A Phase 2 interventional study of Imetelstat 4.7 mg/kg and Imetelstat 9.4 mg/kg in Myelofibrosis, sponsored by Geron Corporation. Completed at 72 sites in 11 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2021-09-14.
Sponsored by Geron Corporation · Phase 2, Interventional, and Treatment
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.
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.
Exclusion Criteria:
Drug: Imetelstat 4.7 mg/kg
Drug: Imetelstat 9.4 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.
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.
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
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
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)
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)
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)
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)
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)
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)
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)
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)
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)
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
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)
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
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)
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)
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)
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)
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)
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)
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)
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)
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.
| Milestone | Imetelstat 4.7 mg/kg | Imetelstat 9.4 mg/kg |
|---|---|---|
| Started | 48 | 59 |
| Treated | 48 | 59 |
| Completed | 0 | 0 |
| Not completed | 48 | 59 |
| Withdrew: Death | 33 | 36 |
| Withdrew: Lost to follow-up | 2 | 0 |
| Withdrew: Study terminated by sponsor | 5 | 14 |
| Withdrew: Withdrawal by subject | 8 | 9 |
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 | Imetelstat 4.7 mg/kg | Imetelstat 9.4 mg/kg |
|---|---|---|
| Percentage of Participants With Spleen Response | 0 (0 to 7.4) | 10.2 (3.8 to 20.8) |
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.
| percentage of participants | Imetelstat 4.7 mg/kg | Imetelstat 9.4 mg/kg |
|---|---|---|
| Percentage of Participants With Symptom Response | 6.3 (1.3 to 17.2) | 32.2 (20.6 to 45.6) |
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.
| percentage of participants | Imetelstat 4.7 mg/kg | 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 | 0 (NA to NA) | 1.7 (0.0 to 9.1) |
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.
| percentage of participants | Imetelstat 4.7 mg/kg | Imetelstat 9.4 mg/kg |
|---|---|---|
| Percentage of Participants With Clinical Improvement (CI) Per Modified 2013 IWG-MRT Criteria | 16.7 | 25.4 |
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 | Imetelstat 4.7 mg/kg | Imetelstat 9.4 mg/kg |
|---|---|---|
| Percentage of Participants With Clinical Response Per Modified 2013 IWG-MRT | 16.7 (7.5 to 30.2) | 27.1 (16.4 to 40.3) |
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 | Imetelstat 4.7 mg/kg | Imetelstat 9.4 mg/kg |
|---|---|---|
| Spleen response with CI | 0 | 3.4 |
| Spleen response without CI | 2.1 | 0 |
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 | Imetelstat 4.7 mg/kg | Imetelstat 9.4 mg/kg |
|---|---|---|
| Symptom response with CI | 14.6 | 22.0 |
| Symptom response without CI | 4.2 | 8.5 |
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.
| percentage of participants | Imetelstat 4.7 mg/kg | Imetelstat 9.4 mg/kg |
|---|---|---|
| Anemia response with CI | 4.2 | 6.8 |
| Anemia response without CI | 0 | 1.7 |
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.
| weeks | Imetelstat 4.7 mg/kg | Imetelstat 9.4 mg/kg |
|---|---|---|
| Duration of Response (PR/CI/RWCI) as Per IWG-MRT Criteria | 36.3 (11.9 to 60.0) | 38.3 (27.0 to 48.3) |
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.
| months | Imetelstat 4.7 mg/kg | Imetelstat 9.4 mg/kg |
|---|---|---|
| Overall Survival | 19.91 (17.05 to 33.87) | 28.09 (22.80 to 31.61) |
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.
| percentage of participants | Imetelstat 4.7 mg/kg | 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 | 22.2 | 36.4 |
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.
| score on a scale | Imetelstat 4.7 mg/kg | Imetelstat 9.4 mg/kg |
|---|---|---|
| EQ-5D-5L: Utility Score | 0.498 ± 0.2999 | 0.626 ± 0.2117 |
| EQ-5D-5L: VAS | 51.28 ± 21.143 | 47.73 ± 16.398 |
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 | Imetelstat 4.7 mg/kg | Imetelstat 9.4 mg/kg |
|---|---|---|
| Pain at its Worst: Improvement | 50.0 | 75.8 |
| Pain at its Least: Improvement | 44.4 | 51.5 |
| Pain on the Average: Improvement | 55.6 | 66.7 |
| Pain Right Now: Improvement | 61.1 | 66.7 |
| Relief Pain Treatments Provided: Improvement | 50.0 | 53.1 |
| Pain Interfered General Activity: Improvement | 72.2 | 68.8 |
| Pain Interfered with Mood: Improvement | 50.0 | 59.4 |
| Pain Interfered Walking Ability: Improvement | 38.9 | 78.1 |
| Pain Interfered with Normal Work: Improvement | 61.1 | 62.5 |
| Pain Interfered with Relations: Improvement | 44.4 | 53.1 |
| Pain Interfered with Sleep: Improvement | 61.1 | 78.1 |
| Pain Interfered Enjoyment of Life: Improvement | 61.1 | 62.5 |
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).
| score on a scale | Imetelstat 4.7 mg/kg | Imetelstat 9.4 mg/kg |
|---|---|---|
| Patient's Global Impression of Change (PGIC) | 4.82 ± 1.237 | 3.97 ± 1.571 |
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.
| Participants | Imetelstat 4.7 mg/kg | Imetelstat 9.4 mg/kg |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 47 | 59 |
| μg/mL | PK: Imetelstat 4.7 mg/kg | PK: Imetelstat 9.4 mg/kg |
|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) of Imetelstat | 57.0 ± 72.3 | 81.9 ± 40.0 |
| hr | PK: Imetelstat 4.7 mg/kg | PK: Imetelstat 9.4 mg/kg |
|---|---|---|
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of Imetelstat | 2.00 (1.93 to 2.20) | 2.00 (1.00 to 2.75) |
| μg*hr/mL | PK: Imetelstat 4.7 mg/kg | PK: Imetelstat 9.4 mg/kg |
|---|---|---|
| Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC 0-24) of Imetelstat | 171 ± 135 | 501 ± 283 |
| μg*h/mL | PK: Imetelstat 4.7 mg/kg | PK: Imetelstat 9.4 mg/kg |
|---|---|---|
| Area Under the Plasma Concentration-Time Profile From Time Zero to Infinity (AUC0-inf) of Imetelstat | 193 ± 156 | 524 ± 297 |
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).
| hr | PK: Imetelstat 4.7 mg/kg | PK: Imetelstat 9.4 mg/kg |
|---|---|---|
| Elimination Half-Life (t1/2) of Imetelstat | 4.6 ± 1.6 | 5.5 ± 1.5 |
| L/hr/kg | PK: Imetelstat 4.7 mg/kg | PK: Imetelstat 9.4 mg/kg |
|---|---|---|
| Total Systemic Clearance (CL) of Imetelstat | 0.0329 ± 0.0138 | 0.0252 ± 0.0157 |
| L/kg | PK: Imetelstat 4.7 mg/kg | PK: Imetelstat 9.4 mg/kg |
|---|---|---|
| Volume of Distribution (Vd) of Imetelstat | 0.198 ± 0.0770 | 0.190 ± 0.104 |
Collected over Up to end of extension phase (approximately up to 4.2 years). Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Imetelstat 4.7 mg/kg | 34/48 (70.8%) | 24/48 (50%) | 47/48 (97.9%) |
| Imetelstat 9.4 mg/kg | 36/59 (61%) | 21/59 (35.6%) | 59/59 (100%) |
| Imetelstat Dose Escalated From 4.7 mg/kg to 9.4 mg/kg | 1/12 (8.3%) | 4/12 (33.3%) | 12/12 (100%) |
| Event | Imetelstat 4.7 mg/kg | Imetelstat 9.4 mg/kg | Imetelstat Dose Escalated From 4.7 mg/kg to 9.4 mg/kg |
|---|---|---|---|
| CellulitisInfections and infestations | 1/48 | 0/59 | 1/12 |
| Urinary tract infectionInfections and infestations | 1/48 | 0/59 | 1/12 |
| DyspnoeaRespiratory, thoracic and mediastinal disorders | 4/48 | 1/59 | 1/12 |
| Rotator cuff syndromeMusculoskeletal and connective tissue disorders | 0/48 | 0/59 | 1/12 |
| MyelofibrosisNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 0/48 | 0/59 | 1/12 |
| Cerebral haemorrhageNervous system disorders | 0/48 | 0/59 | 1/12 |
| EncephalopathyNervous system disorders | 0/48 | 0/59 | 1/12 |
| Splenic infarctionBlood and lymphatic system disorders | 2/48 | 0/59 | 0/12 |
| Abdominal painGastrointestinal disorders | 2/48 | 0/59 | 0/12 |
| PneumoniaInfections and infestations | 2/48 | 1/59 | 0/12 |
| Event | Imetelstat 4.7 mg/kg | Imetelstat 9.4 mg/kg | Imetelstat Dose Escalated From 4.7 mg/kg to 9.4 mg/kg |
|---|---|---|---|
| ThrombocytopeniaBlood and lymphatic system disorders | 11/48 | 29/59 | 4/12 |
| AnaemiaBlood and lymphatic system disorders | 15/48 | 26/59 | 5/12 |
| DiarrhoeaGastrointestinal disorders | 18/48 | 18/59 | 3/12 |
| NeutropeniaBlood and lymphatic system disorders | 5/48 | 21/59 | 3/12 |
| NauseaGastrointestinal disorders | 15/48 | 20/59 | 1/12 |
| Oedema peripheralGeneral disorders | 13/48 | 10/59 | 3/12 |
| FatigueGeneral disorders | 10/48 | 15/59 | 1/12 |
| DyspnoeaRespiratory, thoracic and mediastinal disorders | 7/48 | 15/59 | 1/12 |
| Abdominal painGastrointestinal disorders | 9/48 | 14/59 | 0/12 |
| AstheniaGeneral disorders | 9/48 | 14/59 | 1/12 |
Intent-to-Treat (ITT) analysis set included all participants randomized into the study and classified according to their assigned treatment group.
| Age, Continuous(years) | Imetelstat 4.7 mg/kg | Imetelstat 9.4 mg/kg | Total |
|---|---|---|---|
| Mean | 68.0 ± 8.95 | 66.5 ± 9.39 | 67.2 ± 9.18 |
| Sex: Female, Male(Participants) | Imetelstat 4.7 mg/kg | Imetelstat 9.4 mg/kg | Total |
|---|---|---|---|
| Female | 16 | 24 | 40 |
| Male | 32 | 35 | 67 |
| Race/Ethnicity, Customized(Participants) | Imetelstat 4.7 mg/kg | Imetelstat 9.4 mg/kg | Total |
|---|---|---|---|
| Hispanic or Latino | 2 | 8 | 10 |
| Not Hispanic or Latino | 41 | 44 | 85 |
| Unknown | 2 | 3 | 5 |
| Not Reported | 3 | 4 | 7 |
| Race/Ethnicity, Customized(Participants) | Imetelstat 4.7 mg/kg | Imetelstat 9.4 mg/kg | Total |
|---|---|---|---|
| White | 40 | 48 | 88 |
| Black/African American | 2 | 2 | 4 |
| Asian | 2 | 3 | 5 |
| Multiple | 1 | 0 | 1 |
| Not Reported | 3 | 6 | 9 |
| Region(Participants) | Imetelstat 4.7 mg/kg | Imetelstat 9.4 mg/kg | Total |
|---|---|---|---|
| United States/Canada | 25 | 18 | 43 |
| European Union | 19 | 34 | 53 |
| Rest of World | 4 | 7 | 11 |
| Spleen Size by Palpation(centimeter (cm)) | Imetelstat 4.7 mg/kg | Imetelstat 9.4 mg/kg | Total |
|---|---|---|---|
| Mean | 17.6 ± 7.62 | 17.3 ± 7.51 | 17.4 ± 7.53 |
| Platelet Count(Participants) | Imetelstat 4.7 mg/kg | Imetelstat 9.4 mg/kg | Total |
|---|---|---|---|
| <75 (10^9/L) | 1 | 2 | 3 |
| 75 - <150 (10^9/L) | 23 | 31 | 54 |
| ≥150 (10^9/L) | 24 | 26 | 50 |
| Eastern Cooperative Oncology Group (ECOG) Score(Participants) | Imetelstat 4.7 mg/kg | Imetelstat 9.4 mg/kg | Total |
|---|---|---|---|
| 0: Asymptomatic | 11 | 14 | 25 |
| 1: Symptomatic fully ambulatory | 26 | 34 | 60 |
| 2: Self care | 11 | 11 | 22 |
4 further baseline measures are reported on the registry.
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