Evaluation of Ponatinib, Alone or with Chemotherapy, for Minimal Residual Disease and Hematologic Relapse in Adult Ph+ Acute Lymphoblastic Leukemia

The primary objective of this study is to evaluate the rate of patients achieving **minimal residual disease** (MRD) negativity or MRD reduction following treatment with ponatinib, either alone or in combination with systemic chemotherapy, after 3 months of treatment. This objective is clinically relevant as achieving MRD negativity is associated with improved prognosis and reduced risk of relapse in patients with Ph+ Acute Lymphoblastic Leukemia (Ph+ ALL). The analysis will be conducted separately for two groups: patients with MRD positivity and those with hematologically and extra-hematologically relapsed or refractory disease.

Secondary objectives include:

• The duration of complete molecular remission (CMR), if achieved.
• The achievement of hematologic remission in patients treated for hematologic and extra-hematologic relapse and for refractory disease.
• The best molecular response.
• Safety profile.
• Mutational analysis.
• The correlation between biological and MRD parameters.
• Disease-free survival (DFS).
• Overall survival (OS).
• Cumulative incidence of relapse (CIR).
• The role of clinical and biological parameters on survival outcome.

The clinical trial involves participants diagnosed with **Philadelphia chromosome-positive Acute Lymphoblastic Leukemia (Ph+ ALL)**. The study population includes both male and female subjects aged 18 years and older, with no upper age limit specified. Participants are required to have adequate hepatic and pancreatic function, as defined by specific laboratory criteria. The trial population was selected based on the presence of minimal residual disease (MRD) or hematologic and extra-hematologic relapse/refractoriness after any previous treatment. The study does not specify the total number of participants, as this information was not provided by the sponsor. Lifestyle considerations such as diet and physical activity are not detailed in the available data. The trial includes a vulnerable population, and both genders are represented. Key inclusion criteria include a negative pregnancy test for females of childbearing potential and the use of effective contraception for all fertile participants. The trial requires signed written informed consent in accordance with ICH/EU/GCP and national local laws.

The clinical trial is designed to evaluate the efficacy of **ponatinib**, either alone or in combination with chemotherapy, in inducing remission in patients with **Ph+ Acute Lymphoblastic Leukemia**. This study is a Phase II, randomized, double-blind, controlled trial with an estimated duration extending until October 2026. The trial aims to assess the rate of patients achieving minimal residual disease (MRD) negativity or reduction after three months of treatment. Participants will be randomly assigned to receive either ponatinib alone or in combination with systemic chemotherapy. The trial will include a series of study visits to monitor patient progress and ensure safety.

The sequence of study visits begins with an inclusion (screening) visit, where eligibility criteria are confirmed, including age, hepatic and pancreatic function, and a negative pregnancy test for females of childbearing potential. Following the screening, participants will undergo regular follow-up visits to assess treatment efficacy and monitor for adverse events. The end-of-study visit will conclude the trial, evaluating the primary and secondary endpoints, including the duration of complete molecular remission (CMR) and the safety profile in terms of adverse events and toxicities.

Participant involvement is expected to last for the duration of the treatment period, which is up to three months, with additional follow-up as required. Conditions that may lead to early termination from the study include the occurrence of severe adverse events, non-compliance with study protocols, or withdrawal of consent. The trial will adhere to ethical guidelines, ensuring informed consent is obtained from all participants, and will be conducted in accordance with Good Clinical Practice (GCP) standards.

The clinical trial involves the administration of several **experimental medications** and auxiliary treatments. **Cytarabine** is utilized in the form of a solution for injection. It is administered **intrathecally** with a maximum daily dose of 40 mg and a total dose not exceeding 280 mg over a treatment period of 7 days. The active substance is of chemical origin.

**Methylprednisolone** is provided as a powder for solution for injection or infusion. It is also administered intrathecally, with a maximum daily dose of 20 mg and a total dose of 140 mg over 7 days. The active substance is chemically derived.

**Iclusig**, containing the active substance **ponatinib**, is administered orally in the form of film-coated tablets. The maximum daily dose is 45 mg, with a total dose of 3.78 g over a 3-day treatment period. Ponatinib is a chemical compound.

**Methotrexate** is administered as a solution for injection, intrathecally, with a maximum daily dose of 10 mg and a total dose of 70 mg over 7 days. The active substance is of chemical origin.

**Vincristine** is provided as a solution for injection and is administered intravenously. The maximum daily dose is 2 mg/m², with a total dose of 2 mg/m² over a single day of treatment. The origin of the active substance is not specified.

**Ponatinib** is also administered as a film-coated tablet, orally, with a maximum daily dose of 45 mg and a total dose of 3.78 g over a 3-day treatment period. The active substance is chemically derived.

**Prednisone** is administered orally in tablet form, with a maximum daily dose of 60 mg/m² and a total dose of 1900 mg/m² over a 29-day treatment period. The active substance is of chemical origin.

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 efficacy of these treatments in managing minimal residual disease and hematologic relapse in adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia.

The efficacy of the clinical trial will be assessed primarily by evaluating the rate of patients achieving **minimal residual disease (MRD)** negativity or MRD reduction following treatment with Ponatinib, either alone or in combination with systemic chemotherapy, after a period of 3 months. This primary endpoint will be analyzed separately for two groups: patients with MRD positivity and those with hematologically and extra-hematologically relapsed or refractory disease. Secondary endpoints include the duration of complete molecular remission (CMR), the rate of hematologic remission in patients treated for hematologic and extra-hematologic relapse or refractory disease, and the best molecular response achieved during the study. Additional secondary endpoints involve the safety profile, assessed by the incidence of grade >3 CTC-NCI side effects and toxicities, mutational analysis of BCR-ABL1 kinase domain mutations, and correlations between CMR achievement and duration with the type of fusion protein and genomic lesions. Long-term outcomes such as disease-free survival (DFS), overall survival (OS), and cumulative incidence of relapse (CIR) at 24 months will also be evaluated. The role of clinical and biological assessments at baseline, including the type of fusion protein and presence of additional genomic lesions and mutations, will be analyzed in relation to CMR duration, OS, and DFS.