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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier De Versailles

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

19 Jun 2019 → ongoing

Decision date (initial)

2024-07-25

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

INCYTE

External identifiers

EU CT number

2024-516048-24-00

EudraCT number

2017-004674-34

ClinicalTrials.gov

NCT03895671

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

The primary objective of this study is to determine the overall survival of patients with AP-CML (cohort A) and MBC-CML (cohort-B) treated with the combination of ponatinib and 5-azacitidine by 2 years.

Secondary objectives 9

1. To determine the safety of selected therapies
2. To assess the rate of CHR
3. To assess the cytogenetic response
4. To assess the molecular response
5. To assess the rate of reversion to chronic phase CML
6. To estimate the event free survival and duration of response
7. To investigate the relationship between clinical efficacy and biological marker: mutations and methylation status
8. To estimate the rate of patients bridged to allogeneic transplant
9. To estimate survival after transplant and post-transplant relapse rate

Conditions and MedDRA coding

CHRONIC MYELOGENOUS LEUKAEMIA IN ACCELERATED PHASE OR IN MYELOID BLAST CRISIS

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Patient aged 18 years or more
2. Signed informed consent
3. Patient with Philadelphia chromosome positive CML in blast crisis: MBC-CML is defined by the presence of ≥ 20% 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: a. Total serum bilirubin ≤ 1.5 × ULN, unless due to Gilbert’s syndrome or CML / b. Alanine aminotransferase (ALT) ≤ 2.5 × ULN, or ≤ 5 × ULN unless related to the disease / c. Aspartate aminotransferase (AST) ≤ 2.5 × ULN, or ≤ 5 × ULN unless related to the disease
7. Have normal pancreatic status as defined by serum lipase and/or 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 enrolment (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
12. Patient affiliated to or beneficiary of the French National Health Service

Exclusion criteria 13

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 ( appendix 9)
7. Previously treated by 5-azacitidine or cytotoxic chemotherapy other than hydroxyurea
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. Active viral infection with Human Immunodeficiency Virus (HIV) or Hepatitis type B or C
10. Intake of medications with a known risk of Torsades de Pointes
11. Have active central nervous system (CNS) disease as evidenced by cytology or pathology.
12. Have uncontrolled hypertension (diastolic blood pressure > 90 mmHg; systolic > 150 mmHg). Patients with hypertension should be under treatment on study entry to affect blood pressure control.
13. Have any condition or illness that, in the opinion of the investigator, would compromise patient’s safety or interfere with the evaluation of the drug

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint is Overall Survival by 2 years

Secondary endpoints 9

1. Adverse events - CTCAE Version 4.0
2. Cumulative rate of patients achieving CHR
3. Cumulative rate of patients achieving complete cytogenetic responses
4. Cumulative rate of patients achieving molecular responses
5. Cumulative rate of patients reverting to chronic phase CML
6. Analysis of clonal architecture, methylation profile, bcr-abl mutations and cytogenetics in blast crisis and AP at baseline, and in case of relapse or failure
7. Event free survival, duration of response
8. Number of patients allocated to allogenic transplant
9. Survival after transplant and post-transplantation relapse rate

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier De Versailles

Sponsor organisation

Centre Hospitalier De Versailles

Address

177 Rue De Versailles, Le Chesnay Le Chesnay

City

Le Chesnay Rocquencourt

Postcode

78150

Country

France

Scientific contact point

Organisation

Centre Hospitalier De Versailles

Contact name

Project manager

Public contact point

Organisation

Centre Hospitalier De Versailles

Contact name

Project manager

Locations

1 EU/EEA country · 37 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 5 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications