg + cytarabine 40 mg
+ dexamethasone 4 mg IT (day 1). Maintenance: ponatinib 15 mg/day PO QD continuously 24
months. (Doses of IV methotrexate and cytarabine are reduced in patients >55 years.)
Inclusion Criteria:
- Patients with newly diagnosed, previously untreated, Ph-positive [either t(9;22)
and/or BCR-ABL positive] B-precursor acute lymphoblastic leukemia;
- Age 18-65 years;
- Eligible to intensive chemotherapy, due to general health status;
- ECOG (Eastern Cooperative Oncology Group) performance status ≤2;
- Absence of significant liver disease, as defined by the following criteria: total
serum bilirubin ≤1.5 x upper limit of normal (ULN), unless due to Gilbert's syndrome,
alanine aminotransferase (ALT) ≤2.5 × ULN or ≤5 x ULN if leukemic involvement of the
liver is present, and aspartate aminotransferase (AST) ≤2.5 × ULN or ≤5 x ULN if
leukemic involvement of the liver is present;
- Adequate pancreatic function as defined by serum amylase and lipase ≤1.5 × ULN;
- Diagnostic sample of bone marrow (or peripheral blood with >50% of blasts) available
for central MRD assessment;
- Subject has provided written informed consent prior to any screening procedure.
Exclusion Criteria:
- Lymphoid blast crisis of chronic myelocytic leukemia (CML);
- Active serious infection not controlled by oral or intravenous antibiotics;
- Active known hepatitis B virus (HBV) or hepatitis C virus (HCV) or positive HIV
serology;
- History of acute pancreatitis within 1 year of study or history of chronic
pancreatitis;
- Uncontrolled hypertriglyceridemia (triglycerides > 5.1 µmol/L);
- Clinically significant, uncontrolled or active cardiovascular disease, specifically
including, but not restricted to: any history of myocardial infarction, stroke, or
revascularization; unstable angina or transient ischemic attack within 6 months prior
to enrolment; congestive heart failure within 6 months prior to enrolment or left
ventricular ejection fraction (LVEF) less than lower limit of normal per local
institutional standards; history of clinically significant (as determined by the
treating physician) atrial arrhythmia; any history of ventricular arrhythmia; any
history of venous thromboembolism including deep venous thrombosis or pulmonary
embolism;
- Uncontrolled hypertension (diastolic blood pressure >90 mmHg; systolic >140 mmHg).
Patients with hypertension should be under treatment on study entry to effect blood
pressure control;
- Creatinine levels > 160 µmol/L or estimated creatinine clearance of < 50 mL/min;
- GI disease and/or major GI surgery that may significantly alter the absorption of
study drug
- Hypersensitivity to the active substance or to any of the excipients, especially
galactose intolerance.
- Taking any medications or herbal supplements that are known to be strong inhibitors of
CYP3A4 within at least 14 days before the first dose of ponatinib;
- Female patients who are pregnant or breast feeding or patients of childbearing
potential not willing to use a highly effective method of contraception during the
study and for 3 months following the last dose of study drug;
- Male patients whose sexual partner(s) are women of childbearing potential who are not
willing to use a highly effective method of contraception, one of which includes a
condom, during the study;
- Patients with a history of another primary malignancy that is currently clinically
significant or currently requires active intervention;
- Any concurrent severe and/or uncontrolled medical condition, which could, in the
opinion of the investigator, compromise participation in the study;
- Concurrent participation in another clinical study with an investigational medical
product.
