Clinical Trial Results:
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
Summary
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EudraCT number |
2015-000946-41 |
Trial protocol |
BE DE GB ES FR IT |
Global end of trial date |
07 Feb 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
22 Feb 2021
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First version publication date |
22 Feb 2021
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
63935937MYF2001
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02426086 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Geron Corporation
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Sponsor organisation address |
919 E. Hillsdale Boulevard, Suite 250, Foster City, CA, United States, 94404
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Public contact |
Clinical Trial Enquiries, Geron Corporation, myf2001-info@Geron.com
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Scientific contact |
Clinical Trial Enquiries, Geron Corporation, myf2001-info@Geron.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
07 Feb 2020
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
07 Feb 2020
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objectives of this study was to evaluate the efficacy and safety of 2 dose regimens of imetelstat (9.4 milligram/kilogram [mg/kg] and 4.7 mg/kg imetelstat given intravenous [IV] every 3 weeks) in subjects with intermediate-2 or high-risk MF who relapsed after or refractory to JAK inhibitor treatment.
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Protection of trial subjects |
The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
28 Aug 2015
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Spain: 8
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Country: Number of subjects enrolled |
United Kingdom: 4
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Country: Number of subjects enrolled |
Belgium: 5
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Country: Number of subjects enrolled |
France: 8
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Country: Number of subjects enrolled |
Germany: 14
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Country: Number of subjects enrolled |
Italy: 14
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Country: Number of subjects enrolled |
Canada: 1
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Country: Number of subjects enrolled |
Israel: 7
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Country: Number of subjects enrolled |
Korea, Republic of: 3
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Country: Number of subjects enrolled |
Taiwan: 1
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Country: Number of subjects enrolled |
United States: 42
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Worldwide total number of subjects |
107
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EEA total number of subjects |
53
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
34
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From 65 to 84 years |
72
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85 years and over |
1
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Recruitment
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Recruitment details |
Subjects were enrolled at 55 investigative sites in Belgium, Canada, France, Germany, Israel, Italy, Korea, Spain, Taiwan, United Kingdom, and the United States from 28 August 2015 to 25 October 2016. Data analyses include all data through the cut-off date 07 February 2020. | |||||||||||||||||||||||||||
Pre-assignment
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Screening details |
A total of 107 subjects with Intermediate-2 or High-Risk Myelofibrosis (MF) Relapsed/Refractory to Janus Kinase (JAK) Inhibitor were randomly assigned to 1 of 2 treatment arms into 1:1 ratio to imetelstat 4.7 or imetelstat 9.4 mg/kg of body weight. Disposition data is reported till the end of study. | |||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Single blind | |||||||||||||||||||||||||||
Roles blinded |
Subject | |||||||||||||||||||||||||||
Blinding implementation details |
Initially single-blind; treatments unmasked after 1st Interim Analysis and continued as open-label treatment.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Imetelstat 4.7 mg/kg | |||||||||||||||||||||||||||
Arm description |
Subjects received imetelstat 4.7 mg/kg of body weight as intravenous infusion on Day 1 of each 21-day cycle until disease progression, unacceptable toxicity, or study end. After the first interim analysis, treatment for all subjects was unblinded and subjects 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. After the end of main study, subjects who were receiving benefit from study treatment opted to continue to receive imetelstat during the Extension Phase until there is loss of benefit or unacceptable toxicity. (Maximum duration on study was approximately 2.3 years and Maximum duration on extension phase was approximately 1.8 years). | |||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||
Investigational medicinal product name |
Imetelstat
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Investigational medicinal product code |
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Other name |
GRN163L, JNJ-63935937
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Subjects received imetelstat 4.7 mg/kg of body weight as intravenous infusion on Day 1 of each 21-day cycle until disease progression, unacceptable toxicity, or study end. After the first interim analysis, treatment for all subjects was unblinded and subjects 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. After the end of main study, subjects who were receiving benefit from study treatment opted to continue to receive imetelstat during the Extension Phase until there is loss of benefit or unacceptable toxicity.
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Arm title
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Imetelstat 9.4 mg/kg | |||||||||||||||||||||||||||
Arm description |
Subjects received imetelstat 9.4 mg/kg of body weight as intravenous infusion on Day 1 of each 21-days cycle until disease progression, unacceptable toxicity, or study end. After the end of the main study, subjects who were receiving benefit from study treatment opted to continue to receive imetelstat during the Extension Phase until there is loss of benefit or unacceptable toxicity. (Maximum duration on study was approximately 2.3 years and Maximum duration on extension phase was approximately 1.8 years). | |||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||
Investigational medicinal product name |
Imetelstat 9.4 mg/kg
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Investigational medicinal product code |
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Other name |
GRN163L, JNJ-63935937
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Subjects received imetelstat 9.4 mg/kg of body weight as intravenous infusion on Day 1 of each 21-days cycle until disease progression, unacceptable toxicity, or study end. After the end of the main study, subjects who were receiving benefit from study treatment opted to continue to receive imetelstat during the Extension Phase until there is loss of benefit or unacceptable toxicity.
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Baseline characteristics reporting groups
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Reporting group title |
Imetelstat 4.7 mg/kg
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Reporting group description |
Subjects received imetelstat 4.7 mg/kg of body weight as intravenous infusion on Day 1 of each 21-day cycle until disease progression, unacceptable toxicity, or study end. After the first interim analysis, treatment for all subjects was unblinded and subjects 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. After the end of main study, subjects who were receiving benefit from study treatment opted to continue to receive imetelstat during the Extension Phase until there is loss of benefit or unacceptable toxicity. (Maximum duration on study was approximately 2.3 years and Maximum duration on extension phase was approximately 1.8 years). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Imetelstat 9.4 mg/kg
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Reporting group description |
Subjects received imetelstat 9.4 mg/kg of body weight as intravenous infusion on Day 1 of each 21-days cycle until disease progression, unacceptable toxicity, or study end. After the end of the main study, subjects who were receiving benefit from study treatment opted to continue to receive imetelstat during the Extension Phase until there is loss of benefit or unacceptable toxicity. (Maximum duration on study was approximately 2.3 years and Maximum duration on extension phase was approximately 1.8 years). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Imetelstat 4.7 mg/kg
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Reporting group description |
Subjects received imetelstat 4.7 mg/kg of body weight as intravenous infusion on Day 1 of each 21-day cycle until disease progression, unacceptable toxicity, or study end. After the first interim analysis, treatment for all subjects was unblinded and subjects 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. After the end of main study, subjects who were receiving benefit from study treatment opted to continue to receive imetelstat during the Extension Phase until there is loss of benefit or unacceptable toxicity. (Maximum duration on study was approximately 2.3 years and Maximum duration on extension phase was approximately 1.8 years). | ||
Reporting group title |
Imetelstat 9.4 mg/kg
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Reporting group description |
Subjects received imetelstat 9.4 mg/kg of body weight as intravenous infusion on Day 1 of each 21-days cycle until disease progression, unacceptable toxicity, or study end. After the end of the main study, subjects who were receiving benefit from study treatment opted to continue to receive imetelstat during the Extension Phase until there is loss of benefit or unacceptable toxicity. (Maximum duration on study was approximately 2.3 years and Maximum duration on extension phase was approximately 1.8 years). | ||
Subject analysis set title |
PK: Imetelstat 4.7 mg/kg
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects received imetelstat 4.7 mg/kg of body weight as intravenous infusion on Day 1 of cycle 1 and those who had serial PK samples collected.
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Subject analysis set title |
PK: Imetelstat 9.4 mg/kg
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects received imetelstat 9.4 mg/kg of body weight as intravenous infusion on Day 1 of cycle 1 and those who had serial PK samples collected.
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End point title |
Percentage of Subjects with Spleen Response [1] | ||||||||||||
End point description |
Spleen response rate is defined as the percentage of subjects who achieved ≥35% reduction in spleen volume at Week 24 from baseline performed by the IRC using magnetic resonance imaging (MRI). Treated analysis set included all subjects who received at least 1 dose of study drug.
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End point type |
Primary
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End point timeframe |
Week 24
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Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The percentage and 95% CI are the statistical analysis per protocol. |
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No statistical analyses for this end point |
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End point title |
Percentage of Subjects with Symptom Response [2] | ||||||||||||
End point description |
Symptom response rate is defined as percentage of subjects 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. Treated analysis set included all subjects who received at least 1 dose of study drug.
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End point type |
Primary
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End point timeframe |
Week 24
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Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The percentage and 95% CI are the statistical analysis per protocol. |
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No statistical analyses for this end point |
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End point title |
Percentage of Subjects With Overall Response as Per Modified 2013 International Working Group - Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Criteria | ||||||||||||
End point description |
Overall response rate (ORR): % of subjects with complete remission (CR) or partial R (PR).CR: bone marrow(BM): normocellular <5% blasts, ≤ Grade 1 fibrosis; immature myeloid cells (IMC) in peripheral blood (PB): <2%; 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 hematopoeisis (EMH): no non-hepato-splenic EMH; symptoms: >70% improvement in symptom score. 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. Response categories benefit last >12 weeks to qualify as response. Treated analysis set was used. Upper and lower limits of 95% CI not estimable due to limited number of events and indicate by 99999.
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End point type |
Secondary
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End point timeframe |
Every 12 weeks up to Week 48 then every 24 weeks (approximately up to 2.3 years)
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No statistical analyses for this end point |
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End point title |
Percentage of Subjects With Clinical Improvement (CI) Per Modified 2013 IWG-MRT Criteria | ||||||||||||
End point description |
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. Treated analysis set: subjects who received ≥ 1 dose of study drug.
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End point type |
Secondary
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End point timeframe |
Every 12 weeks up to Week 48 then every 24 weeks (approximately up to 2.3 years)
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No statistical analyses for this end point |
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End point title |
Percentage of Subjects With Clinical Response Per Modified 2013 IWG-MRT | ||||||||||||
End point description |
Clinical response rate (CRR): % of subjects 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. 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. CI: achievement of anemia, spleen or symptoms response without PD or increase in severity of anemia, thrombocytopenia, or neutropenia. Treated analysis set: subjects who received ≥ 1 dose of study drug.
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End point type |
Secondary
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End point timeframe |
Every 12 weeks up to Week 48 then every 24 weeks (approximately up to 2.3 years)
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No statistical analyses for this end point |
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End point title |
Percentage of Subjects With Spleen Response Per Modified 2013 IWG-MRT Criteria | ||||||||||||||||||
End point description |
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. Subjects who achieved CI per modified IWG-MRT criteria considered as response with clinical improvement. Subjects 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. Treated analysis set included all subjects who received at least 1 dose of study drug.
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End point type |
Secondary
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End point timeframe |
Every 12 weeks up to Week 48 then every 24 weeks (approximately up to 2.3 years)
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No statistical analyses for this end point |
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End point title |
Percentage of Subjects With Symptom Response Per Modified 2013 IWG-MRT Criteria | ||||||||||||||||||
End point description |
Symptom 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. Subjects who achieved CI per modified IWG-MRT criteria considered as response with clinical improvement. Subjects 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. Treated analysis set included all subjects who received at least 1 dose of study drug.
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End point type |
Secondary
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End point timeframe |
Every 12 weeks up to Week 48 then every 24 weeks (approximately up to 2.3 years)
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No statistical analyses for this end point |
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End point title |
Percentage of Subjects With Anemia Response Per Modified 2013 IWG-MRT Criteria | ||||||||||||||||||
End point description |
Anemia response per modified 2013 IWG-MRT criteria. Anemia response is defined as subjects with baseline Hb <10 g/dL but not meeting strict criteria for transfusion dependency: a ≥ 2 g/dL increase in Hb; Transfusion dependent subjects 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. Subjects who achieved CI per modified IWG-MRT criteria considered as response with clinical improvement. Subjects 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. Treated analysis set included all subjects who received at least 1 dose of study drug.
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End point type |
Secondary
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End point timeframe |
Every 12 weeks up to Week 48 then every 24 weeks (approximately up to 2.3 years)
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No statistical analyses for this end point |
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End point title |
Duration of Response (PR/CI/RWCI) as Per IWG-MRT Criteria | ||||||||||||
End point description |
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: Subjects who met criteria for response but had worsening cytopenias. PD: Splenomegaly requires MRI showing ≥25% increase in spleen volume. Treated analysis set included all subjects who received at least 1 dose of study drug. Overall number of subjects analysed ("N") = subjects who were responders (PR/CI/RWCI) at any time.
