Phase I/II Evaluation of Brigatinib in Pediatric and Young Adult Patients with ALK-Positive Anaplastic Large Cell Lymphoma and Inflammatory Myofibroblastic Tumors

The primary objective of this study is to determine the **maximum tolerated dose (MTD)** and recommended phase 2 dose (RP2D) regimen of **brigatinib** monotherapy when administered to pediatric and adolescent young adult (AYA) patients with ALK-positive Anaplastic Large Cell Lymphoma (ALCL) or ALK-positive solid tumors, including ALK-positive Inflammatory Myofibroblastic Tumors (IMT). Additionally, the study aims to characterize the pharmacokinetics (PK) of brigatinib in this patient population and to establish its anti-tumor activity and efficacy, particularly in children with ALK-positive IMT and ALK-positive ALCL over a duration of two years without planned hematopoietic stem cell transplantation (HSCT) in consolidation. These objectives are clinically relevant as they aim to optimize dosing regimens and evaluate the therapeutic potential of brigatinib in treating these specific malignancies, which could lead to improved treatment outcomes and patient management strategies.

Secondary objectives include:

• Assessing the safety and tolerability of brigatinib as monotherapy in pediatric and AYA patients during the first course, and evaluating cumulative toxicities in patients receiving multiple courses.
• Evaluating the acceptability and palatability of brigatinib.
• Describing long-term toxicity, with a focus on ocular, pulmonary, endocrine adverse events, and growth abnormalities over a period of up to five years post-study inclusion.
• For Cohort B1, estimating the activity of brigatinib in terms of time to best response, duration of response (DOR), complete resection rates, cumulative incidence of non-response or relapse, event-free survival (EFS), overall survival (OS), and on-treatment survival.
• For Cohort B2, estimating the activity of brigatinib in terms of overall response rate (ORR) after one course and best ORR during treatment, time to best response, DOR, cumulative incidence of non-response or relapse, OS, on-treatment survival, and describing outcomes for ALCL patients with and without HSCT after remission induced with brigatinib, as well as anti-tumor activity in patients re-challenged with brigatinib after relapse.

The clinical trial involves a total of **11 participants** who are pediatric and adolescent young adult (AYA) patients diagnosed with **Anaplastic Large Cell Lymphoma (ALCL)**, **Inflammatory Myofibroblastic Tumors (IMT)**, or other solid tumors. The study population includes both male and female subjects, aged between 1 and 26 years, who are able to swallow brigatinib tablets and have a minimum weight of 10 kg. Participants were selected based on their histologically confirmed diagnosis of cancer and the presence of an activating ALK aberration in the tumor. The trial includes a vulnerable population, as it involves pediatric and AYA patients. Participants must not be receiving other investigational medications within 30 days of the first dose of the study drug. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The selection criteria ensure that participants have relapsed or refractory disease, or in the case of IMT, are not suitable for curative surgical resection without causing mutilation. The trial aims to determine the maximum tolerated dose and recommended phase 2 dose regimen of brigatinib monotherapy, as well as to characterize its pharmacokinetics and establish its anti-tumor activity and efficacy in the specified patient population.

The clinical trial is designed as an integrated Phase I/II study to evaluate the safety, pharmacokinetics, and efficacy of **brigatinib** in pediatric and young adult patients with ALK-positive Anaplastic Large Cell Lymphoma (ALCL), Inflammatory Myofibroblastic Tumors (IMT), or other solid tumors. The trial employs a randomized, double-blind, controlled methodology to ensure the reliability and validity of the results. The estimated duration of the trial extends until July 2030, with recruitment having commenced in August 2022.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, ability to swallow tablets, and histological confirmation of cancer with an activating ALK aberration. The trial is structured to include multiple follow-up visits to monitor dose-limiting toxicities, pharmacokinetic parameters, and overall response rates. The end-of-study visit will conclude the participant's involvement, assessing the long-term efficacy and safety of the treatment.

The expected length of participant involvement varies, with the treatment duration potentially extending up to two years, depending on individual response and tolerance. Conditions that may lead to early termination from the study include the occurrence of unacceptable toxicities, withdrawal of consent, or any significant protocol deviations. The primary endpoints focus on determining the maximum tolerated dose and recommended Phase II dose, while secondary endpoints include evaluating the overall response rate and event-free survival.

The clinical trial involves the administration of **Brigatinib**, marketed under the name Alunbrig, in three different dosages: 30 mg, 90 mg, and 180 mg. Each dosage is provided in the form of **film-coated tablets**. The active substance, **Brigatinib**, is a chemical compound with the synonym AP26113. The tablets are manufactured by Takeda Pharma A/S and are authorized for use in the European Union. The route of administration for all dosages is **oral**. The trial aims to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of Brigatinib monotherapy in pediatric and young adult patients with ALK-positive anaplastic large cell lymphoma (ALCL) or ALK-positive solid tumors, including inflammatory myofibroblastic tumors (IMT).

The Alunbrig 90 mg film-coated tablets are designed for oral administration and are part of the trial to assess the pharmacokinetics and anti-tumor activity of Brigatinib. The 90 mg dosage is intended to be administered once daily, with the frequency and duration of administration being determined by the study protocol. Compliance with the dosing schedule is monitored through regular assessments and patient reporting.

The Alunbrig 180 mg film-coated tablets are also administered orally and are included in the trial to evaluate the efficacy of Brigatinib as a single agent in treating ALK-positive ALCL and ALK-positive solid tumors. The 180 mg dosage is administered once daily, and participant adherence to the treatment regimen is closely monitored to ensure accurate assessment of the drug's efficacy and safety.

The Alunbrig 30 mg film-coated tablets serve as an additional dosage option within the trial, providing flexibility in dosing to achieve the optimal therapeutic effect while minimizing potential side effects. The 30 mg tablets are administered orally, with the dosing schedule tailored to the individual needs of the participants as outlined in the study protocol. Monitoring of participant compliance is conducted to maintain the integrity of the trial data.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial documentation. The focus remains on the administration and evaluation of Brigatinib monotherapy in the specified patient population.

The efficacy of **brigatinib** in the clinical trial will be assessed through several primary endpoints. In Phase 1, the primary endpoints include the evaluation of dose-limiting toxicities (DLTs) during the first course of therapy and the determination of brigatinib plasma pharmacokinetic (PK) parameters. These PK parameters include the maximum observed concentration (Cmax), the time of first occurrence of maximum observed concentration (Tmax), and the area under the concentration-time curve from time 0 to the time of the last quantifiable concentration (AUClast). The recommended Phase 2 dose (RP2D) will be selected based on achieving PK exposure equivalent to adult values and observing fewer than two out of six patients experiencing a DLT at this dose level, while also considering responses observed in Phase 1.

In Cohort B1, the overall response rate (ORR) will be assessed, defined as the percentage of patients achieving complete response (CR) or partial response (PR) according to RECIST 1.1 criteria after one course and the best ORR during brigatinib treatment. For Cohort B2, event-free survival (EFS) will be evaluated using the International Pediatric Non-Hodgkin Lymphoma (IPNHL) response criteria. EFS is defined as the time between the start of study treatment and the first event, which could be progressive disease, relapse, death from any cause, or the occurrence of second malignancies, whichever occurs first. Patients who undergo hematopoietic stem cell transplantation (HSCT) will be censored in this analysis.