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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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02426086
Recruitment Status : Completed
First Posted : April 24, 2015
Results First Posted : September 14, 2021
Last Update Posted : September 14, 2021
Sponsor:
Information provided by (Responsible Party):
Geron Corporation

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.

Condition or disease Intervention/treatment Phase
Myelofibrosis Drug: Imetelstat 4.7 mg/kg Drug: Imetelstat 9.4 mg/kg Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 107 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Masking Description: Initially single-blind; treatments unmasked after 1st Interim Analysis and continued as open-label treatment.
Primary Purpose: Treatment
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
Actual Study Start Date : August 28, 2015
Actual Primary Completion Date : April 26, 2018
Actual Study Completion Date : February 7, 2020


Arm Intervention/treatment
Experimental: Imetelstat 4.7 mg/kg Drug: Imetelstat 4.7 mg/kg
Participants received imetelstat 4.7 mg/kg of body weight as intravenous infusion on Day 1 of each 21-day cycle. Study drug was administered intravenously until disease progression, unacceptable toxicity, or study end.

Experimental: Imetelstat 9.4 mg/kg Drug: Imetelstat 9.4 mg/kg
Participants received imetelstat 9.4 mg/kg of body weight as intravenous infusion on Day 1 of each 21-day cycle until disease progression, unacceptable toxicity, or study end.




Primary Outcome Measures :
  1. Percentage of Participants With Spleen Response [ Time Frame: Week 24 ]
    Spleen response rate is defined as the percentage of participants who achieved ≥ 35% reduction in spleen volume at Week 24 from baseline performed by the IRC using magnetic resonance imaging (MRI).

  2. Percentage of Participants With Symptom Response [ Time Frame: Week 24 ]
    Symptom response rate is defined as percentage of participants who achieved ≥ 50% reduction in total symptom score (TSS) at Week 24 from baseline as measured by the modified Myelofibrosis Symptom Assessment Form (MFSAF) version 2.0 diary. The MFSAF assessed following symptoms due to Myelofibrosis (MF): night sweats, itchiness, abdominal discomfort, pain under ribs on left side, feeling of fullness, bone or muscle pain and degree of inactivity. Each item is scored on a scale of 0 (absent) to 10 (worst imaginable) with higher scores indicating more severe symptoms and greater inactivity. The total score ranges from 0-70, where 0 indicates absent/as good as it can be and 70 indicates worst imaginable/as bad as it can be.


Secondary Outcome Measures :
  1. Percentage of Participants With Overall Response as Per Modified 2013 International Working Group - Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Criteria [ Time Frame: Every 12 weeks up to Week 48 then every 24 weeks (approximately up to 2.3 years) ]
    Overall Response Rate: % of participants with complete remission (CR) or partial remission (PR) per modified IWG-MRT.CR: bone marrow: normocellular <5% blasts, ≤Grade 1 fibrosis; immature myeloid cells in peripheral blood (PB):<2%;hemoglobin (Hb):10 g/dL-upper limit of normal (ULN); neutrophils:1*10^9/L-ULN; platelets: 100*10^9/L-ULN; spleen:not palpable and ≤350ml volume; extramedullary hematopoiesis (EMH): no non-hepato-splenic EMH; symptoms: >70% improvement in symptom score per modified MFSAF v2.0 TSS. PR: bone marrow: normocellular: <5% blasts ≤ Grade 1 fibrosis or not meeting bone marrow remission criteria; Immature myeloid cells in PB: <2%; Hb: 8.5 -<10 g/dL-ULN or 10 g/dL-ULN; neutrophils: 1*10^9/L-ULN; platelets: 50 -<100*10^9/L-ULN; spleen: ≥35% splenic volumetric reduction by MRI or not palpable; EMH: no non-hepato-splenic EMH;symptoms: >50% improvement in symptom score per modified MFSAF v2.0 TSS. All response categories, benefit must last >12 weeks to qualify as response.

  2. Percentage of Participants With Clinical Improvement (CI) Per Modified 2013 IWG-MRT Criteria [ Time Frame: Every 12 weeks up to Week 48 then every 24 weeks (approximately up to 2.3 years) ]
    CI per the modified 2013 IWG-MRT criteria defined as the achievement of anemia, spleen or symptoms response without progressive disease or increase in severity of anemia, thrombocytopenia, or neutropenia (Increase in severity of anemia constitutes the occurrence of new transfusion dependency or a ≥ 2.0 g/dL decrease in hemoglobin level from pretreatment baseline that lasts for at least 12 weeks. Increase in severity of thrombocytopenia or neutropenia is defined as a 2-grade decline, from pretreatment baseline, in platelet count or ANC, according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. In addition, assignment to CI requires a minimum platelet count of ≥ 25,000*10^9/L and ANC of ≥ 0.5*10^9/L.) For all response categories, benefit must last for >12 weeks to qualify as a response.

