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

Phase 2

Recruiting

• Conditions: CHRONIC MYELOGENOUS LEUKAEMIA IN MYELOID BLAST CRISIS; CHRONIC MYELOGENOUS LEUKAEMIA IN ACCELERATED PHASE
• Interventions: Drug: Ponatinib; Drug: Azacitidine

• Registration Number: NCT03895671
• Lead Sponsor: 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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2019-03-25
• Study First Submitted QC: 2019-03-27
• Study First Posted: 2019-03-29
• Study Start: 2019-06-19
• Status Verified: 2020-08
• Last Update Submitted: 2020-08-06
• Last Update Posted: 2020-08-07
• Primary Completion: 2023-12-01
• Study Completion: 2024-12-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 40

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
AP-CML	Ponatinib	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);
AP-CML	Azacitidine	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);
MBC-CML	Ponatinib	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.
MBC-CML	Azacitidine	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.

Primary Outcome Measures

Name	Time	Method
Overall Survival	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

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

Trial Locations

Locations (29)

Institut Bergonie; 🇫🇷 Bordeaux, France

Centre Hospitalier Universitaire de Nantes; 🇫🇷 Nantes, France

Centre Henri Becquerel; 🇫🇷 Rouen, France

Hopital Avicenne; 🇫🇷 Bobigny, France

Centre Hospitalier Universitaire D'Amiens; 🇫🇷 Amiens, France

Centre Hospitalier D'Avignon; 🇫🇷 Avignon, France

Centre Hospitalier de La Cote Basque; 🇫🇷 Bayonne, France

Centre Hospitalier de Caen-Normandie; 🇫🇷 Caen, France

Centre Hospitalier Universitaire de Clermont Ferrand; 🇫🇷 Clermont-Ferrand, France

Hopital Henri Mondor; 🇫🇷 Créteil, France

Centre Hospitalier Universitaire de Dijon; 🇫🇷 Dijon, France

Centre Hospitalier Universitaire de Grenoble; 🇫🇷 Grenoble, France

Hopital Bicetre; 🇫🇷 Le Kremlin-Bicêtre, France

Centre Hospitalier Regional Universitaire de Lille; 🇫🇷 Lille, France

Centre Hospitalier Universitaire de Limoges; 🇫🇷 Limoges, France

Centre Leon Berard; 🇫🇷 Lyon, France

Hospices Civils de Lyon; 🇫🇷 Pierre-Bénite, France

Centre Hospitalier Annecy Genevois; 🇫🇷 Pringy, France

Hopital Pitie-Salpetriere; 🇫🇷 Paris, France

Hopital St Antoine; 🇫🇷 Paris, France

Hopital St Louis; 🇫🇷 Paris, France

Centre Hospitalier de Perpignan; 🇫🇷 Perpignan, France

Centre Hospitalier Universitaire de Rennes; 🇫🇷 Rennes, France

Centre Hospitalier de Strasbourg; 🇫🇷 Strasbourg, France

Centre Hospitalier de Versailles; 🇫🇷 Versailles, France

Institut Universitaire Du Cancer Toulouse; 🇫🇷 Toulouse, France

Chru de Nancy; 🇫🇷 Vandœuvre-lès-Nancy, France

Intitut Gustave Roussy; 🇫🇷 Villejuif, France

Centre Hospitalier Metropole Savoie; 🇫🇷 Chambéry, France