Phase 3 Randomized Open-Label Study of Axatilimab Versus Best Available Therapy in Chronic Graft-Versus-Host Disease Post Two Systemic Therapy Lines

The primary objective of this study is to compare the **efficacy** of axatilimab monotherapy versus Best Available Therapy (BAT) in patients with Chronic Graft-Versus-Host Disease (cGVHD). This comparison is clinically relevant as it aims to determine the potential of axatilimab to improve treatment outcomes in cGVHD, a condition that often requires multiple lines of systemic therapy.

Secondary objectives include: - Evaluating the clinical benefit of axatilimab monotherapy versus BAT with respect to Failure-Free Survival (FFS). - Assessing the clinical benefit concerning secondary endpoints. - Evaluating and comparing the effect on overall corticosteroid use. - Assessing the safety and tolerability of axatilimab monotherapy versus BAT in cGVHD.

The clinical trial involves a total of **17 participants** diagnosed with **Chronic Graft-Versus-Host Disease (cGVHD)**. The study population includes both male and female subjects, aged 12 years and older, with a focus on individuals who have a history of allogeneic hematopoietic cell transplantation (allo-HCT) and are experiencing active, moderate to severe cGVHD requiring systemic immune suppression. Participants have previously undergone at least two lines of systemic therapy, including corticosteroids and ruxolitinib. The trial population was selected based on their ability to comprehend and sign an informed consent form, with additional consent provided by a parent or guardian for pediatric participants. The study includes individuals with a Karnofsky Performance Status (KPS) score of 60 or higher for those aged 16 years or older, and a Lansky Performance Status (LPS) score of 60 or higher for those under 16. Participants are required to avoid pregnancy or fathering children during the trial. The trial allows for the concomitant use of systemic corticosteroids and requires participants to be treated with one of several specified Best Available Therapy (BAT) options. The study population is considered vulnerable, reflecting the complex health status and treatment history of the participants.

The clinical trial is a **Phase 3**, randomized, open-label study designed to evaluate the efficacy of **axatilimab** monotherapy compared to the best available therapy (BAT) in participants with **chronic graft-versus-host disease** (cGVHD) who have undergone at least two prior lines of systemic therapy. The trial will involve participants aged 12 years and older, with active, moderate to severe cGVHD requiring systemic immune suppression. The study will be conducted over an estimated period, with recruitment starting in June 2025 and expected to conclude by November 2032.

Participants will be randomly assigned to receive either axatilimab or BAT, with axatilimab administered as a **solution for infusion** via **intravenous use**. The maximum daily dose of axatilimab is set at 0.3 mg/kg, with a total treatment period not exceeding 24 months. The primary endpoint is the overall response (OR) at six months, defined as complete response (CR) or partial response (PR) in the absence of new systemic therapy for cGVHD. Secondary endpoints include failure-free survival (FFS), symptom response, and overall survival (OS), among others.

The trial will include several study visits, beginning with a screening visit to assess eligibility based on inclusion criteria such as age, ability to provide informed consent, and history of allogeneic hematopoietic cell transplantation (allo-HCT). Follow-up visits will be scheduled to monitor treatment response, safety, and tolerability, with assessments based on the 2014 NIH Consensus Development Project on Criteria for Clinical Trials in cGVHD. The end-of-study visit will occur upon completion of the treatment period or in the event of early termination.

Participant involvement is expected to last up to 24 months, depending on individual response and treatment tolerability. Conditions that may lead to early termination from the study include the initiation of another systemic therapy for cGVHD, relapse of the underlying disease, or any adverse events that compromise participant safety. The study aims to provide valuable insights into the management of cGVHD, contributing to the development of more effective treatment strategies.

The clinical trial involves the administration of **Axatilimab (INCA034176)**, a **solution for infusion** developed by Incyte Corporation. Axatilimab is an experimental medication being evaluated for its efficacy in treating chronic graft-versus-host disease (cGVHD) in participants who have undergone at least two prior lines of systemic therapy. The active substance in Axatilimab is a protein of other origin, specifically designed for intravenous use. The dosing regimen for Axatilimab is set at a maximum daily dose of 0.3 mg/kg, with the total dose not exceeding 0.3 mg/kg. The treatment period is capped at 24 weeks, ensuring a controlled and monitored administration schedule.

In this study, Axatilimab is compared against the best available therapy (BAT), which serves as the non-experimental treatment. BAT is considered the standard-of-care therapy for participants with cGVHD and is used as a comparator to evaluate the relative efficacy of Axatilimab. The trial is designed as a Phase 3, randomized, open-label study, allowing for a direct comparison between the experimental and standard treatments. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol and to accurately assess the outcomes of the treatment.

The efficacy of Axatilimab in the treatment of chronic **Graft-Versus-Host Disease** (cGVHD) will be assessed through a series of primary and secondary endpoints. The primary endpoint is the Overall Response (OR) at 6 months, defined as either Complete Response (CR) or Partial Response (PR) at 6 months (C7D1) without the initiation of new systemic therapy for cGVHD. This response will be evaluated using the 2014 NIH Consensus Development Project criteria for cGVHD, specifically focusing on disease in joints and fascia.

Secondary endpoints include several measures: Failure-Free Survival (FFS), which is the time from randomization to the addition or initiation of another systemic therapy for cGVHD, relapse of the underlying disease, or death from any cause; Symptom response, defined as a ≥ 7-point improvement in the modified Lee Symptom Scale (mLSS) total score; OR at 12 months, defined as CR or PR at 12 months without new systemic therapy; Best Overall Response (BOR) within the first 6 months and at any time before new therapy initiation; Duration of Response (DOR) for responders, calculated from the first response to progression, new treatment, or death; Organ-specific response; Overall Survival (OS) from randomization to death from any cause; Non-Relapse Mortality (NRM) from randomization to death not preceded by relapse; Time to primary hematologic disease relapse; and the percent reduction in daily corticosteroid dose at C7D1, including participants successfully tapered off all corticosteroids at C7D1.

Safety and tolerability will also be evaluated by monitoring the frequency and severity of adverse events (AEs), including serious adverse events (SAEs), and changes in clinical and laboratory assessments, as well as Karnofsky Performance Status (KPS) and Lansky Performance Status (LPS) scores.