Evaluation of Ponatinib Combined with Chemotherapy in Adult Patients with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia
- Trial ID
- 2023-510240-20-00
- Protocol
- GIMEMA ALL2922
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **clinical response** in terms of minimal residual disease (MRD) negativity in patients with a BCR/ABL1-like profile, treated with a combination of Ponatinib and chemotherapy. This is clinically relevant as achieving MRD negativity is associated with improved long-term outcomes in patients with Adult Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia.
Secondary objectives include:
- Monitoring MRD at different time points during the study treatment.
- Assessing **disease-free survival** and event-free survival.
- Evaluating the cumulative incidence of relapse and overall survival.
- Determining treatment-related mortality (TRM) and clinical response.
- Assessing the feasibility of a combination approach with Ponatinib and chemotherapy.
- Evaluating the safety profile of the treatment regimen.
Participants
The clinical trial involves participants diagnosed with **Adult Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia**. The study population includes both male and female subjects, aged between 18 and 65 years, with a BCR/ABL1-like profile. Participants are required to have adequate liver and pancreatic function, as well as no history of dyslipidemia, thrombotic events, or cardiac disease. The trial population was selected based on these criteria, and all participants must provide signed informed consent. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified. The trial includes a vulnerable population, and both genders are represented. Key inclusion criteria include a WHO score of 2 and the requirement for females of childbearing potential to have a negative pregnancy test and for all fertile participants to use effective contraception during and after the trial.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **ponatinib** in combination with chemotherapy as a frontline treatment for patients with Adult Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia. This is a Phase II, randomized, double-blind, controlled study. The trial is expected to last until May 31, 2029, with recruitment having commenced on October 5, 2022. The primary objective is to assess the clinical response in terms of minimal residual disease (MRD) negativity in patients with a BCR/ABL1-like profile. The trial will also evaluate secondary endpoints such as disease-free survival (DFS), event-free survival (EFS), and overall survival (OS) at 24 months, among others.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (18-65 years), adequate liver and pancreatic function, and absence of certain medical histories. Following the screening, participants will be randomized to receive either the investigational treatment or a control. The treatment phase will include multiple cycles, with MRD negativity assessed after three cycles (TP2). Follow-up visits will occur at specified intervals to monitor the clinical response and any adverse events. The end-of-study visit will conclude the participant's involvement, with data collected on long-term outcomes.
The expected length of participant involvement is approximately 32 weeks, corresponding to the maximum treatment period for the investigational product. Conditions that may lead to early termination from the study include the occurrence of serious adverse events, withdrawal of consent, or failure to adhere to the study protocol. Participants will be monitored closely throughout the trial to ensure safety and compliance with the study requirements.
Treatment
The clinical trial involves the administration of **Ponatinib**, marketed as Iclusig, in the form of 15 mg film-coated tablets. Ponatinib is a chemical compound with the active substance name **PONATINIB**. It is administered orally with a maximum daily dose of 15 mg, and the treatment period can extend up to 32 days. The pharmaceutical form is a film-coated tablet, and the product is authorized for use in the European Union under the marketing authorization number EU/1/13/839/001. The maximum total dose for the treatment period is 12.26 grams.
**Dexamethasone Disodium Phosphate** is used as an auxiliary treatment in the trial. It is provided as a solution for injection, with the active substance being **DEXAMETHASONE DISODIUM PHOSPHATE**. The route of administration is intravenous, with a maximum daily dose of 10 mg/m² and a total dose of 300 mg/m² over a 30-day period.
**Vincristine Sulfate** is another auxiliary treatment, available as a solution for injection or infusion. The active substance is **VINCRISTINE SULFATE**, administered via intravenous infusion. The maximum daily dose is 2 mg/m², with a total dose of 32 mg/m² over a 16-day treatment period.
**Mercaptopurine** is administered in tablet form, with the active substance being **MERCAPTOPURINE**. It is taken orally, with a maximum daily dose of 75 mg/m² and a total dose of 45,250 mg/m² over a 22-day period.
**Filgrastim** is provided as a solution for infusion, with the active substance **FILGRASTIM**. It is administered subcutaneously, with a maximum daily dose of 5 µg/kg and a total dose of 840 µg/kg over a 24-day period.
**Idarubicin Hydrochloride** is used in the trial as a powder for solution for injection. The active substance is **IDARUBICIN HYDROCHLORIDE**, administered intravenously. The maximum daily dose is 12 mg/m², with a total dose of 84 mg/m² over a 7-day period.
**Lenograstim** is administered as a solution for injection or infusion, with the active substance **LENOGRASTIM**. It is given subcutaneously, with a maximum daily dose of 5 µg/kg and a total dose of 840 µg/kg over a 24-day period.
**Prednisone** is provided in tablet form, with the active substance **PREDNISONE**. It is administered orally, with a maximum daily dose of 40 mg/m² and a total dose of 1,600 mg/m² over a 40-day period.
**Cyclophosphamide** is used as a powder for solution for infusion, with the active substance **CYCLOPHOSPHAMIDE**. It is administered intravenously, with a maximum daily dose of 1,000 mg/m² and a total dose of 5,200 mg/m² over a 13-day period.
**Cytarabine** is available as a powder and solvent for solution for injection, with the active substance **CYTARABINE**. It can be administered intravenously or subcutaneously, with a maximum daily dose of 4,000 mg/m² and a total dose of 16,900 mg/m² over a 16-day period.
**Folinic Acid** is provided as a powder and solvent for solution for injection, with the active substance **FOLINIC ACID**. It is administered via intravenous infusion, with a maximum daily dose of 37.5 mg/m² and a total dose of 787.5 mg/m² over a 6-day period.
**Methotrexate** is used in two forms: as a solution for injection and as a powder and solvent for solution for injection. The active substance is **METHOTREXATE**, administered intravenously. The maximum daily dose is 2,500 mg/m², with a total dose of 8,580 mg/m² over a 75-day period for the solution form, and 12.5 mg with a total dose of 150 mg over a 12-day period for the powder form.
**Methylprednisolone Sodium Succinate** is provided as a powder and solvent for solution for injection, with the active substance **METHYLPREDNISOLONE SODIUM SUCCINATE**. It is administered intravenously, with a maximum daily dose of 20 mg and a total dose of 240 mg over a 12-day period.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimen. The trial aims to evaluate the clinical response in terms of minimal residual disease (MRD) negativity in patients with BCR/ABL1-like Acute Lymphoblastic Leukemia (ALL) treated with Ponatinib in combination with chemotherapy.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the evaluation of the clinical response in terms of **MRD (Minimal Residual Disease) negativity** in patients with BCR/ABL1-like Acute Lymphoblastic Leukemia (ALL) treated with Ponatinib in combination with chemotherapy. The primary endpoint is the MRD negativity rate after three cycles (TP2) of treatment. Secondary endpoints include the rate of MRD negativity at additional timepoints (TP1, TP3), disease-free survival (DFS) at 24 months, event-free survival (EFS) at 24 months, cumulative incidence of relapse (CIR) estimation from complete remission (CR) achievement at 24 months, overall survival (OS) at 24 months, treatment-related mortality (TRM), the rate of patients in CR after TP2, the rate of patients who undergo transplantation and complete the chemotherapy plus Ponatinib scheme, and the rate of adverse events (AEs) and serious AEs related to Ponatinib.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age18-65 years.
- De novo Ph+-like ALL, as defined by the BCR/ABL1-like predictor (13).
- WHO score =2
- Adequate liver function, as defined by the following criteria: total serum bilirubin =1.5 x upper limit of normal (ULN), unless due to Gilbert's syndrome, alanine aminotransferase (ALT) =2.5 ×ULN or aspartate aminotransferase (AST) =2.5 x ULN or leukemia related.
- Adequate pancreatic function as defined by serum lipase and amylase =1.5 × ULN or leukemia related
- No history of dyslipidemia, thrombotic events or cardiac disease.
- For females of childbearing potential, a negative pregnancy test must be documented. Female and male patients who are fertile must agree to use an effective form of contraception with their sexual partners from enrollment through 12 months after the end of treatment.
- Signed informed consent, according to ICH/EU/GCP and national regulation.
Exclusion Criteria
- WHO performance status >2.
- Taking any medications or herbal supplements that are known to be strong inhibitors of CYP3A4 within at least 14 days before the first dose of ponatinib.
- Creatinine levels > 2.5mg/dl or glomerular filtration rate (GFR) < 20 ml/min or proteinuria >3.5 g/day.
- Active HBV or HCV hepatitis, or AST/ALT > 2.5 x ULN and bilirubin > 1.5 x ULN.
- History of acute pancreatitis within 1 year of study or history of chronic pancreatitis.
- History of alcohol abuse
- Ongoing or active infections
- Uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL).
- Clinically significant, uncontrolled or active cardiovascular disease, specifically including, but not restricted to: - Any history of myocardial infarction, stroke, or revascularization, unstable angina or transient ischemic attack within 6 months prior to enrollment, - Congestive heart failure within 6 months prior to enrollment, or left ventricular ejection fraction (LVEF) less than lower limit of normal per local institutional standards, - History of clinically significant (as determined by the treating physician) atrial arrhythmia, - Any history of ventricular arrhythmia, - Any history of venous thromboembolism including deep venous thrombosis or pulmonary embolism.
- Uncontrolled hypertension (diastolic blood pressure >90 mm Hg; systolic >140 mm Hg). Patients with hypertension should be under treatment on study entry to effect blood pressure control.
- Taking medications that are known to be associated with torsades de pointes
- Gastrointestinal (GI) function impairment, or a GI disease that may significantly alter the absorption of study drugs.
- Patients who are currently receiving treatment with any of the medications with potential to prolong QT interval (listed in Appendix F) if the medications cannot be either discontinued or switched to a different medication prior to starting study drug
- Patients who have received any investigational drug = 4 weeks.
- Patients who have undergone major surgery = 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy
- Patients who are pregnant or breast feeding and adults of reproductive potential not employing an effective method of birth control (women of childbearing potential must have a negative serum pregnancy test within 48 hrs. prior to administration of Ponatinib). Postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. Male and female patients must agree to employ two effective reliable methods of birth control throughout the study and for up to 12 months following discontinuation of study drugs
- Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention
- Patients unwilling or unable to comply with the protocol
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Recruiting | 05 Oct 2022 | 32 |
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 USE | 30 | 32 | PRD4872103 |
CYTARABINE | Other | — | INTRAVENOUS (IV) OR SUBCUTANEOUS (SC) | 4000 | 16 | SUB06880MIG |
CYCLOPHOSPHAMIDE | Other | — | INTRAVENOUS | 1000 | 13 | SUB06859MIG |
LENOGRASTIM | Other | — | SUBCUTANEOUS | 5 | 24 | SUB02888MIG |
VINCRISTINE SULFATE | Other | — | INTRAVENIOUS INFUSION | 2 | 16 | SUB05101MIG |
IDARUBICIN HYDROCHLORIDE | Other | — | INTRAVENOUS | 12 | 7 | SUB02635MIG |
PREDNISONE | Other | — | ORAL | 40 | 40 | SUB10020MIG |
METHOTREXATE | Other | — | INTRAVENOUS | 2500 | 75 | SUB08856MIG |
METHOTREXATE | Other | — | INTRAVENOUS | 12.5 | 12 | SUB08856MIG |
METHYLPREDNISOLONE SODIUM SUCCINATE | Other | — | INTRAVENOUS | 20 | 12 | SUB14562MIG |