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Ponatinib With Chemotherapy for Young Adults Ph Positive Acute Lymphoblastic Leukemia (PONALFIL)

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ClinicalTrials.gov Identifier: NCT02776605
Recruitment Status : Recruiting
First Posted : May 18, 2016
Last Update Posted : January 18, 2019
Sponsor:
Information provided by (Responsible Party):
PETHEMA Foundation

Brief Summary:

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).


Condition or disease Intervention/treatment Phase
ALL Drug: Prednisone Drug: Vincristine Drug: Daunorubicin Drug: Ponatinib Drug: Mercaptopurine Drug: Methotrexate Drug: VP-16 Drug: ARA-C: Drug: TIT Procedure: Autologous transplantation Procedure: Allo transplantation Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Concurrent Ponatinib With Chemotherapy for Young Adults With Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia
Actual Study Start Date : June 2016
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2020


Arm Intervention/treatment
Experimental: Ponatinib
  1. Pre-phase (maximum 7 days, -7 to -1) with Prednisone and triple intrathecal therapy (TIT)
  2. 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.
  3. 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".
  4. HSCT (performed ideally within 1 month from the end of consolidation).
  5. Post HSCT therapy (MRD monitoring)
Drug: Prednisone
Prednisone 60 mg/m2/day IV over 7 days (-7 a -1) and triple intrathecal therapy (TIT)

Drug: Vincristine
Vincristine (VCR): 1.5 mg/m2 (maximum 2 mg) IV days 1, 8, 15 and 22.

Drug: Daunorubicin
Daunorubicin (DNR): 45 mg/m2 IV days 1, 8, 15 and 22.

Drug: Prednisone
Prednisone (PDN): 60 mg/m2/day, IV or PO, days 1 to 27.

Drug: Ponatinib
Ponatinib 30 mg, PO from day 1 to consolidation

Drug: Mercaptopurine
Mercaptopurine (MP): 50 mg/m2, PO days 1 to 7, 28 to 35 and 56 to 63.

Drug: Methotrexate
MTX: 1,5 g/m2, IV (24 h continuous infusion) days 1, 28 and 56

Drug: VP-16
VP-16: 100 mg/m2/12 h, IV, days 14 and 42

Drug: ARA-C:
ARA-C: 1000 mg/m2/12 h, IV, days 14-15 and 42-43.

Drug: TIT
TIT (MTX: 12 mg, ARA-C: 30 mg, hydrocortisone: 20 mg), , days 1, 28 and 56.

Drug: Ponatinib
Ponatinib 30 mg/d PO, from day 1 to 15 days before HSCT.

Procedure: Autologous transplantation
Myeloablative conditioning with cyclophosphamide and total body irradiation (TBI) whenever possible and autologous transplantation

Procedure: Allo transplantation
Myeloablative conditioning with cyclophosphamide and total body irradiation (TBI) whenever possible and allo transplantation




Primary Outcome Measures :
  1. Overall response [ Time Frame: 2 years ]
    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. Event free survival [ Time Frame: 2 years ]
    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



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02776605


Locations
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Spain
Hospital Germans Trias i Pujol Recruiting
Badalona, Spain
Contact: Josep Mª Ribera, Dr       jribera@iconcologia.net   
Hospital Clinic Recruiting
Barcelona, Spain, 08036
Contact: Jordi Esteve, Dr       JESTEVE@clinic.ub.es   
Hospital 12 de Octubre Recruiting
Madrid, Spain
Contact: Mª Pilar Martinez Sánchez, Dr       mpmartinezs.hdoc@salud.madrid.org   
Hospital Virgen de la Victoria Recruiting
Málaga, Spain
Contact: Mª José Moreno, Dr       mjmorenorico@hotmail.com   
Hospital Clinico Universitario de Salamanca Recruiting
Salamanca, Spain
Contact: Jesús Maria Hernández Rivas, Dr       jmhr@usal.es   
Hospital Marques de Valdecilla Recruiting
Santander, Spain
Contact: Mª Aranzazu Bermudez, Dr       mbermudez@humv.es   
C H Santiago de Compostela Recruiting
Santiago de Compostela, Spain
Contact: Natalia Alonso, Dr       natalia.alonso.vence@sergas.es   
Hospital Virgen del Rocio Recruiting
Sevilla, Spain
Contact: Jose Gonzalez Campos, Dr       jose.gonzalez.sspa@juntadeandalucia.es   
Hospital Clinico de Valencia Recruiting
Valencia, Spain
Contact: Mª del Mar Tormo, Dr       tormo_mar@gva.es   
Hospital La Fe Recruiting
Valencia, Spain
Contact: Pau Montesinos, Dr       montesinos_pau@gva.es   
Sponsors and Collaborators
PETHEMA Foundation

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Responsible Party: PETHEMA Foundation
ClinicalTrials.gov Identifier: NCT02776605     History of Changes
Other Study ID Numbers: PONALFIL
First Posted: May 18, 2016    Key Record Dates
Last Update Posted: January 18, 2019
Last Verified: May 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Additional relevant MeSH terms:
Layout table for MeSH terms
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Leukemia
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cytarabine
Prednisone
Methotrexate
Mercaptopurine
Vincristine
Daunorubicin
Etoposide
Ponatinib
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors