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)

Phase 1

Conditions: Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis with Severe Thrombocytopenia
MedDRA version: 20.0Level: SOCClassification code 10029104Term: Neoplasms benign, malignant and unspecified (incl cysts and polyps)System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2021-000369-34-PL

Lead Sponsor: S Pharma, Inc.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 120

Inclusion Criteria

1. Able to provide written informed consent prior to enrollment into the study.
2. Males and females =18 years of age.
3. Primary MF, post-PVMF or post-ETMF according to the DIPSS risk categories of intermediate-2 or high-risk MF.
4. Spleen volume of at least 450 cm3 measured by MRI (or by CT for applicable subjects). This baseline scan will be centrally reviewed for spleen volume.
5. Total symptom score (TSS) =10 on MFSAF v4.0. The TSS from the first 7 consecutive days of entry through the screening period will be used for eligibility.
6. Platelet count < 50,000/µL. Two results taken at least 7 days apart during screening are needed. Each result must be <50,000/µL
7. No MF-directed treatment (other than ruxolitnib) for at least 2 weeks prior to initiation of NS- 018, including 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. Subjects treated with a ruxolitnib will be required to taper off the ruxolitnib before initiation of NS-018 at Cycle 1 Day 1. The dose of ruxolitnib should be decreased every 7 days by up to 50% until the smallest dose possible has been given for a minimum duration for the total tapering period of 14 days. Ruxolitnib should then be stopped 1 day before starting NS-018. Subjects who are taking 5 mg QD of a ruxolitnib are already on the lowest dose possible; therefore, tapering is not applicable in this case. If recurrence of MF-related symptoms (upon discontinuation of a ruxolitnib therapy) is noted, it is strongly suggested that therapy with a ruxolitnib be restarted. If restart is not possible, then prompt therapy with corticosteroids (eg, prednisone 60 mg QD) is recommended.

Subjects who are not benefitting from ruxolitinib treatment may be enrolled in the study per the Investigator’s discretion.
8. ECOG performance status =2.
9. QTcF =480 msec.
10. Peripheral blood blast count <10%.
11. Estimated creatinine clearance (CrCl) =40 mL/min/1.73 m2 calculated using the Cockcroft and Gault equation.
12. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =3 × upper limit of normal (ULN) and a direct bilirubin =1.5 × ULN.
13. Absolute neutrophil count >500/µL.
14. Negative serum pregnancy test within 7 days prior to the first dose of study drug (if subject is a female of childbearing potential).
15. No treatment with any investigational agent within 28 days or five times the half-life of the drug prior to initiation of NS-018., whichever is longer (not shorter). COVID-19 vaccines that are commercially available or approved by local regulatory authorities and are administered outside of an investigational clinical study are not considered as investigational agents.
16. Male or non-pregnant, non-lactating female subjects. Male and female subjects who are fertile and their partners must agree to use 2 highly effective methods of contraception from screening through 180 days (for male subjects with partners who are women of childbearing potential [WOCBP], pregnant or breast feeding) and 180 days (for females) following discontinuation of study treatment.

For Germany and UK Only:
Male or non-pregnant, non-lactating female subjects. Male and female subjects who are fertile and their partners must agree to use 2 highly effective methods of contraception from screening through 180 days for male subjects with partners who are WOCBP), pregnant or br

Exclusion Criteria

1. Active, uncontrolled systemic infection. including active tuberculosis. Inactive (latent) tuberculosis infection testing will be done for UK and South Korea only.
2. Any prior treatment with more than 2 JAK inhibitors. Subjects with any contraindication to BAT (see the product label) are excluded.
3. Subjects receiving any clinical benefits from JAK inhibitor per the Investigator's discretion.
4. Previous treatment with NS-018. Subjects with hypersensitivity to NS-018, any excipient of NS-018 tablets and to any JAK2 inhibitor will be excluded from study participation.
5. Subjects actively receiving a concurrent investigational agent.
6. Subjects with any unresolved AE greater than Grade 1 other than hematological AEs from previous anticancer therapy.
7. Potentially curative therapy is available:
- Candidates for hematopoietic stem cell transplant in which transplant is an available and viable option and of higher priority than this study are excluded.
- If the subject has declined hematopoietic stem cell transplant, has no donor for transplant, or in the judgment of the Investigator is not suitable for transplant, the subject may be enrolled.
8. Currently taking medication that is substantially metabolized by cytochrome P450 (CYP) 1A2 or CYP3A4 or taking medication known to be strong inhibitors or inducers of CYP3A4 .
9. Pregnancy or lactation.
10. Radiation therapy for splenomegaly within 6 months prior to study entry (Screening).
11. History of splenectomy or planning to undergo splenectomy.
12. Known human immunodeficiency virus [HIV] positive status.
13. Known active hepatitis, or a history of viral hepatitis B or hepatitis C.
14. Subjects with a serious cardiac condition within the past 6 months such as uncontrolled arrhythmias, myocardial infarction, angina, or heart disease as defined by the New York Heart Association Class III or IV.
15. Subjects diagnosed with another malignancy within 2 years prior to an enrollment. Subjects with prior malignancies must have completed all treatments with no recurrence within 2 years to an enrollment. Subjects with early stage squamous cell carcinoma of the skin, basal cell carcinoma of the skin, or cervical intraepithelial neoplasia may be eligible for participation at the Investigator’s discretion.
16. 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.
17. Other concurrent disease and/or medical condition including cardiac condition, which, in the judgment of the Investigator, would prevent the subject’s participation.
18. Unwilling or unable to comply with the protocol.
19. Subjects with suspected (case definition A or B), probable, or confirmed diagnosis of COVID-19 based on the World Health Organization diagnostic criteria (Table 2).

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: • To compare the efficacy of the dose of 300 mg BID of NS-018 to the Best Available Therapy (BAT), in subjects with PMF, post-PVMF, or post-ETMF with severe thrombocytopenia<br>• To compare the effect on MF-associated symptoms as measured by Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0) to the BAT;Secondary Objective: • To compare the best splenic response of 300 mg BID of NS-018 to the BAT <br>• To compare the safety of 300 mg BID of NS-018 to the BAT;Primary end point(s): • Proportion of subjects who achieve =35% reduction in spleen volume from baseline to Week 24 as measured by MRI (or by CT for applicable subjects)<br>• Proportion of subjects who achieve =50% reduction in total symptom score from baseline to Week 24 as measured by the MFSAF v4.0;Timepoint(s) of evaluation of this end point: Week 24

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): • Proportion of subjects who achieve =35% reduction in spleen volume from baseline at any time up to Week 24 as measured by MRI (or by CT for applicable subjects)<br>• Comparison of the safety of NS-018 versus BAT;Timepoint(s) of evaluation of this end point: Week 24

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