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PONAZA : A COMBINATION OF PONATINIB AND 5-AZACITIDINE IN CHRONIC MYELOGENOUS LEUKAEMIA IN ACCELERATED PHASE OR IN MYELOID BLAST CRISIS (PONAZA)

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ClinicalTrials.gov Identifier: NCT03895671
Recruitment Status : Recruiting
First Posted : March 29, 2019
Last Update Posted : August 12, 2019
Sponsor:
Information provided by (Responsible Party):
Philippe ROUSSELOT, Versailles Hospital

Brief Summary:

This project is strategy aiming to improve the survival of patients with chronic myelogenous leukemia in advanced phase and myeloid blast crisis.

The basis of this strategy is to add the demethylating agent 5-Azacitidine to the tyrosine kinase inhibitor ponatinib and evaluate its activity in 2 cohorts of patients with either chronic myelogenous leukemia in advanced phase or myeloid blast crisis.


Condition or disease Intervention/treatment Phase
CHRONIC MYELOGENOUS LEUKAEMIA IN ACCELERATED PHASE CHRONIC MYELOGENOUS LEUKAEMIA IN MYELOID BLAST CRISIS Drug: Ponatinib Drug: Azacitidine Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: OPEN LABEL PHASE 2 STUDY ON THE EFFICACY AND TOLERANCE OF A COMBINATION OF PONATINIB AND 5-AZACITIDINE IN CHRONIC MYELOGENOUS LEUKAEMIA IN ACCELERATED PHASE OR IN MYELOID BLAST CRISIS - PONAZA TRIAL
Actual Study Start Date : June 19, 2019
Estimated Primary Completion Date : December 1, 2023
Estimated Study Completion Date : December 1, 2024


Arm Intervention/treatment
Experimental: AP-CML
Patient with Philadelphia chromosome positive CML in accelerated phase is defined by the presence of 15-29% blasts in peripheral blood (PB) or bone marrow (BM), ≥ 20% basophils in PB or BM, ≥ 30% blasts plus promyelocytes (with blasts <30%) in PB or BM, <100 x109/L platelets unrelated to therapy, or by clonal cytogenetics evolution (i.e., the presence of cytogenetic abnormalities other than the Philadelphia chromosome);
Drug: Ponatinib

Induction phase (first three cycles)

- ponatinib: 45 mg/day orally continuously

Following the results of disease evaluation after 3 cycles:

  • Cohort A: AP-CML If a CHR and complete cytogenetic response are obtained after 3 months, ponatinib will be decreased at 30mg/day. If CHR and/or CCyR are not reached, ponatinib may be maintained at 45mg/day for another 3 cycles if decided by the investigator.
  • Cohort B: MBC-CML If a CHR is obtained during the induction phase, ponatinib daily dose will be reduced to 30 mg/day. If CHR is not reached, ponatinib may be maintained at 45mg/day for another 3 cycles if decided by the investigator.

Maintenance therapy:

Ponatinib will be decreased to 30 mg/day. During maintenance therapy, If a major molecular response is reached, ponatinib will be decreased to 15mg/day


Drug: Azacitidine

Induction phase (first three cycles), Following the results of disease evaluation after 3 cycles and Maintenance therapy:

- 5-azacitidine : 75 mg/m² subcutaneously day 1 to day 7, every 4 weeks

No dose modification of 5-Azacitidine is planned in both cohorts. Azacitidine may be stopped at 24 months in case of MR4 defined as 0.0032%<MR4≤0.01%;


Experimental: MBC-CML
Patient with Philadelphia chromosome positive CML in myeloid blast crisis is defined by the presence of ≥ 30% blasts in the bone marrow and/or peripheral blood or the presence of extramedullary disease.
Drug: Ponatinib

Induction phase (first three cycles)

- ponatinib: 45 mg/day orally continuously

Following the results of disease evaluation after 3 cycles:

  • Cohort A: AP-CML If a CHR and complete cytogenetic response are obtained after 3 months, ponatinib will be decreased at 30mg/day. If CHR and/or CCyR are not reached, ponatinib may be maintained at 45mg/day for another 3 cycles if decided by the investigator.
  • Cohort B: MBC-CML If a CHR is obtained during the induction phase, ponatinib daily dose will be reduced to 30 mg/day. If CHR is not reached, ponatinib may be maintained at 45mg/day for another 3 cycles if decided by the investigator.

