Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, Post-Essential Thrombocythemia Myelofibrosis
Conditions
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
Brief summary
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
This is a Phase 1/2 study that is currently enrolling Janus kinase 2 (JAK2) failures into the Phase 2 portion of the study.
Interventions
DRUGNS-018
Treatment will be administered continuously as oral daily therapy in cycles of 4 weeks in duration (28 day treatment cycles).
Sponsors
NS Pharma, Inc.
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Phase 1: 75, 125, 200, 300, 400 mg QD and 100, 200, 250, 300, 400 mg BID Phase 2: 300 mg QD
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | From screening to until study discontinuation (approximate 8 years 10 months) | 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. |
| Part 2: Number of Patient With Objective Response Using International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European Leukemia Net (ELN) | Cycle 7 Day 1 (duration of cycle was 4 weeks) | 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. |
| Part 2: Change From Baseline in Spleen Size | From Baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks) | Change from baseline in spleen size was assessed by magnetic resonance imaging (MRI) (computed tomography \[CT\] scan for patients not able to tolerate MRI). |
| Part 2: Change From Baseline in Bone Marrow Assessment | From baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 2: Change From Baseline in Quality of Life Assessments Using Myeloproliferative Neoplasm Symptom Assessment Form (MPN SAF (MPN 10) | From baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks) | 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. |
| Part 1 and Part 2: Change in Baseline in Janus Kinase 2 (JAK2) V617F Allele Burden Levels | Part 1 and Part 2: From baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks) | The JAK2 V617F allele burden mean changes from baseline (%) are presented as pharmacodynamics parameters. |
| Part 2: Change From Baseline in Phosphorylated Signal Transducer and Activator of Transcription 3 (Phospho-STAT3) | From Baseline to Pre-dose at Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1 (duration of cycle was 4 weeks) | 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. |
| Part1 and Part 2: Observed Maximum Concentration (Cmax) | 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) | To determine the Cmax as pharmacokinetic parameters of NS-018. |
| Part 1: Number of Patients With Objective Response Using International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) | Cycle 7 Day 1 (duration of cycle was 4 weeks) | 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. |
| Part1 and Part 2: Area Under the Plasma Concentration-time Curve (AUC0-24) | 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) | To determine the AUC0-24 as pharmacokinetic parameters of NS-018. |
| Part 1 and Part 2: Terminal Elimination Half-life (t½) | 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) | To determine the t½ as pharmacokinetic parameters of NS-018. |
| Part1 and Part 2: Accumulation Ratio (AR) | Part 1 and Part 2: Cycle 2 Day 1 (duration of cycle was 4 weeks) | 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: Time to Maximum Plasma Concentration (Tmax) | 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) | To determine the Tmax as pharmacokinetic parameters of NS-018. |
| Part 1: Change From Baseline in Spleen Size | From Baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks) | Change from baseline in spleen size was assessed by palpation. |
| Part 1: Change From Baseline in Bone Marrow Assessment | From baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks) | 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. |
| Part 1: Change From Baseline in Quality of Life Assessments Using Myelofibrosis Symptom Assessment Form (MF-SAF) | From baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks) | 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. |
Countries
United States
Participant flow
Recruitment details
Subjects who met all the inclusion and none of the exclusion criteria were enrolled at 09 sites in the USA. The conduct of this study started on 02 June 2011 (the first patient screened) and the last patient last visit was on 22 April 2020. A total of 48 and 29 patients were enrolled during Phase 1 and Phase 2 of the study respectively. Participants could be reduced or escalated to the noted dose at physician discretion.
Pre-assignment details
The screening period was from Day -14 to Day 0 for Phase I and Phase II. Informed consent form (ICF) was signed prior to screening procedures. All the study assessments were performed as per the schedule of assessment.
Participants by arm
| Arm | Count |
|---|---|
| Part 1: 75 mg QD Patients self-administered orally 75 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | 3 |
| Part 1: 125 mg QD Patients self-administered orally 125 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | 3 |
| Part 1: 200 mg QD Patients self-administered orally 200 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | 3 |
| Part 1: 300 mg QD Patients self-administered orally 300 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | 6 |
| Part 1: 400 mg QD Patients self-administered orally 400 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | 3 |
| Part 1: 100 mg BID Patients self-administered orally 100 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | 3 |
| Part 1: 200 mg BID Patients self-administered orally 200 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | 3 |
| Part 1: 250 mg BID Patients self-administered orally 250 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | 8 |
| Part 1: 300 mg BID Patients self-administered orally 300 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | 8 |
| Part 1: 400 mg BID Patients self-administered orally 400 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | 8 |
| Part 2: 300 mg QD Patients self-administered orally 300 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | 29 |
| Total | 77 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Whole Study | Adverse Event | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 3 | 3 | 2 | 3 |
| Whole Study | Disease progression | 2 | 1 | 1 | 4 | 1 | 3 | 1 | 4 | 0 | 2 | 10 |
| Whole Study | Physician Decision | 0 | 1 | 2 | 0 | 2 | 0 | 2 | 1 | 3 | 4 | 12 |
| Whole Study | Withdrawal by Subject | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0 | 4 |
Baseline characteristics
| Characteristic | Part 1: 75 mg QD | Part 1: 125 mg QD | Part 1: 200 mg QD | Part 1: 300 mg QD | Part 1: 400 mg QD | Part 1: 100 mg BID | Part 1: 200 mg BID | Part 1: 250 mg BID | Part 1: 300 mg BID | Part 1: 400 mg BID | Total | Part 2: 300 mg QD |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous Part 1 | 72.7 Years STANDARD_DEVIATION 1.5 | 70.3 Years STANDARD_DEVIATION 14.8 | 63.7 Years STANDARD_DEVIATION 12.9 | 67.3 Years STANDARD_DEVIATION 9.4 | 67.3 Years STANDARD_DEVIATION 3.8 | 65.0 Years STANDARD_DEVIATION 8.9 | 69.0 Years STANDARD_DEVIATION 3.6 | 63.0 Years STANDARD_DEVIATION 11.8 | 62.4 Years STANDARD_DEVIATION 11.9 | 69.3 Years STANDARD_DEVIATION 7.7 | 66.4 Years STANDARD_DEVIATION 9.6 | — |
| Age, Continuous Part 2 | — | — | — | — | — | — | — | — | — | — | 67.2 Years STANDARD_DEVIATION 9.3 | 67.2 Years STANDARD_DEVIATION 9.3 |
| Race/Ethnicity, Customized Asian/Oriental | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Black/African Heritage | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White/Caucasian | 3 Participants | 3 Participants | 2 Participants | 6 Participants | 2 Participants | 3 Participants | 2 Participants | 8 Participants | 8 Participants | 8 Participants | 71 Participants | 26 Participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 0 Participants | 3 Participants | 2 Participants | 1 Participants | 0 Participants | 3 Participants | 6 Participants | 3 Participants | 33 Participants | 14 Participants |
| Sex: Female, Male Male | 3 Participants | 2 Participants | 3 Participants | 3 Participants | 1 Participants | 2 Participants | 3 Participants | 5 Participants | 2 Participants | 5 Participants | 44 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 4 | 0 / 10 | 0 / 15 | 0 / 4 | 0 / 5 | 0 / 13 | 0 / 8 | 0 / 12 | 0 / 8 | 1 / 29 |
| other Total, other adverse events | 3 / 3 | 4 / 4 | 9 / 10 | 14 / 15 | 4 / 4 | 4 / 5 | 11 / 13 | 8 / 8 | 12 / 12 | 7 / 8 | 29 / 29 |
| serious Total, serious adverse events | 2 / 3 | 2 / 4 | 2 / 10 | 6 / 15 | 1 / 4 | 1 / 5 | 4 / 13 | 3 / 8 | 4 / 12 | 3 / 8 | 13 / 29 |
Outcome results
Primary
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)
Population: The safety population included all patients who received at least 1 dose of study drug.~NS-018-101 study was dose-finding study, Principal investigator (PI) could increase or decrease dose-level per protocol. Totals are based on number of patients and not on dose-level cohort. Patients can appear in more than one dose-level cohort.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1: 75 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Drug Related TEAE | 1 Participants |
| Part 1: 75 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | TEAE Leading to Discontinuation of study drug | 1 Participants |
| Part 1: 75 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Not TEAE | 0 Participants |
| Part 1: 75 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Any AE | 3 Participants |
| Part 1: 75 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Death | 0 Participants |
| Part 1: 75 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Any Treatment Emergent AE | 3 Participants |
| Part 1: 75 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Any Serious TEAE | 2 Participants |
| Part 1: 75 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Hospitalization or Prolongation of Existing Hospitalization | 1 Participants |
| Part 1: 125 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Any Serious TEAE | 2 Participants |
| Part 1: 125 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Death | 0 Participants |
| Part 1: 125 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Hospitalization or Prolongation of Existing Hospitalization | 2 Participants |
| Part 1: 125 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Not TEAE | 0 Participants |
| Part 1: 125 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Any Treatment Emergent AE | 4 Participants |
| Part 1: 125 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | TEAE Leading to Discontinuation of study drug | 0 Participants |
| Part 1: 125 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Any AE | 4 Participants |
| Part 1: 125 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Drug Related TEAE | 1 Participants |
| Part 1: 200 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Any Serious TEAE | 2 Participants |
| Part 1: 200 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Hospitalization or Prolongation of Existing Hospitalization | 2 Participants |
| Part 1: 200 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Death | 0 Participants |
| Part 1: 200 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Drug Related TEAE | 8 Participants |
| Part 1: 200 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Any AE | 9 Participants |
| Part 1: 200 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Not TEAE | 0 Participants |
| Part 1: 200 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | TEAE Leading to Discontinuation of study drug | 0 Participants |
| Part 1: 200 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Any Treatment Emergent AE | 9 Participants |
| Part 1: 300 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Not TEAE | 0 Participants |
| Part 1: 300 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Drug Related TEAE | 11 Participants |
| Part 1: 300 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Death | 0 Participants |
| Part 1: 300 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Any AE | 14 Participants |
| Part 1: 300 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | TEAE Leading to Discontinuation of study drug | 4 Participants |
| Part 1: 300 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Hospitalization or Prolongation of Existing Hospitalization | 6 Participants |
| Part 1: 300 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Any Treatment Emergent AE | 14 Participants |
| Part 1: 300 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Any Serious TEAE | 6 Participants |
| Part 1: 400 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Hospitalization or Prolongation of Existing Hospitalization | 1 Participants |
| Part 1: 400 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Death | 0 Participants |
| Part 1: 400 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Drug Related TEAE | 4 Participants |
| Part 1: 400 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Not TEAE | 1 Participants |
| Part 1: 400 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Any Serious TEAE | 1 Participants |
| Part 1: 400 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | TEAE Leading to Discontinuation of study drug | 0 Participants |
| Part 1: 400 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Any Treatment Emergent AE | 4 Participants |
| Part 1: 400 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Any AE | 4 Participants |
| Part 1: 100 mg BID | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Any Treatment Emergent AE | 4 Participants |
| Part 1: 100 mg BID | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Any AE | 4 Participants |
| Part 1: 100 mg BID | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Drug Related TEAE | 2 Participants |
| Part 1: 100 mg BID | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Any Serious TEAE | 1 Participants |
| Part 1: 100 mg BID | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | TEAE Leading to Discontinuation of study drug | 0 Participants |
| Part 1: 100 mg BID | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Hospitalization or Prolongation of Existing Hospitalization | 1 Participants |
| Part 1: 100 mg BID | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Death | 0 Participants |
| Part 1: 100 mg BID | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Not TEAE | 2 Participants |
| Part 1: 200 mg BID | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Hospitalization or Prolongation of Existing Hospitalization | 3 Participants |
| Part 1: 200 mg BID | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Death | 0 Participants |
| Part 1: 200 mg BID | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | TEAE Leading to Discontinuation of study drug | 0 Participants |
| Part 1: 200 mg BID | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Any AE | 11 Participants |
| Part 1: 200 mg BID | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Any Treatment Emergent AE | 11 Participants |
| Part 1: 200 mg BID | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Any Serious TEAE | 4 Participants |
| Part 1: 200 mg BID | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Not TEAE | 1 Participants |
| Part 1: 200 mg BID | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Drug Related TEAE | 4 Participants |
| Part 1: 250 mg BID | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Not TEAE | 3 Participants |
| Part 1: 250 mg BID | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Any Treatment Emergent AE | 8 Participants |
| Part 1: 250 mg BID | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Death | 0 Participants |
| Part 1: 250 mg BID | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | TEAE Leading to Discontinuation of study drug | 3 Participants |
| Part 1: 250 mg BID | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Drug Related TEAE | 5 Participants |
| Part 1: 250 mg BID | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Any AE | 8 Participants |
| Part 1: 250 mg BID | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Hospitalization or Prolongation of Existing Hospitalization | 2 Participants |
| Part 1: 250 mg BID | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Any Serious TEAE | 3 Participants |
| Part 1: 300 mg BID | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | TEAE Leading to Discontinuation of study drug | 4 Participants |
| Part 1: 300 mg BID | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Drug Related TEAE | 10 Participants |
| Part 1: 300 mg BID | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Any Serious TEAE | 4 Participants |
| Part 1: 300 mg BID | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Any Treatment Emergent AE | 12 Participants |
| Part 1: 300 mg BID | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Hospitalization or Prolongation of Existing Hospitalization | 3 Participants |
| Part 1: 300 mg BID | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Death | 0 Participants |
| Part 1: 300 mg BID | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Not TEAE | 4 Participants |
| Part 1: 300 mg BID | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Any AE | 12 Participants |
| Part 1: 400 mg BID | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Any AE | 8 Participants |
| Part 1: 400 mg BID | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Death | 0 Participants |
| Part 1: 400 mg BID | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Any Serious TEAE | 3 Participants |
| Part 1: 400 mg BID | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Any Treatment Emergent AE | 8 Participants |
| Part 1: 400 mg BID | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | TEAE Leading to Discontinuation of study drug | 2 Participants |
| Part 1: 400 mg BID | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Drug Related TEAE | 7 Participants |
| Part 1: 400 mg BID | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Hospitalization or Prolongation of Existing Hospitalization | 1 Participants |
| Part 1: 400 mg BID | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Not TEAE | 2 Participants |
| Part 2: 300 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Not TEAE | 6 Participants |
| Part 2: 300 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Any AE | 29 Participants |
| Part 2: 300 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Death | 1 Participants |
| Part 2: 300 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Hospitalization or Prolongation of Existing Hospitalization | 11 Participants |
| Part 2: 300 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | TEAE Leading to Discontinuation of study drug | 5 Participants |
| Part 2: 300 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Any Serious TEAE | 13 Participants |
| Part 2: 300 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Drug Related TEAE | 24 Participants |
| Part 2: 300 mg QD | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event | Any Treatment Emergent AE | 29 Participants |
Primary
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)
Population: The efficacy population included all patients who received at least one dose of study drug and had one baseline and at least one post-baseline efficacy assessment. Here, the overall number of subjects analyzed signifies only the subjects with available data that were analyzed evaluated on that specific cycle day.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1: 75 mg QD | Part 2: Change From Baseline in Bone Marrow Assessment | Increased by at least 1 grade level | 1 Participants |
| Part 1: 75 mg QD | Part 2: Change From Baseline in Bone Marrow Assessment | Increased by at least 2 grade level | 0 Participants |
| Part 1: 75 mg QD | Part 2: Change From Baseline in Bone Marrow Assessment | Decreased by at least 1 grade level | 2 Participants |
| Part 1: 75 mg QD | Part 2: Change From Baseline in Bone Marrow Assessment | Decreased by at least 2 grade level | 0 Participants |
Primary
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)
Population: The efficacy population included all patients who received at least one dose of study drug and had one baseline and at least one post-baseline efficacy assessment. Here, the overall number of subjects analyzed signifies only the subjects with available data that were analyzed evaluated on that specific cycle day.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: 75 mg QD | Part 2: Change From Baseline in Spleen Size | -335918.1 cubic millimeter (mm3) | Standard Deviation 558459.9 |
Primary
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)
Population: The efficacy population included all patients who received at least one dose of study drug and had one baseline and at least one post-baseline efficacy assessment. Here, the overall number of subjects analyzed signifies only the subjects with available data that were analyzed evaluated on that specific cycle day.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: 75 mg QD | Part 2: Number of Patient With Objective Response Using International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European Leukemia Net (ELN) | 1 Participants |
Secondary
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)
Population: The PK Population includes all patients who received at least one dose of study drug and have at least 50% of the planned samples above the limit of quantitation to provide evaluable PK profile (i.e. at least Cmax and AUC evaluable), regardless of whether derived from parent drug or metabolites.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: 75 mg QD | Part1 and Part 2: Accumulation Ratio (AR) | 0.9778 Ratio | — |
| Part 1: 125 mg QD | Part1 and Part 2: Accumulation Ratio (AR) | 1.2517 Ratio | Standard Deviation 0.5579 |
| Part 1: 200 mg QD | Part1 and Part 2: Accumulation Ratio (AR) | 1.1728 Ratio | Standard Deviation 0.0372 |
| Part 1: 300 mg QD | Part1 and Part 2: Accumulation Ratio (AR) | 1.3581 Ratio | Standard Deviation 0.3108 |
| Part 1: 400 mg QD | Part1 and Part 2: Accumulation Ratio (AR) | 1.2026 Ratio | Standard Deviation 0.4755 |
| Part 1: 100 mg BID | Part1 and Part 2: Accumulation Ratio (AR) | 1.9941 Ratio | Standard Deviation 0.614 |
| Part 1: 200 mg BID | Part1 and Part 2: Accumulation Ratio (AR) | 3.3229 Ratio | Standard Deviation 0.3197 |
| Part 1: 250 mg BID | Part1 and Part 2: Accumulation Ratio (AR) | 3.0501 Ratio | Standard Deviation 2.6306 |
| Part 1: 300 mg BID | Part1 and Part 2: Accumulation Ratio (AR) | 1.5452 Ratio | Standard Deviation 0.4025 |
| Part 1: 400 mg BID | Part1 and Part 2: Accumulation Ratio (AR) | 1.2514 Ratio | — |
| Part 2: 300 mg QD | Part1 and Part 2: Accumulation Ratio (AR) | 1.0543 Ratio | Standard Deviation 0.2572 |
Secondary
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)
Population: The PK Population includes all patients who received at least one dose of study drug and have at least 50% of the planned samples above the limit of quantitation to provide evaluable PK profile, regardless of whether derived from parent drug or metabolites.~Part 2: One patient was completely excluded from the PK Population due to critical samples missing; Two patients were excluded from the analysis due to sample missing at time point. so the overall number of participants analyzed was 26.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: 75 mg QD | Part1 and Part 2: Area Under the Plasma Concentration-time Curve (AUC0-24) | Cycle 1 Day 1 | 246.3454 hour*nanogram/milliliter (h*ng/mL) | Standard Deviation 325.7347 |
| Part 1: 75 mg QD | Part1 and Part 2: Area Under the Plasma Concentration-time Curve (AUC0-24) | Cycle 2 Day 1 (Part 1 only) | 253.6953 hour*nanogram/milliliter (h*ng/mL) | Standard Deviation 306.7728 |
| Part 1: 125 mg QD | Part1 and Part 2: Area Under the Plasma Concentration-time Curve (AUC0-24) | Cycle 2 Day 1 (Part 1 only) | 1905.2058 hour*nanogram/milliliter (h*ng/mL) | Standard Deviation 938.2984 |
| Part 1: 125 mg QD | Part1 and Part 2: Area Under the Plasma Concentration-time Curve (AUC0-24) | Cycle 1 Day 1 | 1510.0507 hour*nanogram/milliliter (h*ng/mL) | Standard Deviation 123.2939 |
| Part 1: 200 mg QD | Part1 and Part 2: Area Under the Plasma Concentration-time Curve (AUC0-24) | Cycle 2 Day 1 (Part 1 only) | 1816.8251 hour*nanogram/milliliter (h*ng/mL) | Standard Deviation 559.9071 |
| Part 1: 200 mg QD | Part1 and Part 2: Area Under the Plasma Concentration-time Curve (AUC0-24) | Cycle 1 Day 1 | 1326.3929 hour*nanogram/milliliter (h*ng/mL) | Standard Deviation 815.0175 |
| Part 1: 300 mg QD | Part1 and Part 2: Area Under the Plasma Concentration-time Curve (AUC0-24) | Cycle 1 Day 1 | 2299.2216 hour*nanogram/milliliter (h*ng/mL) | Standard Deviation 877.2554 |
| Part 1: 300 mg QD | Part1 and Part 2: Area Under the Plasma Concentration-time Curve (AUC0-24) | Cycle 2 Day 1 (Part 1 only) | 3175.6938 hour*nanogram/milliliter (h*ng/mL) | Standard Deviation 794.6091 |
| Part 1: 400 mg QD | Part1 and Part 2: Area Under the Plasma Concentration-time Curve (AUC0-24) | Cycle 1 Day 1 | 5162.4119 hour*nanogram/milliliter (h*ng/mL) | Standard Deviation 2485.9489 |
| Part 1: 400 mg QD | Part1 and Part 2: Area Under the Plasma Concentration-time Curve (AUC0-24) | Cycle 2 Day 1 (Part 1 only) | 5443.2874 hour*nanogram/milliliter (h*ng/mL) | Standard Deviation 986.8497 |
| Part 1: 100 mg BID | Part1 and Part 2: Area Under the Plasma Concentration-time Curve (AUC0-24) | Cycle 2 Day 1 (Part 1 only) | 1561.1245 hour*nanogram/milliliter (h*ng/mL) | Standard Deviation 621.5414 |
| Part 1: 100 mg BID | Part1 and Part 2: Area Under the Plasma Concentration-time Curve (AUC0-24) | Cycle 1 Day 1 | 1022.0977 hour*nanogram/milliliter (h*ng/mL) | Standard Deviation 521.6626 |
| Part 1: 200 mg BID | Part1 and Part 2: Area Under the Plasma Concentration-time Curve (AUC0-24) | Cycle 2 Day 1 (Part 1 only) | 3470.6269 hour*nanogram/milliliter (h*ng/mL) | Standard Deviation 2587.3663 |
| Part 1: 200 mg BID | Part1 and Part 2: Area Under the Plasma Concentration-time Curve (AUC0-24) | Cycle 1 Day 1 | 1241.5005 hour*nanogram/milliliter (h*ng/mL) | Standard Deviation 461.601 |
| Part 1: 250 mg BID | Part1 and Part 2: Area Under the Plasma Concentration-time Curve (AUC0-24) | Cycle 1 Day 1 | 2117.1396 hour*nanogram/milliliter (h*ng/mL) | Standard Deviation 449.2456 |
| Part 1: 250 mg BID | Part1 and Part 2: Area Under the Plasma Concentration-time Curve (AUC0-24) | Cycle 2 Day 1 (Part 1 only) | 5876.1106 hour*nanogram/milliliter (h*ng/mL) | Standard Deviation 5133.4208 |
| Part 1: 300 mg BID | Part1 and Part 2: Area Under the Plasma Concentration-time Curve (AUC0-24) | Cycle 1 Day 1 | 5666.7063 hour*nanogram/milliliter (h*ng/mL) | Standard Deviation 5182.5571 |
| Part 1: 300 mg BID | Part1 and Part 2: Area Under the Plasma Concentration-time Curve (AUC0-24) | Cycle 2 Day 1 (Part 1 only) | 6132.2596 hour*nanogram/milliliter (h*ng/mL) | Standard Deviation 3393.0644 |
| Part 1: 400 mg BID | Part1 and Part 2: Area Under the Plasma Concentration-time Curve (AUC0-24) | Cycle 2 Day 1 (Part 1 only) | 3828.0995 hour*nanogram/milliliter (h*ng/mL) | — |
| Part 1: 400 mg BID | Part1 and Part 2: Area Under the Plasma Concentration-time Curve (AUC0-24) | Cycle 1 Day 1 | 7592.4070 hour*nanogram/milliliter (h*ng/mL) | Standard Deviation 3031.4332 |
| Part 2: 300 mg QD | Part1 and Part 2: Area Under the Plasma Concentration-time Curve (AUC0-24) | Cycle 1 Day 1 | 3672.2041 hour*nanogram/milliliter (h*ng/mL) | Standard Deviation 1551.7435 |
Secondary
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)
Population: The PD population included all patients who received at least one dose of study drug and had a baseline and at least one post-baseline PD assessment (for at least one PD parameter). Here, the overall number of subjects analyzed signifies only the subjects with available data that were analyzed evaluated on that specific cycle day.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: 125 mg QD | Part 1 and Part 2: Change in Baseline in Janus Kinase 2 (JAK2) V617F Allele Burden Levels | 4.360 Percentage of JAK2 V617F Level | — |
| Part 1: 200 mg QD | Part 1 and Part 2: Change in Baseline in Janus Kinase 2 (JAK2) V617F Allele Burden Levels | -0.210 Percentage of JAK2 V617F Level | — |
| Part 1: 300 mg QD | Part 1 and Part 2: Change in Baseline in Janus Kinase 2 (JAK2) V617F Allele Burden Levels | 7.410 Percentage of JAK2 V617F Level | Standard Deviation 2.758 |
| Part 1: 100 mg BID | Part 1 and Part 2: Change in Baseline in Janus Kinase 2 (JAK2) V617F Allele Burden Levels | -6.720 Percentage of JAK2 V617F Level | Standard Deviation 10.479 |
| Part 1: 200 mg BID | Part 1 and Part 2: Change in Baseline in Janus Kinase 2 (JAK2) V617F Allele Burden Levels | 8.255 Percentage of JAK2 V617F Level | Standard Deviation 4.32 |
| Part 1: 250 mg BID | Part 1 and Part 2: Change in Baseline in Janus Kinase 2 (JAK2) V617F Allele Burden Levels | -4.900 Percentage of JAK2 V617F Level | Standard Deviation 9.065 |
| Part 1: 300 mg BID | Part 1 and Part 2: Change in Baseline in Janus Kinase 2 (JAK2) V617F Allele Burden Levels | -9.033 Percentage of JAK2 V617F Level | Standard Deviation 5.352 |
| Part 1: 400 mg BID | Part 1 and Part 2: Change in Baseline in Janus Kinase 2 (JAK2) V617F Allele Burden Levels | -4.368 Percentage of JAK2 V617F Level | Standard Deviation 14.602 |
| Part 2: 300 mg QD | Part 1 and Part 2: Change in Baseline in Janus Kinase 2 (JAK2) V617F Allele Burden Levels | 1.782 Percentage of JAK2 V617F Level | Standard Deviation 8.978 |
Secondary
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)
Population: The PK population include all patients who received at least one dose of study drug and have at least 50% of the planned samples above the limit of quantitation to provide evaluable PK profile, Here, number analyzed reflects number of patients evaluated on that specific cycle day.~Part 2: 1 patient was completely excluded from PK Population due to critical samples missing, 1 patient was excluded from the analysis due to sample missing at timepoint, So the overall number of participants was 27.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: 75 mg QD | Part1 and Part 2: Observed Maximum Concentration (Cmax) | Cycle 1 Day 1 | 66.5600 nanogram/milliliter (ng/mL) | Standard Deviation 79.0171 |
| Part 1: 75 mg QD | Part1 and Part 2: Observed Maximum Concentration (Cmax) | Cycle 2 Day 1 | 67.6467 nanogram/milliliter (ng/mL) | Standard Deviation 55.625 |
| Part 1: 75 mg QD | Part1 and Part 2: Observed Maximum Concentration (Cmax) | Cycle 1 Day 8 (Part 1 only) | 30.6700 nanogram/milliliter (ng/mL) | Standard Deviation 13.3077 |
| Part 1: 125 mg QD | Part1 and Part 2: Observed Maximum Concentration (Cmax) | Cycle 1 Day 8 (Part 1 only) | 324.8667 nanogram/milliliter (ng/mL) | Standard Deviation 57.328 |
| Part 1: 125 mg QD | Part1 and Part 2: Observed Maximum Concentration (Cmax) | Cycle 2 Day 1 | 450.6667 nanogram/milliliter (ng/mL) | Standard Deviation 187.4735 |
| Part 1: 125 mg QD | Part1 and Part 2: Observed Maximum Concentration (Cmax) | Cycle 1 Day 1 | 404.5333 nanogram/milliliter (ng/mL) | Standard Deviation 26.4258 |
| Part 1: 200 mg QD | Part1 and Part 2: Observed Maximum Concentration (Cmax) | Cycle 2 Day 1 | 556.9000 nanogram/milliliter (ng/mL) | Standard Deviation 52.8463 |
| Part 1: 200 mg QD | Part1 and Part 2: Observed Maximum Concentration (Cmax) | Cycle 1 Day 1 | 377.8000 nanogram/milliliter (ng/mL) | Standard Deviation 184.2086 |
| Part 1: 200 mg QD | Part1 and Part 2: Observed Maximum Concentration (Cmax) | Cycle 1 Day 8 (Part 1 only) | 539.6667 nanogram/milliliter (ng/mL) | Standard Deviation 160.0954 |
| Part 1: 300 mg QD | Part1 and Part 2: Observed Maximum Concentration (Cmax) | Cycle 1 Day 8 (Part 1 only) | 805.4333 nanogram/milliliter (ng/mL) | Standard Deviation 236.8877 |
| Part 1: 300 mg QD | Part1 and Part 2: Observed Maximum Concentration (Cmax) | Cycle 1 Day 1 | 726.0667 nanogram/milliliter (ng/mL) | Standard Deviation 232.0338 |
| Part 1: 300 mg QD | Part1 and Part 2: Observed Maximum Concentration (Cmax) | Cycle 2 Day 1 | 1066.0000 nanogram/milliliter (ng/mL) | Standard Deviation 271.1854 |
| Part 1: 400 mg QD | Part1 and Part 2: Observed Maximum Concentration (Cmax) | Cycle 2 Day 1 | 1556.0000 nanogram/milliliter (ng/mL) | Standard Deviation 676.3941 |
| Part 1: 400 mg QD | Part1 and Part 2: Observed Maximum Concentration (Cmax) | Cycle 1 Day 1 | 1643.0333 nanogram/milliliter (ng/mL) | Standard Deviation 789.0036 |
| Part 1: 400 mg QD | Part1 and Part 2: Observed Maximum Concentration (Cmax) | Cycle 1 Day 8 (Part 1 only) | 1554.6667 nanogram/milliliter (ng/mL) | Standard Deviation 351.6765 |
| Part 1: 100 mg BID | Part1 and Part 2: Observed Maximum Concentration (Cmax) | Cycle 1 Day 1 | 242.0333 nanogram/milliliter (ng/mL) | Standard Deviation 174.3374 |
| Part 1: 100 mg BID | Part1 and Part 2: Observed Maximum Concentration (Cmax) | Cycle 1 Day 8 (Part 1 only) | 412.8000 nanogram/milliliter (ng/mL) | Standard Deviation 232.9342 |
| Part 1: 100 mg BID | Part1 and Part 2: Observed Maximum Concentration (Cmax) | Cycle 2 Day 1 | 408.6000 nanogram/milliliter (ng/mL) | Standard Deviation 127.0765 |
| Part 1: 200 mg BID | Part1 and Part 2: Observed Maximum Concentration (Cmax) | Cycle 1 Day 1 | 351.0000 nanogram/milliliter (ng/mL) | Standard Deviation 257.1729 |
| Part 1: 200 mg BID | Part1 and Part 2: Observed Maximum Concentration (Cmax) | Cycle 1 Day 8 (Part 1 only) | 606.8333 nanogram/milliliter (ng/mL) | Standard Deviation 233.7812 |
| Part 1: 200 mg BID | Part1 and Part 2: Observed Maximum Concentration (Cmax) | Cycle 2 Day 1 | 596.1333 nanogram/milliliter (ng/mL) | Standard Deviation 362.6751 |
| Part 1: 250 mg BID | Part1 and Part 2: Observed Maximum Concentration (Cmax) | Cycle 1 Day 8 (Part 1 only) | 806.8333 nanogram/milliliter (ng/mL) | Standard Deviation 464.3206 |
| Part 1: 250 mg BID | Part1 and Part 2: Observed Maximum Concentration (Cmax) | Cycle 1 Day 1 | 853.5833 nanogram/milliliter (ng/mL) | Standard Deviation 271.79 |
| Part 1: 250 mg BID | Part1 and Part 2: Observed Maximum Concentration (Cmax) | Cycle 2 Day 1 | 830.7333 nanogram/milliliter (ng/mL) | Standard Deviation 166.0701 |
| Part 1: 300 mg BID | Part1 and Part 2: Observed Maximum Concentration (Cmax) | Cycle 2 Day 1 | 1272.5600 nanogram/milliliter (ng/mL) | Standard Deviation 420.7722 |
| Part 1: 300 mg BID | Part1 and Part 2: Observed Maximum Concentration (Cmax) | Cycle 1 Day 8 (Part 1 only) | 969.0167 nanogram/milliliter (ng/mL) | Standard Deviation 342.309 |
| Part 1: 300 mg BID | Part1 and Part 2: Observed Maximum Concentration (Cmax) | Cycle 1 Day 1 | 1077.4750 nanogram/milliliter (ng/mL) | Standard Deviation 366.9158 |
| Part 1: 400 mg BID | Part1 and Part 2: Observed Maximum Concentration (Cmax) | Cycle 1 Day 8 (Part 1 only) | 1352.2200 nanogram/milliliter (ng/mL) | Standard Deviation 307.1358 |
| Part 1: 400 mg BID | Part1 and Part 2: Observed Maximum Concentration (Cmax) | Cycle 2 Day 1 | 1040.6500 nanogram/milliliter (ng/mL) | Standard Deviation 321.5215 |
| Part 1: 400 mg BID | Part1 and Part 2: Observed Maximum Concentration (Cmax) | Cycle 1 Day 1 | 1261.7000 nanogram/milliliter (ng/mL) | Standard Deviation 658.9141 |
| Part 2: 300 mg QD | Part1 and Part 2: Observed Maximum Concentration (Cmax) | Cycle 2 Day 1 | 1035.3087 nanogram/milliliter (ng/mL) | Standard Deviation 445.9895 |
| Part 2: 300 mg QD | Part1 and Part 2: Observed Maximum Concentration (Cmax) | Cycle 1 Day 15 (Part 2 only) | 732.5000 nanogram/milliliter (ng/mL) | Standard Deviation 313.5822 |
| Part 2: 300 mg QD | Part1 and Part 2: Observed Maximum Concentration (Cmax) | Cycle 1 Day 1 | 957.9852 nanogram/milliliter (ng/mL) | Standard Deviation 306.7937 |
Secondary
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)
Population: The PK population include all patients who received at least one dose of study drug and have at least 50% of the planned samples above the limit of quantitation to provide evaluable PK profile, Here, number analyzed reflects number of patients evaluated on that specific cycle day.~Part 2: 1 patient was completely excluded from PK Population due to critical samples missing, 1 patient was excluded from the analysis due to sample missing at timepoint, So the overall number of participants was 27.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: 75 mg QD | Part 1 and Part 2: Terminal Elimination Half-life (t½) | Cycle 2 Day 1 | 3.7488 hour (h) | Standard Deviation 2.9554 |
| Part 1: 75 mg QD | Part 1 and Part 2: Terminal Elimination Half-life (t½) | Cycle 1 Day 1 | 2.4878 hour (h) | Standard Deviation 2.1008 |
| Part 1: 75 mg QD | Part 1 and Part 2: Terminal Elimination Half-life (t½) | Cycle 1 Day 8 (Part 1 only) | 1.9170 hour (h) | Standard Deviation 0.5066 |
| Part 1: 125 mg QD | Part 1 and Part 2: Terminal Elimination Half-life (t½) | Cycle 1 Day 1 | 5.1659 hour (h) | Standard Deviation 0.5209 |
| Part 1: 125 mg QD | Part 1 and Part 2: Terminal Elimination Half-life (t½) | Cycle 2 Day 1 | 5.6743 hour (h) | Standard Deviation 1.3845 |
| Part 1: 125 mg QD | Part 1 and Part 2: Terminal Elimination Half-life (t½) | Cycle 1 Day 8 (Part 1 only) | 2.4735 hour (h) | Standard Deviation 0.3469 |
| Part 1: 200 mg QD | Part 1 and Part 2: Terminal Elimination Half-life (t½) | Cycle 2 Day 1 | 5.4356 hour (h) | Standard Deviation 0.7253 |
| Part 1: 200 mg QD | Part 1 and Part 2: Terminal Elimination Half-life (t½) | Cycle 1 Day 8 (Part 1 only) | 2.0217 hour (h) | Standard Deviation 0.2653 |
| Part 1: 200 mg QD | Part 1 and Part 2: Terminal Elimination Half-life (t½) | Cycle 1 Day 1 | 3.6685 hour (h) | Standard Deviation 2.2953 |
| Part 1: 300 mg QD | Part 1 and Part 2: Terminal Elimination Half-life (t½) | Cycle 2 Day 1 | 5.9316 hour (h) | Standard Deviation 0.85 |
| Part 1: 300 mg QD | Part 1 and Part 2: Terminal Elimination Half-life (t½) | Cycle 1 Day 1 | 4.4899 hour (h) | Standard Deviation 1.5478 |
| Part 1: 300 mg QD | Part 1 and Part 2: Terminal Elimination Half-life (t½) | Cycle 1 Day 8 (Part 1 only) | 2.6237 hour (h) | Standard Deviation 0.505 |
| Part 1: 400 mg QD | Part 1 and Part 2: Terminal Elimination Half-life (t½) | Cycle 1 Day 8 (Part 1 only) | 2.8480 hour (h) | Standard Deviation 1.3889 |
| Part 1: 400 mg QD | Part 1 and Part 2: Terminal Elimination Half-life (t½) | Cycle 1 Day 1 | 6.0302 hour (h) | Standard Deviation 2.473 |
| Part 1: 400 mg QD | Part 1 and Part 2: Terminal Elimination Half-life (t½) | Cycle 2 Day 1 | 8.5232 hour (h) | Standard Deviation 5.0118 |
| Part 1: 100 mg BID | Part 1 and Part 2: Terminal Elimination Half-life (t½) | Cycle 1 Day 8 (Part 1 only) | 2.3007 hour (h) | Standard Deviation 0.0899 |
| Part 1: 100 mg BID | Part 1 and Part 2: Terminal Elimination Half-life (t½) | Cycle 2 Day 1 | 16.5535 hour (h) | Standard Deviation 6.8417 |
| Part 1: 100 mg BID | Part 1 and Part 2: Terminal Elimination Half-life (t½) | Cycle 1 Day 1 | 9.7153 hour (h) | Standard Deviation 5.2865 |
| Part 1: 200 mg BID | Part 1 and Part 2: Terminal Elimination Half-life (t½) | Cycle 1 Day 1 | 10.0780 hour (h) | Standard Deviation 1.3932 |
| Part 1: 200 mg BID | Part 1 and Part 2: Terminal Elimination Half-life (t½) | Cycle 2 Day 1 | 8.7138 hour (h) | Standard Deviation 6.8781 |
| Part 1: 200 mg BID | Part 1 and Part 2: Terminal Elimination Half-life (t½) | Cycle 1 Day 8 (Part 1 only) | 3.5204 hour (h) | Standard Deviation 1.6584 |
| Part 1: 250 mg BID | Part 1 and Part 2: Terminal Elimination Half-life (t½) | Cycle 2 Day 1 | 10.8357 hour (h) | Standard Deviation 1.0282 |
| Part 1: 250 mg BID | Part 1 and Part 2: Terminal Elimination Half-life (t½) | Cycle 1 Day 1 | 5.9468 hour (h) | Standard Deviation 3.85 |
| Part 1: 250 mg BID | Part 1 and Part 2: Terminal Elimination Half-life (t½) | Cycle 1 Day 8 (Part 1 only) | 2.6280 hour (h) | Standard Deviation 0.8577 |
| Part 1: 300 mg BID | Part 1 and Part 2: Terminal Elimination Half-life (t½) | Cycle 1 Day 1 | 30.0521 hour (h) | Standard Deviation 42.0129 |
| Part 1: 300 mg BID | Part 1 and Part 2: Terminal Elimination Half-life (t½) | Cycle 2 Day 1 | 13.7574 hour (h) | Standard Deviation 8.1372 |
| Part 1: 300 mg BID | Part 1 and Part 2: Terminal Elimination Half-life (t½) | Cycle 1 Day 8 (Part 1 only) | 3.2062 hour (h) | Standard Deviation 0.8054 |
| Part 1: 400 mg BID | Part 1 and Part 2: Terminal Elimination Half-life (t½) | Cycle 1 Day 8 (Part 1 only) | 2.8287 hour (h) | Standard Deviation 1.2416 |
| Part 1: 400 mg BID | Part 1 and Part 2: Terminal Elimination Half-life (t½) | Cycle 2 Day 1 | 7.7683 hour (h) | Standard Deviation 5.3755 |
| Part 1: 400 mg BID | Part 1 and Part 2: Terminal Elimination Half-life (t½) | Cycle 1 Day 1 | 13.4566 hour (h) | Standard Deviation 7.3992 |
| Part 2: 300 mg QD | Part 1 and Part 2: Terminal Elimination Half-life (t½) | Cycle 1 Day 1 | 5.4384 hour (h) | Standard Deviation 1.7469 |
| Part 2: 300 mg QD | Part 1 and Part 2: Terminal Elimination Half-life (t½) | Cycle 2 Day 1 | 2.8030 hour (h) | Standard Deviation 1.2594 |
Secondary
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)
Population: The PK population include all patients who received at least one dose of study drug and have at least 50% of the planned samples above the limit of quantitation to provide evaluable PK profile, Here, number analyzed reflects number of patients evaluated on that specific cycle day.~Part 2: 1 patient was completely excluded from PK Population due to critical samples missing, 1 patient was excluded from the analysis due to sample missing at timepoint, So the overall number of participants was 27.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part 1: 75 mg QD | Part 1 and Part 2: Time to Maximum Plasma Concentration (Tmax) | Cycle 2 Day 1 | 1.00 hours (h) |
| Part 1: 75 mg QD | Part 1 and Part 2: Time to Maximum Plasma Concentration (Tmax) | Cycle 1 Day 8 (Part 1 only) | 0.78 hours (h) |
| Part 1: 75 mg QD | Part 1 and Part 2: Time to Maximum Plasma Concentration (Tmax) | Cycle 1 Day 1 | 1.00 hours (h) |
| Part 1: 125 mg QD | Part 1 and Part 2: Time to Maximum Plasma Concentration (Tmax) | Cycle 1 Day 8 (Part 1 only) | 1.00 hours (h) |
| Part 1: 125 mg QD | Part 1 and Part 2: Time to Maximum Plasma Concentration (Tmax) | Cycle 1 Day 1 | 1.08 hours (h) |
| Part 1: 125 mg QD | Part 1 and Part 2: Time to Maximum Plasma Concentration (Tmax) | Cycle 2 Day 1 | 1.00 hours (h) |
| Part 1: 200 mg QD | Part 1 and Part 2: Time to Maximum Plasma Concentration (Tmax) | Cycle 2 Day 1 | 1.00 hours (h) |
| Part 1: 200 mg QD | Part 1 and Part 2: Time to Maximum Plasma Concentration (Tmax) | Cycle 1 Day 1 | 2.00 hours (h) |
| Part 1: 200 mg QD | Part 1 and Part 2: Time to Maximum Plasma Concentration (Tmax) | Cycle 1 Day 8 (Part 1 only) | 1.00 hours (h) |
| Part 1: 300 mg QD | Part 1 and Part 2: Time to Maximum Plasma Concentration (Tmax) | Cycle 1 Day 8 (Part 1 only) | 1.54 hours (h) |
| Part 1: 300 mg QD | Part 1 and Part 2: Time to Maximum Plasma Concentration (Tmax) | Cycle 1 Day 1 | 1.04 hours (h) |
| Part 1: 300 mg QD | Part 1 and Part 2: Time to Maximum Plasma Concentration (Tmax) | Cycle 2 Day 1 | 1.05 hours (h) |
| Part 1: 400 mg QD | Part 1 and Part 2: Time to Maximum Plasma Concentration (Tmax) | Cycle 2 Day 1 | 1.00 hours (h) |
| Part 1: 400 mg QD | Part 1 and Part 2: Time to Maximum Plasma Concentration (Tmax) | Cycle 1 Day 1 | 1.00 hours (h) |
| Part 1: 400 mg QD | Part 1 and Part 2: Time to Maximum Plasma Concentration (Tmax) | Cycle 1 Day 8 (Part 1 only) | 2.00 hours (h) |
| Part 1: 100 mg BID | Part 1 and Part 2: Time to Maximum Plasma Concentration (Tmax) | Cycle 1 Day 8 (Part 1 only) | 1.00 hours (h) |
| Part 1: 100 mg BID | Part 1 and Part 2: Time to Maximum Plasma Concentration (Tmax) | Cycle 1 Day 1 | 1.00 hours (h) |
| Part 1: 100 mg BID | Part 1 and Part 2: Time to Maximum Plasma Concentration (Tmax) | Cycle 2 Day 1 | 1.00 hours (h) |
| Part 1: 200 mg BID | Part 1 and Part 2: Time to Maximum Plasma Concentration (Tmax) | Cycle 1 Day 8 (Part 1 only) | 1.00 hours (h) |
| Part 1: 200 mg BID | Part 1 and Part 2: Time to Maximum Plasma Concentration (Tmax) | Cycle 1 Day 1 | 1.00 hours (h) |
| Part 1: 200 mg BID | Part 1 and Part 2: Time to Maximum Plasma Concentration (Tmax) | Cycle 2 Day 1 | 1.00 hours (h) |
| Part 1: 250 mg BID | Part 1 and Part 2: Time to Maximum Plasma Concentration (Tmax) | Cycle 1 Day 1 | 1.46 hours (h) |
| Part 1: 250 mg BID | Part 1 and Part 2: Time to Maximum Plasma Concentration (Tmax) | Cycle 1 Day 8 (Part 1 only) | 1.98 hours (h) |
| Part 1: 250 mg BID | Part 1 and Part 2: Time to Maximum Plasma Concentration (Tmax) | Cycle 2 Day 1 | 2.07 hours (h) |
| Part 1: 300 mg BID | Part 1 and Part 2: Time to Maximum Plasma Concentration (Tmax) | Cycle 1 Day 8 (Part 1 only) | 1.52 hours (h) |
| Part 1: 300 mg BID | Part 1 and Part 2: Time to Maximum Plasma Concentration (Tmax) | Cycle 1 Day 1 | 1.02 hours (h) |
| Part 1: 300 mg BID | Part 1 and Part 2: Time to Maximum Plasma Concentration (Tmax) | Cycle 2 Day 1 | 2.08 hours (h) |
| Part 1: 400 mg BID | Part 1 and Part 2: Time to Maximum Plasma Concentration (Tmax) | Cycle 2 Day 1 | 2.00 hours (h) |
| Part 1: 400 mg BID | Part 1 and Part 2: Time to Maximum Plasma Concentration (Tmax) | Cycle 1 Day 8 (Part 1 only) | 2.03 hours (h) |
| Part 1: 400 mg BID | Part 1 and Part 2: Time to Maximum Plasma Concentration (Tmax) | Cycle 1 Day 1 | 2.00 hours (h) |
| Part 2: 300 mg QD | Part 1 and Part 2: Time to Maximum Plasma Concentration (Tmax) | Cycle 2 Day 1 | 1.08 hours (h) |
| Part 2: 300 mg QD | Part 1 and Part 2: Time to Maximum Plasma Concentration (Tmax) | Cycle 1 Day 1 | 2.00 hours (h) |
Secondary
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)
Population: The efficacy population included all patients who received at least one dose of study drug and had one baseline and at least one post-baseline efficacy assessment. Here, the overall number of subjects analyzed signifies only the subjects with available data that were analyzed evaluated on that specific cycle day.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1: 125 mg QD | Part 1: Change From Baseline in Bone Marrow Assessment | Increased by at least 1 grade level | 0 Participants |
| Part 1: 125 mg QD | Part 1: Change From Baseline in Bone Marrow Assessment | Decreased by at least 1 grade level | 1 Participants |
| Part 1: 125 mg QD | Part 1: Change From Baseline in Bone Marrow Assessment | Decreased by at least 2 grade level | 0 Participants |
| Part 1: 125 mg QD | Part 1: Change From Baseline in Bone Marrow Assessment | Increased by at least 2 grade level | 0 Participants |
| Part 1: 300 mg QD | Part 1: Change From Baseline in Bone Marrow Assessment | Increased by at least 2 grade level | 0 Participants |
