Trial Outcomes & Findings for Study to Evaluate Activity of 2 Dose Levels of Imetelstat in Participants With Intermediate-2 or High-Risk Myelofibrosis (MF) Previously Treated With Janus Kinase (JAK) Inhibitor (NCT NCT02426086)

Last Updated: 2021-09-14

Results Overview

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).

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

107 participants

Primary outcome timeframe

Week 24

Results posted on

2021-09-14

Participant Flow

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.

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).

Participant milestones

Participant milestones
Measure	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).	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).
Overall Study STARTED	48	59
Overall Study Treated	48	59
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	48	59

Reasons for withdrawal

Reasons for withdrawal
Measure	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).	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).
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

Number analyzed signifies the number of participants with data available for spleen size palpitation.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Imetelstat 4.7 mg/kg n=48 Participants 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).	Imetelstat 9.4 mg/kg n=59 Participants 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).	Total n=107 Participants Total of all reporting groups
Age, Continuous	68.0 years STANDARD_DEVIATION 8.95 • n=48 Participants	66.5 years STANDARD_DEVIATION 9.39 • n=59 Participants	67.2 years STANDARD_DEVIATION 9.18 • n=107 Participants
Sex: Female, Male Female	16 Participants n=48 Participants	24 Participants n=59 Participants	40 Participants n=107 Participants
Sex: Female, Male Male	32 Participants n=48 Participants	35 Participants n=59 Participants	67 Participants n=107 Participants
Race/Ethnicity, Customized Hispanic or Latino	2 Participants n=48 Participants	8 Participants n=59 Participants	10 Participants n=107 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	41 Participants n=48 Participants	44 Participants n=59 Participants	85 Participants n=107 Participants
Race/Ethnicity, Customized Unknown	2 Participants n=48 Participants	3 Participants n=59 Participants	5 Participants n=107 Participants
Race/Ethnicity, Customized Not Reported	3 Participants n=48 Participants	6 Participants n=59 Participants	9 Participants n=107 Participants
Race/Ethnicity, Customized White	40 Participants n=48 Participants	48 Participants n=59 Participants	88 Participants n=107 Participants
Race/Ethnicity, Customized Black/African American	2 Participants n=48 Participants	2 Participants n=59 Participants	4 Participants n=107 Participants
Race/Ethnicity, Customized Asian	2 Participants n=48 Participants	3 Participants n=59 Participants	5 Participants n=107 Participants
Race/Ethnicity, Customized Multiple	1 Participants n=48 Participants	0 Participants n=59 Participants	1 Participants n=107 Participants
Region United States/Canada	25 Participants n=48 Participants	18 Participants n=59 Participants	43 Participants n=107 Participants
Region European Union	19 Participants n=48 Participants	34 Participants n=59 Participants	53 Participants n=107 Participants
Region Rest of World	4 Participants n=48 Participants	7 Participants n=59 Participants	11 Participants n=107 Participants
Spleen Size by Palpation	17.6 centimeter (cm) STANDARD_DEVIATION 7.62 • n=47 Participants • Number analyzed signifies the number of participants with data available for spleen size palpitation.	17.3 centimeter (cm) STANDARD_DEVIATION 7.51 • n=59 Participants • Number analyzed signifies the number of participants with data available for spleen size palpitation.	17.4 centimeter (cm) STANDARD_DEVIATION 7.53 • n=106 Participants • Number analyzed signifies the number of participants with data available for spleen size palpitation.
Platelet Count <75 (10^9/L)	1 Participants n=48 Participants	2 Participants n=59 Participants	3 Participants n=107 Participants
Platelet Count 75 - <150 (10^9/L)	23 Participants n=48 Participants	31 Participants n=59 Participants	54 Participants n=107 Participants
Platelet Count ≥150 (10^9/L)	24 Participants n=48 Participants	26 Participants n=59 Participants	50 Participants n=107 Participants
Eastern Cooperative Oncology Group (ECOG) Score 0: Asymptomatic	11 Participants n=48 Participants	14 Participants n=59 Participants	25 Participants n=107 Participants
Eastern Cooperative Oncology Group (ECOG) Score 1: Symptomatic fully ambulatory	26 Participants n=48 Participants	34 Participants n=59 Participants	60 Participants n=107 Participants
Eastern Cooperative Oncology Group (ECOG) Score 2: Self care	11 Participants n=48 Participants	11 Participants n=59 Participants	22 Participants n=107 Participants
Time from Last JAKi Treatment	1.4 months n=48 Participants	1.7 months n=59 Participants	1.7 months n=107 Participants
Duration of Prior JAKi Treatment	22.3 months n=48 Participants	24.5 months n=59 Participants	23.0 months n=107 Participants
Dynamic International Prognostic Scoring System (DIPSS) Intermediate 2	28 Participants n=48 Participants	34 Participants n=59 Participants	62 Participants n=107 Participants
Dynamic International Prognostic Scoring System (DIPSS) High Risk	19 Participants n=48 Participants	25 Participants n=59 Participants	44 Participants n=107 Participants
Dynamic International Prognostic Scoring System (DIPSS) Missing	1 Participants n=48 Participants	0 Participants n=59 Participants	1 Participants n=107 Participants
Type of Myelofibrosis (MF) Primary MF (PMF)	27 Participants n=48 Participants	36 Participants n=59 Participants	63 Participants n=107 Participants
Type of Myelofibrosis (MF) Post Essential Thrombocythemia (PET)	9 Participants n=48 Participants	10 Participants n=59 Participants	19 Participants n=107 Participants
Type of Myelofibrosis (MF) Post Polycythemia Vera (PPV)	12 Participants n=48 Participants	13 Participants n=59 Participants	25 Participants n=107 Participants

PRIMARY outcome

Timeframe: Week 24

Population: Treated analysis set included all participants who received at least 1 dose of study drug.

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).

Outcome measures

Outcome measures
Measure	Imetelstat 4.7 mg/kg n=48 Participants 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).	Imetelstat 9.4 mg/kg n=59 Participants 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).
Percentage of Participants With Spleen Response	0 percentage of participants Interval 0.0 to 7.4	10.2 percentage of participants Interval 3.8 to 20.8

PRIMARY outcome

Timeframe: Week 24

Population: Treated analysis set included all participants who received at least 1 dose of study drug.

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.

Outcome measures

Outcome measures
Measure	Imetelstat 4.7 mg/kg n=48 Participants 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).	Imetelstat 9.4 mg/kg n=59 Participants 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).
Percentage of Participants With Symptom Response	6.3 percentage of participants Interval 1.3 to 17.2	32.2 percentage of participants Interval 20.6 to 45.6

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Imetelstat 4.7 mg/kg n=48 Participants 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).	Imetelstat 9.4 mg/kg n=59 Participants 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).
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 Upper and lower limits of 95% CI was not estimable due to limited number of participants with the event.	1.7 percentage of participants Interval 0.0 to 9.1

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Imetelstat 4.7 mg/kg n=48 Participants 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).	Imetelstat 9.4 mg/kg n=59 Participants 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).
Percentage of Participants With Clinical Improvement (CI) Per Modified 2013 IWG-MRT Criteria	16.7 percentage of participants	25.4 percentage of participants

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Imetelstat 4.7 mg/kg n=48 Participants 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).	Imetelstat 9.4 mg/kg n=59 Participants 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).
Percentage of Participants With Clinical Response Per Modified 2013 IWG-MRT	16.7 percentage of participants Interval 7.5 to 30.2	27.1 percentage of participants Interval 16.4 to 40.3

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Imetelstat 4.7 mg/kg n=48 Participants 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).	Imetelstat 9.4 mg/kg n=59 Participants 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).
Percentage of Participants With Spleen Response Per Modified 2013 IWG-MRT Criteria Spleen response with CI	0 percentage of participants	3.4 percentage of participants
Percentage of Participants With Spleen Response Per Modified 2013 IWG-MRT Criteria Spleen response without CI	2.1 percentage of participants	0 percentage of participants

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Imetelstat 4.7 mg/kg n=48 Participants 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).	Imetelstat 9.4 mg/kg n=59 Participants 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).
Percentage of Participants With Symptoms Response Per Modified 2013 IWG-MRT Criteria Symptom response with CI	14.6 percentage of participants	22.0 percentage of participants
Percentage of Participants With Symptoms Response Per Modified 2013 IWG-MRT Criteria Symptom response without CI	4.2 percentage of participants	8.5 percentage of participants

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Imetelstat 4.7 mg/kg n=48 Participants 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).	Imetelstat 9.4 mg/kg n=59 Participants 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).
Percentage of Participants With Anemia Response Per Modified 2013 IWG-MRT Criteria Anemia response with CI	4.2 percentage of participants	6.8 percentage of participants
Percentage of Participants With Anemia Response Per Modified 2013 IWG-MRT Criteria Anemia response without CI	0 percentage of participants	1.7 percentage of participants

SECONDARY outcome

Timeframe: From date of initial documentation of a response to the date of first documented evidence of PD or death, whichever occurs first (approximately up to 2.3 years)

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.

Outcome measures

Outcome measures
Measure	Imetelstat 4.7 mg/kg n=11 Participants 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).	Imetelstat 9.4 mg/kg n=21 Participants 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).
Duration of Response (PR/CI/RWCI) as Per IWG-MRT Criteria	36.3 weeks Interval 11.9 to 60.0	38.3 weeks Interval 27.0 to 48.3

SECONDARY outcome

Timeframe: Day 1 of Cycle 1 (each cycle was of 21 days), up to the date of the participant's death (approximately up to 4.1 years)

Population: Treated analysis set included all participants who received at least 1 dose of study drug.

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.

Outcome measures

Outcome measures
Measure	Imetelstat 4.7 mg/kg n=48 Participants 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).	Imetelstat 9.4 mg/kg n=59 Participants 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).
Overall Survival	19.91 months Interval 17.05 to 33.87	28.09 months Interval 22.8 to 31.61

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Imetelstat 4.7 mg/kg n=18 Participants 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).	Imetelstat 9.4 mg/kg n=33 Participants 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).
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	36.4 percentage of participants

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Imetelstat 4.7 mg/kg n=18 Participants 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).	Imetelstat 9.4 mg/kg n=33 Participants 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).
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	0.626 score on a scale Standard Deviation 0.2117
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	47.73 score on a scale Standard Deviation 16.398

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Imetelstat 4.7 mg/kg n=18 Participants 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).	Imetelstat 9.4 mg/kg n=33 Participants 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).
Percentage of Participants With Clinically Meaningful Improvement in Brief Pain Inventory (BPI) Pain at its Worst: Improvement	50.0 percentage of participants	75.8 percentage of participants
Percentage of Participants With Clinically Meaningful Improvement in Brief Pain Inventory (BPI) Pain at its Least: Improvement	44.4 percentage of participants	51.5 percentage of participants
Percentage of Participants With Clinically Meaningful Improvement in Brief Pain Inventory (BPI) Pain on the Average: Improvement	55.6 percentage of participants	66.7 percentage of participants
Percentage of Participants With Clinically Meaningful Improvement in Brief Pain Inventory (BPI) Pain Right Now: Improvement	61.1 percentage of participants	66.7 percentage of participants
Percentage of Participants With Clinically Meaningful Improvement in Brief Pain Inventory (BPI) Relief Pain Treatments Provided: Improvement	50.0 percentage of participants	53.1 percentage of participants
Percentage of Participants With Clinically Meaningful Improvement in Brief Pain Inventory (BPI) Pain Interfered General Activity: Improvement	72.2 percentage of participants	68.8 percentage of participants
Percentage of Participants With Clinically Meaningful Improvement in Brief Pain Inventory (BPI) Pain Interfered with Mood: Improvement	50.0 percentage of participants	59.4 percentage of participants
Percentage of Participants With Clinically Meaningful Improvement in Brief Pain Inventory (BPI) Pain Interfered Walking Ability: Improvement	38.9 percentage of participants	78.1 percentage of participants
Percentage of Participants With Clinically Meaningful Improvement in Brief Pain Inventory (BPI) Pain Interfered with Normal Work: Improvement	61.1 percentage of participants	62.5 percentage of participants
Percentage of Participants With Clinically Meaningful Improvement in Brief Pain Inventory (BPI) Pain Interfered with Relations: Improvement	44.4 percentage of participants	53.1 percentage of participants
Percentage of Participants With Clinically Meaningful Improvement in Brief Pain Inventory (BPI) Pain Interfered with Sleep: Improvement	61.1 percentage of participants	78.1 percentage of participants
Percentage of Participants With Clinically Meaningful Improvement in Brief Pain Inventory (BPI) Pain Interfered Enjoyment of Life: Improvement	61.1 percentage of participants	62.5 percentage of participants

SECONDARY outcome

Timeframe: 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.

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).

Outcome measures

Outcome measures
Measure	Imetelstat 4.7 mg/kg n=17 Participants 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).	Imetelstat 9.4 mg/kg n=33 Participants 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).
Patient's Global Impression of Change (PGIC)	4.82 score on a scale Standard Deviation 1.237	3.97 score on a scale Standard Deviation 1.571

SECONDARY outcome

Timeframe: 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.

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.