Study to Assess Efficacy and Safety of NS-018 Compared to BAT in Patients With Myelofibrosis

Study Overview
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Brief Summary
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This study will enroll male and female subjects who are 18 years of age or older with Primary Myelofibrosis, post-polycythemia Vera Myelofibrosis, or post-essential Thrombocythemia Myelofibrosis with severe thrombocytopenia (platelet count <50,000/µL) including subjects with intermediate-2 or high-risk MF according to the Dynamic International Prognostic Scoring System (DIPSS).

Detailed Description
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NS-018 will be self-administered orally at a dose of 300 mg BID. The BAT will be administered according to manufacturer's instructions and Investigator discretion. Subjects will complete study visits at Screening, Day 1 and Day 15 of Cycle 1, 2, 3, 4, 5, 6 and Day 1 of every cycle thereafter. At these visits, blood/urine sampling, spleen measurements, bone marrow assessments, patient-reported outcome (PRO) assessments, and safety assessments may be performed.

Official Title
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A Phase 2b, Open-label, Multicenter, Randomized, Controlled, 2-Arm Study to Assess the Efficacy and Safety of Orally Administered NS-018 Versus Best Available Therapy in Subjects With Primary Myelofibrosis, Post Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis With Severe Thrombocytopenia (Platelet Count <50,000/μL)

Conditions
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Primary Myelofibrosis, Post-essential Thrombocythemia Myelofibrosis, Post-polycythemia Vera Myelofibrosis

Intervention / Treatment
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* Drug: NS-018
* Drug: Best Available Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Primary MF, post-PVMF or post-ETMF according to the DIPSS risk categories of intermediate-2 or high-risk MF Average platelet count of <50,000/µL at Screening based on 2 measurements taken on different days; both measurements must be <50,000/µL. ECOG performance status ≤2. Life expectancy >6 months. Spleen volume of at least 450 cm3 measured by MRI (or by CT for applicable subjects). Total Symptom Score (TSS) ≥10 on the Myelofibrosis Symptom Assessment Form (MFSAF) version 4.0. Peripheral blast count <10%. No MF-directed treatment for at least 2 weeks prior to initiation of NS-018, including JAK inhibitor, erythropoietic, thrombopoietic agent, or any use of corticosteroids for MF symptom or blood count management. Low dose corticosteroids <10 mg/day prednisone or equivalent is allowed for non-MF purposes. Exclusion Criteria: Active, uncontrolled systemic infection. Any prior treatment with more than two JAK inhibitors. Previous treatment with NS-018. Subjects actively receiving a concurrent investigational agent. Subjects with any unresolved AE greater than Grade 1 other than hematological AEs from previous anticancer therapy. Currently taking medication that is substantially metabolized by cytochrome P450 (CYP) 1A2 or CYP3A4 (see Appendix 5) or taking medication known to be strong inhibitors or inducers of CYP3A4 (see Appendix 5). Radiation therapy for splenomegaly within 6 months prior to study entry (screening). History of splenectomy or planning to undergo splenectomy. Subjects with a serious cardiac condition within the past 6 months such as uncontrolled arrhythmias, myocardial infarction, angina or heart disease Subjects diagnosed with another malignancy within 2 years prior to an enrollment. Subjects who have had surgery (other than placement of vascular access and bone marrow biopsy) within 4 weeks of study entry (screening), or subjects with incomplete recovery from any prior surgical procedures.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NS-018<br>Self-administered NS-018 300 mg orally, twice daily, preferably at the same time each day in consecutive 4-week (28-day) cycles | Drug: NS-018<br>* Experimental<br>|
| Active Comparator: Best Available Therapy (BAT)<br>Single agent per Investigator discretion or no therapy | Drug: Best Available Therapy<br>* Active Comparator<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in spleen volume | Proportion of subjects who achieve ≥35% change in spleen volume from baseline to Week 24 as measured by MRI (or by CT for applicable subjects) | from baseline to week 24 | 
| Change in Total Symptom Score (TSS) | Proportion of subjects who achieve ≥50% change in total symptom score from baseline to Week 24 as measured by the MFSAF v4.0 | from baseline to week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in spleen volume | Proportion of subjects in NS-018 vs BAT arm who achieve ≥35% change in spleen volume from baseline at any time up to Week 24 as measured by MRI (or by CT for applicable subjects) | from baseline at anytime up to week 24 | 
| Comparison of treatment-emergent AEs | Laboratory events graded by the NCI CTCAE v5.0 will be assessed in both arms, NS-018 vs BAT. | from baseline to week 24 |