| Part 1: 300 mg QD | Part 1: Change From Baseline in Bone Marrow Assessment | Decreased by at least 2 grade level | 0 Participants |
| Part 1: 300 mg QD | Part 1: Change From Baseline in Bone Marrow Assessment | Increased by at least 1 grade level | 1 Participants |
| Part 1: 300 mg QD | Part 1: Change From Baseline in Bone Marrow Assessment | Decreased by at least 1 grade level | 3 Participants |
| Part 1: 100 mg BID | Part 1: Change From Baseline in Bone Marrow Assessment | Increased by at least 2 grade level | 0 Participants |
| Part 1: 100 mg BID | Part 1: Change From Baseline in Bone Marrow Assessment | Decreased by at least 1 grade level | 0 Participants |
| Part 1: 100 mg BID | Part 1: Change From Baseline in Bone Marrow Assessment | Decreased by at least 2 grade level | 0 Participants |
| Part 1: 100 mg BID | Part 1: Change From Baseline in Bone Marrow Assessment | Increased by at least 1 grade level | 1 Participants |
| Part 1: 300 mg BID | Part 1: Change From Baseline in Bone Marrow Assessment | Increased by at least 2 grade level | 0 Participants |
| Part 1: 300 mg BID | Part 1: Change From Baseline in Bone Marrow Assessment | Decreased by at least 2 grade level | 0 Participants |
| Part 1: 300 mg BID | Part 1: Change From Baseline in Bone Marrow Assessment | Increased by at least 1 grade level | 2 Participants |
| Part 1: 300 mg BID | Part 1: Change From Baseline in Bone Marrow Assessment | Decreased by at least 1 grade level | 0 Participants |
Secondary
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)
Population: The efficacy population included all patients who received at least one dose of study drug and had one baseline and at least one post-baseline efficacy assessment. NS-018-101 study was dose finding study, PI could increase or decrease dose-level per protocol. Patients can appear in more than one dose-level cohort.~For 300 mg QD, data from 7 patients were available. 4 patients were enrolled originally and 2 patients were dose-reduced from 400 mg QD and 1 patient was dose-reduced from 250 mg BID.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: 125 mg QD | Part 1: Change From Baseline in Quality of Life Assessments Using Myelofibrosis Symptom Assessment Form (MF-SAF) | Splenomegaly-associated Symptom Score | 1.3 score on a scale | Standard Deviation 1.3 |
| Part 1: 125 mg QD | Part 1: Change From Baseline in Quality of Life Assessments Using Myelofibrosis Symptom Assessment Form (MF-SAF) | Brief Fatigue Inventory Score | 0.1 score on a scale | Standard Deviation 0.4 |
| Part 1: 125 mg QD | Part 1: Change From Baseline in Quality of Life Assessments Using Myelofibrosis Symptom Assessment Form (MF-SAF) | Overall Quality of Life Score | 0.3 score on a scale | Standard Deviation 0.6 |
| Part 1: 125 mg QD | Part 1: Change From Baseline in Quality of Life Assessments Using Myelofibrosis Symptom Assessment Form (MF-SAF) | Catabolic/Proliferative Symptoms Score | 1.2 score on a scale | Standard Deviation 0.2 |
| Part 1: 200 mg QD | Part 1: Change From Baseline in Quality of Life Assessments Using Myelofibrosis Symptom Assessment Form (MF-SAF) | Overall Quality of Life Score | -1.0 score on a scale | Standard Deviation 1.4 |
| Part 1: 200 mg QD | Part 1: Change From Baseline in Quality of Life Assessments Using Myelofibrosis Symptom Assessment Form (MF-SAF) | Splenomegaly-associated Symptom Score | -0.5 score on a scale | Standard Deviation 1.1 |
| Part 1: 200 mg QD | Part 1: Change From Baseline in Quality of Life Assessments Using Myelofibrosis Symptom Assessment Form (MF-SAF) | Catabolic/Proliferative Symptoms Score | -0.7 score on a scale | Standard Deviation 0.5 |
| Part 1: 200 mg QD | Part 1: Change From Baseline in Quality of Life Assessments Using Myelofibrosis Symptom Assessment Form (MF-SAF) | Brief Fatigue Inventory Score | -1.3 score on a scale | Standard Deviation 2 |
| Part 1: 300 mg QD | Part 1: Change From Baseline in Quality of Life Assessments Using Myelofibrosis Symptom Assessment Form (MF-SAF) | Catabolic/Proliferative Symptoms Score | -0.4 score on a scale | Standard Deviation 2.4 |
| Part 1: 300 mg QD | Part 1: Change From Baseline in Quality of Life Assessments Using Myelofibrosis Symptom Assessment Form (MF-SAF) | Brief Fatigue Inventory Score | 0.8 score on a scale | Standard Deviation 1.3 |
| Part 1: 300 mg QD | Part 1: Change From Baseline in Quality of Life Assessments Using Myelofibrosis Symptom Assessment Form (MF-SAF) | Splenomegaly-associated Symptom Score | 0.5 score on a scale | Standard Deviation 0.8 |
| Part 1: 300 mg QD | Part 1: Change From Baseline in Quality of Life Assessments Using Myelofibrosis Symptom Assessment Form (MF-SAF) | Overall Quality of Life Score | 0.0 score on a scale | Standard Deviation 3.6 |
| Part 1: 100 mg BID | Part 1: Change From Baseline in Quality of Life Assessments Using Myelofibrosis Symptom Assessment Form (MF-SAF) | Overall Quality of Life Score | -1.7 score on a scale | Standard Deviation 2.1 |
| Part 1: 100 mg BID | Part 1: Change From Baseline in Quality of Life Assessments Using Myelofibrosis Symptom Assessment Form (MF-SAF) | Splenomegaly-associated Symptom Score | -0.3 score on a scale | Standard Deviation 1.8 |
| Part 1: 100 mg BID | Part 1: Change From Baseline in Quality of Life Assessments Using Myelofibrosis Symptom Assessment Form (MF-SAF) | Catabolic/Proliferative Symptoms Score | -0.4 score on a scale | Standard Deviation 1 |
| Part 1: 100 mg BID | Part 1: Change From Baseline in Quality of Life Assessments Using Myelofibrosis Symptom Assessment Form (MF-SAF) | Brief Fatigue Inventory Score | -1.9 score on a scale | Standard Deviation 0.1 |
| Part 1: 200 mg BID | Part 1: Change From Baseline in Quality of Life Assessments Using Myelofibrosis Symptom Assessment Form (MF-SAF) | Splenomegaly-associated Symptom Score | -1.1 score on a scale | Standard Deviation 1.2 |
| Part 1: 200 mg BID | Part 1: Change From Baseline in Quality of Life Assessments Using Myelofibrosis Symptom Assessment Form (MF-SAF) | Catabolic/Proliferative Symptoms Score | 1.5 score on a scale | Standard Deviation 1.6 |
| Part 1: 200 mg BID | Part 1: Change From Baseline in Quality of Life Assessments Using Myelofibrosis Symptom Assessment Form (MF-SAF) | Brief Fatigue Inventory Score | 0.4 score on a scale | Standard Deviation 0.2 |
| Part 1: 200 mg BID | Part 1: Change From Baseline in Quality of Life Assessments Using Myelofibrosis Symptom Assessment Form (MF-SAF) | Overall Quality of Life Score | -1.5 score on a scale | Standard Deviation 2.1 |
| Part 1: 250 mg BID | Part 1: Change From Baseline in Quality of Life Assessments Using Myelofibrosis Symptom Assessment Form (MF-SAF) | Catabolic/Proliferative Symptoms Score | -8.0 score on a scale | — |
| Part 1: 250 mg BID | Part 1: Change From Baseline in Quality of Life Assessments Using Myelofibrosis Symptom Assessment Form (MF-SAF) | Splenomegaly-associated Symptom Score | -4.0 score on a scale | — |
| Part 1: 250 mg BID | Part 1: Change From Baseline in Quality of Life Assessments Using Myelofibrosis Symptom Assessment Form (MF-SAF) | Overall Quality of Life Score | 0.0 score on a scale | — |
| Part 1: 250 mg BID | Part 1: Change From Baseline in Quality of Life Assessments Using Myelofibrosis Symptom Assessment Form (MF-SAF) | Brief Fatigue Inventory Score | 0.7 score on a scale | — |
| Part 1: 300 mg BID | Part 1: Change From Baseline in Quality of Life Assessments Using Myelofibrosis Symptom Assessment Form (MF-SAF) | Overall Quality of Life Score | -1.7 score on a scale | Standard Deviation 1.5 |
| Part 1: 300 mg BID | Part 1: Change From Baseline in Quality of Life Assessments Using Myelofibrosis Symptom Assessment Form (MF-SAF) | Brief Fatigue Inventory Score | -0.8 score on a scale | Standard Deviation 1.1 |
| Part 1: 300 mg BID | Part 1: Change From Baseline in Quality of Life Assessments Using Myelofibrosis Symptom Assessment Form (MF-SAF) | Catabolic/Proliferative Symptoms Score | -0.6 score on a scale | Standard Deviation 1 |
