Clinical trial NCT03895671: PONAZA : 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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: CHRONIC MYELOGENOUS LEUKAEMIA IN ACCELERATED PHASE
CHRONIC MYELOGENOUS LEUKAEMIA IN MYELOID BLAST CRISIS
Lead sponsor: Versailles Hospital
Sponsor class: OTHER
First posted: 2019-03-29
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Overall Survival
timeFrame: 2 years
Secondary outcomes:
measure: safety of combination of ponatinib and 5-azacitidine
timeFrame: 1 year
measure: rate of Complete Hematologic Response (CHR)
timeFrame: 1 year
measure: cytogenetic response
timeFrame: 1 year
measure: molecular response
timeFrame: 1 year
measure: rate of reversion to chronic phase CML
timeFrame: 1 year
measure: duration of response
timeFrame: 1 year
measure: duration of event free survival
timeFrame: 1 year
measure: relationship between clinical efficacy and biological markers (mutations and methylation status
timeFrame: 1 year
measure: allogenic transplant
timeFrame: 1 year
measure: Survival after transplant
timeFrame: 1 year
Other outcomes:
Locations:
city: Amiens
country: France
facility: Centre Hospitalier Universitaire D'Amiens
city: Avignon
country: France
facility: Centre Hospitalier D'Avignon
city: Bayonne
country: France
facility: Centre Hospitalier de La Cote Basque
city: Bobigny
country: France
facility: Hopital Avicenne
city: Bordeaux
country: France
facility: Institut Bergonie
city: Caen
country: France
facility: Centre Hospitalier de Caen-Normandie
city: Chambéry
country: France
facility: Centre Hospitalier Metropole Savoie
city: Clermont-Ferrand
country: France
facility: Centre Hospitalier Universitaire de Clermont Ferrand
city: Créteil
country: France
facility: Hopital Henri Mondor
city: Dijon
country: France
facility: Centre Hospitalier Universitaire de Dijon
city: Grenoble
country: France
facility: Centre Hospitalier Universitaire de Grenoble
city: Le Kremlin-Bicêtre
country: France
facility: Hopital Bicetre
city: Lille
country: France
facility: Centre Hospitalier Regional Universitaire de Lille
city: Limoges
country: France
facility: Centre Hospitalier Universitaire de Limoges
city: Lyon
country: France
facility: Centre Leon Berard
city: Nantes
country: France
facility: Centre Hospitalier Universitaire de Nantes
city: Paris
country: France
facility: Hopital Pitie-Salpetriere
city: Paris
country: France
facility: Hopital St Antoine
city: Paris
country: France
facility: Hopital St Louis
city: Perpignan
country: France
facility: Centre Hospitalier de Perpignan
city: Pierre-Bénite
country: France
facility: Hospices Civils de Lyon
city: Pringy
country: France
facility: Centre Hospitalier Annecy Genevois
city: Rennes
country: France
facility: Centre Hospitalier Universitaire de Rennes
city: Rouen
country: France
facility: Centre Henri Becquerel
city: Strasbourg
country: France
facility: Centre Hospitalier de Strasbourg
city: Toulouse
country: France
facility: Institut Universitaire Du Cancer Toulouse
city: Vandœuvre-lès-Nancy
country: France
facility: Chru de Nancy
city: Versailles
country: France
facility: Centre Hospitalier de Versailles
city: Villejuif
country: France
facility: Intitut Gustave Roussy
Study officials:
References: