Evaluation of Navtemadlin Versus Best Available Therapy in Myelofibrosis Patients Refractory to JAK Inhibitors

The primary objective of this study is to evaluate the **spleen response** in subjects with primary or secondary myelofibrosis (MF) who are relapsed or refractory to Janus Kinase (JAK) inhibitor treatment. This is clinically relevant as spleen enlargement is a common and debilitating symptom in MF, and its reduction can significantly improve patient quality of life. Additionally, the study aims to compare the spleen volume reduction (SVR) at Week 24 between two treatment arms, which is crucial for assessing the efficacy of the investigational treatment compared to the best available therapy.

Secondary objectives include: - Determining the change in modified MPN-SAF Total Symptom Score (TSS) at Weeks 24 and 48. - Assessing the duration of spleen response and spleen size reduction as measured by palpation. - Evaluating red blood cell (RBC) transfusion usage. - Determining the clinical response rate at Week 24 and overall survival (OS) rate. - Assessing the safety and tolerability of KRT-232 and its pharmacokinetic/pharmacodynamic (PK/PD) profile. - Comparing the improvement of TSS at Week 24 between the two arms. - Comparing OS and progression-free survival (PFS) between the two arms. - Comparing the overall SVR at any time in each study arm and evaluating the spleen response duration between the arms. - Comparing the rate of conversion from RBC transfusion dependence to independence at Week 24 between the arms. - Evaluating the safety between the two arms. - Monitoring the PK of KRT-232 in Arm 1 only.

The clinical trial involves a total of **194 participants** diagnosed with **Primary or Secondary Myelofibrosis (MF)**, specifically those with intermediate or high-risk TP53 wild-type who are relapsed or refractory to Janus Kinase (JAK) inhibitor treatment. The study population includes both male and female adults aged 18 years and older. Participants were selected based on their confirmed diagnosis of PMF, post-PV MF, or post-ET MF, and their risk level as determined by the Dynamic International Prognostic System (DIPSS). The trial includes individuals who have experienced failure of prior treatment with a JAK inhibitor and have an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. The study population is characterized by a vulnerable group, indicating careful consideration of their health status and treatment history. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized**, controlled, open-label study to evaluate the efficacy of KRT 232 in subjects with **myelofibrosis** who are relapsed or refractory to Janus Kinase (JAK) inhibitor treatment. The trial is divided into two parts, Part A and Part B, with specific objectives for each. Part A aims to determine the spleen response, while Part B focuses on comparing spleen volume reduction at Week 24 between two arms. The trial is expected to conclude by August 31, 2025, with recruitment having started on December 11, 2018.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, prior treatment failure with JAK inhibitors, and risk assessment using the Dynamic International Prognostic System (DIPSS). Follow-up visits will be scheduled to monitor the primary endpoint, which is the proportion of subjects achieving a ≥35% spleen volume reduction from baseline to Week 24, assessed by MRI or CT scan. Secondary endpoints include symptom score reduction, duration of spleen volume reduction, and red blood cell transfusion independence at Week 24. The end-of-study visit will assess the overall outcomes and any adverse events experienced by participants.

The expected length of participant involvement is up to 72 weeks, depending on the treatment arm and response. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with study procedures. The trial involves multiple investigational products, including **navtemadlin**, administered orally, with a maximum daily dose of 360 mg for certain formulations. The study is conducted under strict regulatory guidelines to ensure the safety and well-being of all participants.

The clinical trial involves the administration of several treatments, including both experimental and comparator medications. The experimental medication, **Navtemadlin**, is provided in various dosages and forms, including Navtemadlin 10-15, Navtemadlin 10-60, Navtemadlin 25-15, Navtemadlin 25-30, Navtemadlin 25-60, and Navtemadlin 25-120. These are formulated as tablets and are administered orally. The maximum daily dose for Navtemadlin 10-15 and Navtemadlin 10-60 is 360 mg, while for the other formulations, it is 240 mg. The maximum treatment period for Navtemadlin 10-15 and Navtemadlin 10-60 is 72 weeks, whereas for the other formulations, it is 54 weeks. Participant compliance is monitored throughout the trial to ensure adherence to the dosing schedule.

**Peginterferon alfa-2a** is used as a comparator treatment in the form of Pegasys 180 micrograms solution for injection in a pre-filled syringe. This medication is administered subcutaneously. The dosing schedule and frequency are determined based on the trial protocol, and participant compliance is closely monitored to ensure accurate administration.

Another comparator treatment, **Hydroxycarbamide**, is provided as HYDREA 500 mg capsules. This medication is administered orally, and the dosing schedule is aligned with the trial protocol. Compliance monitoring is implemented to ensure participants adhere to the prescribed regimen.

**Lenalidomide** is also used as a comparator, available as Lenalidomide Accord 5 mg hard capsules. This medication is administered orally, with dosing schedules tailored to the trial's requirements. Participant adherence is monitored to maintain consistency in treatment administration.

**Prednisone** is included in the trial as Prednison 10 mg GALEN® tablets. This medication is administered orally, and the dosing schedule is specified in the trial protocol. Compliance monitoring is conducted to ensure participants follow the prescribed regimen.

**Danazol** is used in two forms: Danatrol 50 mg capsule rigide and DANAZOL POLFARMEX, 200 mg tablets. Both forms are administered orally, with dosing schedules defined by the trial protocol. Participant compliance is monitored to ensure adherence to the treatment plan.

All medications in the trial are of chemical origin, except for Peginterferon alfa-2a, which is a protein-based treatment. The trial protocol includes detailed instructions for dosing schedules and participant compliance monitoring to ensure the integrity of the study results.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include the proportion of subjects achieving a ≥35% spleen volume reduction from baseline to Week 24, as assessed by magnetic resonance imaging (MRI) or computed tomography (CT) scan. This will be evaluated for both Part A and Part B of the study, with a central review for Part B. Secondary endpoints will include the proportion of subjects with a reduction in total symptom score, the duration of spleen volume reduction, the need for red blood cell (RBC) transfusion, and the proportion of subjects achieving RBC transfusion independence at Week 24. Additionally, the study will assess complete and partial remission, time to death from any cause, and the pharmacokinetic/pharmacodynamic (PK/PD) profile of KRT-232.

For Part B, secondary endpoints will also include progression-free survival (PFS), time from initial spleen volume reduction until the first occurrence of disease progression, and the proportion of subjects achieving spleen volume reduction. The efficacy parameters will be measured and collected at specified timepoints, such as baseline and Week 24, using validated imaging techniques like MRI and CT scans. The analysis will be conducted centrally to ensure consistency and accuracy in the evaluation of the endpoints. The trial aims to provide comprehensive data on the efficacy of the treatment in subjects with primary myelofibrosis (PMF), post-polycythemia vera MF (Post-PV-MF), or post-essential thrombocythemia MF (Post-ET-MF) who are relapsed or refractory to Janus Kinase (JAK) inhibitor treatment.