| Part 1: 300 mg BID | Part 1: Change From Baseline in Quality of Life Assessments Using Myelofibrosis Symptom Assessment Form (MF-SAF) | Splenomegaly-associated Symptom Score | -1.8 score on a scale | Standard Deviation 1.5 |
Secondary
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)
Population: The efficacy population included all patients who received at least one dose of study drug and had one baseline and at least one post-baseline efficacy assessment. NS-018-101 study was dose finding study, PI could increase or decrease dose-level per protocol. Patients can appear in more than one dose-level cohort.~At 200 mg BID cohort, 3 patients were enrolled originally, 2 patients were dose-escalated from 100 mg BID cohort and 8 patients were dose-reduced from 300 mg BID or 400 mg BID cohort.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: 125 mg QD | Part 1: Change From Baseline in Spleen Size | -0.67 cm | Standard Deviation 2.89 |
| Part 1: 200 mg QD | Part 1: Change From Baseline in Spleen Size | -8.25 cm | Standard Deviation 3.18 |
| Part 1: 300 mg QD | Part 1: Change From Baseline in Spleen Size | -3.17 cm | Standard Deviation 3.97 |
| Part 1: 100 mg BID | Part 1: Change From Baseline in Spleen Size | -3.00 cm | Standard Deviation 3 |
| Part 1: 200 mg BID | Part 1: Change From Baseline in Spleen Size | -4.33 cm | Standard Deviation 6.66 |
| Part 1: 250 mg BID | Part 1: Change From Baseline in Spleen Size | -7.00 cm | — |
| Part 1: 300 mg BID | Part 1: Change From Baseline in Spleen Size | -2.00 cm | Standard Deviation 3 |
Secondary
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)
Population: The efficacy population included all patients who received at least one dose of study drug and had one baseline and at least one post-baseline efficacy assessment. NS-018-101 study was dose finding study, PI could increase or decrease dose-level per protocol. Patients can appear in more than one dose-level cohort.~For 300 mg QD, data from 7 patients were available. 4 patients were enrolled originally and 2 patients were dose-reduced from 400 mg QD and 1 patient was dose-reduced from 250 mg BID.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: 75 mg QD | Part 1: Number of Patients With Objective Response Using International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) | 0 Participants |
| Part 1: 125 mg QD | Part 1: Number of Patients With Objective Response Using International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) | 0 Participants |
| Part 1: 200 mg QD | Part 1: Number of Patients With Objective Response Using International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) | 0 Participants |
| Part 1: 300 mg QD | Part 1: Number of Patients With Objective Response Using International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) | 2 Participants |
| Part 1: 400 mg QD | Part 1: Number of Patients With Objective Response Using International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) | 0 Participants |
| Part 1: 100 mg BID | Part 1: Number of Patients With Objective Response Using International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) | 0 Participants |
| Part 1: 200 mg BID | Part 1: Number of Patients With Objective Response Using International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) | 1 Participants |
| Part 1: 250 mg BID | Part 1: Number of Patients With Objective Response Using International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) | 0 Participants |
| Part 1: 300 mg BID | Part 1: Number of Patients With Objective Response Using International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) | 1 Participants |
| Part 1: 400 mg BID | Part 1: Number of Patients With Objective Response Using International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) | 0 Participants |
Secondary
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)
Population: The PD population included all patients who received at least one dose of study drug and had a baseline and at least one post-baseline PD assessment (for at least one PD parameter). Here, number analyzed reflects number of patients evaluated on that specific cycle day.~Data from 17 out of 24 participants were available and contributed to the analysis. Samples from 7 patients were analyzed, but data were not available due to quantities not sufficient.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: 75 mg QD | Part 2: Change From Baseline in Phosphorylated Signal Transducer and Activator of Transcription 3 (Phospho-STAT3) | Cycle 1 Day 1: Change percentage of Phospho-STAT3 Levels in CD14+ Positive cells | -9.406 Percentage of Phospho-STAT 3 Levels | Standard Deviation 19.357 |
| Part 1: 75 mg QD | Part 2: Change From Baseline in Phosphorylated Signal Transducer and Activator of Transcription 3 (Phospho-STAT3) | Cycle 1 Day 15: Change percentage of Phospho-STAT3 Levels in CD14+ Positive cells | -2.738 Percentage of Phospho-STAT 3 Levels | Standard Deviation 16.191 |
| Part 1: 75 mg QD | Part 2: Change From Baseline in Phosphorylated Signal Transducer and Activator of Transcription 3 (Phospho-STAT3) | Cycle 2 Day 1: Change percentage of Phospho-STAT3 Levels in CD3+ CD4+ Positive cells | -5.878 Percentage of Phospho-STAT 3 Levels | Standard Deviation 16.304 |
| Part 1: 75 mg QD | Part 2: Change From Baseline in Phosphorylated Signal Transducer and Activator of Transcription 3 (Phospho-STAT3) | Cycle 1 Day 1: Change percentage of Phospho-STAT3 Levels in CD3+ CD8+ Positive cells | -3.707 Percentage of Phospho-STAT 3 Levels | Standard Deviation 11.222 |
| Part 1: 75 mg QD | Part 2: Change From Baseline in Phosphorylated Signal Transducer and Activator of Transcription 3 (Phospho-STAT3) | Cycle 1 Day 15: Change percentage of Phospho-STAT3 Levels in CD3+ CD8+ Positive cells | 5.533 Percentage of Phospho-STAT 3 Levels | Standard Deviation 14.513 |
| Part 1: 75 mg QD | Part 2: Change From Baseline in Phosphorylated Signal Transducer and Activator of Transcription 3 (Phospho-STAT3) | Cycle 2 Day 1: Change percentage of Phospho-STAT3 Levels in CD3+ CD8+ Positive cells | -1.644 Percentage of Phospho-STAT 3 Levels | Standard Deviation 6.615 |
| Part 1: 75 mg QD | Part 2: Change From Baseline in Phosphorylated Signal Transducer and Activator of Transcription 3 (Phospho-STAT3) | Cycle 2 Day 1: Change percentage of Phospho-STAT3 Levels in CD14+ Positive cells | -0.422 Percentage of Phospho-STAT 3 Levels | Standard Deviation 20.092 |
| Part 1: 75 mg QD | Part 2: Change From Baseline in Phosphorylated Signal Transducer and Activator of Transcription 3 (Phospho-STAT3) | Cycle 1 Day 1: Change percentage of Phospho-STAT3 Levels in CD3+ CD4+ Positive cells | -10.614 Percentage of Phospho-STAT 3 Levels | Standard Deviation 11.178 |
| Part 1: 75 mg QD | Part 2: Change From Baseline in Phosphorylated Signal Transducer and Activator of Transcription 3 (Phospho-STAT3) | Cycle 1 Day 15: Change percentage of Phospho-STAT3 Levels in CD3+ CD4+ Positive cells | 6.217 Percentage of Phospho-STAT 3 Levels | Standard Deviation 20.717 |
Secondary
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)
Population: The efficacy population included all patients who received at least one dose of study drug and had one baseline and at least one post-baseline efficacy assessment. Here, the overall number of subjects analyzed signifies only the subjects with available data that were analyzed evaluated on that specific cycle day.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: 75 mg QD | Part 2: Change From Baseline in Quality of Life Assessments Using Myeloproliferative Neoplasm Symptom Assessment Form (MPN SAF (MPN 10) | -0.7 score on a scale | Standard Deviation 3.4 |