Safety and Tolerability Study of Oral NS-018 in Patients With Primary Myelofibrosis (MF), Post-polycythemia Vera MF or Post-essential Thrombocythemia MF

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety and tolerability of orally administered NS-018 in patients with Primary Myelofibrosis (PMF), Post-polycythemia Vera Myelofibrosis (post-PV MF), or Post-essential Thrombocythemia Myelofibrosis (post-ET MF)

Detailed Description
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This is a Phase 1/2 study that is currently enrolling Janus kinase 2 (JAK2) failures into the Phase 2 portion of the study.

Official Title
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A Phase 1/2, Open-label, Dose-Escalation Multi-center Study to Assess the Safety, Tolerability, PK and PD of Orally Administered NS-018 in Patients With Primary Myelofibrosis (MF), Post-polycythemia Vera MF, or Post-essential Thrombocythemia MF

Conditions
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Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, Post-Essential Thrombocythemia Myelofibrosis

Intervention / Treatment
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* Drug: NS-018


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Primary myelofibrosis, post-PV MF, or post-ET MF that requires therapy MF patients must have received prior JAK2 inhibitor therapy, and been found to be intolerant, or refractory/relapsed from prior JAK2 inhibitor therapy, based on investigator assessment ≥18 years old ECOG Performance Status of ≤ 3 Estimated life expectancy of ≥12 weeks Male or non-pregnant, non-lactating female patients Serum creatinine of ≤1.5 × the upper limit of normal (ULN)OR estimated creatinine clearance (CrCl) ≥ 40 ml/min/1.73 m2 Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 × the upper limit of normal (ULN) and total bilirubin ≤1.5 × ULN. If the total bilirubin is elevated between 1.5 x and 3 x ULN, patients with a direct bilirubin ≤ 1.5 X ULN are eligible during the Phase II portion. Absolute neutrophil count (ANC) >1000/μL and Platelet count > 25,000/μL QTcB ≤ 480 msec No MF-directed treatment for at least 2 weeks prior to initiation of NS-018, including any use of corticosteroids for Myelofibrosis symptom or blood count management. Low dose corticosteroids ≤ 10 mg/day prednisone or equivalent is allowed for non-myelofibrosis purposes. Exclusion Criteria: Active, uncontrolled systemic infection Patients with any unresolved toxicity greater than Grade 1 from previous anticancer therapy Potentially curative therapy is available 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 Patients with a serious cardiac condition within the past 6 months Pregnant or lactating Radiation therapy for splenomegaly within 6 months prior to study entry Splenectomy (Phase 2 portion of the study only) Known HIV positive status Known active hepatitis, a history of viral hepatitis B or hepatitis C

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
Intervention Model: Sequential Assignment
Interventional Model Description: Phase 1: 75, 125, 200, 300, 400 mg QD and 100, 200, 250, 300, 400 mg BID Phase 2: 300 mg QD
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention: Drug: NS-018<br>In Phase 1 part, subjects were treated with oral NS-018 at a dose of 75 - 400 mg once daily or 100 - 400 mg twice daily. In Phase 2 part, subjects were treated with oral NS-018 at a dose of 300 mg once daily. | Drug: NS-018<br>* Treatment will be administered continuously as oral daily therapy in cycles of 4 weeks in duration (28 day treatment cycles).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | AEs (non-serious, serious) as variables of safety and tolerability of NS-018 were assesed. The number of patients were presented as Overall summary of AEs including treatment-emergent AEs (TEAEs); Treatment-emergent SAEs; Drug-related TEAEs; Treatment-emergent AEs leading to permanent discontinuation of study drug; Hospitalization or prolongation of existing hospitalization; Death. | From screening to until study discontinuation (approximate 8 years 10 months) | 
| Part 2: Number of Patient With Objective Response Using International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European Leukemia Net (ELN) | Six response categories are listed: complete remission (CR) and partial remission signify treatment effects that are consistent with disease modification, whereas drug-induced improvements in MF-symptomatic burden were annotated as clinical improvement, anemia response, spleen response, orsymptoms response. Additional criteria are provided for progressive disease, stable disease, and relapse. The objective response was defined as the number of patients with confirmed complete remission (CR) + partial response (PR) + clinical improvement (CI) during the treatment period. | Cycle 7 Day 1 (duration of cycle was 4 weeks) | 
| Part 2: Change From Baseline in Spleen Size | Change from baseline in spleen size was assessed by magnetic resonance imaging (MRI) (computed tomography [CT] scan for patients not able to tolerate MRI). | From Baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks) | 
| Part 2: Change From Baseline in Bone Marrow Assessment | Bone marrow was assessed by aspiration and biopsy for grade changes in osteomyelofibrosis. Fibrosis was graded according to European Consensus Myelofibrosis Grading Criteria, ranging from grade 0, which corresponds to normal bone marrow, to grade 3, in which coarse bundles of collagen fibrosis are identifiable with significant osteosclerosis. | From baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Number of Patients With Objective Response Using International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) | Six response categories are listed: complete remission (CR) and partial remission signify treatment effects that are consistent with disease modification, whereas drug-induced improvements in MF-symptomatic burden were annotated as clinical improvement, anemia response, spleen response, orsymptoms response. Additional criteria are provided for progressive disease, stable disease, and relapse. The objective response was defined as the number of patients with confirmed complete remission (CR) + partial response (PR) + clinical improvement (CI) during the treatment period. | Cycle 7 Day 1 (duration of cycle was 4 weeks) | 
| Part 1: Change From Baseline in Spleen Size | Change from baseline in spleen size was assessed by palpation. | From Baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks) | 
| Part 1: Change From Baseline in Bone Marrow Assessment | Bone marrow was assessed by aspiration and biopsy for grade changes in osteomyelofibrosis. Fibrosis was graded according to European Consensus Myelofibrosis Grading Criteria, ranging from grade 0, which corresponds to normal bone marrow, to grade 3, in which coarse bundles of collagen fibrosis are identifiable with significant osteosclerosis. | From baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks) | 
| Part 1: Change From Baseline in Quality of Life Assessments Using Myelofibrosis Symptom Assessment Form (MF-SAF) | MF SAF is a 20-item instrument comprised of 4 subscales: 1) the Brief Fatigue Inventory [= average of 9 fatigue scores], 2) Splenomegaly associated symptoms [= average of 4 splenomegaly and associated scores], 3) Catabolic/proliferative Symptoms [= average of 3 catabolic/proliferative associated scores] and 4) Overall Quality of Life. The items were on a scale from 1 to 10 where 1= most favorable, and 10= least favorable. | From baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks) | 
| Part 2: Change From Baseline in Quality of Life Assessments Using Myeloproliferative Neoplasm Symptom Assessment Form (MPN SAF (MPN 10) | Symptoms are evaluated by the MPN-SAF Total Symptom Score (TSS). The MPN-SAF TSS is assessed by the patients themselves and this includes fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fevers. Scoring is from 0 (absent/as good as it can be) to 10 (worst imaginable/as bad as it can be) for each item. The MPN-SAF TSS is the summation of all the individual scores (0-100 scale). Symptoms response requires >50% reduction in the MPN-SAF TSS. | From baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks) | 
| Part 1 and Part 2: Change in Baseline in Janus Kinase 2 (JAK2) V617F Allele Burden Levels | The JAK2 V617F allele burden mean changes from baseline (%) are presented as pharmacodynamics parameters. | Part 1 and Part 2: From baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks) | 
| Part 2: Change From Baseline in Phosphorylated Signal Transducer and Activator of Transcription 3 (Phospho-STAT3) | The Phospho-STAT3 mean changes from baseline (%) are presented as pharmacodynamics parameters. For phospho-STAT3 values (Phase 2 only), study samples were incubated (± IL-6) and labeled with CD markers. Surface markers included CD3+ (CD4+ [helper T cells] and CD8+ [cytotoxic T cells]) and CD14+ (monocytes) to which intracellular phospho STAT3 was targeted. The levels of phospho-STAT3 in CD14+, CD3+CD4+ and CD3+CD8+ cell subtypes were quantified. Phosphorylated-STAT3 levels were evaluated in the cell types before and after IL-6 incubation (stimulation) and reported both as mean fluorescence intensity (MFI) and the percentage of positive cells. For each sample time point, the MFI was normalized to a fold change. The fold change was calculated by MFI after IL-6 treatment/MFI before IL-6 treatment. The percent positive cells were normalized by subtracting the percent positive cells before IL-6 treatment from the percent positive cells after IL-6 treatment. | From Baseline to Pre-dose at Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1 (duration of cycle was 4 weeks) | 
| Part1 and Part 2: Observed Maximum Concentration (Cmax) | To determine the Cmax as pharmacokinetic parameters of NS-018. | Pre-dose, 0.5 to 24 hours post-dose for Part 1: Cycle 1 Day 1, Cycle 1 Day 8, Cycle 2 Day 1 and for Part 2: Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1 (duration of cycle was 4 weeks) | 
| Part 1 and Part 2: Time to Maximum Plasma Concentration (Tmax) | To determine the Tmax as pharmacokinetic parameters of NS-018. | Pre-dose, 0.5 to 24 hours post-dose for Part 1: Cycle 1 Day 1, Cycle 1 Day 8, Cycle 2 Day 1 and for Part 2: Cycle 1 Day 1, Cycle 2 Day 1 (duration of cycle was 4 weeks) | 
| Part1 and Part 2: Area Under the Plasma Concentration-time Curve (AUC0-24) | To determine the AUC0-24 as pharmacokinetic parameters of NS-018. | Pre-dose, 0.5 to 24 hours post-dose for Part 1: Cycle 1 Day 1, Cycle 2 Day 1 and for Part 2: Cycle 1 Day 1 (duration of cycle was 4 weeks) | 
| Part 1 and Part 2: Terminal Elimination Half-life (t½) | To determine the t½ as pharmacokinetic parameters of NS-018. | Pre-dose, 0.5 to 24 hours post-dose for Part 1: Cycle 1 Day 1, Cycle 1 Day 8, Cycle 2 Day 1 and for Part 2: Cycle 1 Day 1, Cycle 2 Day 1 (duration of cycle was 4 weeks) | 
| Part1 and Part 2: Accumulation Ratio (AR) | To determine the AR as pharmacokinetic parameters of NS-018. AR was calculated as AR = (AUC0-24) Cycle 2 Day 1/ (AUC0-24) Cycle 1 Day 1. | Part 1 and Part 2: Cycle 2 Day 1 (duration of cycle was 4 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PMF, Keywords provided by NS Pharma, Inc.:, JAK2 kinase inhibitor, NS-018, Myeloproliferative Neoplasms, Primary Myelofibrosis, post-Polycythemia Vera Myelofibrosis, post-Essential Thrombocythemia Myelofibrosis, Additional relevant MeSH terms:, Bone Marrow Diseases, Hematologic Diseases, Polycythemia Vera, Thrombocythemia, Essential, post-PV MF, post-ET MF