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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

NCT03895671

Description:

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.

Related Conditions:
  • Chronic Myeloid Leukemia
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief 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
  • 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

Clinical Trial IDs

  • ORG STUDY ID: P16/23 PONAZA
  • NCT ID: NCT03895671

Conditions

  • CHRONIC MYELOGENOUS LEUKAEMIA IN ACCELERATED PHASE
  • CHRONIC MYELOGENOUS LEUKAEMIA IN MYELOID BLAST CRISIS

Interventions

DrugSynonymsArms
PonatinibAP-CML
AzacitidineAP-CML

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
AP-CMLExperimentalPatient 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);
  • Ponatinib
  • Azacitidine
MBC-CMLExperimentalPatient 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.
  • Ponatinib
  • Azacitidine

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Survival
Time Frame:2 years
Safety Issue:
Description: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

Measure:safety of combination of ponatinib and 5-azacitidine
Time Frame:1 year
Safety Issue:
Description:To determine the safety of combination ofponatinib and 5-azacitidine: number adverse events related to ponatinib assessed by CTCAE V4.0
Measure:rate of Complete Hematologic Response (CHR)
Time Frame:1 year
Safety Issue:
Description:To assess the rate of CHR : number de patient in complete hematologic response
Measure:cytogenetic response
Time Frame:1 year
Safety Issue:
Description:To assess the complete cytogenetic response by caryotype analysis
Measure:molecular response
Time Frame:1 year
Safety Issue:
Description:To assess the major molecular responseby BCR-ABL IS quantification
Measure:rate of reversion to chronic phase CML
Time Frame:1 year
Safety Issue:
Description:To assess the rate of reversion to chronic phase CML
Measure:duration of response
Time Frame:1 year
Safety Issue:
Description:To estimate the duration of response
Measure:duration of event free survival
Time Frame:1 year
Safety Issue:
Description:To estimate the duration of event-free survival
Measure:relationship between clinical efficacy and biological markers (mutations and methylation status
Time Frame:1 year
Safety Issue:
Description:To investigate the relationship between clinical efficacy and biological markers: mutations and methylation status.
Measure:allogenic transplant
Time Frame:1 year
Safety Issue:
Description:To estimate the rate of patients bridged to allogenic transplant
Measure:Survival after transplant
Time Frame:1 year
Safety Issue:
Description:To follow up event-free survival after transplant

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Versailles Hospital

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