Phase IIA Evaluation of Inotuzumab Ozogamicin Efficacy in Adult B-Cell Acute Lymphoblastic Leukemia with Minimal Residual Disease Pre-Transplantation

The primary objective of this study is to determine the **effectiveness** of Inotuzumab Ozogamicin in achieving minimal residual disease (MRD) negativity in adult patients with B-cell Acute Lymphoblastic Leukemia (ALL) who are MRD positive prior to any hematopoietic stem cell transplantation. Achieving MRD negativity is clinically significant as it is associated with improved prognosis and reduced risk of relapse in patients with ALL.

Secondary objectives include:

• Establishing the survival of the treatment population, which is crucial for understanding the long-term benefits of the therapy.
• Defining treatment safety and the incidence of adverse events in the MRD positive population, which is essential for evaluating the risk-benefit profile of the treatment.
• Determining the number of patients who can use Inotuzumab as a bridge to transplantation, considering only those eligible for transplantation, which is important for planning subsequent therapeutic strategies.

The clinical trial involves participants diagnosed with **Acute B-cell Lymphoblastic Leukemia** with minimal residual positive disease prior to hematopoietic stem cell transplantation. The study population includes both male and female adults aged 18 years and older, with no upper age limit specified. Participants are required to have a life expectancy greater than 12 weeks and must demonstrate adequate hepatic and pancreatic function. The trial population was selected based on specific inclusion criteria, including the presence of measurable MRD positivity and being in the first or second complete remission. The study does not specify the total number of participants, as this information was not provided by the sponsor. Participants are expected to adhere to certain lifestyle considerations, such as using effective contraception and refraining from sperm donation during and after the treatment period. The trial includes a vulnerable population, indicating that additional ethical considerations are in place to protect the participants involved.

The clinical trial is designed to evaluate the **effectiveness** of **Inotuzumab Ozogamicin** in achieving minimal residual disease (MRD) negativity in adult patients with **Acute B-cell Lymphoblastic Leukemia** who are MRD positive prior to hematopoietic stem cell transplantation. This is a Phase II study, characterized by a randomized, double-blind, controlled design, ensuring the reliability and validity of the results. The trial is expected to run until December 31, 2027, with participant recruitment having commenced on October 30, 2019.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, life expectancy, and adequate hepatic and pancreatic function. The primary endpoint is the percentage of MRD negativity after the second course of treatment. Secondary endpoints include molecular disease progression, overall survival, and event-free survival, among others. Follow-up visits will be scheduled to monitor treatment response and adverse events, with the end-of-study visit marking the conclusion of the participant's involvement.

The expected length of participant involvement varies, with the maximum treatment period for **Inotuzumab Ozogamicin** being six months. Conditions that may lead to early termination from the study include disease progression, severe adverse events, or withdrawal of consent. Participants are required to adhere to specific contraceptive measures and discontinue breastfeeding during treatment. The trial aims to provide valuable insights into the treatment efficacy and safety profile of **Inotuzumab Ozogamicin** in this patient population.

The clinical trial involves the administration of several **experimental medications** to evaluate their effectiveness in treating B-Cell Acute Lymphoblastic Leukemia with positive Minimal Residual Disease. **Cyclophosphamide** is administered as a **powder for solution for injection or infusion**. The dosage is calculated based on body surface area, with a maximum daily dose of 100 mg/m² and a total dose not exceeding 800 mg/m² over a treatment period of up to 8 weeks. The route of administration is **intravenous**.

**Methotrexate** is provided as a **solution for injection**. It is administered intravenously with a maximum daily dose of 15 mg/m² and a total dose of 135 mg/m² over a maximum treatment period of 9 weeks. The administration schedule is designed to ensure optimal therapeutic levels while monitoring for potential adverse effects.

**Prednisone** is administered orally in **tablet** form. The dosage is 40 mg/m² per day, with a total dose not exceeding 200 mg/m² over a 5-week treatment period. Compliance with the oral administration schedule is monitored to ensure adherence to the treatment protocol.

**Ponatinib** is provided as a **film-coated tablet** for oral administration. The maximum daily dose is 45 mg, with a total dose of 3.78 grams over a 12-month period. The dosing schedule is designed to maintain therapeutic efficacy while minimizing potential side effects.

**Vincristine** is administered as a **solution for injection**. The intravenous route is used, with a maximum daily and total dose of 1 mg/m², administered over a single treatment period. The administration is closely monitored to ensure safety and efficacy.

**Inotuzumab ozogamicin**, marketed as **BESPONSA**, is provided as a **powder for concentrate for solution for infusion**. It is administered intravenously with a maximum daily dose of 500 µg/m² and a total dose of 3 mg/m² over a 6-week period. This medication is designated as an orphan drug, highlighting its use in rare conditions.

**Mercaptopurine**, marketed as **PURINETHOL**, is administered orally in **tablet** form. The dosage is 75 mg/m² per day, with a total dose not exceeding 4725 mg/m² over a 9-month period. Adherence to the oral dosing schedule is critical for achieving the desired therapeutic outcomes.

Throughout the trial, participant compliance with the dosing schedules is monitored through regular assessments and follow-ups. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments. The focus remains on evaluating the effectiveness of the experimental medications in achieving the primary objective of the study.

The efficacy of the clinical trial will be assessed primarily by evaluating the percentage of patients achieving **Minimal Residual Disease (MRD)** negativity after the second course of treatment, or after the first course if only one course is performed. This primary endpoint is crucial in determining the effectiveness of Inotuzumab Ozogamicin in adult patients with B-Cell Acute Lymphoblastic Leukemia (ALL) who are MRD positive before any hematopoietic stem cell transplantation.

Secondary endpoints include several measures of disease progression and patient survival. These include Molecular Disease Progression, defined as a rise of more than 2 log in MRD from any previous determination, and Disease Progression, which is equivalent to treatment failure or lack of efficacy. Overall Survival (OS) will be measured as the number of days from the first administration of the study drug to death from any cause or loss to follow-up. Event-Free Survival (EFS) will be assessed as the number of days from the first study drug administration to any event, including disease progression or death. Disease-Free Survival (DFS) will be defined as the interval between the date of response achievement and the date of death, relapse, or last follow-up.

Additional secondary endpoints will include the incidence, severity, and nature of any adverse events, particularly those related to treatment safety, such as Grade 3 or 4 non-hematological toxicities. The frequency of clinically significant abnormalities in physical examinations, safety laboratory tests, vital signs, and 12-Lead ECGs will also be monitored. The occurrence of Veno-Occlusive Disease (VOD) during or after protocol or transplant procedures will be tracked for up to two years.