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

Browse trials for

• Primary Myelofibrosis 431
• Myeloproliferative Disorders 640
• Bone Marrow Diseases 203
• Hematologic Diseases 476
• Polycythemia Vera 238
• Thrombocythemia, Essential 195

Keywords

• 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
• PMF
• post-PV MF
• post-ET MF

Primary Myelofibrosis

431 studies on the registry are indexed under Primary Myelofibrosis; 118 are open to participants now.

This study's enrollment of 77 is above the median of 44 across 355 interventional studies indexed under Primary Myelofibrosis.

Lead sponsor

NS Pharma, Inc. is the lead sponsor of 15 studies on the registry; 2 are open to participants now.

Of its 5 completed or terminated interventional studies of FDA-regulated products, 5 (100%) have results posted.

Study arms

• Experimental
  Intervention: Drug: NS-018

  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

Interventions

• DrugNS-018

  Treatment will be administered continuously as oral daily therapy in cycles of 4 weeks in duration (28 day treatment cycles).

Primary outcomes

1. 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.

   Time frame: From screening to until study discontinuation (approximate 8 years 10 months)

2. 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.

   Time frame: Cycle 7 Day 1 (duration of cycle was 4 weeks)

3. 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).

   Time frame: From Baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks)

4. 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.

   Time frame: From baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks)

Secondary outcomes

1. 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.

   Time frame: Cycle 7 Day 1 (duration of cycle was 4 weeks)

2. Part 1: Change From Baseline in Spleen Size

   Change from baseline in spleen size was assessed by palpation.

   Time frame: From Baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks)

3. 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.

   Time frame: From baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks)

4. 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.

   Time frame: From baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks)

5. 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.

   Time frame: From baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks)

6. 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.

   Time frame: Part 1 and Part 2: From baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks)

7. 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.

   Time frame: From Baseline to Pre-dose at Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1 (duration of cycle was 4 weeks)

8. Part1 and Part 2: Observed Maximum Concentration (Cmax)

   To determine the Cmax as pharmacokinetic parameters of NS-018.

   Time frame: 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)

9. Part 1 and Part 2: Time to Maximum Plasma Concentration (Tmax)

   To determine the Tmax as pharmacokinetic parameters of NS-018.

   Time frame: 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)

10. Part1 and Part 2: Area Under the Plasma Concentration-time Curve (AUC0-24)

    To determine the AUC0-24 as pharmacokinetic parameters of NS-018.

    Time frame: 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)

11. Part 1 and Part 2: Terminal Elimination Half-life (t½)

    To determine the t½ as pharmacokinetic parameters of NS-018.

    Time frame: 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)

12. 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.

    Time frame: Part 1 and Part 2: Cycle 2 Day 1 (duration of cycle was 4 weeks)

Baseline characteristics

Publications

• Verstovsek S, Talpaz M, Ritchie E, Wadleigh M, Odenike O, Jamieson C, Stein B, Uno T, Mesa RA. A phase I, open-label, dose-escalation, multicenter study of the JAK2 inhibitor NS-018 in patients with myelofibrosis. Leukemia. 2017 Feb;31(2):393-402. doi: 10.1038/leu.2016.215. Epub 2016 Aug 1. PubMed 27479177 ↗

Study documents

• Protocol and statistical analysis plan · Apr 21, 2015

Documents are hosted by the registry — open the source record to download them.