Phase 3 Randomized Controlled Trial of Pacritinib Versus Physician's Choice in Myelofibrosis Patients with Severe Thrombocytopenia

The primary objective of this study is to evaluate the **efficacy** of pacritinib compared to physician's choice (P/C) therapy in patients with primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis with severe thrombocytopenia. This is assessed by the proportion of patients achieving a ≥35% spleen volume reduction (SVR) from baseline at Week 24, as measured by magnetic resonance imaging (MRI) or computed tomography (CT) scans. Additionally, the study aims to compare the efficacy of pacritinib with P/C therapy by assessing the proportion of patients achieving a ≥50% reduction in Total Symptom Score (TSS) from baseline at Week 24. These objectives are clinically relevant as they address the management of spleen size and symptom burden, which are critical factors in the quality of life and disease progression in myelofibrosis patients.

Secondary objectives include:

• Comparing the percentage of patients who self-assess as "very much improved" or "much improved" as measured by the Patient Global Impression of Change (PGIC) in patients treated with pacritinib versus those treated with P/C.
• Comparing the overall survival (OS) of patients treated with pacritinib versus those treated with P/C.
• Comparing the safety of pacritinib versus P/C therapy.

The clinical trial involves a total of **196 participants** diagnosed with **Primary Myelofibrosis**, **Post-Polycythaemia Vera Myelofibrosis**, or **Post-Essential Thrombocythaemia Myelofibrosis**. The study population includes both male and female subjects, aged 18 years and older, with an Eastern Cooperative Oncology Group performance status ranging from 0 to 2, indicating they are ambulatory and capable of self-care. Participants were selected based on specific health criteria, including adequate liver and renal function, a left ventricular cardiac ejection fraction of at least 50%, and a platelet count of less than 50,000/μL at screening. Lifestyle considerations such as the ability to undergo frequent MRI or CT scans and the willingness to use highly effective birth control methods if fertile were also taken into account. The trial does not include a vulnerable population, ensuring that all participants are capable of providing informed consent and completing symptom assessments using a patient-reported outcome instrument.

The clinical trial is designed as a **randomized, controlled, Phase 3 study** to evaluate the efficacy of **pacritinib** compared to physician's choice therapy in patients with **primary myelofibrosis**, **post-polycythemia vera myelofibrosis**, or **post-essential thrombocythemia myelofibrosis** with severe thrombocytopenia. The trial aims to assess the proportion of patients achieving a ≥35% spleen volume reduction and a ≥50% reduction in Total Symptom Score from baseline at Week 24. The study is expected to conclude by June 30, 2027, with recruitment having started on August 10, 2019.

Participants will undergo a series of study visits, beginning with a screening visit conducted between Day -35 and Day -3 to confirm eligibility based on inclusion criteria such as platelet count and spleen size. Following randomization, participants will attend regular follow-up visits to monitor treatment efficacy and safety, including assessments via MRI or CT scans. The end-of-study visit will occur 30 days after the completion of treatment, during which final evaluations will be conducted.

The expected duration of participant involvement is approximately 30 days of treatment, with additional time for follow-up assessments. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or failure to adhere to study protocols. The trial is conducted under strict regulatory guidelines to ensure the safety and well-being of all participants.

The clinical trial involves the administration of several **experimental medications** and comparator treatments. **Pacritinib** is the primary experimental medication, administered in the form of a hard capsule. It is a potent and selective inhibitor of JAK2 and FLT3 kinases. The maximum daily dose is 400 mg, with a total treatment period of 30 days. The route of administration is oral. Pacritinib is provided by Swedish Orphan Biovitrum AB and is not a pediatric formulation.

**Ruxolitinib** is used as a comparator treatment in the trial. It is administered as a tablet with a maximum daily dose of 50 mg. The treatment period is also 30 days, and the route of administration is oral. Ruxolitinib is classified as an antineoplastic agent and protein kinase inhibitor.

**Danazol** is another comparator treatment, provided in the form of a hard capsule. It is an anabolic steroid with androgenic activity. The maximum daily dose is 800 mg, and the treatment period is 30 days. The administration route is oral.

**Hydroxycarbamide** is administered as a hard capsule, with a maximum daily dose of 80 mg/kg. It is classified as an antineoplastic agent. The treatment period is 30 days, and the route of administration is oral.

**Methylprednisolone** is used in two forms, both as a tablet. It is a glucocorticosteroid with a maximum daily dose of 360 mg. The treatment period is 30 days, and the administration route is oral.

**Prednisolone** is another glucocorticosteroid used in the trial, administered as a tablet. The maximum daily dose is 60 mg, with a treatment period of 30 days. The route of administration is oral.

**Dexamethasone** is administered in a form identified as PHF00169MIG, with a maximum daily dose of 10 mg. It is classified as a corticosteroid for systemic use, specifically a glucocorticoid. The treatment period is 30 days, and the route of administration is oral.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to compare the efficacy of pacritinib with that of physician's choice therapy, focusing on spleen volume reduction and symptom score reduction in patients with myelofibrosis and severe thrombocytopenia.

The efficacy of the clinical trial will be assessed by evaluating the primary endpoints, which include the percentage of patients achieving at least a 35% reduction in spleen volume from baseline at Week 24, as measured by magnetic resonance imaging (MRI) or computed tomography (CT) scans. Additionally, the trial will assess the percentage of patients achieving at least a 50% reduction in Total Symptom Score (TSS) from baseline at Week 24, using the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF TSS 2.0), excluding the "tiredness" component.

Secondary endpoints will include the percentage of patients who self-assess as "very much improved" or "much improved" at Week 24, the time from randomization to the date of death due to any cause, and the incidence and severity of treatment-emergent adverse events (TEAEs), including serious adverse events (SAEs) and deaths. Laboratory values and vital signs, including cardiac evaluations, will also be monitored from the time of randomization until 30 days after the completion of treatment with **pacritinib** and/or physician's choice therapy.