Maintenance therapy:

Ponatinib will be decreased to 30 mg/day. During maintenance therapy, If a major molecular response is reached, ponatinib will be decreased to 15mg/day


Drug: Azacitidine

Induction phase (first three cycles), Following the results of disease evaluation after 3 cycles and Maintenance therapy:

- 5-azacitidine : 75 mg/m² subcutaneously day 1 to day 7, every 4 weeks

No dose modification of 5-Azacitidine is planned in both cohorts. Azacitidine may be stopped at 24 months in case of MR4 defined as 0.0032%<MR4≤0.01%;





Primary Outcome Measures :
  1. Overall Survival [ Time Frame: 2 years ]
    To determine the overall survival of patients with AP-CML (cohort A) and MBC-CML (cohort-B) treated with the combination ponatinib and 5-azacitidine


Secondary Outcome Measures :
  1. safety of combination of ponatinib and 5-azacitidine [ Time Frame: 1 year ]
    To determine the safety of combination ofponatinib and 5-azacitidine: number adverse events related to ponatinib assessed by CTCAE V4.0

  2. rate of Complete Hematologic Response (CHR) [ Time Frame: 1 year ]
    To assess the rate of CHR : number de patient in complete hematologic response

  3. cytogenetic response [ Time Frame: 1 year ]
    To assess the complete cytogenetic response by caryotype analysis

  4. molecular response [ Time Frame: 1 year ]
    To assess the major molecular responseby BCR-ABL IS quantification

  5. rate of reversion to chronic phase CML [ Time Frame: 1 year ]
    To assess the rate of reversion to chronic phase CML

  6. duration of response [ Time Frame: 1 year ]
    To estimate the duration of response

  7. duration of event free survival [ Time Frame: 1 year ]
    To estimate the duration of event-free survival

  8. relationship between clinical efficacy and biological markers (mutations and methylation status [ Time Frame: 1 year ]
    To investigate the relationship between clinical efficacy and biological markers: mutations and methylation status.

  9. allogenic transplant [ Time Frame: 1 year ]
    To estimate the rate of patients bridged to allogenic transplant

  10. Survival after transplant [ Time Frame: 1 year ]
    To follow up event-free survival after transplant



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patient aged 18 years or more
  2. Signed informed consent
  3. Patient with Philadelphia chromosome positive CML in first blast crisis or first accelerated phase:

    • AP-CML is defined by the presence of any of the following features:

      • 15-29% blasts in peripheral blood (PB) or bone marrow (BM)
      • ≥ 20% basophils in PB
      • ≥ 30% blasts plus promyelocytes (with blasts <30%) in PB or BM,
      • <100 x10(9)/L platelets unrelated to therapy, or by clonal cytogenetics evolution (i.e., the presence of cytogenetic abnormalities other than the Philadelphia chromosome);
    • MBC-CML is defined by the presence of ≥ 30% blasts in the bone marrow and/or peripheral blood or the presence of extramedullary disease.
  4. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, 2 or 3
  5. Have adequate renal function as defined by the following criterion: Serum creatinine ≤ 1.5 × upper limit of normal (ULN) for institution
  6. Have adequate hepatic function as defined by the following criteria:

    1. Total serum bilirubin ≤ 1.5 × ULN, unless due to Gilbert's syndrome or CML
    2. Alanine aminotransferase (ALT) ≤ 2.5 × ULN, or ≤ 5 × ULN if leukemic infiltration of the liver is present
    3. Aspartate aminotransferase (AST) ≤ 2.5 × ULN, or ≤ 5 × ULN if leukemic infiltration of the liver is present
  7. Have normal pancreatic status as defined by the following criterion: Serum lipase and amylase ≤ 1.5 × ULN
  8. Have normal QTcF interval on screening electrocardiogram (ECG) evaluation, defined as QTcF of ≤ 450 ms in males or ≤ 470 ms in females.
  9. Have a negative pregnancy test documented prior to enrollment (for females of childbearing potential).
  10. Agree to use an effective form of contraception with sexual partners throughout study participation (for female and male patients who are fertile).
  11. Have fully recovered (≤ grade 1, returned to baseline, or deemed irreversible) from the acute effects of prior cancer therapy before initiation of study drug

Exclusion Criteria:

  1. Pregnant or lactating women,
  2. Participation in another clinical trial with any investigative drug within 30 days prior to study enrolment,
  3. Prior history of hematopoietic stem cell transplantation
  4. Cardiovascular disease:

    • Stage II to IV congestive heart failure (CHF) as determined by the New York Heart Association (NYHA) classification system for heart failure.
    • Myocardial infarction within the previous 6 months
    • Symptomatic cardiac arrhythmia requiring treatment
  5. Individuals with another active malignancy
  6. Patients at high risk or very high risk of arterio-veinous occlusive disease defined by European CVD score
  7. Previous treatment with azacitidine,
  8. Diagnosis of malignant disease within the previous 12 months (excluding base cell carcinoma, "in-situ" carcinoma of the cervix or breast or other local malignancy excised or irradiated with a high probability of cure)
  9. Known active viral infection with Human Immunodeficiency Virus (HIV) or Hepatitis type B or C

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): NCT03895671


Contacts
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Contact: Mélody FORT +33139239776 mfort@ch-versailles.fr
Contact: Laure Morisset +33139239785 lmorisset@ch-versailles.fr

Locations
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France
Centre Hospitalier Universitaire D'Amiens Recruiting
Amiens, France
Contact: Delphine LEBON    03 22 45 59 14    lebon.delphine@chu-amiens.fr   
Centre Hospitalier D'Avignon Not yet recruiting
Avignon, France
Contact: Harcène ZERAZHI    04 32 75 93 30    Hzerazhi@ch-avignon.fr   
Centre Hospitalier de La Cote Basque Not yet recruiting
Bayonne, France
Contact: Frédéric BAUDUER    05 59 44 38 41    bauduer.frederic@neuf.fr   
Hopital Avicenne Not yet recruiting
Bobigny, France
Contact: Thorsten BRAUN    01 48 95 70 51    thorsten.braun@avc.aphp.fr   
Institut Bergonie Not yet recruiting
Bordeaux, France
Contact: Gabriel ETIENNE    05 24 07 19 16    g.etienne@bordeaux.unicancer.fr   
Centre Hospitalier de Caen-Normandie Not yet recruiting
Caen, France
Contact: Sylvain CHANTEPIE    02 31 27 25 39    chantepie-s@chu-caen.fr   
Centre Hospitalier Metropole Savoie Recruiting
Chambéry, France
Contact: Gian Matteo PICA    04 79 96 51 05    gian-matteo.pica@ch-chambery.fr   
Centre Hospitalier Universitaire de Clermont Ferrand Not yet recruiting
Clermont-Ferrand, France
Contact: Eric HERMET    04 73 75 00 65    ehermet@chu-clermontferrand.fr   
Hopital Henri Mondor Not yet recruiting
Créteil, France
Contact: Lydia ROY    01 49 81 20 57    lydia.roy@aphp.fr   
Centre Hospitalier Universitaire de Dijon Not yet recruiting
Dijon, France
Contact: Marie-Lorraine CHRETIEN    01 30 80 29 50    marie-lorraine.chretien@chu-dijon.fr   
Centre Hospitalier Universitaire de Grenoble Recruiting
Grenoble, France
Contact: Stéphane COURBY    04 76 76 57 12    scourby@chu-grenoble.fr   
Hopital Bicetre Not yet recruiting
Le Kremlin-Bicêtre, France
Contact: Ali TURHAN    01 45 21 35 94    ali.turhan@aphp.fr   
Centre Hospitalier Regional Universitaire de Lille Not yet recruiting
Lille, France
Contact: Bruno QUESNEL    03 20 44 66 40    bruno.quesnel@chru-lille.fr   
Centre Hospitalier Universitaire de Limoges Not yet recruiting
Limoges, France
Contact: Pascal TURLURE    05 55 05 80 39    pascal.turlure@chu-limoges.fr   
Centre Leon Berard Not yet recruiting
Lyon, France
Contact: Franck NICOLINI    04 69 85 61 93    franck-emmanuel.nicolini@lyon.unicancer.fr   
Centre Hospitalier Universitaire de Nantes Not yet recruiting
Nantes, France
Contact: Viviane DUBRUILLE    02 40 08 32 71    viviane.dubruille@chu-nantes.fr   
Hopital Pitie-Salpetriere Not yet recruiting
Paris, France
Contact: Madalina UZUNOV    01 42 16 28 20    madalina.uzunov@psl.aphp.fr   
Hopital St Antoine Not yet recruiting
Paris, France
Contact: Simona LAPUSAN    01 49 28 34 42    simona.lapusan@aphp.fr   
Hopital St Louis Recruiting
Paris, France
Contact: Emmanuel RAFFOUX    01 42 49 96 49    emmanuel.raffoux@aphp.fr   
Centre Hospitalier de Perpignan Not yet recruiting
Perpignan, France
Contact: Fabienne VACHERET    04 68 61 64 48    fabienne.vacheret@ch-perpignan.fr   
Hospices Civils de Lyon Not yet recruiting
Pierre-Bénite, France
Contact: Marie BALSAT    04 78 86 22 50    marie.balsat@chu-lyon.fr   
Centre Hospitalier Annecy Genevois Not yet recruiting
Pringy, France
Contact: Pascale CONY-MAKHOUL    04 50 63 64 31    pconymakhoul@ch-annecygenevois.fr   
Centre Hospitalier Universitaire de Rennes Not yet recruiting
Rennes, France
Contact: Martine ESCOFFRE- BARBE    02 99 28 42 32    martine.escoffre-barbe@chu-rennes.fr   
Centre Henri Becquerel Not yet recruiting
Rouen, France
Contact: Pascal LENAIN    04 78 86 22 50    pascal.lenain@chb.unicancer.fr   
Centre Hospitalier de Strasbourg Not yet recruiting
Strasbourg, France
Contact: Shanti NATARAJAN-AME    03 88 12 76 73    shanti.ame@chru-strasbourg.fr   
Institut Universitaire Du Cancer Toulouse Not yet recruiting
Toulouse, France
Contact: Suzanne TAVITIAN    05 31 15 63 04    tavitian.suzanne@iuct-oncopole.fr   
Chru de Nancy Not yet recruiting
Vandœuvre-lès-Nancy, France
Contact: Agnes GUERCI-BRESLER    03 83 15 33 50    a.guerci@chru-nancy.fr   
Centre Hospitalier de Versailles Recruiting
Versailles, France
Contact: Philippe ROUSSELOT    0139638622    phrousselot@ch-versailles.fr   
Intitut Gustave Roussy Not yet recruiting
Villejuif, France
Contact: Stéphane DE BOTTON    01 42 11 40 79    stephane.debotton@igr.fr   
Sponsors and Collaborators
Versailles Hospital

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Responsible Party: Philippe ROUSSELOT, Clinical coordinator, Versailles Hospital
ClinicalTrials.gov Identifier: NCT03895671     History of Changes
Other Study ID Numbers: P16/23 PONAZA
First Posted: March 29, 2019    Key Record Dates
Last Update Posted: August 12, 2019
Last Verified: August 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Blast Crisis
Neoplasms by Histologic Type
Neoplasms
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Cell Transformation, Neoplastic
Carcinogenesis
Neoplastic Processes
Pathologic Processes
Azacitidine
Ponatinib
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors
Protein Kinase Inhibitors