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

August 6, 2020 updated by: Philippe ROUSSELOT, Versailles Hospital

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

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Anticipated)

40

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • France
      • Amiens, France
        • Recruiting
        • Centre Hospitalier Universitaire d'Amiens
        • Contact:
      • Avignon, France
        • Not yet recruiting
        • Centre Hospitalier d'Avignon
        • Contact:
      • Bayonne, France
        • Not yet recruiting
        • Centre Hospitalier de la Cote Basque
        • Contact:
      • Bobigny, France
      • Bordeaux, France
      • Caen, France
        • Not yet recruiting
        • Centre Hospitalier de Caen-Normandie
        • Contact:
      • Chambéry, France
      • Clermont-Ferrand, France
        • Not yet recruiting
        • Centre Hospitalier Universitaire de Clermont Ferrand
        • Contact:
      • Créteil, France
        • Not yet recruiting
        • Hopital Henri Mondor
        • Contact:
      • Dijon, France
      • Grenoble, France
        • Recruiting
        • Centre Hospitalier Universitaire de Grenoble
        • Contact:
      • Le Kremlin-Bicêtre, France
        • Not yet recruiting
        • Hôpital Bicêtre
        • Contact:
      • Lille, France
        • Not yet recruiting
        • Centre Hospitalier Regional Universitaire de Lille
        • Contact:
      • Limoges, France
        • Not yet recruiting
        • Centre Hospitalier Universitaire de Limoges
        • Contact:
      • Lyon, France
      • Nantes, France
        • Not yet recruiting
        • Centre Hospitalier Universitaire de Nantes
        • Contact:
      • Paris, France
        • Not yet recruiting
        • Hôpital Pitié-Salpétrière
        • Contact:
      • Paris, France
        • Not yet recruiting
        • Hopital St Antoine
        • Contact:
      • Paris, France
      • Perpignan, France
      • Pierre-Bénite, France
        • Not yet recruiting
        • Hospices Civils de Lyon
        • Contact:
      • Pringy, France
      • Rennes, France
      • Rouen, France
      • Strasbourg, France
        • Not yet recruiting
        • Centre Hospitalier de Strasbourg
        • Contact:
      • Toulouse, France
      • Vandœuvre-lès-Nancy, France
        • Not yet recruiting
        • CHRU de Nancy
        • Contact:
      • Versailles, France
      • Villejuif, France
        • Not yet recruiting
        • Intitut Gustave Roussy
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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%

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%

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
2 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
1 year
rate of Complete Hematologic Response (CHR)
Time Frame: 1 year
To assess the rate of CHR : number de patient in complete hematologic response
1 year
cytogenetic response
Time Frame: 1 year
To assess the complete cytogenetic response by caryotype analysis
1 year
molecular response
Time Frame: 1 year
To assess the major molecular responseby BCR-ABL IS quantification
1 year
rate of reversion to chronic phase CML
Time Frame: 1 year
To assess the rate of reversion to chronic phase CML
1 year
duration of response
Time Frame: 1 year
To estimate the duration of response
1 year
duration of event free survival
Time Frame: 1 year
To estimate the duration of event-free survival
1 year
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.
1 year
allogenic transplant
Time Frame: 1 year
To estimate the rate of patients bridged to allogenic transplant
1 year
Survival after transplant
Time Frame: 1 year
To follow up event-free survival after transplant
1 year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Versailles Hospital

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 19, 2019

Primary Completion (Anticipated)

December 1, 2023

Study Completion (Anticipated)

December 1, 2024

Study Registration Dates

First Submitted

March 25, 2019

First Submitted That Met QC Criteria

March 27, 2019

First Posted (Actual)

March 29, 2019

Study Record Updates

Last Update Posted (Actual)

August 7, 2020

Last Update Submitted That Met QC Criteria

August 6, 2020

Last Verified

August 1, 2020

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • P16/23 PONAZA

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on CHRONIC MYELOGENOUS LEUKAEMIA IN ACCELERATED PHASE

Clinical Trials on Ponatinib

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Romania

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe