Blood and Lymph Conditions

All Conditions

Neoplasms

Heart and Blood Diseases

Rare Diseases

Myeloproliferative Disorders

Polycythemia Vera

Polycythemia

Primary Myelofibrosis

Bone Marrow Diseases

Thrombocytosis

Thrombocythemia, Essential

Hematologic Diseases

Bone Marrow Neoplasms

Hematologic Neoplasms

Blood Platelet Disorders

Hemostatic Disorders

Blood Coagulation Disorders

Hemorrhagic Disorders

Chronic Myeloproliferative Disorders

Essential Thrombocythemia

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.

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

NS-018

Srdan Verstovsek, M.D., Ph.D.

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)

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

Phase 1: 75, 125, 200, 300, 400 mg QD and 100, 200, 250, 300, 400 mg BID Phase 2: 300 mg QD

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

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

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.

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.

Change from baseline in spleen size was assessed by magnetic resonance imaging (MRI) (computed tomography \[CT\] scan for patients not able to tolerate MRI).

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.

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.

Change from baseline in spleen size was assessed by palpation.

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.

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.

The JAK2 V617F allele burden mean changes from baseline (%) are presented as pharmacodynamics parameters.

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.

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

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

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

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

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.

NS Pharma, Inc.

Safety population: NS-018-101 study was dose finding study, 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.

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.

Part 1: 75 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.

Part 1: 125 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.

Part 1: 200 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.

Part 1: 300 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.

Part 1: 400 mg QD

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.

Part 1: 100 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.

Part 1: 200 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.

Part 1: 250 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.

Part 1: 300 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.

Part 1: 400 mg BID

Part 2: 300 mg QD

Total

Part 1

Part 2

For Age continuous, Part 1 and Part 2 data are presented in different rows (48+29=77).

Age, Continuous

Sex: Female, Male

White/Caucasian

Black/African Heritage

Asian/Oriental

Other

Race/Ethnicity, Customized

Medical Affairs

Not TEAE

Any AE

Any Treatment Emergent AE

Drug Related TEAE

Any Serious TEAE

TEAE Leading to Discontinuation of study drug

Hospitalization or Prolongation of Existing Hospitalization

Death

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.

Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event

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.

Part 2: Number of Patient With Objective Response Using International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European Leukemia Net (ELN)

Part 2: Change From Baseline in Spleen Size

Part 2: Change From Baseline in Bone Marrow Assessment

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.

Part 1: Number of Patients With Objective Response Using International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT)

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.

Part 1: Change From Baseline in Spleen Size

Part 1: Change From Baseline in Bone Marrow Assessment

Brief Fatigue Inventory Score

Splenomegaly-associated Symptom Score

Catabolic/Proliferative Symptoms Score

Overall Quality of Life Score

Part 1: Change From Baseline in Quality of Life Assessments Using Myelofibrosis Symptom Assessment Form (MF-SAF)

Part 2: Change From Baseline in Quality of Life Assessments Using Myeloproliferative Neoplasm Symptom Assessment Form (MPN SAF (MPN 10)

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.

Part 1 and Part 2: Change in Baseline in Janus Kinase 2 (JAK2) V617F Allele Burden Levels

Cycle 1 Day 1: Change percentage of Phospho-STAT3 Levels in CD14+ Positive cells

Cycle 1 Day 15: Change percentage of Phospho-STAT3 Levels in CD14+ Positive cells

Cycle 2 Day 1: Change percentage of Phospho-STAT3 Levels in CD14+ Positive cells

Cycle 1 Day 1: Change percentage of Phospho-STAT3 Levels in CD3+ CD4+ Positive cells

Cycle 1 Day 15: Change percentage of Phospho-STAT3 Levels in CD3+ CD4+ Positive cells

Cycle 2 Day 1: Change percentage of Phospho-STAT3 Levels in CD3+ CD4+ Positive cells

Cycle 1 Day 1: Change percentage of Phospho-STAT3 Levels in CD3+ CD8+ Positive cells

Cycle 1 Day 15: Change percentage of Phospho-STAT3 Levels in CD3+ CD8+ Positive cells

Cycle 2 Day 1: Change percentage of Phospho-STAT3 Levels in CD3+ CD8+ Positive cells

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.

Part 2: Change From Baseline in Phosphorylated Signal Transducer and Activator of Transcription 3 (Phospho-STAT3)

Cycle 1 Day 1

Cycle 1 Day 8 (Part 1 only)

Cycle 1 Day 15 (Part 2 only)

Cycle 2 Day 1

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.

Part1 and Part 2: Observed Maximum Concentration (Cmax)

Patients self-administered orally 250 mg of NS-018 twice 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.

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

Cycle 2 Day 1 (Part 1 only)

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.

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

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

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Safety and Tolerability Study of Oral NS-018 in Patients With Primary Myelofibrosis (MF), Post-polycythemia Vera MF or Post-essential Thrombocythemia MF	NCT01423851	Primary Myelofi... Post-Polycythem... Post-Essential ...	NS-018	18 Years -	NS Pharma, Inc.
Safety and Tolerability Study of Oral NS-018 in Patients With Primary Myelofibrosis (MF), Post-polycythemia Vera MF or Post-essential Thrombocythemia MF	NCT01423851	Primary Myelofi... Post-Polycythem... Post-Essential ...	NS-018	18 Years -	NS Pharma, Inc.

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