Phase 2 Open-Label Study on Efficacy and Tolerance of Ponatinib and 5-Azacitidine in Accelerated Phase or Myeloid Blast Crisis Chronic Myelogenous Leukemia
- Trial ID
- 2024-516048-24-00
- Protocol
- PONAZA_P16/23
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to determine the **overall survival** of patients with Chronic Myelogenous Leukemia (CML) in accelerated phase (AP-CML) and myeloid blast crisis (MBC-CML) treated with a combination of ponatinib and 5-azacitidine over a period of two years. This objective is clinically relevant as it aims to evaluate the efficacy of the treatment regimen in extending the lifespan of patients with these advanced stages of CML, which are associated with poor prognosis.
Secondary objectives include:
- To determine the safety of selected therapies.
- To assess the rate of complete hematologic response (CHR).
- To assess the cytogenetic response.
- To assess the molecular response.
- To assess the rate of reversion to chronic phase CML.
- To estimate the event-free survival and duration of response.
- To investigate the relationship between clinical efficacy and biological markers, including mutations and methylation status.
- To estimate the rate of patients bridged to allogeneic transplant.
- To estimate survival after transplant and post-transplant relapse rate.
These secondary objectives are crucial for understanding the broader impact of the treatment on disease progression, patient safety, and potential for long-term remission or cure.
Participants
The clinical trial involves participants diagnosed with **chronic myelogenous leukemia** (CML) in either the accelerated phase or myeloid blast crisis. The study population includes both male and female subjects aged 18 years or older. Participants are required to have a Philadelphia chromosome-positive CML in blast crisis, characterized by the presence of 20% or more blasts in the bone marrow and/or peripheral blood, or the presence of extramedullary disease. The trial does not include a vulnerable population. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 3 and must meet specific health criteria, including adequate renal and hepatic function, normal pancreatic status, and a normal QTcF interval on screening electrocardiogram. The sponsor has not provided information regarding the total number of participants in the study. Participants are expected to adhere to lifestyle considerations such as using effective contraception if fertile and recovering from prior cancer therapy before the initiation of the study drug. The trial population was selected based on these criteria, ensuring that participants are affiliated with or beneficiaries of the French National Health Service and have provided signed informed consent.
Plans and Procedures
The clinical trial is designed as an open-label, phase 2 study to evaluate the efficacy and tolerance of a combination of **ponatinib** and **azacitidine** in patients with **chronic myelogenous leukaemia** (CML) in accelerated phase or in myeloid blast crisis. The primary objective is to determine the overall survival of patients treated with this combination over a period of two years. The trial is expected to conclude by June 2025, with recruitment having commenced in June 2019. Participants will be involved in the study for a maximum treatment period of 24 months, depending on their cohort assignment and response to treatment.
The trial follows a structured sequence of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as age, health status, and previous treatment recovery. Participants must be 18 years or older, have adequate renal and hepatic function, and meet other health-related criteria. Following the screening, eligible participants will undergo regular follow-up visits to monitor treatment efficacy and safety, including assessments of adverse events, complete haematologic response, and cytogenetic and molecular responses. The end-of-study visit will evaluate the overall outcomes and any long-term effects of the treatment.
Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with study protocols, or if the investigator deems it necessary for their safety. The study employs a combination of **subcutaneous injection** for azacitidine and **oral** administration for ponatinib, with specific dosing regimens tailored to each participant's condition and response. The trial's primary endpoint is overall survival by two years, with secondary endpoints including adverse events, response rates, and survival post-transplantation. The study aims to provide valuable insights into the treatment of CML in advanced stages, contributing to the development of more effective therapeutic strategies.
Treatment
The clinical trial involves the administration of **Azacitidine**, marketed as Azacitidine Arrow 25 mg/mL, in the form of a **suspension for injection**. This experimental medication is administered via **subcutaneous injection**. The dosage is set at a maximum of 75 mg/m² per day, with a treatment period not exceeding 7 days. The active substance, azacitidine, is of chemical origin and is provided by EUGIA PHARMA (MALTA) LTD. Participant compliance with the dosing schedule will be monitored throughout the trial.
In addition to azacitidine, the study includes the administration of **Ponatinib**, available as Iclusig 15 mg and 30 mg **film-coated tablets**. Ponatinib is administered **orally** with a maximum daily dose of 45 mg. The treatment period for ponatinib extends up to 24 months. The active substance, ponatinib, is also of chemical origin and is supplied by INCYTE BIOSCIENCES DISTRIBUTION B.V. The trial aims to evaluate the efficacy and tolerance of the combination of ponatinib and azacitidine in patients with chronic myelogenous leukemia in accelerated phase or in myeloid blast crisis. Compliance with the oral administration schedule will be closely monitored to ensure adherence to the treatment protocol.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the measurement of **Overall Survival** by 2 years. This primary endpoint will provide a direct evaluation of the treatment's impact on patient longevity. Secondary endpoints will include a range of additional efficacy parameters, such as the cumulative rate of patients achieving Complete Hematologic Response (CHR), complete cytogenetic responses, and molecular responses. The trial will also assess the cumulative rate of patients reverting to the chronic phase of Chronic Myelogenous Leukemia (CML), as well as event-free survival and duration of response.
Further analysis will involve the examination of clonal architecture, methylation profiles, bcr-abl mutations, and cytogenetics in patients experiencing blast crisis and accelerated phase at baseline, and in cases of relapse or failure. The number of patients allocated to allogenic transplant, survival after transplant, and post-transplantation relapse rates will also be evaluated. Adverse events will be monitored using the CTCAE Version 4.0 to ensure comprehensive safety and efficacy profiling. These assessments will be conducted at specified intervals throughout the trial to ensure accurate and timely data collection.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patient aged 18 years or more
- Signed informed consent
- 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.
- 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: 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
- Have normal pancreatic status as defined by serum lipase and/or 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 enrolment (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
- Patient affiliated to or beneficiary of the French National Health Service
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 ( appendix 9)
- Previously treated by 5-azacitidine or cytotoxic chemotherapy other than hydroxyurea
- 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)
- Active viral infection with Human Immunodeficiency Virus (HIV) or Hepatitis type B or C
- Intake of medications with a known risk of Torsades de Pointes
- Have active central nervous system (CNS) disease as evidenced by cytology or pathology.
- 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.
- 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
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 19 Jun 2019 | 40 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Iclusig 15 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 45 | 24 | PRD4563018 |
AZACITIDINE ARROW 25 mg/mL, poudre pour suspension injectable | Other | POUDRE POUR SUSPENSION INJECTABLE | SUBCUTANEOUS INJECTION | 75 | 7 | PRD10117193 |