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

Sponsor

Versailles Hospital (Other)

Overall Status

Recruiting

CT.gov ID

NCT03895671

Collaborator

(none)

Enrollment

Locations

Arms

65.4

Anticipated Duration (Months)

1.4

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
CHRONIC MYELOGENOUS LEUKAEMIA IN ACCELERATED PHASE CHRONIC MYELOGENOUS LEUKAEMIA IN MYELOID BLAST CRISIS	Drug: Ponatinib Drug: Azacitidine	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

40 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Jun 19, 2019

Anticipated Primary Completion Date :

Dec 1, 2023

Anticipated Study Completion Date :

Dec 1, 2024

Arms and Interventions

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%<MR4≤0.01%;
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%<MR4≤0.01%;

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%<MR4≤0.01%;

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

Drug: Azacitidine

Outcome Measures

Primary Outcome Measures

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

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 Complete Hematologic Response (CHR) [1 year]
To assess the rate of CHR : number de patient in complete hematologic response
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
rate of reversion to chronic phase CML [1 year]
To assess the rate of reversion to chronic phase CML
duration of response [1 year]
To estimate the duration of response
duration of event free survival [1 year]
To estimate the duration of event-free survival
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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country
1	Centre Hospitalier Universitaire D'Amiens	Amiens	France
2	Centre Hospitalier D'Avignon	Avignon	France
3	Centre Hospitalier de La Cote Basque	Bayonne	France
4	Hopital Avicenne	Bobigny	France
5	Institut Bergonie	Bordeaux	France
6	Centre Hospitalier de Caen-Normandie	Caen	France
7	Centre Hospitalier Metropole Savoie	Chambéry	France
8	Centre Hospitalier Universitaire de Clermont Ferrand	Clermont-Ferrand	France
9	Hopital Henri Mondor	Créteil	France
10	Centre Hospitalier Universitaire de Dijon	Dijon	France
11	Centre Hospitalier Universitaire de Grenoble	Grenoble	France
12	Hopital Bicetre	Le Kremlin-Bicêtre	France
13	Centre Hospitalier Regional Universitaire de Lille	Lille	France
14	Centre Hospitalier Universitaire de Limoges	Limoges	France
15	Centre Leon Berard	Lyon	France
16	Centre Hospitalier Universitaire de Nantes	Nantes	France
17	Hopital Pitie-Salpetriere	Paris	France
18	Hopital St Antoine	Paris	France
19	Hopital St Louis	Paris	France
20	Centre Hospitalier de Perpignan	Perpignan	France
21	Hospices Civils de Lyon	Pierre-Bénite	France
22	Centre Hospitalier Annecy Genevois	Pringy	France
23	Centre Hospitalier Universitaire de Rennes	Rennes	France
24	Centre Henri Becquerel	Rouen	France
25	Centre Hospitalier de Strasbourg	Strasbourg	France
26	Institut Universitaire Du Cancer Toulouse	Toulouse	France
27	Chru de Nancy	Vandœuvre-lès-Nancy	France
28	Centre Hospitalier de Versailles	Versailles	France
29	Intitut Gustave Roussy	Villejuif	France