Phase 2 Multicenter Study Evaluating Axatilimab Efficacy, Safety, and Tolerability in Recurrent/Refractory Chronic Graft Versus Host Disease

The primary objective of this study is to evaluate the **overall response rate (ORR)** of axatilimab administered at three different dosages (0.3 mg/kg IV Q2W, 1 mg/kg IV Q2W, and 3 mg/kg IV Q4W) in patients with chronic graft versus host disease (cGVHD) who have not responded to at least two prior lines of systemic therapy. This is clinically relevant as it aims to determine the efficacy of axatilimab in improving patient outcomes in a population with limited treatment options.

Secondary objectives include:

• Evaluating key secondary measures of clinical benefit.
• Evaluating secondary measures of clinical benefit.
• Assessing the safety and tolerability of axatilimab in patients with cGVHD.
• Assessing the plasma population pharmacokinetic (PK) profile of axatilimab in patients with cGVHD.
• Assessing the pharmacodynamic profile of axatilimab.
• Determining or assessing changes in monocyte levels with response.
• Determining or assessing the baseline monocyte levels with response.

The clinical trial involves a total of **173 participants** diagnosed with **chronic graft versus host disease (cGVHD)**. The study population includes both male and female subjects, aged 18 years and older, who are recipients of allogeneic hematopoietic stem cell transplantation (HSCT) and require systemic immune suppression due to active cGVHD. Participants have experienced refractory or recurrent active cGVHD despite at least two prior lines of systemic therapy. The trial population was selected based on specific inclusion criteria, including adequate organ and bone marrow function, and a Karnofsky Performance Scale of 60 or higher for adults. Lifestyle considerations such as the use of systemic corticosteroids and calcineurin or mTOR inhibitors are allowed but not mandatory. The study also includes vulnerable populations, ensuring comprehensive representation of the affected demographic. Participants must have a creatinine clearance of 30 milliliters per minute or higher, and contraceptive use must align with local regulations. The selection process ensures that participants are capable of providing informed consent, with provisions for pediatric assent where applicable.

The clinical trial is designed to evaluate the **efficacy**, safety, and tolerability of **axatilimab** in patients with recurrent or refractory active chronic graft versus host disease (cGVHD) who have received at least two lines of systemic therapy. This is a Phase 2, open-label, randomized, multicenter study. Participants will be randomly assigned to receive axatilimab at one of three different doses: 0.3 mg/kg intravenously every two weeks, 1 mg/kg intravenously every two weeks, or 3 mg/kg intravenously every four weeks. The trial aims to assess the overall response rate (ORR) within the first six cycles, as defined by the 2014 National Institutes of Health (NIH) Consensus Development Project on Criteria for Clinical Trials in cGVHD.

The trial will span an estimated duration from July 19, 2021, to December 31, 2025. Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and organ function. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety, including assessments of vital signs, laboratory parameters, and performance scales. The end-of-study visit will conclude the participant's involvement, with a comprehensive evaluation of treatment outcomes and any adverse events.

Participant involvement is expected to last up to 24 months, depending on individual response and tolerance to the treatment. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. The study will allow the concomitant use of certain medications, such as calcineurin inhibitors and systemic corticosteroids, provided they meet specific stability criteria prior to the start of the trial. The trial's primary endpoint is the ORR, while secondary endpoints include measures such as duration of response, safety assessments, and pharmacokinetic parameters.

The clinical trial involves the administration of **Axatilimab**, an investigational medication, to evaluate its efficacy, safety, and tolerability in patients with recurrent or refractory active chronic graft versus host disease (cGVHD) who have received at least two lines of systemic therapy. **Axatilimab** is provided as a **solution for infusion** and is administered via the **intravenous route**. The trial explores three different dosing regimens: 0.3 mg/kg every two weeks (Q2W), 1 mg/kg every two weeks (Q2W), and 3 mg/kg every four weeks (Q4W). The maximum daily dose is 3 mg/kg, with a total maximum dose of 72 mg/kg over a treatment period of up to 24 weeks. The active substance in **Axatilimab** is a protein-based compound, specifically an anti-CSF1R monoclonal antibody, which is a human-rattus norvegicus monoclonal antibody targeting the human colony-stimulating factor 1 receptor.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on the administration of **Axatilimab** to assess its therapeutic potential in the specified patient population. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol and to accurately evaluate the outcomes associated with each dosing regimen.

The efficacy of **axatilimab** in the clinical trial will be assessed primarily through the overall response rate (ORR) in patients with recurrent or refractory active chronic graft versus host disease (cGVHD) who have received at least two lines of systemic therapy. The ORR will be evaluated during the first six cycles of treatment, as defined by the 2014 National Institutes of Health (NIH) Consensus Development Project on Criteria for Clinical Trials in cGVHD. Secondary endpoints include the modified Lee Symptom Scale (mLSS), duration of response (DOR), sustained response rate (SRR), organ-specific and joints and fascia response rate, average daily corticosteroid dose, discontinuation of corticosteroids, average daily calcineurin inhibitor (CNI) dose, and discontinuation of CNI. Additional assessments will include adverse events (AEs) and serious adverse events (SAEs), vital signs, safety laboratory parameters, physical and neurological examinations, electrocardiograms (ECG), and Karnofsky/Lansky performance scales.

Pharmacokinetic (PK) parameters and patient factors will also be analyzed, alongside biomarker evaluations such as CSF-1 and IL-34 levels, and circulating monocyte number and phenotype. These efficacy parameters will be measured and collected at specified timepoints throughout the trial, using validated scales and laboratory tests. The trial is designed to provide comprehensive data on the efficacy of axatilimab in this patient population, with the aim of improving treatment outcomes for individuals with cGVHD.