  3. Percentage of Participants With Clinical Response Per Modified 2013 IWG-MRT [ Time Frame: Every 12 weeks up to Week 48 then every 24 weeks (approximately up to 2.3 years) ]
    Clinical response rate (CRR) was defined as percentage of participants who achieved CR, PR, or CI per modified 2013 IWG-MRT criteria. CR: bone marrow: normocellular <5% blasts, ≤Grade 1 fibrosis; immature myeloid cells in PB: <2%; Hb: 10 g/dL-ULN; neutrophils: 1*10^9/L-ULN; platelets: 100*10^9/L-ULN; spleen: not palpable and ≤350ml volume; EMH: no non-hepato-splenic EMH; symptoms: >70% improvement in symptom score per modified MFSAF v2.0 TSS. PR: bone marrow: normocellular: <5% blasts ≤ Grade 1 fibrosis or not meeting bone marrow remission criteria; Immature myeloid cells in PB: <2%; Hb: 8.5 -<10 g/dL-ULN or 10 g/dL-ULN; neutrophils: 1*10^9/L-ULN; platelets: 50 -<100*10^9/L-ULN; spleen: ≥35% splenic volumetric reduction by MRI or not palpable; EMH: no non-hepato-splenic EMH; symptoms: >50% improvement in symptom score per modified MFSAF v2.0 TSS. CI: achievement of anemia, spleen or symptoms response without PD or increase in severity of anemia, thrombocytopenia, or neutropenia.

  4. Percentage of Participants With Spleen Response Per Modified 2013 IWG-MRT Criteria [ Time Frame: Every 12 weeks up to Week 48 then every 24 weeks (approximately up to 2.3 years) ]
    Spleen response per modified 2013 IWG-MRT criteria. Spleen response: a baseline splenomegaly that is palpable at 5-10 cm, below the left costal margin (LCM), becomes not palpable or a baseline splenomegaly that is palpable at >10 cm, below the LCM, decreases by ≥50%; A spleen response requires confirmation by MRI showing >35% spleen volume reduction (SVR). For response categories, benefit must last for >12 weeks to qualify as a response. Participants who achieved CI per modified IWG-MRT criteria considered as response with clinical improvement. Participants who met criteria for spleen response but had worsening cytopenias (and therefore did not meet criteria for clinical improvement) were considered to have a response without clinical improvement. The clinical improvement in IWG-MRT is defined as the achievement of anemia, spleen or symptoms response without progressive disease or increase in severity of anemia, thrombocytopenia, or neutropenia.

  5. Percentage of Participants With Symptoms Response Per Modified 2013 IWG-MRT Criteria [ Time Frame: Every 12 weeks up to Week 48 then every 24 weeks (approximately up to 2.3 years) ]
    Symptoms response per modified 2013 IWG-MRT criteria. Symptoms Response: a ≥50% reduction in the modified MFSAF v2.0 TSS. For response category, benefit must last for >12 weeks to qualify as a response. Participants who achieved CI per modified IWG-MRT criteria considered as response with clinical improvement. Participants who met criteria for symptom response but had worsening cytopenias (and therefore did not meet criteria for clinical improvement) were considered to have a response without clinical improvement. The clinical improvement in IWG-MRT is defined as the achievement of anemia, spleen or symptoms response without progressive disease or increase in severity of anemia, thrombocytopenia, or neutropenia.

  6. Percentage of Participants With Anemia Response Per Modified 2013 IWG-MRT Criteria [ Time Frame: Every 12 weeks up to Week 48 then every 24 weeks (approximately up to 2.3 years) ]
    Anemia response per modified 2013 IWG-MRT criteria. Anemia response is defined as participants with baseline Hb <10 g/dL but not meeting strict criteria for transfusion dependency: a ≥ 2 g/dL increase in Hb; Transfusion dependent participants at baseline: becoming transfusion independent. Transfusion independence is defined as absence of any pRBC transfusions for at least 12 "rolling" weeks. For response categories, benefit must last for >12 weeks to qualify as a response. Participants who achieved CI per modified IWG-MRT criteria considered as response with clinical improvement. Participants who met criteria for anemia response but had worsening cytopenias (and therefore did not meet criteria for clinical improvement) were considered to have a response without clinical improvement. The clinical improvement in IWG-MRT is defined as the achievement of anemia, spleen or symptoms response without progressive disease or increase in severity of anemia, thrombocytopenia, or neutropenia.

  7. Duration of Response (PR/CI/RWCI) as Per IWG-MRT Criteria [ Time Frame: 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) ]
    Duration of response (PR/CI/RWCI) is the duration from the date of initial documentation of a response to date of first documented evidence of PD or death, whichever occurs first. PR: BM: normocellular: <5% blasts ≤Grade 1 fibrosis/not meeting BM remission criteria; IMC in PB: <2%; Hb: 8.5 -<10 g/dL-ULN or 10 g/dL- ULN; neutrophils: 1*10^9/L-ULN; platelets: 50 -<100*10^9/L-ULN; spleen: ≥35% splenic volumetric reduction by MRI/not palpable; EMH: no non-hepato-splenic EMH; symptoms: >50% improvement in symptom score. CI: achievement of anemia, spleen or symptoms response without PD or increase in severity of anemia, thrombocytopenia, neutropenia. RWCI: Participants who met criteria for response but had worsening cytopenias. PD: Splenomegaly requires MRI showing ≥25% increase in spleen volume.

