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

Study Overview
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Brief Summary
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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.

Official Title
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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 - PONAZA TRIAL

Conditions
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CHRONIC MYELOGENOUS LEUKAEMIA IN ACCELERATED PHASE, CHRONIC MYELOGENOUS LEUKAEMIA IN MYELOID BLAST CRISIS

Intervention / Treatment
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* Drug: Ponatinib
* Drug: Azacitidine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient aged 18 years or more Signed informed consent 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. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, 2 or 3 Have adequate renal function as defined by the following criterion: Serum creatinine ≤ 1.5 × upper limit of normal (ULN) for institution Have adequate hepatic function as defined by the following criteria: Total serum bilirubin ≤ 1.5 × ULN, unless due to Gilbert's syndrome or CML Alanine aminotransferase (ALT) ≤ 2.5 × ULN, or ≤ 5 × ULN if leukemic infiltration of the liver is present Aspartate aminotransferase (AST) ≤ 2.5 × ULN, or ≤ 5 × ULN if leukemic infiltration of the liver is present Have normal pancreatic status as defined by the following criterion: Serum lipase and amylase ≤ 1.5 × ULN Have normal QTcF interval on screening electrocardiogram (ECG) evaluation, defined as QTcF of ≤ 450 ms in males or ≤ 470 ms in females. Have a negative pregnancy test documented prior to enrollment (for females of childbearing potential). Agree to use an effective form of contraception with sexual partners throughout study participation (for female and male patients who are fertile). 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: Pregnant or lactating women, Participation in another clinical trial with any investigative drug within 30 days prior to study enrolment, Prior history of hematopoietic stem cell transplantation 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 Individuals with another active malignancy Patients at high risk or very high risk of arterio-veinous occlusive disease defined by European CVD score Previous treatment with azacitidine, 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) Known active viral infection with Human Immunodeficiency Virus (HIV) or Hepatitis type B or C

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AP-CML<br>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<br>* 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<br>Drug: Azacitidine<br>* 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%;<br>|
| Experimental: MBC-CML<br>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<br>* 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<br>Drug: Azacitidine<br>* 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%;<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | 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 | 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) | To assess the rate of CHR : number de patient in complete hematologic response | 1 year | 
| cytogenetic response | To assess the complete cytogenetic response by caryotype analysis | 1 year | 
| molecular response | To assess the major molecular responseby BCR-ABL IS quantification | 1 year | 
| rate of reversion to chronic phase CML | To assess the rate of reversion to chronic phase CML | 1 year | 
| duration of response | To estimate the duration of response | 1 year | 
| duration of event free survival | To estimate the duration of event-free survival | 1 year | 
| relationship between clinical efficacy and biological markers (mutations and methylation status | To investigate the relationship between clinical efficacy and biological markers: mutations and methylation status. | 1 year | 
| allogenic transplant | To estimate the rate of patients bridged to allogenic transplant | 1 year | 
| Survival after transplant | To follow up event-free survival after transplant | 1 year |