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

Primary Myelofibrosis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01423851
• Other study ID #: NS-018-101
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: June 2011
• Est. completion date: April 22, 2020

Study information

• Verified date: February 2022
• Source: NS Pharma, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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)

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 77
• Est. completion date: April 22, 2020
• Est. primary completion date: April 22, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Polycythemia
• Polycythemia Vera
• Post-Essential Thrombocythemia Myelofibrosis
• Post-Polycythemia Vera Myelofibrosis
• Primary Myelofibrosis
• Thrombocythemia, Essential
• Thrombocytosis

Intervention

Drug:
• NS-018
Treatment will be administered continuously as oral daily therapy in cycles of 4 weeks in duration (28 day treatment cycles).

Locations

Country	Name	City	State
United States	University of Michigan	Ann Arbor	Michigan
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Northwestern University	Chicago	Illinois
United States	University of Chicago	Chicago	Illinois
United States	MD Anderson Cancer Center, Department of Leukemia	Houston	Texas
United States	Mayo Clinic, Jacksonville	Jacksonville	Florida
United States	Weill Cornell Medical College	New York	New York
United States	UC San Diego Moores Cancer Center	San Diego	California
United States	Mayo Clinic Scottsdale Recruiting	Scottsdale	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
NS Pharma, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	From screening to until study discontinuation (approximate 8 years 10 months)
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.	Cycle 7 Day 1 (duration of cycle was 4 weeks)
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).	From Baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks)
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.	From baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks)
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.	Cycle 7 Day 1 (duration of cycle was 4 weeks)
Secondary	Part 1: Change From Baseline in Spleen Size	Change from baseline in spleen size was assessed by palpation.	From Baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks)
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.	From baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks)
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.	From baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks)
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.	From baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks)
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.	Part 1 and Part 2: From baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks)
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.	From Baseline to Pre-dose at Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1 (duration of cycle was 4 weeks)
Secondary	Part1 and Part 2: Observed Maximum Concentration (Cmax)	To determine the Cmax as pharmacokinetic parameters of NS-018.	Pre-dose, 0.5 to 24 hours post-dose for Part 1: Cycle 1 Day 1, Cycle 1 Day 8, Cycle 2 Day 1 and for Part 2: Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1 (duration of cycle was 4 weeks)
Secondary	Part 1 and Part 2: Time to Maximum Plasma Concentration (Tmax)	To determine the Tmax as pharmacokinetic parameters of NS-018.	Pre-dose, 0.5 to 24 hours post-dose for Part 1: Cycle 1 Day 1, Cycle 1 Day 8, Cycle 2 Day 1 and for Part 2: Cycle 1 Day 1, Cycle 2 Day 1 (duration of cycle was 4 weeks)
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.	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)
Secondary	Part 1 and Part 2: Terminal Elimination Half-life (t½)	To determine the t½ as pharmacokinetic parameters of NS-018.	Pre-dose, 0.5 to 24 hours post-dose for Part 1: Cycle 1 Day 1, Cycle 1 Day 8, Cycle 2 Day 1 and for Part 2: Cycle 1 Day 1, Cycle 2 Day 1 (duration of cycle was 4 weeks)
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.	Part 1 and Part 2: Cycle 2 Day 1 (duration of cycle was 4 weeks)