Myelofibrosis, Primary Myelofibrosis, Post-polycythemia Vera Myelofibrosis, Post-essential Thrombocythemia Myelofibrosis
Conditions
Keywords
Pelabresib, Ruxolitinib
Brief summary
A Phase 3, randomized, blinded study comparing pelabresib (CPI-0610) and ruxolitinib with placebo and ruxolitinib in myelofibrosis (MF) patients that have not been previously treated with Janus kinase inhibitors (JAKi). Pelabresib is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins.
Interventions
DRUGPelabresib
Double-blind treatment (pelabresib or matching placebo) will be administered daily for 14 consecutive days followed by a 7-day break, which is considered 1 cycle of treatment (1 cycle = 21 days). Pelabresib is a small molecule inhibitor of BET proteins with a novel mechanism of action and potential for disease-modifying effects in MF.
DRUGRuxolitinib
Ruxolitinib is a JAK inhibitor and a current, approved treatment option for MF.
DRUGPlacebo
Placebo tablets are designed to match pelabresib tablets. Each placebo tablet contains no active pharmaceutical ingredient and is visibly identical to experimental drug in size, shape, and packaging. Placebo dosing follows the same dosing conventions as pelabresib.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
This study has a double-blind design in which patients and investigators are blinded to study drug; study drugs will be packaged identically. All patients will be randomly assigned to either treatment group in a 1:1 ratio. The blind should only be broken in the case of emergency.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Aged ≥ 18 years * Confirmed diagnosis of myelofibrosis (primary, post-polycythemia vera, or post essential thrombocythemia) * Adequate hematologic, renal, and hepatic function * Have at least 2 symptoms with an average score ≥ 3 or an average total score of ≥ 10 over the 7-day period prior to randomization using the MFSAF v4.0 * Prognostic risk-factor score of Intermediate-1 or higher per Dynamic International Prognostic Scoring System (DIPSS) scoring system * Spleen volume of ≥ 450 cm\^3 * Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
Exclusion criteria
* Splenectomy or splenic irradiation in the previous 6 months * Chronic or active conditions and/or concomitant medication use that would prohibit treatment * Had prior treatment with any JAKi or BET inhibitor for treatment of a myeloproliferative neoplasm
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Splenic Response by Central Radiology Reads at Week 24 | Week 24 | Splenic response was characterized by a reduction of at least 35% in spleen volume from baseline (SVR35), as determined by magnetic resonance imaging (MRI) or computerized tomography (CT), and evaluated through a blinded central radiology review at Week 24. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Key Secondary: Number of Participants With TSS50 Response at Week 24 | Week 24 | The probability of a TSS response at Week 24 was estimated by calculating the TSS response rate, defined as the percentage of patients who achieved a TSS50 response at Week 24 in each of the two treatment groups. The Total Symptom Score (TSS) response was defined as a ≥50% reduction from baseline in TSS, as measured by the Myelofibrosis Symptom Assessment Form v4.0. |
| Percent Change From Baseline in Total Symptom Score (TSS) at Week 24 | Baseline, Week 24 | Percent Change From Baseline in Total Symptom Score (TSS) at Week 24 measured the change in a patient's symptoms after 24 weeks of treatment, relative to baseline. A negative value indicates symptom improvement, and a reduction of ≥50% is typically considered a meaningful clinical response. |
| Number of Participants With Improvement From Baseline in Bone Marrow Fibrosis of at Least 1 Grade at Week 24 | Baseline, Week 24 | Improvement in bone marrow fibrosis by at least 1 grade, as assessed by central read compared to baseline, was analyzed by treatment group and overall. The improvement in bone marrow fibrosis grade was defined as a decrease by at least 1 grade in bone marrow fibrosis grade when compared to baseline, where a grade of MF-3 was the most severe, and MF-0 was the least severe. |
| Number of Participants With Splenic Response by Central Radiology Reads at Week 48 | Week 48 | Splenic response is characterized by a reduction of at least 35% in spleen volume from baseline (SVR35), as determined by magnetic resonance imaging (MRI) or computerized tomography (CT), and evaluated through a blinded central radiology review at Week 48. |
| Number of Participants With TSS50 Response at Week 48 | Week 48 | The probability of a TSS response at Week 48 is estimated by calculating the TSS response rate, defined as the percentage of patients who achieve a TSS50 response at Week 48 in each of the two treatment groups. The Total Symptom Score (TSS) response is defined as a ≥50% reduction from baseline in TSS, as measured by the Myelofibrosis Symptom Assessment Form v4.0. |
| Absolute Change From Baseline in Total Symptom Score (TSS) at Week 48 | Baseline, Week 48 | The Total Symptom Score (TSS) at Week 48, compared to baseline, is measured using the Myelofibrosis Symptom Assessment Form v4.0. This score represents the sum of seven individual symptom items, each rated on a 0-10 scale, resulting in a possible total daily score ranging from 0 to 70. A higher TSS reflects a greater disease burden and therefore a worse outcome. The baseline TSS is calculated as the average of non-missing daily total symptom scores over the seven-day period preceding the day of randomization. The TSS for each treatment week is determined as the average of non-missing daily total symptom scores for that week. However, if fewer than four daily scores are available for a given week, the weekly TSS is considered missing. |
| Rate of Red Blood Cell (RBC) Transfusion Over First 24 Weeks of Treatment | Week 24 | The rate of RBC transfusions was defined as the average number of RBC units transfused per patient month (4 weeks) during the first 24 weeks of treatment. The average number of RBC units per patient-month was calculated by dividing the total (ie, for all patients) number of RBC units in the whole exposure time by the sum of patient-months. |
| Number of Participants Who Transitioned From Red Blood Cell (RBC) Transfusion Dependence to Transfusion Independence | From 12-week baseline period prior to dosing to any 12-week period post baseline, up to 24 weeks | Transfusion dependence (TD) was defined as having received ≥6 units of RBCs during the 12-week baseline period prior to dosing and Transfusion independence (TI) was defined as the absence of RBC transfusions during any continuous 12-week period of the double-blind treatment phase. The conversion from TD to TI was evaluated and defined as the proportion of patients who transitioned from transfusion dependence to transfusion independence. Patients who remained in the double-blind treatment period and had not received any RBC transfusions during the most recent 12 weeks were considered responders. Patients who discontinued from the double-blind treatment before Week 12 were classified as non-responders. |
| Category Change From Baseline of Patient Global Impression of Change (PGIC) at Week 24 | Baseline, Week 24 | The Patient Global Impression of Change (PGIC) was a single-item measure of the patient's perceived change in MF symptoms since starting treatment. Patients responded to: Since beginning this study treatment, your myelofibrosis symptoms were: (1) Very much improved, (2) Much improved, (3) Minimally improved, (4) No change, (5) Minimally worse, (6) Much worse, (7) Very much worse. |
| Progression-Free Survival (PFS) | Through study completion, an average of 6 years | Progression-Free Survival (PFS), defined as the time from randomization until documented progression, or until death from any cause for patients without documented progression |
| Overall Survival (OS) | Through study completion, an average of 6 years | OS, defined as the time from randomization until death from any cause |
| Key Secondary: Absolute Change From Baseline in Total Symptom Score (TSS) at Week 24 | Baseline, Week 24 | The Total Symptom Score (TSS) at Week 24, compared to baseline, was measured using the Myelofibrosis Symptom Assessment Form v4.0. This score represented the sum of seven individual symptom items, each rated on a 0-10 scale, resulting in a possible total daily score ranging from 0 to 70. A higher TSS reflected a greater disease burden and therefore a worse outcome. The baseline TSS was calculated as the average of non-missing daily total symptom scores over the seven-day period preceding the day of randomization. The TSS for each treatment week was determined as the average of non-missing daily total symptom scores for that week. However, if fewer than four daily scores were available for a given week, the weekly TSS was considered missing. |
| Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Through study completion, an average of 6 years | A treatment-emergent adverse event (TEAE) for the double-blind treatment period is defined as an AE that has a start date on or after the first dose of the pelabresib/placebo and before 30 days after the last dose of pelabresib/placebo or before the start of alternative (off-study) treatment for MF, whichever occurs first. If the AE has a start date before the date of first dose but increases in severity after first dose and before 30 days post last dose will be considered a TEAE as well. An AE that occurs after the administration of the first dose of open-label pelabresib treatment will be considered treatment-emergent for the crossover treatment period. However, a TEAE for the crossover treatment period that occurs within 30 days after the last dose of pelabresib/placebo will be considered treatment emergent for the double-blind treatment period as well. |
| Pharmacokinetic (PK) Parameters for Pelabresib: Area Under the Plasma Concentration-time Curve From Time Zero to Time t (AUC0-t) | Cycle 1 Day 1, Cycle 1 Day 14 and Cycle 9 Day 1: Predose, 30 minutes to 1 hour post-dose, 3 to 4.5 hours post-dose. Cycle 3 and Cycle 7 Day 1: Predose, 5 minutes post ECG assessment. 1 Cycle = 21 days | Pharmacokinetic (PK) parameters will be calculated based on Pelabresib plasma concentrations and actual sampling time points. AUC0-t will be listed and summarized using descriptive statistics. |
| Pharmacokinetic (PK) Parameters for Pelabresib: Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) | Cycle 1 Day 1, Cycle 1 Day 14 and Cycle 9 Day 1: Predose, 30 minutes to 1 hour post-dose, 3 to 4.5 hours post-dose. Cycle 3 and Cycle 7 Day 1: Predose, 5 minutes post ECG assessment. 1 Cycle = 21 days | Pharmacokinetic (PK) parameters will be calculated based on Pelabresib plasma concentrations and actual sampling time points. AUC0-t will be listed and summarized using descriptive statistics. Tmax will be listed and summarized using descriptive statistics. |
| Pharmacokinetic (PK) Parameters for Pelabresib: Maximum (Peak) Plasma Drug Concentration (Cmax) | Cycle 1 Day 1, Cycle 1 Day 14 and Cycle 9 Day 1: Predose, 30 minutes to 1 hour post-dose, 3 to 4.5 hours post-dose. Cycle 3 and Cycle 7 Day 1: Predose, 5 minutes post ECG assessment. 1 Cycle = 21 days | Pharmacokinetic (PK) parameters will be calculated based on Pelabresib plasma concentrations and actual sampling time points. AUC0-t will be listed and summarized using descriptive statistics. Cmax will be listed and summarized using descriptive statistics. |
| Pharmacokinetic (PK) Parameters for Pelabresib: Effective Half-Life (T1/2) | Cycle 1 Day 1, Cycle 1 Day 14 and Cycle 9 Day 1: Predose, 30 minutes to 1 hour post-dose, 3 to 4.5 hours post-dose. Cycle 3 and Cycle 7 Day 1: Predose, 5 minutes post ECG assessment. 1 Cycle = 21 days | Pharmacokinetic (PK) parameters will be calculated based on Pelabresib plasma concentrations and actual sampling time points. T1/2 will be listed and summarized using descriptive statistics. |
| Pharmacokinetic (PK) Parameters for Pelabresib: Apparent Volume of Distribution After Non-intravenous Administration (Vd/F) | Cycle 1 Day 1, Cycle 1 Day 14 and Cycle 9 Day 1: Predose, 30 minutes to 1 hour post-dose, 3 to 4.5 hours post-dose. Cycle 3 and Cycle 7 Day 1: Predose, 5 minutes post ECG assessment. 1 Cycle = 21 days | Pharmacokinetic (PK) parameters will be calculated based on Pelabresib plasma concentrations and actual sampling time points. Vd/F will be listed and summarized using descriptive statistics. |
| Pharmacokinetic (PK) Parameters for Pelabresib: Apparent Total Clearance of the Drug From Plasma After Oral Administration (CL/F) | Cycle 1 Day 1, Cycle 1 Day 14 and Cycle 9 Day 1: Predose, 30 minutes to 1 hour post-dose, 3 to 4.5 hours post-dose. Cycle 3 and Cycle 7 Day 1: Predose, 5 minutes post ECG assessment. 1 Cycle = 21 days | Pharmacokinetic (PK) parameters will be calculated based on Pelabresib plasma concentrations and actual sampling time points. CL/F will be listed and summarized using descriptive statistics. |
| Ruxolitinib Plasma Concentrations in the Presence or Absence of Pelabresib | Cycle 1 Day 1, Cycle 1 Day 14 and Cycle 9 Day 1: Predose, 30 minutes to 1 hour post-dose, 3 to 4.5 hours post-dose. Cycle 3 and Cycle 7 Day 1: Predose, 5 minutes post ECG assessment. 1 Cycle = 21 days | Blood samples (approximately 4 mL each) will be collected at the time points specified in the Schedule of Assessments (SOA) to determine plasma concentrations of Ruxolitinib plasma concentrations in the presence or absence of Pelabresib |
