Phase 3 Randomized Study of Navtemadlin and Ruxolitinib Versus Placebo and Ruxolitinib in Myelofibrosis Patients with Suboptimal Ruxolitinib Response

The primary objectives of this Phase 3, randomized, double-blind study are to evaluate the efficacy of **navtemadlin** plus **ruxolitinib** compared to placebo plus ruxolitinib in patients with **myelofibrosis** who have a suboptimal response to ruxolitinib. Specifically, the study aims to compare the reduction in spleen volume (SVR35) and the reduction in total symptom score (TSS50) between the two treatment arms. These objectives are clinically relevant as they address key symptoms and quality of life indicators in myelofibrosis, a condition characterized by bone marrow fibrosis, splenomegaly, and debilitating symptoms.

Secondary objectives include:

• Comparing spleen volume reduction between Arm 1 and Arm 2.
• Comparing total symptom score reduction between Arm 1 and Arm 2.
• Comparing overall survival (OS) between Arm 1 and Arm 2.
• Comparing time to progression between Arm 1 and Arm 2.
• Comparing the safety and tolerability of navtemadlin versus placebo as add-on therapy to ruxolitinib.

The clinical trial involves a total of **67 participants** diagnosed with **Primary Myelofibrosis** or **Secondary Myelofibrosis**, including conditions such as myelofibrosis post-Polycythemia Vera or post-Essential Thrombocythemia. The study population comprises adults aged 18 years and older, encompassing both male and female subjects. Participants were selected based on their ability to provide informed consent and a confirmed diagnosis of the specified conditions, as assessed by the treating physician according to the World Health Organization criteria. The trial includes individuals with a high, Intermediate-1, or Intermediate-2 risk category according to the International Prognosis System Score and an Eastern Cooperative Oncology Group performance status of 0 to 2. Participants are JAK-inhibitor treatment naive and have a suboptimal response to run-in ruxolitinib therapy. The trial population includes a vulnerable population, and lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is a **Phase 3**, randomized, double-blind, controlled study designed to evaluate the safety and efficacy of **Navtemadlin** plus **Ruxolitinib** compared to placebo plus Ruxolitinib in patients with **myelofibrosis** who have a suboptimal response to Ruxolitinib. The trial is expected to commence recruitment on September 20, 2024, and conclude by May 31, 2029. Participants will be randomly assigned to one of two arms: Arm 1 receiving Navtemadlin plus Ruxolitinib, and Arm 2 receiving placebo plus Ruxolitinib. The primary endpoints include the proportion of subjects achieving a 35% reduction in spleen volume (SVR35) and a 50% reduction in total symptom score (TSS50) as assessed by MRI/CT scan and the Myelofibrosis Symptom Assessment Form (MFSAF) v4.0, respectively.

The trial will involve several study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of primary or secondary myelofibrosis, and performance status. Following the screening, participants will enter a Ruxolitinib run-in period to establish a stable dose. Randomization will occur after confirming a suboptimal response to Ruxolitinib. Follow-up visits will be scheduled to monitor safety and efficacy, including physical examinations, laboratory tests, and imaging studies. The end-of-study visit will assess the final outcomes and any adverse events. The expected duration of participant involvement is up to 50 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 protocol non-compliance.

The clinical trial involves several treatments, including both experimental and non-experimental medications. **Navtemadlin** is an experimental medication used in this study. It is administered in the form of a **tablet** and is taken orally. The maximum daily dose is 240 mg, with a total maximum dose of 75,600 mg over a treatment period of 45 days. Navtemadlin acts as an **MDM2 inhibitor** and is provided by Kartos Therapeutics Inc. The product is identified by the sponsor product code KRT-232 and is available in various dosages, including 25-30 mg, 25-60 mg, and 25-120 mg tablets.

**Ruxolitinib** is another experimental medication used in the trial. It is also administered orally in the form of a **tablet**. The maximum daily dose is 50 mg, with a total maximum dose of 70,000 mg over a treatment period of 50 days. Ruxolitinib is classified as an **antineoplastic agent** and is used as a comparator treatment in the study.

**Loperamide Hydrochloride** is included as a non-experimental treatment. It is administered orally in the form of a **tablet** with a dosage of 2 mg per tablet. The maximum daily dose is 16 mg, with a total maximum dose of 56 mg over a treatment period of 24 days. The product is manufactured by Zakłady Farmaceutyczne Polpharma S.A. and is used to manage symptoms related to the study.

**Ondansetron** is another non-experimental treatment used in the study. It is administered orally in the form of a **film-coated tablet**. The maximum daily dose is 16 mg, with a total maximum dose of 2,688 mg over a treatment period of 24 days. Ondansetron functions as a **5-HT3 antagonist** and is used to prevent nausea and vomiting associated with the trial treatments.

Placebos are used to match the experimental medications, including **placebos for navtemadlin** in various dosages (30 mg, 60 mg, 120 mg, and 180 mg) and **placebos for loperamide**. These placebos are administered in the same form and route as their corresponding active medications to maintain the double-blind nature of the study.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment regimen. The study aims to evaluate the safety and efficacy of the experimental treatments in patients with **myelofibrosis** who have a suboptimal response to Ruxolitinib.

The efficacy of the clinical trial will be assessed through co-primary endpoints, which include the comparison of **spleen volume reduction** (SVR35) and total symptom score reduction (TSS50) between the two study arms. The proportion of subjects achieving SVR35 will be evaluated using MRI/CT scans with central review, while TSS50 will be measured using the Myelofibrosis Symptom Assessment Form (MFSAF) v4.0. These assessments will provide a quantitative measure of the treatment's impact on patients with **myelofibrosis** who have a suboptimal response to ruxolitinib.

Secondary endpoints will further evaluate the efficacy by comparing the proportion of subjects with spleen volume and symptom score reductions between the study arms. Additionally, time to death from any cause and time to progression or death from any cause will be analyzed for subjects in each arm. These endpoints will be crucial in understanding the long-term benefits and potential survival advantages of the treatment regimen. The trial is designed to ensure rigorous and objective assessment of efficacy through validated tools and standardized procedures.