NEWLY DIAGNOSED PHILADELPHIA CHROMOSOME-POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA. MedDRA version: 18.1 Level: LLT Classification code 10000845 Term: Acute lymphoblastic leukemia System Organ Class: 100000004864
Conditions
Interventions
Trade Name: ICLUSIG® 15mg comprimidos
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Ponatinib
CAS Number: 943319-70-8
Other descriptive name: PONATINIB
Concentration unit: mg milligram(
Sponsors
Fundación PETHEMA
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Age 18-55 yr. 2. De novo Ph+ (BCR-ABL)ALL, 3. ECOG score ?2 unless due to ALL 4. 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. 5. Adequate pancreatic function as defined by serum lipase and amylase ?1.5 × ULN. 6. No history of dyslipidemia, hypertension, thrombotic events or cardiac disease. 7. For females of childbearing potential, a negative pregnancy test must be documented prior to randomization. Female and male patients who are fertile must agree to use an effective form of contraception with their sexual partners from randomization through 4 months after the end of treatment. 8. Informed consent signed, according to national regulation. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 30 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1. Lymphoid blast crisis of CML, 2. WHO performance status ? 50% (Karnofsky) or ? 3 (ECOG). 3. Active HBV or HCV hepatitis, or AST/ALT ? 2.5 x ULN and bilirubin ? 1.5 x ULN. 4. History of acute pancreatitis within 1 year of study or history of chronic pancreatitis. 5. History of alcohol abuse. 6. Ongoing or active infections. 7. Uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL). 8. 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 enrollment - Congestive heart failure within 6 months prior to enrollment, 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. 9. Uncontrolled hypertension (diastolic blood pressure >90 mm Hg; systolic >140 mm Hg). Patients with hypertension should be under treatment on study entry to effect blood pressure control. 10. Taking medications that are known to be associated with torsades de pointes. 11. 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. 12. Creatinine levels > 2.5mg/dl or glomerular filtration rate (GFR) 3.5 g/day. 13. Gastrointestinal (GI) function impairment, or a GI disease that may significantly alter the absorption of study drugs. 14. Patients who are currently receiving treatment with any of the medications with potential to prolong QT interval (listed in Appendix 4) if the medications cannot be either discontinued or switched to a different medication prior to starting study drug. 15. Patients who have received any investigational drug ? 4 weeks. 16. Patients who have undergone major surgery ? 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy. 17. 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). Postmenopausal women must be amenorrheic 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 4 months following discontinuation of study drugs. 18. Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention. 19. Patients unwilling or unable to comply with the protocol.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the response (complete hematologic response [CHR], complete cytogenetic response [CCyR], major molecular response [MMR], complete molecular response [CMR] and the event free survival (EFS) of the combination of ponatinib with standard chemotherapy (according to PETHEMA ALL Ph08 trial) in young patients with newly diagnosed Ph+ (BCR-ABL) ALL .;Secondary Objective: 1. To evaluate the rate of patients receiving an allogeneic hematopoietic stem cell transplant (alloHSCT) in first CR 2. To evaluate the frequency of MMR and CMR at the time of alloHSCT 3. To evaluate the transplant-related mortality (TRM) 4. To evaluate the CR duration and overall survival (OS) of the combination of ponatinib with standard chemotherapy (according to PETHEMA ALL Ph08 trial) in young patients with Ph+ (BCR-ABL) ALL. 5. To evaluate the outcome measures (CR duration, OS and EFS) in context of those observed in the PETHEMA ALL Ph08 trial. 6. To observe the type and number of BCR-ABL kinase domain mutations developing during and after the study. 7. To evaluate side effects, adverse events (AE) and serious AE (SAE).;Primary end point(s): All the patients who have been enrolled will be counted for any efficacy and safety observation and variable, according to the intention-to-treat principle. The frequency of the AE and the rate of permanent discontinuation for AE will also be calculated based on all patients. The compliance to the dose (dose density) will be calculated by dividing the administered dose by the dose that was actually given, over the whole treatment period. The kinetics of hematologic, cytogenetic and molecular responses, i.e. the time to achieve the respective responses, will be calculated using Kaplan & Meier?s product limit estimates. Response duration, failure-free survival, event-free survival and overall survival will be calculated using the same method. For comparisons of OS, EFS and FFS and response duration the Log-Rank will be used. Cumulativ | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): The expected period of enrollment will be 1.5 years (18 month) The overall duration of the therapy will be approximately 2.5 years: -expected time interval between induction and HSCT: 0.5 years; -duration of maintenance therapy with ponatinib after HSCT: 2 years -In patients submitted to alloHSCT, maintenance therapy of 2 years with ponatinib only in patients with MRD + (patients will be monthly monitored during the following 2 years from alloHSCT to detect MRD in case of relapse) The period of follow-up after treatment will be of 1 year With an expected period of enrollment of 1.5 years, and a period of follow-up after treatment in case of relapse of 1 year, the duration of the study will be approximately 5 to 7.5 years (enrollment + therapy duration + follow-up).;Timepoint(s) of evaluation of this end point: The expected period of enrollment will be 1.5 years (18 month) The overall duration of the therapy will be approximately 2.5 years: -expected time interval between induction and HSCT: 0.5 years; -duration of maintenance therapy with ponatinib after HSCT: 2 years -In patients submitted to alloHSCT, maintenance therapy of 2 years with ponatinib only in patients with MRD + (patients will be monthly monitored during the following 2 years from alloHSCT to detect MRD in case of relapse) The period of follow-up after treatment will be of 1 year With an expected period of enrollment of 1.5 years, and a period of follow-up after treatment in case of relapse of 1 year, the duration of the study will be approximately 5 to 7.5 years (enrollment + therapy duration + follow-up). | — |
Countries
Spain
Contacts
Public ContactInvestigación clínica
CABYC, S.L.
Outcome results
None listed