Safety and Efficacy of Asciminib, Blinatumomab, and Combination Therapy in Pediatric and Young Adult Patients with Relapsed/Refractory BCR::ABL1+ or Ph-like ALL

The primary objective of Part 1 dose escalation is to determine the recommended phase 2 dose (RP2D) by evaluating the incidence of dose-limiting toxicities (DLTs), adverse events (AEs), and laboratory safety findings. In Part 2 dose expansion, the primary objective is to assess complete remission (CR) rates at the conclusion of cycle 1 in evaluable patients with acute lymphoblastic leukemia (ALL). This study focuses on patients with relapsed or refractory BCR::ABL1-positive or ABL-class Ph-like disease.

Secondary objectives include:

• Assessment of the safety and tolerability of asciminib in combination with the specified treatment regimen, including low-intensity chemotherapy during debulking induction and blinatumomab during consolidation.
• Evaluation of overall response, specifically complete remission with incomplete hematologic recovery (CRi), at the end of cycles 1, 2, and 3.
• Measurement of efficacy endpoints regarding minimal residual disease (MRD) negativity as determined by multiparametric flow cytometry (MFC) and/or next-generation sequencing (NGS).
• Characterization of the pharmacokinetics (PK) of asciminib when administered with the study treatment regimen.

This clinical trial involves a total of 27 participants. The study population consists of male and female patients between the ages of 1 and 30 years. Eligible individuals must have a documented history of relapsed or refractory acute lymphoblastic leukemia (ALL) characterized by BCR::ABL1-positive or BCR::ABL1-like status involving ABL1 or ABL2 rearrangements. Participants must present with active B-cell ALL at screening, as defined by flow cytometry or polymerase chain reaction showing blast levels greater than 0.01%. Specific inclusions require documented CD19 expression in the peripheral blood or bone marrow. The study population may include patients with central nervous system involvement at screening.

This multi-center, open-label, phase I/II study is designed to evaluate the safety and efficacy of asciminib in combination with chemotherapy followed by blinatumomab. The research targets pediatric, adolescent, and young adult patients with relapsed or refractory BCR::ABL1-positive (Ph+) or ABL-class Ph-like acute lymphoblastic leukemia (ALL). The study is divided into two distinct parts: Part 1 focuses on dose escalation to determine the recommended phase 2 dose (RP2D) by monitoring dose-limiting toxicities (DLTs) and adverse events, while Part 2 involves dose expansion to assess complete remission (CR) rates. Participants undergo a screening process to confirm genetic alterations and disease status prior to treatment. The therapeutic regimen includes various agents such as vincristine sulfate and dexamethasone, alongside auxiliary treatments like cytarabine and methotrexate. Secondary endpoints include disease-free survival, overall survival, and minimal residual disease (MRD) negativity rates. The estimated trial duration extends through January 2036.

Asciminib hydrochloride is an orphan drug administered as film-coated granules via the oral route.

Blinatumomab is an orphan drug administered via intravenous infusion.

Dexamethasone is administered through oral routes, while dexamethasone sodium phosphate is administered via intravenous infusion.

Vincristine sulfate is administered via intravenous infusion.

Methotrexate, provided as a solution for injection, is administered through intrathecal use. Cytarabine is also administered via intrathecal use. Hydrocortisone and prednisolone acetate ph. eur. are utilized via intrathecal use.

The evaluation of efficacy and safety in this clinical trial for acute lymphoblastic leukemia is divided into two parts. In Part 1 dose escalation, the assessment focuses on determining the recommended phase 2 dose through the monitoring of dose-limiting toxicities occurring during the first cycle of debulking induction, the incidence of adverse events severity, and laboratory safety findings. In Part 2 dose expansion, the primary efficacy endpoint is the proportion of participants evaluable for complete remission who achieve this state at the end of cycle 1 while treated at the recommended dose.

Secondary efficacy and safety parameters include:

• The proportion of participants achieving complete remission at the end of cycle 2 and cycle 3.
• The proportion of participants achieving complete remission or complete remission with incomplete hematologic recovery by the end of cycles 1, 2, and 3.
• The minimal residual disease negative rate as measured by next-generation sequencing at the end of cycles 1, 2, and 3.
• The minimal residual disease negative rate as measured by multiparametric flow cytometry at the end of cycles 1, 2, and 3.
• Disease-free survival and overall survival.
• Safety assessments involving the type, frequency, and severity of treatment-emergent adverse events, changes in laboratory parameters, electrocardiogram findings, and other safety data.
• Pharmacokinetic parameters of asciminib at steady state, including area under the curve, maximum concentration, time to maximum concentration, and trough concentration via sparse sampling.