Evaluation of TL-895 in Myelofibrosis, Indolent Systemic Mastocytosis, and Mast Cell Activation Syndrome: A Phase 2 Multicenter Study

The primary objective of this Phase 2 multicenter study is to determine the recommended phase 2 and phase 3 doses of **TL-895** in subjects with Myelofibrosis, Indolent Systemic Mastocytosis, Monoclonal Mast Cell Activation Syndrome, or Non-Monoclonal Mast Cell Activation Syndrome. This is crucial for establishing the optimal dosing regimen that maximizes therapeutic efficacy while minimizing adverse effects, thereby enhancing patient outcomes in these conditions.

Secondary objectives include:

• Part A Cohorts 1-4: To determine the Spleen Volume Reduction (SVR) rate and improvement in Total Symptom Score (TSS) at Week 24, and to characterize the pharmacokinetic (PK) profile of TL-895.
• Part A Cohort 5: To assess changes in ISM symptoms, compare time to reduction in TSS, compare reduction in BSC medications, determine the effects on quality of life, and characterize the PK profile of TL-895.
• Part A Cohort 6: To assess changes in MCAS symptoms, compare reduction in BSC medications, determine the effects on quality of life, and characterize the PK profile of TL-895.
• Part B Cohorts 1-4: To determine the platelet response rate, duration of platelet response, incidence of platelet transfusion, incidence of bleeding events, and SVR rate at Week 24.
• Part B Cohort 5: To assess changes in ISM symptoms, compare time to reduction in total symptom score, compare reduction in BSC medications, determine the effects on quality of life, and characterize the PK profile of TL-895.
• Part B Cohort 6: To assess changes in MCAS symptoms, compare time to reduction in TSS, compare reduction in BSC medications, determine the effects on quality of life, and characterize the PK profile of TL-895.

The clinical trial involves a total of **101 participants** diagnosed with **Mast Cell Activation Syndrome**, **Indolent Systemic Mastocytosis**, or **Myelofibrosis**. The study population includes both male and female adults aged 18 years and older. Participants were selected based on specific inclusion criteria, such as having a confirmed diagnosis of the relevant conditions according to the World Health Organization criteria and possessing an Eastern Cooperative Oncology Group performance status of 2 or less. The trial also considers individuals with adequate hematologic, hepatic, and renal functions. The population includes vulnerable groups, and participants are required to have moderate-to-severe symptoms for certain cohorts. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized**, **double-blind**, and **controlled** study to evaluate the efficacy and safety of TL-895, a **film-coated tablet** administered orally, in subjects with **myelofibrosis**, **indolent systemic mastocytosis**, and **mast cell activation syndrome**. The trial is structured into two parts, Part A and Part B, with specific objectives for each cohort. Part A aims to determine the recommended phase 2 and phase 3 doses of TL-895, while Part B focuses on assessing symptom improvement at Week 24 for each condition. The trial is expected to conclude by December 31, 2029, with recruitment having commenced on October 30, 2020.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and **Eastern Cooperative Oncology Group (ECOG) performance status**. Follow-up visits will be scheduled to monitor the participants' response to the treatment and to assess any changes in symptoms. The end-of-study visit will evaluate the overall outcomes and safety of the treatment. The expected length of participant involvement is up to 60 days, with a maximum daily dose of 300 mg/kg and a total dose not exceeding 547,500 mg/kg. Conditions that may lead to early termination from the study include adverse reactions, non-compliance with the study protocol, or withdrawal of consent by the participant.

The clinical trial involves the administration of the experimental medication **TL-895**, which is provided in the form of a **film-coated tablet**. The active substance in TL-895 is chemically derived and identified as 1-4-{[6-amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino]-methyl}-4-fluoro-piperidin-1-yl)-propenone. The medication is administered orally, with a maximum daily dose of 300 mg/kg and a total maximum dose of 547,500 mg/kg over a treatment period of up to 60 days. The pharmaceutical form and administration route are consistent across all cohorts in the study, ensuring uniformity in treatment delivery.

In addition to the experimental medication, a **placebo** matching TL-895 is utilized in the study. The placebo is designed to mimic the appearance of the TL-895 film-coated tablet but does not contain the active substance. The use of a placebo allows for the assessment of the experimental drug's efficacy and safety by providing a control for comparison. The placebo is administered under the same conditions as TL-895, ensuring that any observed effects can be attributed to the active medication rather than external factors.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen. This monitoring is crucial for maintaining the integrity of the study data and for accurately assessing the therapeutic potential of TL-895. The trial aims to determine the recommended phase 2 and phase 3 doses of TL-895 for various cohorts, focusing on conditions such as myelofibrosis, indolent systemic mastocytosis, monoclonal mast cell activation syndrome, and non-monoclonal mast cell activation syndrome.

The efficacy of the investigational product **TL-895** will be assessed in a Phase 2 multicenter study involving subjects with Myelofibrosis, Indolent Systemic Mastocytosis, Monoclonal Mast Cell Activation Syndrome, or Non-Monoclonal Mast Cell Activation Syndrome. The primary endpoints for efficacy evaluation include determining the recommended phase 2 and phase 3 doses, as well as assessing improvement in total symptom score at Week 24. Additionally, changes in symptoms specific to Indolent Systemic Mastocytosis (ISM) and Mast Cell Activation Syndrome (MCAS) will be evaluated.

For Part B of the study, the improvement in total symptom score will be measured at Week 24. The assessment of changes in ISM and MCAS symptoms will be conducted after treatment with **TL-895**. The efficacy parameters will be collected and analyzed using validated scales and patient-reported outcomes. The schedule for measuring these parameters includes specific timepoints, such as Week 24, to ensure consistent and reliable data collection throughout the trial duration.