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End point type |
Secondary
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End point 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)
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No statistical analyses for this end point |
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End point title |
Overall Survival | ||||||||||||
End point description |
Overall Survival is measured from the date of Cycle 1, Day 1 to the date of the subject’s death. If the subject was alive or the vital status was unknown, OS was censored at the date that the subject is last known to be alive. Treated analysis set included all subjects who received at least 1 dose of study drug.
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End point type |
Secondary
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End point timeframe |
Day 1 of Cycle 1 (each cycle was of 21 days) up to the date of the subject’s death (approximately up to 4.1 years)
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No statistical analyses for this end point |
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End point title |
Percentage of Subjects with Clinically Meaningful Improvement in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-30 (QLQ-C30): Global Health Status | |||||||||||||||
End point description |
EORTC QLQ-C30 is a questionnaire to assess quality of life of cancer subjects. 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. Treated analysis set included all subjects who received at least 1 dose of study drug. Here "N"= subjects who had data at both baseline and end of treatment.
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End point type |
Secondary
|
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End point timeframe |
Up to end of the treatment (approximately up to 2.3 years)
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No statistical analyses for this end point |
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End point title |
EuroQol 5 Dimension 5 Level (EQ-5D-5L): Utility Score and Visual Analog Scale (VAS) | ||||||||||||||||||
End point description |
EQ-5D-5L is standardized health-related quality of life questionnaire developed by EuroQol Group to provide a simple, generic measure of health for clinical and economic appraisal. EQ-5D-5L consists of two components: 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. 5D-5L systems are converted into single index utility score between 0 to 1, where higher score indicates a better health state. EQ-5D-5L- VAS is designed to rate subject's current health state on scale from 0 to 100, where 0 represents worst imaginable health state and 100 represents best imaginable health state. Treated analysis set was used. “n”= number of subjects with data available for each specified category and "N"= subjects who had data at both baseline and end of treatment.
|
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End point type |
Secondary
|
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End point timeframe |
Baseline up to end of treatment (approximately up to 2.3 years)
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No statistical analyses for this end point |
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End point title |
Percentage of Subjects With Clinically Meaningful Improvement in Brief Pain Inventory (BPI) | ||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
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 (Imp) in BPI defined as change greater than half of the standard deviation at baseline. Treated analysis set included all subjects who received at least 1 dose of study drug. Here, “N” signifies number of subjects who had data at both baseline and end of treatment and “n” is the number of subjects with data available for each specified category.
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End point type |
Secondary
|
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End point timeframe |
Up to end of treatment (approximately up to 2.3 years)
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No statistical analyses for this end point |
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End point title |
Patient’s Global Impression of Change (PGIC) | ||||||||||||
End point description |
The PGIC was used to capture the subject'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. Treated analysis set included all subjects who received at least 1 dose of study drug. Here, "N" signifies number of subjects who had data at both baseline and end of treatment.
|
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End point type |
Secondary
|
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End point timeframe |
Up to end of treatment (approximately up to 2.3 years)
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No statistical analyses for this end point |
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End point title |
Number of Subjects with Treatment-emergent Adverse Events (TEAEs) | ||||||||||||
End point description |
An AE is any untoward medical occurrence in a subject or clinical investigation subjects 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. Safety analysis set included all subjects who received at least 1 dose of study treatment.
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End point type |
Secondary
|
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End point timeframe |
Up to end of extension phase (approximately up to 4.2 years)
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No statistical analyses for this end point |
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End point title |
Maximum Observed Plasma Concentration (Cmax) of Imetelstat | ||||||||||||
End point description |
Pharmacokinetic (PK) subset included all subjects who had serial PK sampling during cycle 1 treatment to determine the maximum plasma concentration of Imetelstat by noncompartmental PK analysis.
|
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End point type |
Secondary
|
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End point 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)
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No statistical analyses for this end point |
|
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End point title |
Time to Reach Maximum Observed Plasma Concentration (Tmax) of Imetelstat | ||||||||||||
End point description |
PK subset included all subjects who had serial PK sampling during cycle 1 treatment to determine the time to reach maximum plasma concentration of imetelstat by noncompartmental PK analysis.
