Clinical trial NCT02426086: Study to Evaluate Activity of 2 Dose Levels of Imetelstat in Participants With Intermediate-2 or High-Risk Myelofibrosis (MF) Previously Treated With Janus Kinase (JAK) Inhibitor
Official title: A Randomized, Single-Blind, Multicenter Phase 2 Study to Evaluate the Activity of 2 Dose Levels of Imetelstat in Subjects With Intermediate-2 or High-Risk Myelofibrosis (MF) Relapsed/Refractory to Janus Kinase (JAK) Inhibitor
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Myelofibrosis
Keywords: Myelofibrosis
Imetelstat
GRN163L
Relapsed/refractory to JAKi
IMbark
Lead sponsor: Geron Corporation
Sponsor class: INDUSTRY
First posted: 2015-04-24
Enrollment: 107
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the efficacy and safety of 2 dose regimens of imetelstat in participants with intermediate-2 or high-risk myelofibrosis (MF) whose disease is relapsed after or is refractory to Janus Kinase (JAK) inhibitor treatment. Key secondary endpoint includes overall survival.

Detailed description: This is a randomized (study medication assigned to participants by chance), multicenter (more than one hospital, medical school team or medical clinic work on a medical research study) study of 2 dosing regimens (treatment arms) of single-agent imetelstat in participants with intermediate-2 or high risk myelofibrosis (MF) whose disease is relapsed after or refractory to Janus Kinase (JAK) inhibitor treatment. The main study consists of 3 parts: Screening Phase (21 days before randomization); Treatment Phase (from randomization until study drug discontinuation); and Follow up Phase (until death, lost to follow-up, withdrawal of consent or study end, whichever occurs first). Participants received imetelstat 9.4 milligram (mg)/kilogram (kg) intravenously (IV) for every 3 weeks until disease progression, unacceptable toxicity, or study end OR imetelstat 4.7 mg/kg IV for every 3 weeks until disease progression, unacceptable toxicity, or study end. Initially, all participants were blinded to the treatment. After the first interim analysis, treatment for all participants was unblinded and participants assigned to the imetelstat 4.7 mg/kg arm could continue with their same imetelstat dose or have it increased to 9.4 mg/kg at the investigator's discretion. The percentage of spleen response and symptom response were evaluated as co-primary endpoints. Following completion of the primary analysis, participants benefiting from study treatment could continue to receive imetelstat in Extension phase for up to 2 years or until loss of benefit or unacceptable toxicity. Participants who had already stopped study treatment could enter the Extension phase to continue follow up for safety via serious adverse event collection and for survival status.

Eligibility criteria: Inclusion Criteria:

* Diagnosis of primary myelofibrosis (PMF) according to the revised WHO criteria; or post-essential thrombocythemia-myelofibrosis (PET-MF) or post-polycythemia vera-myelofibrosis (PPV-MF) according to the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria.
* Dynamic International Prognostic Scoring System (DIPSS) intermediate-2 or highrisk MF.
* Measurable splenomegaly prior to study entry as demonstrated by palpable spleen measuring ≥ 5 cm below the left costal margin OR spleen volume of ≥ 450 cm\^3 measured by magnetic resonance imaging (MRI).
* Active symptoms of MF as demonstrated by a symptom score of at least 5 points (on a 0 to 10 scale) on at least one of the symptoms or a score of 3 or greater on at least 2 of the symptoms.
* Documented progressive disease during or after Janus kinase (JAK) inhibitor therapy.
* Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2.

Exclusion Criteria:

* Peripheral blood blast count of ≥ 10% or bone marrow blast count of ≥ 10%.
* Prior treatment with imetelstat.
* Any chemotherapy or MF-directed therapy, investigational drug, hydroxyurea, immunomodulatory or immunosuppressive therapy, corticosteroids or JAK inhibitor therapy ≤14 days prior to randomization.
* Major surgery within 4 weeks prior to randomization.
* Active systemic hepatitis infection requiring treatment (carriers of hepatitis virus are permitted to enter the study), of any type or known acute or chronic liver disease including cirrhosis.
* Prior history of hematopoietic stem cell transplant.

Primary outcomes:
measure: Percentage of Participants With Spleen Response
timeFrame: Week 24
measure: Percentage of Participants With Symptom Response
timeFrame: Week 24
Secondary outcomes:
measure: Percentage of Participants With Overall Response as Per Modified 2013 International Working Group - Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Criteria
timeFrame: Every 12 weeks up to Week 48 then every 24 weeks (approximately up to 2.3 years)
measure: Percentage of Participants With Clinical Improvement (CI) Per Modified 2013 IWG-MRT Criteria
timeFrame: Every 12 weeks up to Week 48 then every 24 weeks (approximately up to 2.3 years)
measure: Percentage of Participants With Clinical Response Per Modified 2013 IWG-MRT
timeFrame: Every 12 weeks up to Week 48 then every 24 weeks (approximately up to 2.3 years)
measure: Percentage of Participants With Spleen Response Per Modified 2013 IWG-MRT Criteria
timeFrame: Every 12 weeks up to Week 48 then every 24 weeks (approximately up to 2.3 years)
measure: Percentage of Participants With Symptoms Response Per Modified 2013 IWG-MRT Criteria
timeFrame: Every 12 weeks up to Week 48 then every 24 weeks (approximately up to 2.3 years)
measure: Percentage of Participants With Anemia Response Per Modified 2013 IWG-MRT Criteria
timeFrame: Every 12 weeks up to Week 48 then every 24 weeks (approximately up to 2.3 years)
measure: Duration of Response (PR/CI/RWCI) as Per IWG-MRT Criteria
timeFrame: From date of initial documentation of a response to the date of first documented evidence of PD or death, whichever occurs first (approximately up to 2.3 years)
measure: Overall Survival
timeFrame: Day 1 of Cycle 1 (each cycle was of 21 days), up to the date of the participant's death (approximately up to 4.1 years)
measure: Percentage of Participants With Clinically Meaningful Improvement in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-30 (QLQ-C30): Global Health Status
timeFrame: Up to end of the treatment (approximately up to 2.3 years)
measure: EuroQol 5 Dimension 5 Level (EQ-5D-5L): Utility Score and Visual Analog Scale (VAS)
timeFrame: At the end of treatment, up to approximately 2.3 years
measure: Percentage of Participants With Clinically Meaningful Improvement in Brief Pain Inventory (BPI)
timeFrame: Up to end of treatment (approximately up to 2.3 years)
measure: Patient's Global Impression of Change (PGIC)
timeFrame: At the end of treatment, up to approximately 2.3 years
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
timeFrame: Up to end of extension phase (approximately up to 4.2 years)
measure: Maximum Observed Plasma Concentration (Cmax) of Imetelstat
timeFrame: 0 (before start of infusion), 1, 2, 3-5, 6-10, 12-16 and 18-24 hours post dose on Day 1 of Cycle 1 (each cycle was of 21 days)
measure: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Imetelstat
timeFrame: 0 (before start of infusion), 1, 2, 3-5, 6-10, 12-16 and 18-24 hours post dose on Day 1 of Cycle 1 (each cycle was of 21 days)
measure: Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC 0-24) of Imetelstat
timeFrame: 0 (before start of infusion), 1, 2, 3-5, 6-10, 12-16 and 18-24 hours post dose on Day 1 of Cycle 1 (each cycle was of 21 days)
measure: Area Under the Plasma Concentration-Time Profile From Time Zero to Infinity (AUC0-inf) of Imetelstat
timeFrame: 0 (before start of infusion), 1, 2, 3-5, 6-10, 12-16 and 18-24 hours post dose on Day 1 of Cycle 1 (each cycle was of 21 days)
measure: Elimination Half-Life (t1/2) of Imetelstat
timeFrame: 0 (before start of infusion), 1, 2, 3-5, 6-10, 12-16 and 18-24 hours post dose on Day 1 of Cycle 1 (each cycle was of 21 days)
measure: Total Systemic Clearance (CL) of Imetelstat
timeFrame: 0 (before start of infusion), 1, 2, 3-5, 6-10, 12-16 and 18-24 hours post dose on Day 1 of Cycle 1 (each cycle was of 21 days)