  8. Overall Survival [ Time Frame: 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) ]
    Overall Survival is measured from the date of Cycle 1, Day 1 to the date of the participants death. If the participant's was alive or the vital status was unknown, OS was censored at the date that the participant is last known to be alive.

  9. 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 [ Time Frame: Up to end of the treatment (approximately up to 2.3 years) ]
    EORTC QLQ-C30 is a questionnaire to assess quality of life of cancer patients. The EORTC QLQ-C30 included 30 items resulting in 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties) which are based on 4-point scale (1= Not at all to 4= Very much); and 1 global health status scale based on 7-point scale (1= Very poor to 7= Excellent). All scales and items are averaged, transformed to 0-100 scale; higher score=better level of functioning. Clinically meaningful improvement defined as change greater than half of the standard deviation at baseline in QLQ-C30 Global Health Status.

  10. EuroQol 5 Dimension 5 Level (EQ-5D-5L): Utility Score and Visual Analog Scale (VAS) [ Time Frame: At the end of treatment, up to approximately 2.3 years ]
    EQ-5D-5L is a standardized health-related quality of life questionnaire developed by EuroQol Group in order to provide a simple, generic measure of health for clinical and economic appraisal. EQ-5D-5L consists of two components: a health state profile and VAS. EQ-5D health state profile comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: 1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems, and 5=extreme problems. The 5D-5L systems are converted into a single index utility score between 0 to 1, where higher score indicates a better health state. EQ-5D-5L- VAS is designed to rate the participant's current health state on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state.

  11. Percentage of Participants With Clinically Meaningful Improvement in Brief Pain Inventory (BPI) [ Time Frame: Up to end of treatment (approximately up to 2.3 years) ]
    The BPI rates the intensity of pain on 4 items (right now, worst, least, and average), and the interference in 7 areas (general activity, mood, walking ability, normal work, relations, sleep, enjoyment of life). Minimum value = 0; maximum value = 10. Higher scores indicate greater symptom severity/worse outcomes. Clinically meaningful improvement in BPI defined as change greater than half of the standard deviation at baseline.

  12. Patient's Global Impression of Change (PGIC) [ Time Frame: At the end of treatment, up to approximately 2.3 years ]
    The PGIC was used to capture the participant's perspective of improvement or decline in MF symptoms over time. The PGIC had a 7-point response scale ranging from 1 to 7 where, (1=very much improved, 2= somewhat improved, 3= a little improved, 4=no change, 5= a little worse, 6= somewhat worse, 7=very much worse).

  13. Number of Participants With Treatment-emergent Adverse Events (TEAEs) [ Time Frame: Up to end of extension phase (approximately up to 4.2 years) ]
    An AE is any untoward medical occurrence in a participant or clinical investigation participants administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. TEAEs were AEs with onset during or after the first dose of study drug, and within 30 days following the last dose of study drug.

  14. Maximum Observed Plasma Concentration (Cmax) of Imetelstat [ Time Frame: 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) ]
  15. Time to Reach Maximum Observed Plasma Concentration (Tmax) of Imetelstat [ Time Frame: 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) ]
  16. Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC 0-24) of Imetelstat [ Time Frame: 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) ]
  17. Area Under the Plasma Concentration-Time Profile From Time Zero to Infinity (AUC0-inf) of Imetelstat [ Time Frame: 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) ]
  18. Elimination Half-Life (t1/2) of Imetelstat [ Time Frame: 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) ]
    Elimination half-life (t 1/2) is associated with the terminal slope (lambda [z]) of the semi logarithmic drug concentration-time curve, calculated as 0.693/lambda(z).

  19. Total Systemic Clearance (CL) of Imetelstat [ Time Frame: 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) ]
  20. Volume of Distribution (Vd) of Imetelstat [ Time Frame: 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) ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02426086


Locations
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Sponsors and Collaborators
Geron Corporation
Investigators
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Study Director: Study Clinical Team Geron Corporation
  Study Documents (Full-Text)

Documents provided by Geron Corporation:
Study Protocol  [PDF] March 28, 2019
Statistical Analysis Plan  [PDF] May 14, 2018

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Geron Corporation
ClinicalTrials.gov Identifier: NCT02426086    
Other Study ID Numbers: CR107170
63935937MYF2001 ( Other Identifier: Geron Corporation )
2015-000946-41 ( EudraCT Number )
First Posted: April 24, 2015    Key Record Dates
Results First Posted: September 14, 2021
Last Update Posted: September 14, 2021
Last Verified: August 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Keywords provided by Geron Corporation:
Myelofibrosis
Imetelstat
GRN163L
Relapsed/refractory to JAKi
IMbark
Additional relevant MeSH terms:
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Imetelstat
Motesanib diphosphate
Primary Myelofibrosis
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Niacinamide
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Protein Kinase Inhibitors
Vitamin B Complex
Vitamins
Micronutrients
Physiological Effects of Drugs