|
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End point type |
Secondary
|
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End point 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)
|
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|
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No statistical analyses for this end point |
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End point title |
Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC 0-24) of Imetelstat | ||||||||||||
End point description |
PK subset included all subjects who had serial PK sampling during cycle 1 treatment to determine the AUC 0-24 of Imetelstat by noncompartmental PK analysis.
|
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End point type |
Secondary
|
||||||||||||
End point 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)
|
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|
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No statistical analyses for this end point |
|
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End point title |
Area Under the Plasma Concentration-Time Profile From Time Zero to Infinity (AUC0-inf) of Imetelstat | ||||||||||||
End point description |
PK subset included all subjects who had serial PK sampling during cycle 1 treatment to determine AUC 0-inf of Imetelstat by noncompartmental PK analysis.
|
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End point type |
Secondary
|
||||||||||||
End point 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)
|
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|
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No statistical analyses for this end point |
|
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End point title |
Elimination Half-Life (t1/2) of Imetelstat | ||||||||||||
End point description |
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). PK subset included all subjects who had serial PK sampling during cycle 1 treatment to determine the t1/2 of Imetelstat by noncompartmental PK analysis.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point 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)
|
||||||||||||
|
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No statistical analyses for this end point |
|
|||||||||||||
End point title |
Total Systemic Clearance (CL) of Imetelstat | ||||||||||||
End point description |
PK subset included all subjects who had serial PK sampling during cycle 1 treatment to determine the CL of Imetelstat by noncompartmental PK analysis.
|
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End point type |
Secondary
|
||||||||||||
End point 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)
|
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|
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No statistical analyses for this end point |
|
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End point title |
Volume of Distribution (Vd) of Imetelstat | ||||||||||||
End point description |
PK population analysis set included all subjects who received at least 1 dose of study drug and had at least 1 sample collected during treatment to determine the drug concentration.
|
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End point type |
Secondary
|
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End point 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)
|
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|
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No statistical analyses for this end point |
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Adverse events information
|
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Timeframe for reporting adverse events |
Up to end of extension phase (approximately up to 4.2 years)
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Adverse event reporting additional description |
Safety analysis set included all subjects who received at least 1 dose of study treatment.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
21.1
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Reporting groups
|
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Reporting group title |
Imetelstat 4.7 mg/kg
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Reporting group description |
Subjects received imetelstat 4.7 mg/kg of body weight as intravenous infusion on Day 1 of each 21-day cycle until disease progression, unacceptable toxicity, or study end. After the first interim analysis, treatment for all subjects was unblinded and subjects 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. After the end of main study, subjects who were receiving benefit from study treatment opted to continue to receive imetelstat during the Extension Phase until there is loss of benefit or unacceptable toxicity. (Maximum duration on study was approximately 2.3 years and Maximum duration on extension phase was approximately 1.8 years). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Imetelstat 9.4 mg/kg
|
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Reporting group description |
Subjects received imetelstat 9.4 mg/kg of body weight as intravenous infusion on Day 1 of each 21-days cycle until disease progression, unacceptable toxicity, or study end. After the end of the main study, subjects who were receiving benefit from study treatment opted to continue to receive imetelstat during the Extension Phase until there is loss of benefit or unacceptable toxicity. (Maximum duration on study was approximately 2.3 years and Maximum duration on extension phase was approximately 1.8 years). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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23 Nov 2015 |
This amendment included revisions to study eligibility criteria based on feedback from investigators and discussion with the independent Hepatic Expert Committee and clarified some aspects of study conduct.
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29 Sep 2016 |
Following the first interim review, this amendment was implemented to suspend enrollment of
new subjects into the 9.4 mg/kg arm and permanently close enrollment into the 4.7 mg/kg arm.
The study was unblinded and randomization was discontinued. This amendment added a second
planned interim review with guidelines for interpretation of results. |
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13 Mar 2018 |
This amendment confirmed the final study analysis would occur per protocol 18 months after the
last subject had been enrolled because sufficient data had been collected. The study was closed to
further subject enrollment. An Extension Phase was added to the protocol to allow continued
treatment for subjects benefiting from treatment with study drug and to continue collection of
survival data for subjects no longer receiving treatment. |
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20 Dec 2018 |
This amendment extended the Extension Phase from 1 year to 2 years. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |