Clinical trial NCT01423851: Safety and Tolerability Study of Oral NS-018 in Patients With Primary Myelofibrosis (MF), Post-polycythemia Vera MF or Post-essential Thrombocythemia MF
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Primary Myelofibrosis
Post-Polycythemia Vera Myelofibrosis
Post-Essential Thrombocythemia Myelofibrosis
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
Lead sponsor: NS Pharma, Inc.
Sponsor class: INDUSTRY
First posted: 2011-08-26
Enrollment: 77
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
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
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event
timeFrame: From screening to until study discontinuation (approximate 8 years 10 months)
measure: Part 2: Number of Patient With Objective Response Using International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European Leukemia Net (ELN)
timeFrame: Cycle 7 Day 1 (duration of cycle was 4 weeks)
measure: Part 2: Change From Baseline in Spleen Size
timeFrame: From Baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks)
measure: Part 2: Change From Baseline in Bone Marrow Assessment
timeFrame: From baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks)
Secondary outcomes:
measure: Part 1: Number of Patients With Objective Response Using International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT)
timeFrame: Cycle 7 Day 1 (duration of cycle was 4 weeks)
measure: Part 1: Change From Baseline in Spleen Size
timeFrame: From Baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks)
measure: Part 1: Change From Baseline in Bone Marrow Assessment
timeFrame: From baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks)
measure: Part 1: Change From Baseline in Quality of Life Assessments Using Myelofibrosis Symptom Assessment Form (MF-SAF)
timeFrame: From baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks)
measure: Part 2: Change From Baseline in Quality of Life Assessments Using Myeloproliferative Neoplasm Symptom Assessment Form (MPN SAF (MPN 10)
timeFrame: From baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks)
measure: Part 1 and Part 2: Change in Baseline in Janus Kinase 2 (JAK2) V617F Allele Burden Levels
timeFrame: Part 1 and Part 2: From baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks)
measure: Part 2: Change From Baseline in Phosphorylated Signal Transducer and Activator of Transcription 3 (Phospho-STAT3)
timeFrame: From Baseline to Pre-dose at Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1 (duration of cycle was 4 weeks)
measure: Part1 and Part 2: Observed Maximum Concentration (Cmax)
timeFrame: 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)
measure: Part 1 and Part 2: Time to Maximum Plasma Concentration (Tmax)
timeFrame: 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)
measure: Part1 and Part 2: Area Under the Plasma Concentration-time Curve (AUC0-24)
timeFrame: 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)
measure: Part 1 and Part 2: Terminal Elimination Half-life (t½)
timeFrame: 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)
measure: Part1 and Part 2: Accumulation Ratio (AR)
timeFrame: Part 1 and Part 2: Cycle 2 Day 1 (duration of cycle was 4 weeks)
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic Scottsdale Recruiting
state: Arizona
city: San Diego
country: United States
facility: UC San Diego Moores Cancer Center
state: California
city: Jacksonville
country: United States
facility: Mayo Clinic, Jacksonville
state: Florida
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: Houston
country: United States
facility: MD Anderson Cancer Center, Department of Leukemia
state: Texas
Study officials:
affiliation: MD Anderson Cancer Center, Houston, TX, 77030
name: Srdan Verstovsek, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Verstovsek S, Talpaz M, Ritchie E, Wadleigh M, Odenike O, Jamieson C, Stein B, Uno T, Mesa RA. A phase I, open-label, dose-escalation, multicenter study of the JAK2 inhibitor NS-018 in patients with myelofibrosis. Leukemia. 2017 Feb;31(2):393-402. doi: 10.1038/leu.2016.215. Epub 2016 Aug 1.