Clinical Trials /

Ponatinib With Chemotherapy for Young Adults Ph Positive Acute Lymphoblastic Leukemia

NCT02776605

Description:

Evaluate the response (complete hematologic response [CHR], complete cytogenetic response [CCyR], major molecular response [MMR] and complete molecular response [CMR] of the combination of ponatinib with standard chemotherapy (according to PETHEMA ALL Ph08 trial) in young patients with Ph+ (BCR-ABL) ALL. All patients are treated with: Pre-phase (maximum 7 days, -7 to -1): Prednisone 60 mg/m2/day IV over 7 days (-7 a -1) and triple intrathecal therapy (TIT) (Methotrexate [MTX]: 12 mg, ARA-C: 30 mg, hydrocortisone: 20 mg). 2. Induction (day 1 to day 28 or up to hematological recovery) Vincristine (VCR): 1.5 mg/m2 (maximum 2 mg) IV days 1, 8, 15 and 22. Daunorubicin (DNR): 45 mg/m2 IV days 1, 8, 15 and 22. Prednisone (PDN): 60 mg/m2/day, IV or PO, days 1 to 27. Ponatinib 30 mg, PO from day 1 to consolidation. TIT, days 1 and 22. 3. Consolidation (day 1 to day 63) Mercaptopurine (MP): 50 mg/m2, PO days 1 to 7, 28 to 35 and 56 to 63. MTX: 1,5 g/m2, IV (24 h continuous infusion) days 1, 28 and 56. VP-16: 100 mg/m2/12 h, IV, days 14 and 42. ARA-C: 1000 mg/m2/12 h, IV, days 14-15 and 42-43. TIT (MTX: 12 mg, ARA-C: 30 mg, hydrocortisone: 20 mg), , days 1, 28 and 56. Ponatinib 30 mg/d PO, from day 1 to 15 days before HSCT. 4. HSCT (performed ideally within 1 month from the end of consolidation). AlloHSCT preferred over autoHSCT (autoHSCT only indicated if alloHSCT not feasible). Myeloablative conditioning with cyclophosphamide and total body irradiation (TBI) whenever possible. 5. Post HSCT therapy After alloHSCT. Frequent monitoring of MRD (every month). I After autoHSCT: Frequent monitoring of MRD (every month).

Related Conditions:
  • Acute Lymphoblastic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Ponatinib With Chemotherapy for Young Adults Ph Positive Acute Lymphoblastic Leukemia
  • Official Title: Concurrent Ponatinib With Chemotherapy for Young Adults With Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

Clinical Trial IDs

  • ORG STUDY ID: PONALFIL
  • NCT ID: NCT02776605

Conditions

  • ALL

Interventions

DrugSynonymsArms
PrednisonePonatinib
VincristinePonatinib
DaunorubicinPonatinib
PrednisonePonatinib
PonatinibPonatinib
MercaptopurinePonatinib
MethotrexatePonatinib
VP-16Ponatinib
ARA-C:Ponatinib
TITPonatinib
PonatinibPonatinib

Purpose

Evaluate the response (complete hematologic response [CHR], complete cytogenetic response [CCyR], major molecular response [MMR] and complete molecular response [CMR] of the combination of ponatinib with standard chemotherapy (according to PETHEMA ALL Ph08 trial) in young patients with Ph+ (BCR-ABL) ALL. All patients are treated with: Pre-phase (maximum 7 days, -7 to -1): Prednisone 60 mg/m2/day IV over 7 days (-7 a -1) and triple intrathecal therapy (TIT) (Methotrexate [MTX]: 12 mg, ARA-C: 30 mg, hydrocortisone: 20 mg). 2. Induction (day 1 to day 28 or up to hematological recovery) Vincristine (VCR): 1.5 mg/m2 (maximum 2 mg) IV days 1, 8, 15 and 22. Daunorubicin (DNR): 45 mg/m2 IV days 1, 8, 15 and 22. Prednisone (PDN): 60 mg/m2/day, IV or PO, days 1 to 27. Ponatinib 30 mg, PO from day 1 to consolidation. TIT, days 1 and 22. 3. Consolidation (day 1 to day 63) Mercaptopurine (MP): 50 mg/m2, PO days 1 to 7, 28 to 35 and 56 to 63. MTX: 1,5 g/m2, IV (24 h continuous infusion) days 1, 28 and 56. VP-16: 100 mg/m2/12 h, IV, days 14 and 42. ARA-C: 1000 mg/m2/12 h, IV, days 14-15 and 42-43. TIT (MTX: 12 mg, ARA-C: 30 mg, hydrocortisone: 20 mg), , days 1, 28 and 56. Ponatinib 30 mg/d PO, from day 1 to 15 days before HSCT. 4. HSCT (performed ideally within 1 month from the end of consolidation). AlloHSCT preferred over autoHSCT (autoHSCT only indicated if alloHSCT not feasible). Myeloablative conditioning with cyclophosphamide and total body irradiation (TBI) whenever possible. 5. Post HSCT therapy After alloHSCT. Frequent monitoring of MRD (every month). I After autoHSCT: Frequent monitoring of MRD (every month).

Detailed Description

      Objectives Primary

        1. To evaluate the response (complete hematologic response [CHR], complete cytogenetic
           response [CCyR], major molecular response [MMR] and complete molecular response [CMR] of
           the combination of ponatinib with standard chemotherapy (according to PETHEMA ALL Ph08
           trial) in young patients with Ph+ (BCR-ABL) ALL.

        2. To evaluate the event free survival (EFS) of the combination of ponatinib with standard
           chemotherapy (according to PETHEMA ALL Ph08 trial) in young patients with Ph+ (BCR-ABL)
           ALL. Secondary

             -  To evaluate the rate of patients receiving an allogeneic hematopoietic stem cell
                transplant (alloHSCT) in first CR

             -  To evaluate the frequency of MMR and CMR at the time of alloHSCT

             -  To evaluate the transplant-related mortality (TRM)

             -  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.

             -  To evaluate the outcome measures (CR duration, OS and EFS) in context of those
                observed in the PETHEMA ALL Ph08 trial.

             -  To observe the type and number of BCR-ABL kinase domain mutations developing during
                and after the study.

             -  To evaluate side effects, adverse events (AE) and serious AE (SAE).

      Interventions:

        1. Pre-phase (maximum 7 days, -7 to -1):

           Prednisone 60 mg/m2/day IV over 7 days (-7 a -1) and triple intrathecal therapy (TIT)
           (Methotrexate [MTX]: 12 mg, ARA-C: 30 mg, hydrocortisone: 20 mg).

        2. Induction (day 1 to day 28 or up to hematological recovery) Vincristine (VCR): 1.5 mg/m2
           (maximum 2 mg) IV days 1, 8, 15 and 22. Daunorubicin (DNR): 45 mg/m2 IV days 1, 8, 15
           and 22. Prednisone (PDN): 60 mg/m2/day, IV or PO, days 1 to 27. Ponatinib 30 mg, PO from
           day 1 to consolidation. TIT, days 1 and 22.

        3. Consolidation (day 1 to day 63) Mercaptopurine (MP): 50 mg/m2, PO days 1 to 7, 28 to 35
           and 56 to 63. MTX: 1,5 g/m2, IV (24 h continuous infusion) days 1, 28 and 56. VP-16: 100
           mg/m2/12 h, IV, days 14 and 42. ARA-C: 1000 mg/m2/12 h, IV, days 14-15 and 42-43. TIT
           (MTX: 12 mg, ARA-C: 30 mg, hydrocortisone: 20 mg), , days 1, 28 and 56. Ponatinib 30
           mg/d PO, from day 1 to 15 days before HSCT.

        4. HSCT (performed ideally within 1 month from the end of consolidation). AlloHSCT
           preferred over autoHSCT (autoHSCT only indicated if alloHSCT not feasible).
           Myeloablative conditioning with cyclophosphamide and total body irradiation (TBI)
           whenever possible.

        5. Post HSCT therapy After alloHSCT. Frequent monitoring of MRD (every month). If MRD
           negative: no therapy. If MRD positive, Ponatinib 30 mg/d, po, until 2 yr. after HSCT.
           The ponatinib dose will be reduced to 15 mg/d in the second year in patients with
           sustained molecular response. After autoHSCT: Frequent monitoring of MRD (every month).
           All patients will receive Ponatinib: 30 mg/d, PO, mercaptopurine, (40 mg/m2/d, PO) and
           methotrexate (15 mg/m2/week, IM), during the first year after HSCT. The ponatinib dose
           will be reduced to 15 mg/d in the second year in patients with sustained molecular
           response.
    

Trial Arms

NameTypeDescriptionInterventions
PonatinibExperimentalPre-phase (maximum 7 days, -7 to -1) with Prednisone and triple intrathecal therapy (TIT) Induction (day 1 to day 28 or up to hematological recovery) Vincristine (VCR): 1.5 mg/m2 IV days 1, 8, 15 and 22. Daunorubicin (DNR): 45 mg/m2 IV days 1, 8, 15 and 22. Prednisone (PDN): 60 mg/m2/day, IV or PO, days 1 to 27. Ponatinib 30 mg, PO from day 1 to consolidation. TIT, days 1 and 22. Consolidation Mercaptopurine (MP): 50 mg/m2, PO days 1 to 7, 28 to 35 and 56 to 63. MTX: 1,5 g/m2, IV days 1, 28 and 56. VP-16: 100 mg/m2/12 h, IV, days 14 and 42. ARA-C: 1000 mg/m2/12 h, IV, days 14-15 and 42-43. TIT days 1, 28 and 56. Ponatinib 30 mg/d PO, from day 1 to day 7 before HSCT". HSCT (performed ideally within 1 month from the end of consolidation). Post HSCT therapy (MRD monitoring)
  • Prednisone
  • Vincristine
  • Daunorubicin
  • Prednisone
  • Ponatinib
  • Mercaptopurine
  • Methotrexate
  • VP-16
  • ARA-C:
  • TIT
  • Ponatinib

Eligibility Criteria

        Inclusion Criteria:

          -  Age 18-55 yr.

          -  De novo Ph+ (BCR-ABL)ALL

          -  ECOG score ≤2 unless due to ALL

          -  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 lipase and amylase ≤1.5 × ULN.

          -  No history of dyslipidemia, hypertension, thrombotic events or cardiac disease.

          -  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.

          -  informed consent signed, according to national regulation

          -  Patients aged between 56 and 60 years may be selected who could be included in the
             study with the authorization of the Coordinating Investigator with the consolidation
             treatment modified as follows:

        Mercaptopurine (MP): 50 mg / m2, PO on days 1 to 7, 28 to 35 and 56 to 63 MTX: 0.75 g / m2,
        IV (continuous infusion 24 h) on days 1, 28 and 56 ARA-C: 500 mg / m2 / 12 h, IV, days
        14-15 and 42-43 TIT (MTX: 12 mg, ARA-C: 30 mg, hydrocortisone: 20 mg), days 1, 28 and 56
        Ponatinib 30 mg / d PO, from day 1 to 7 days before HSCT

        Exclusion Criteria:

          -  Lymphoid blast crisis of CML,

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

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

          -  History of acute pancreatitis within 1 year of study or history of chronic
             pancreatitis.

          -  History of alcohol abuse.

          -  Ongoing or active infections.

          -  Uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL).

          -  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.

          -  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.

          -  Taking medications that are known to be associated with torsades de pointes.

          -  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.

          -  Creatinine levels > 2.5mg/dl or glomerular filtration rate (GFR) < 20 ml/min or
             proteinuria >3.5 g/day.

          -  Gastrointestinal (GI) function impairment, or a GI disease that may significantly
             alter the absorption of study drugs.

          -  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.

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

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

          -  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.

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

          -  Patients unwilling or unable to comply with the protocol
      
Maximum Eligible Age:55 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response
Time Frame:2 years
Safety Issue:
Description:To evaluate the response (complete hematologic response [CHR], complete cytogenetic response [CCyR], major molecular response [MMR] and complete molecular response [CMR] of the combination of ponatinib with standard chemotherapy (according to PETHEMA ALL Ph08 trial) in young patients with Ph+ (BCR-ABL) ALL.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:PETHEMA Foundation

Last Updated

January 16, 2019