measure: Volume of Distribution (Vd) of Imetelstat
timeFrame: 0 (before start of infusion), 1, 2, 3-5, 6-10, 12-16 and 18-24 hours post dose on Day 1 of Cycle 1 (each cycle was of 21 days)
Other outcomes:
Locations:
city: Birmingham
country: United States
state: Alabama
city: Duarte
country: United States
state: California
city: La Jolla
country: United States
state: California
city: Los Angeles
country: United States
state: California
city: Stanford
country: United States
state: California
city: Washington
country: United States
state: District of Columbia
city: Tampa
country: United States
state: Florida
city: West Palm Beach
country: United States
state: Florida
city: Chicago
country: United States
state: Illinois
city: Louisville
country: United States
state: Kentucky
city: Baltimore
country: United States
state: Maryland
city: Ann Arbor
country: United States
state: Michigan
city: Rochester
country: United States
state: Minnesota
city: Saint Louis
country: United States
state: Missouri
city: Bronx
country: United States
state: New York
city: Buffalo
country: United States
state: New York
city: Lake Success
country: United States
state: New York
city: New York
country: United States
state: New York
city: Charlotte
country: United States
state: North Carolina
city: Durham
country: United States
state: North Carolina
city: Winston-Salem
country: United States
state: North Carolina
city: Cincinnati
country: United States
state: Ohio
city: Philadelphia
country: United States
state: Pennsylvania
city: Greenville
country: United States
state: South Carolina
city: Watertown
country: United States
state: South Dakota
city: Nashville
country: United States
state: Tennessee
city: Dallas
country: United States
state: Texas
city: Seattle
country: United States
state: Washington
city: Milwaukee
country: United States
state: Wisconsin
city: Antwerpen
country: Belgium
city: Brugge
country: Belgium
city: Brussel
country: Belgium
city: Leuven
country: Belgium
city: Edmonton
country: Canada
state: Alberta
city: Winnipeg
country: Canada
state: Manitoba
city: Montreal
country: Canada
state: Quebec
city: Angers
country: France
city: Lille
country: France
city: Marseille Cedex 9
country: France
city: Paris
country: France
city: Pierre Benite
country: France
city: Toulouse cedex 9
country: France
city: Aachen
country: Germany
city: Dresden
country: Germany
city: Duesseldorf
country: Germany
city: Frankfurt
country: Germany
city: Hamburg
country: Germany
city: Heidelberg
country: Germany
city: Koeln
country: Germany
city: Leipzig
country: Germany
city: Mannheim
country: Germany
city: Rostock
country: Germany
city: Haifa
country: Israel
city: Jerusalem
country: Israel
city: Kfar Saba
country: Israel
city: Nahariya
country: Israel
city: Ramat Gan
country: Israel
city: Tel Aviv
country: Israel
city: Bergamo
country: Italy
city: Bologna
country: Italy
city: Seoul
country: Korea, Republic of
city: Barcelona
country: Spain
city: Las Palmas De Gran Canaria
country: Spain
city: Madrid
country: Spain
city: Salamanca
country: Spain
city: Valencia
country: Spain
city: Chiayi City
country: Taiwan
city: Taipei
country: Taiwan
city: Birmingham
country: United Kingdom
city: Glasgow
country: United Kingdom
city: London
country: United Kingdom
city: Oxford
country: United Kingdom
Study officials:
affiliation: Geron Corporation
name: Study Clinical Team
role: STUDY_DIRECTOR
References:
citation: Mascarenhas J, Komrokji RS, Palandri F, Martino B, Niederwieser D, Reiter A, Scott BL, Baer MR, Hoffman R, Odenike O, Vannucchi AM, Bussolari J, Zhu E, Rose E, Sherman L, Dougherty S, Sun L, Huang F, Wan Y, Feller FM, Rizo A, Kiladjian JJ. Randomized, Single-Blind, Multicenter Phase II Study of Two Doses of Imetelstat in Relapsed or Refractory Myelofibrosis. J Clin Oncol. 2021 Sep 10;39(26):2881-2892. doi: 10.1200/JCO.20.02864. Epub 2021 Jun 17.