Myelofibrosis
Conditions
Keywords
Myelofibrosis, Imetelstat, GRN163L, Relapsed/refractory to JAKi, IMbark
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.
Interventions
DRUGImetelstat 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.
DRUGImetelstat 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.
Sponsors
Geron Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Masking description
Initially single-blind; treatments unmasked after 1st Interim Analysis and continued as open-label treatment.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Spleen Response | 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). |
| Percentage of Participants With Symptom Response | 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
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Clinical Response Per Modified 2013 IWG-MRT | 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. |
| Percentage of Participants With Spleen Response Per Modified 2013 IWG-MRT Criteria | 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. |
| Percentage of Participants With Symptoms Response Per Modified 2013 IWG-MRT Criteria | 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. |
| Percentage of Participants With Anemia Response Per Modified 2013 IWG-MRT Criteria | 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. |
| Duration of Response (PR/CI/RWCI) as Per IWG-MRT Criteria | 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. |
| Overall Survival | 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. |
| 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 | 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. |
| EuroQol 5 Dimension 5 Level (EQ-5D-5L): Utility Score and Visual Analog Scale (VAS) | 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. |
| Percentage of Participants With Clinically Meaningful Improvement in Brief Pain Inventory (BPI) | 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. |
| Percentage of Participants With Overall Response as Per Modified 2013 International Working Group - Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Criteria | 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. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 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. |
| Maximum Observed Plasma Concentration (Cmax) of Imetelstat | 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) | — |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of Imetelstat | 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) | — |
| Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC 0-24) of Imetelstat | 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) | — |
| Area Under the Plasma Concentration-Time Profile From Time Zero to Infinity (AUC0-inf) of Imetelstat | 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 (t1/2) of Imetelstat | 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). |
| Total Systemic Clearance (CL) of Imetelstat | 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) | — |
| Volume of Distribution (Vd) of Imetelstat | 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) | — |
| Patient's Global Impression of Change (PGIC) | 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). |
| Percentage of Participants With Clinical Improvement (CI) Per Modified 2013 IWG-MRT Criteria | 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. |
Countries
Belgium, Canada, France, Germany, Israel, Italy, South Korea, Spain, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at 55 investigative sites in Belgium, Canada, France, Germany, Israel, Italy, Korea, Spain, Taiwan, United Kingdom, and the United States from August 28, 2015, to 25 October 2016. Data analyses include all data through the data cut-off date February 07, 2020.
Pre-assignment details
A total of 107 participants 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. Eligible participants were stratified based on a) spleen size ≥ 15 cm below the left costal margin by palpation (yes vs. no) and b) platelet count at study entry (platelets ≥75 x 10\^9/L \[Per Liter\] and \<150 x 10\^9L vs. ≥150 x 10\^9L).
Participants by arm
| Arm | Count |
|---|---|
| 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 until disease progression, unacceptable toxicity, or study end. 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. After the end of main study, participants 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). | 48 |
| 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. After the end of the main study, participants 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). | 59 |
| Total | 107 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 33 | 36 |
| Overall Study | Lost to Follow-up | 2 | 0 |
| Overall Study | Study Terminated by Sponsor | 5 | 14 |
| Overall Study | Withdrawal by Subject | 8 | 9 |
Baseline characteristics
| Characteristic | Imetelstat 4.7 mg/kg | Total | Imetelstat 9.4 mg/kg |
|---|---|---|---|
| Age, Continuous | 68.0 years STANDARD_DEVIATION 8.95 | 67.2 years STANDARD_DEVIATION 9.18 | 66.5 years STANDARD_DEVIATION 9.39 |
| Duration of Prior JAKi Treatment | 22.3 months | 23.0 months | 24.5 months |
| Dynamic International Prognostic Scoring System (DIPSS) High Risk | 19 Participants | 44 Participants | 25 Participants |
| Dynamic International Prognostic Scoring System (DIPSS) Intermediate 2 | 28 Participants | 62 Participants | 34 Participants |
| Dynamic International Prognostic Scoring System (DIPSS) Missing | 1 Participants | 1 Participants | 0 Participants |
| Eastern Cooperative Oncology Group (ECOG) Score 0: Asymptomatic | 11 Participants | 25 Participants | 14 Participants |
| Eastern Cooperative Oncology Group (ECOG) Score 1: Symptomatic fully ambulatory | 26 Participants | 60 Participants | 34 Participants |
| Eastern Cooperative Oncology Group (ECOG) Score 2: Self care | 11 Participants | 22 Participants | 11 Participants |
| Platelet Count ≥150 (10^9/L) | 24 Participants | 50 Participants | 26 Participants |
| Platelet Count <75 (10^9/L) | 1 Participants | 3 Participants | 2 Participants |
| Platelet Count 75 - <150 (10^9/L) | 23 Participants | 54 Participants | 31 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants | 5 Participants | 3 Participants |
| Race/Ethnicity, Customized Black/African American | 2 Participants | 4 Participants | 2 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 2 Participants | 10 Participants | 8 Participants |
| Race/Ethnicity, Customized Multiple | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 41 Participants | 85 Participants | 44 Participants |
| Race/Ethnicity, Customized Not Reported | 3 Participants | 9 Participants | 4 Participants |
| Race/Ethnicity, Customized Unknown | 2 Participants | 5 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 40 Participants | 88 Participants | 48 Participants |
| Region European Union | 19 Participants | 53 Participants | 34 Participants |
| Region Rest of World | 4 Participants | 11 Participants | 7 Participants |
| Region United States/Canada | 25 Participants | 43 Participants | 18 Participants |
| Sex: Female, Male Female | 16 Participants | 40 Participants | 24 Participants |
| Sex: Female, Male Male | 32 Participants | 67 Participants | 35 Participants |
| Spleen Size by Palpation | 17.6 centimeter (cm) STANDARD_DEVIATION 7.62 | 17.4 centimeter (cm) STANDARD_DEVIATION 7.53 | 17.3 centimeter (cm) STANDARD_DEVIATION 7.51 |
| Time from Last JAKi Treatment | 1.4 months | 1.7 months | 1.7 months |
| Type of Myelofibrosis (MF) Post Essential Thrombocythemia (PET) | 9 Participants | 19 Participants | 10 Participants |
| Type of Myelofibrosis (MF) Post Polycythemia Vera (PPV) | 12 Participants | 25 Participants | 13 Participants |
| Type of Myelofibrosis (MF) Primary MF (PMF) | 27 Participants | 63 Participants | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 34 / 48 | 36 / 59 | 1 / 12 |
| other Total, other adverse events | 47 / 48 | 59 / 59 | 12 / 12 |
| serious Total, serious adverse events | 24 / 48 | 21 / 59 | 4 / 12 |
Outcome results
Primary
Percentage of Participants With Spleen Response
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).
Time frame: Week 24
Population: Treated analysis set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Imetelstat 4.7 mg/kg | Percentage of Participants With Spleen Response | 0 percentage of participants |
| Imetelstat 9.4 mg/kg | Percentage of Participants With Spleen Response | 10.2 percentage of participants |
Primary
Percentage of Participants With Symptom Response
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.
Time frame: Week 24
Population: Treated analysis set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Imetelstat 4.7 mg/kg | Percentage of Participants With Symptom Response | 6.3 percentage of participants |
| Imetelstat 9.4 mg/kg | Percentage of Participants With Symptom Response | 32.2 percentage of participants |
Secondary
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)
Population: PK subset included all participants who had serial PK sampling during cycle 1 treatment to determine the AUC 0-24 of Imetelstat by noncompartmental PK analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Imetelstat 4.7 mg/kg | Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC 0-24) of Imetelstat | 171 μg*hr/mL | Standard Deviation 135 |
| Imetelstat 9.4 mg/kg | Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC 0-24) of Imetelstat | 501 μg*hr/mL | Standard Deviation 283 |
Secondary
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)
Population: PK subset included all participants who had serial PK sampling during cycle 1 treatment to determine AUC 0-inf of Imetelstat by noncompartmental PK analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Imetelstat 4.7 mg/kg | Area Under the Plasma Concentration-Time Profile From Time Zero to Infinity (AUC0-inf) of Imetelstat | 193 μg*h/mL | Standard Deviation 156 |
| Imetelstat 9.4 mg/kg | Area Under the Plasma Concentration-Time Profile From Time Zero to Infinity (AUC0-inf) of Imetelstat | 524 μg*h/mL | Standard Deviation 297 |
Secondary
Duration of Response (PR/CI/RWCI) as Per IWG-MRT Criteria
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.
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)
Population: Treated analysis set included all participants who received at least 1 dose of study drug. Here, overall number of participants analyzed signifies participants who were responders (PR/CI/RWCI) at any time.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Imetelstat 4.7 mg/kg | Duration of Response (PR/CI/RWCI) as Per IWG-MRT Criteria | 36.3 weeks |
| Imetelstat 9.4 mg/kg | Duration of Response (PR/CI/RWCI) as Per IWG-MRT Criteria | 38.3 weeks |
Secondary
Elimination Half-Life (t1/2) of Imetelstat
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).
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)
Population: PK subset included all participants who had serial PK sampling during cycle 1 treatment to determine the t1/2 of Imetelstat by noncompartmental PK analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Imetelstat 4.7 mg/kg | Elimination Half-Life (t1/2) of Imetelstat | 4.6 hr | Standard Deviation 1.6 |
| Imetelstat 9.4 mg/kg | Elimination Half-Life (t1/2) of Imetelstat | 5.5 hr | Standard Deviation 1.5 |
Secondary
EuroQol 5 Dimension 5 Level (EQ-5D-5L): Utility Score and Visual Analog Scale (VAS)
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.
Time frame: At the end of treatment, up to approximately 2.3 years
Population: Treated analysis set included all participants who received at least 1 dose of study drug. Here N= participants who had data at both baseline and end of treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Imetelstat 4.7 mg/kg | EuroQol 5 Dimension 5 Level (EQ-5D-5L): Utility Score and Visual Analog Scale (VAS) | EQ-5D-5L: Utility Score | 0.498 score on a scale | Standard Deviation 0.2999 |
| Imetelstat 4.7 mg/kg | EuroQol 5 Dimension 5 Level (EQ-5D-5L): Utility Score and Visual Analog Scale (VAS) | EQ-5D-5L: VAS | 51.28 score on a scale | Standard Deviation 21.143 |
| Imetelstat 9.4 mg/kg | EuroQol 5 Dimension 5 Level (EQ-5D-5L): Utility Score and Visual Analog Scale (VAS) | EQ-5D-5L: Utility Score | 0.626 score on a scale | Standard Deviation 0.2117 |
| Imetelstat 9.4 mg/kg | EuroQol 5 Dimension 5 Level (EQ-5D-5L): Utility Score and Visual Analog Scale (VAS) | EQ-5D-5L: VAS | 47.73 score on a scale | Standard Deviation 16.398 |
Secondary
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)
Population: Pharmacokinetic (PK) subset included all participants who had serial PK sampling during cycle 1 treatment to determine the maximum plasma concentration of Imetelstat by noncompartmental PK analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Imetelstat 4.7 mg/kg | Maximum Observed Plasma Concentration (Cmax) of Imetelstat | 57.0 μg/mL | Standard Deviation 72.3 |
| Imetelstat 9.4 mg/kg | Maximum Observed Plasma Concentration (Cmax) of Imetelstat | 81.9 μg/mL | Standard Deviation 40 |
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
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.
Time frame: Up to end of extension phase (approximately up to 4.2 years)
Population: Safety analysis set included all participants who received at least 1 dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Imetelstat 4.7 mg/kg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 47 Participants |
| Imetelstat 9.4 mg/kg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 59 Participants |
Secondary
Overall Survival
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.
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)
Population: Treated analysis set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Imetelstat 4.7 mg/kg | Overall Survival | 19.91 months |
| Imetelstat 9.4 mg/kg | Overall Survival | 28.09 months |
Secondary
Patient's Global Impression of Change (PGIC)
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).
Time frame: At the end of treatment, up to approximately 2.3 years
Population: Treated analysis set included all participants who received at least 1 dose of study drug. Here, overall number of participants analyzed signifies number of subjects who had data at both baseline and end of treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Imetelstat 4.7 mg/kg | Patient's Global Impression of Change (PGIC) | 4.82 score on a scale | Standard Deviation 1.237 |
| Imetelstat 9.4 mg/kg | Patient's Global Impression of Change (PGIC) | 3.97 score on a scale | Standard Deviation 1.571 |
Secondary
Percentage of Participants With Anemia Response Per Modified 2013 IWG-MRT Criteria
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.
Time frame: Every 12 weeks up to Week 48 then every 24 weeks (approximately up to 2.3 years)
Population: Treated analysis set included all participants who received at least 1 dose of study drug. All treated participants were evaluated for each response.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Imetelstat 4.7 mg/kg | Percentage of Participants With Anemia Response Per Modified 2013 IWG-MRT Criteria | Anemia response with CI | 4.2 percentage of participants |
| Imetelstat 4.7 mg/kg | Percentage of Participants With Anemia Response Per Modified 2013 IWG-MRT Criteria | Anemia response without CI | 0 percentage of participants |
| Imetelstat 9.4 mg/kg | Percentage of Participants With Anemia Response Per Modified 2013 IWG-MRT Criteria | Anemia response with CI | 6.8 percentage of participants |
| Imetelstat 9.4 mg/kg | Percentage of Participants With Anemia Response Per Modified 2013 IWG-MRT Criteria | Anemia response without CI | 1.7 percentage of participants |
Secondary
Percentage of Participants With Clinical Improvement (CI) Per Modified 2013 IWG-MRT Criteria
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.
Time frame: Every 12 weeks up to Week 48 then every 24 weeks (approximately up to 2.3 years)
Population: Treated analysis set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Imetelstat 4.7 mg/kg | Percentage of Participants With Clinical Improvement (CI) Per Modified 2013 IWG-MRT Criteria | 16.7 percentage of participants |
| Imetelstat 9.4 mg/kg | Percentage of Participants With Clinical Improvement (CI) Per Modified 2013 IWG-MRT Criteria | 25.4 percentage of participants |
Secondary
Percentage of Participants With Clinically Meaningful Improvement in Brief Pain Inventory (BPI)
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.
Time frame: Up to end of treatment (approximately up to 2.3 years)
Population: Treated analysis set included all participants who received at least 1 dose of study drug. Here, overall number of participants analyzed signifies participants who had data at both baseline and end of treatment and Number analyzed signifies the number of participants with data available for each specified category.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Imetelstat 4.7 mg/kg | Percentage of Participants With Clinically Meaningful Improvement in Brief Pain Inventory (BPI) | Pain at its Worst: Improvement | 50.0 percentage of participants |
| Imetelstat 4.7 mg/kg | Percentage of Participants With Clinically Meaningful Improvement in Brief Pain Inventory (BPI) | Pain at its Least: Improvement | 44.4 percentage of participants |
| Imetelstat 4.7 mg/kg | Percentage of Participants With Clinically Meaningful Improvement in Brief Pain Inventory (BPI) | Pain on the Average: Improvement | 55.6 percentage of participants |
| Imetelstat 4.7 mg/kg | Percentage of Participants With Clinically Meaningful Improvement in Brief Pain Inventory (BPI) | Pain Right Now: Improvement | 61.1 percentage of participants |
| Imetelstat 4.7 mg/kg | Percentage of Participants With Clinically Meaningful Improvement in Brief Pain Inventory (BPI) | Relief Pain Treatments Provided: Improvement | 50.0 percentage of participants |
| Imetelstat 4.7 mg/kg | Percentage of Participants With Clinically Meaningful Improvement in Brief Pain Inventory (BPI) | Pain Interfered General Activity: Improvement | 72.2 percentage of participants |
| Imetelstat 4.7 mg/kg | Percentage of Participants With Clinically Meaningful Improvement in Brief Pain Inventory (BPI) | Pain Interfered with Mood: Improvement | 50.0 percentage of participants |
| Imetelstat 4.7 mg/kg | Percentage of Participants With Clinically Meaningful Improvement in Brief Pain Inventory (BPI) | Pain Interfered Walking Ability: Improvement | 38.9 percentage of participants |
| Imetelstat 4.7 mg/kg | Percentage of Participants With Clinically Meaningful Improvement in Brief Pain Inventory (BPI) | Pain Interfered with Normal Work: Improvement | 61.1 percentage of participants |
| Imetelstat 4.7 mg/kg | Percentage of Participants With Clinically Meaningful Improvement in Brief Pain Inventory (BPI) | Pain Interfered with Relations: Improvement | 44.4 percentage of participants |
| Imetelstat 4.7 mg/kg | Percentage of Participants With Clinically Meaningful Improvement in Brief Pain Inventory (BPI) | Pain Interfered with Sleep: Improvement | 61.1 percentage of participants |
| Imetelstat 4.7 mg/kg | Percentage of Participants With Clinically Meaningful Improvement in Brief Pain Inventory (BPI) | Pain Interfered Enjoyment of Life: Improvement | 61.1 percentage of participants |
| Imetelstat 9.4 mg/kg | Percentage of Participants With Clinically Meaningful Improvement in Brief Pain Inventory (BPI) | Pain Interfered with Sleep: Improvement | 78.1 percentage of participants |
| Imetelstat 9.4 mg/kg | Percentage of Participants With Clinically Meaningful Improvement in Brief Pain Inventory (BPI) | Pain at its Worst: Improvement | 75.8 percentage of participants |
| Imetelstat 9.4 mg/kg | Percentage of Participants With Clinically Meaningful Improvement in Brief Pain Inventory (BPI) | Pain Interfered with Mood: Improvement | 59.4 percentage of participants |
| Imetelstat 9.4 mg/kg | Percentage of Participants With Clinically Meaningful Improvement in Brief Pain Inventory (BPI) | Pain at its Least: Improvement | 51.5 percentage of participants |
| Imetelstat 9.4 mg/kg | Percentage of Participants With Clinically Meaningful Improvement in Brief Pain Inventory (BPI) | Pain Interfered with Relations: Improvement | 53.1 percentage of participants |
| Imetelstat 9.4 mg/kg | Percentage of Participants With Clinically Meaningful Improvement in Brief Pain Inventory (BPI) | Pain on the Average: Improvement | 66.7 percentage of participants |
| Imetelstat 9.4 mg/kg | Percentage of Participants With Clinically Meaningful Improvement in Brief Pain Inventory (BPI) | Pain Interfered Walking Ability: Improvement | 78.1 percentage of participants |
| Imetelstat 9.4 mg/kg | Percentage of Participants With Clinically Meaningful Improvement in Brief Pain Inventory (BPI) | Pain Right Now: Improvement | 66.7 percentage of participants |
| Imetelstat 9.4 mg/kg | Percentage of Participants With Clinically Meaningful Improvement in Brief Pain Inventory (BPI) | Pain Interfered Enjoyment of Life: Improvement | 62.5 percentage of participants |
| Imetelstat 9.4 mg/kg | Percentage of Participants With Clinically Meaningful Improvement in Brief Pain Inventory (BPI) | Relief Pain Treatments Provided: Improvement | 53.1 percentage of participants |
| Imetelstat 9.4 mg/kg | Percentage of Participants With Clinically Meaningful Improvement in Brief Pain Inventory (BPI) | Pain Interfered with Normal Work: Improvement | 62.5 percentage of participants |
| Imetelstat 9.4 mg/kg | Percentage of Participants With Clinically Meaningful Improvement in Brief Pain Inventory (BPI) | Pain Interfered General Activity: Improvement | 68.8 percentage of participants |
Secondary
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
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.
Time frame: Up to end of the treatment (approximately up to 2.3 years)
Population: Treated analysis set included all participants who received at least 1 dose of study drug. Here, overall number of participants analyzed signifies the number of participants who had data at both baseline and end of treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Imetelstat 4.7 mg/kg | 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 | 22.2 percentage of participants |
| Imetelstat 9.4 mg/kg | 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 | 36.4 percentage of participants |
Secondary
Percentage of Participants With Clinical Response Per Modified 2013 IWG-MRT
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.
Time frame: Every 12 weeks up to Week 48 then every 24 weeks (approximately up to 2.3 years)
Population: Treated analysis set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Imetelstat 4.7 mg/kg | Percentage of Participants With Clinical Response Per Modified 2013 IWG-MRT | 16.7 percentage of participants |
| Imetelstat 9.4 mg/kg | Percentage of Participants With Clinical Response Per Modified 2013 IWG-MRT | 27.1 percentage of participants |
Secondary
Percentage of Participants With Overall Response as Per Modified 2013 International Working Group - Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Criteria
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.
Time frame: Every 12 weeks up to Week 48 then every 24 weeks (approximately up to 2.3 years)
Population: Treated analysis set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Imetelstat 4.7 mg/kg | Percentage of Participants With Overall Response as Per Modified 2013 International Working Group - Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Criteria | 0 percentage of participants |
| Imetelstat 9.4 mg/kg | Percentage of Participants With Overall Response as Per Modified 2013 International Working Group - Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Criteria | 1.7 percentage of participants |
Secondary
Percentage of Participants With Spleen Response Per Modified 2013 IWG-MRT Criteria
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.
Time frame: Every 12 weeks up to Week 48 then every 24 weeks (approximately up to 2.3 years)
Population: Treated analysis set included all participants who received at least 1 dose of study drug. All treated participants were evaluated for each response.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Imetelstat 4.7 mg/kg | Percentage of Participants With Spleen Response Per Modified 2013 IWG-MRT Criteria | Spleen response with CI | 0 percentage of participants |
| Imetelstat 4.7 mg/kg | Percentage of Participants With Spleen Response Per Modified 2013 IWG-MRT Criteria | Spleen response without CI | 2.1 percentage of participants |
| Imetelstat 9.4 mg/kg | Percentage of Participants With Spleen Response Per Modified 2013 IWG-MRT Criteria | Spleen response with CI | 3.4 percentage of participants |
| Imetelstat 9.4 mg/kg | Percentage of Participants With Spleen Response Per Modified 2013 IWG-MRT Criteria | Spleen response without CI | 0 percentage of participants |
Secondary
Percentage of Participants With Symptoms Response Per Modified 2013 IWG-MRT Criteria
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.
Time frame: Every 12 weeks up to Week 48 then every 24 weeks (approximately up to 2.3 years)
Population: Treated analysis set included all participants who received at least 1 dose of study drug. All treated participants were evaluated for each response.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Imetelstat 4.7 mg/kg | Percentage of Participants With Symptoms Response Per Modified 2013 IWG-MRT Criteria | Symptom response with CI | 14.6 percentage of participants |
| Imetelstat 4.7 mg/kg | Percentage of Participants With Symptoms Response Per Modified 2013 IWG-MRT Criteria | Symptom response without CI | 4.2 percentage of participants |
| Imetelstat 9.4 mg/kg | Percentage of Participants With Symptoms Response Per Modified 2013 IWG-MRT Criteria | Symptom response with CI | 22.0 percentage of participants |
| Imetelstat 9.4 mg/kg | Percentage of Participants With Symptoms Response Per Modified 2013 IWG-MRT Criteria | Symptom response without CI | 8.5 percentage of participants |
Secondary
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)
Population: PK subset included all participants who had serial PK sampling during cycle 1 treatment to determine the time to reach maximum plasma concentration of imetelstat by noncompartmental PK analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Imetelstat 4.7 mg/kg | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Imetelstat | 2.00 hr |
| Imetelstat 9.4 mg/kg | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Imetelstat | 2.00 hr |
Secondary
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)
Population: PK subset included all participants who had serial PK sampling during cycle 1 treatment to determine the CL of Imetelstat by noncompartmental PK analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Imetelstat 4.7 mg/kg | Total Systemic Clearance (CL) of Imetelstat | 0.0329 L/hr/kg | Standard Deviation 0.0138 |
| Imetelstat 9.4 mg/kg | Total Systemic Clearance (CL) of Imetelstat | 0.0252 L/hr/kg | Standard Deviation 0.0157 |
Secondary
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)
Population: PK population analysis set included all participants who received at least 1 dose of study drug and had at least 1 sample collected during treatment to determine the drug concentration.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Imetelstat 4.7 mg/kg | Volume of Distribution (Vd) of Imetelstat | 0.198 L/kg | Standard Deviation 0.077 |
| Imetelstat 9.4 mg/kg | Volume of Distribution (Vd) of Imetelstat | 0.190 L/kg | Standard Deviation 0.104 |