INCA34176-254: A Phase 2, Open-Label, Randomized, Multicenter Study to Evaluate the Safety and Efficacy of Axatilimab in Combination With Ruxolitinib in Participants With Newly Diagnosed Chronic Graft-Versus-Host Disease

The primary objective of this study is to determine the preliminary **efficacy** of axatilimab in combination with ruxolitinib and to assess the contribution of axatilimab to the combination treatment effect in participants with chronic graft-versus-host disease (cGVHD). This is clinically relevant as cGVHD is a significant complication following allogeneic hematopoietic stem cell transplantation, and effective management is crucial for improving patient outcomes.

Secondary objectives include:

• To determine the safety and tolerability of axatilimab in combination with ruxolitinib in participants with cGVHD.
• To evaluate the clinical benefit of axatilimab in combination with ruxolitinib in participants with cGVHD with respect to secondary endpoints, assessed for each treatment group.
• To assess the pharmacokinetics (PK) of axatilimab in combination with ruxolitinib in participants with cGVHD.

The clinical trial involves a total of **50 participants** diagnosed with **chronic graft-versus-host disease** (cGVHD). The study population includes both male and female subjects, with an age range starting from 12 years and above. However, participants aged 12 to 18 years are not enrolled in Germany, Italy, and the UK. The trial population was selected based on specific criteria, including a history of one allogeneic stem cell transplant (allo-SCT) and the presence of new-onset moderate or severe cGVHD as defined by the 2014 NIH Consensus Criteria. Participants are required to demonstrate a willingness to avoid pregnancy or fathering children during the study. The trial includes a vulnerable population, indicating careful consideration of ethical standards in participant selection. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the **safety** and efficacy of **axatilimab** in combination with **ruxolitinib** in participants with newly diagnosed chronic graft-versus-host disease (cGVHD). This is a Phase 2, open-label, randomized, multicenter study. The trial will involve a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, disease severity, and medical history. Participants must be at least 12 years old, with new-onset moderate or severe cGVHD, and have a history of one allogeneic stem cell transplant. The trial will exclude participants who do not meet these criteria.

The trial will be conducted over an estimated duration ending on January 31, 2030, with recruitment starting on September 30, 2024. Participants will be involved in the study for a maximum treatment period of 24 months. The study design includes regular follow-up visits to monitor the participants' response to treatment and assess any adverse events. The primary endpoint is the overall response at 6 months, defined as complete or partial response without the need for new systemic therapy for cGVHD. Secondary endpoints include safety and tolerability assessments, duration of response, and pharmacokinetic parameters for both axatilimab and ruxolitinib.

Participants will receive axatilimab as a solution for infusion, administered either intravenously or subcutaneously, and ruxolitinib in tablet form, taken orally. The study will also involve the use of prednisone and methylprednisolone as part of the treatment regimen. The expected length of participant involvement is contingent upon the absence of treatment failure or the need for additional systemic therapy. Conditions that may lead to early termination from the study include the initiation of new systemic therapy for cGVHD, death, or treatment failure by Month 6. The study aims to provide valuable insights into the treatment of cGVHD, contributing to the understanding of the combination therapy's efficacy and safety profile.

**Axatilimab (INCA034176)** is an experimental medication used in this clinical trial. It is formulated as a **solution for infusion** and is administered either **intravenously (IV)** or **subcutaneously (SC)**. The dosage is set at a maximum of **0.3 mg/kg** per day, with a total treatment period not exceeding 24 weeks. Axatilimab is a protein-based substance developed by Incyte Corporation, and its role in the trial is to evaluate its efficacy in combination with other treatments for chronic graft-versus-host disease (cGVHD).

**Prednisone** is utilized as a non-experimental treatment in this study. It is available in **tablet** form and is administered **orally**. The maximum daily dose is **100 mg**, with a total treatment period of up to 24 weeks. Prednisone is a chemical-based steroid, commonly used as a standard-of-care therapy in managing cGVHD symptoms.

**Methylprednisolone** is another non-experimental treatment included in the study. It is available as an **injection** and can be administered both **orally and intravenously (IV)**. The maximum daily dose is **100 mg**, with a treatment duration of up to 24 weeks. Methylprednisolone, like prednisone, is a chemical-based steroid used to manage inflammation and immune responses in cGVHD.

**Ruxolitinib**, marketed as Jakavi 5 mg tablets, is included in the trial as a comparator treatment. It is a **tablet** administered **orally**, with a maximum daily dose of **20 mg** over a 24-week period. Ruxolitinib is a chemical-based selective inhibitor of Janus Associated Kinase (JAK) 1, developed by Novartis Europharm Limited, and is used to assess its efficacy in combination with axatilimab for treating cGVHD.

The efficacy of the clinical trial evaluating **axatilimab** in combination with ruxolitinib for participants with newly diagnosed chronic graft-versus-host disease (cGVHD) will be assessed using several parameters. The primary endpoint is the overall response (OR) at 6 months, defined as complete response (CR) or partial response (PR) in the absence of new systemic therapy for cGVHD, based on the 2014 NIH Criteria. Secondary endpoints include safety and tolerability, duration of response (DOR) in responders, and the proportion of participants with a ≥ 7-point improvement in the modified Lee Symptom Scale (mLSS) total score. Additionally, the best overall response in the first 6 months and on study, OR at 12 months, pharmacokinetic (PK) parameters for axatilimab and ruxolitinib, and event-free survival (EFS) will be evaluated.

Response assessments will be conducted at specified intervals, with the primary endpoint measured at 6 months. Secondary endpoints will be evaluated throughout the study duration, including assessments at 12 months. The trial will utilize validated scales and criteria, such as the 2014 NIH Consensus Criteria and mLSS, to ensure accurate and reliable measurement of efficacy outcomes. Data collection and analysis will be performed in accordance with the trial protocol to determine the contribution of axatilimab to the combination treatment effect in participants with cGVHD.