| Duration of the Splenic Response | Through study completion, an average of 6 years | Duration of splenic response, defined as the time from onset of splenic response until the time at which the patient has a \<35% decrease from baseline in spleen volume and a \>25% increase from nadir, as confirmed by the central review) or death, whichever comes first |
| Number of Participants With Modified Total Symptom Score (mTSS) Response at Week 24 | Week 24 | The modified TSS (mTSS) was defined as TSS without the fatigue sub-domain and with a total scale of 60 points versus 70 points for TSS. Patients were classified as responders if the percentage of change from baseline in mTSS was ≤ -50% at Week 24. |
| Duration of the TSS50 Response | Through study completion, an average of 6 years | Duration of TSS response, defined as the time from onset of TSS50 response until the time at which the patient has a \<50% reduction in TSS from baseline and an increase of ≥25% from nadir |
| Proportion of Patients With Transformation to Blast Phase (AML) | Through study completion, an average of 6 years | Patients are categorized as having transformed to Acute Myelogenous Leukemia (AML) when the peripheral blood blast percentage increases to ≥20% and this elevation persists for at least two weeks, or when leukemic transformation is confirmed through disease status assessment. |
Countries
Australia, Austria, Belgium, Canada, Czechia, France, Germany, Greece, Hong Kong, Hungary, Israel, Italy, Malaysia, Netherlands, Poland, South Korea, Spain, Taiwan, Thailand, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
A total of 135 centers enrolled patients in the study in Australia, Austria, Belgium, Canada, Czech Republic, France, Germany, Greece, Hong Kong, Hungary, Israel, Italy, Malaysia, Netherlands, Poland, South Korea, Spain, Taiwan, Thailand, Turkey, United Kingdom, and United States.
Participants by arm
| Arm | Count |
|---|---|
| Pelabresib + Ruxolitinib (Experimental Arm) Pelabresib 125 mg orally (PO) once daily (QD) + ruxolitinib 10 or 15 mg orally (PO) twice a day (BID) for 14 consecutive days followed by ruxolitinib 10 or 15 mg orally (PO) twice a day (BID) for 7 days in a 21-day cycle | 214 |
| Placebo + Ruxolitinib (Control Arm) Matching placebo orally (PO) once daily (QD) + ruxolitinib 10 or 15 mg orally (PO) twice a day (BID) for 14 consecutive days followed by ruxolitinib 10 or 15 mg orally (PO) twice a day (BID) for 7 days in a 21-day cycle | 216 |
| Total | 430 |
Baseline characteristics
| Characteristic | Pelabresib + Ruxolitinib (Experimental Arm) | Placebo + Ruxolitinib (Control Arm) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 120 Participants | 124 Participants | 244 Participants |
| Age, Categorical Between 18 and 65 years | 94 Participants | 92 Participants | 186 Participants |
| Age, Continuous | 64.5 years STANDARD_DEVIATION 11.84 | 64.8 years STANDARD_DEVIATION 11.08 | 64.7 years STANDARD_DEVIATION 11.45 |
| Baseline Total Symptom Score (TSS) | 28.26 units on a scale STANDARD_DEVIATION 12.7 | 27.36 units on a scale STANDARD_DEVIATION 12.3 | 27.81 units on a scale STANDARD_DEVIATION 12.5 |
| Diagnosis Post-Essential Thrombocythemia Myelofibrosis (PET-MF) | 62 Participants | 53 Participants | 115 Participants |
| Diagnosis Post-Polycythemia Vera Myelofibrosis (PPV-MF) | 45 Participants | 53 Participants | 98 Participants |
| Diagnosis Primary Myelofibrosis (PMF) | 107 Participants | 110 Participants | 217 Participants |
| Dynamic International Prognostic Scoring System (DIPSS) risk category High | 11 Participants | 15 Participants | 26 Participants |
| Dynamic International Prognostic Scoring System (DIPSS) risk category Intermediate-1 | 128 Participants | 127 Participants | 255 Participants |
| Dynamic International Prognostic Scoring System (DIPSS) risk category Intermediate-2 | 75 Participants | 74 Participants | 149 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 6 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 194 Participants | 199 Participants | 393 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 17 Participants | 11 Participants | 28 Participants |
| Hemoglobin ≤10 g/dL | 70 Participants | 76 Participants | 146 Participants |
| Hemoglobin >10 g/dL | 144 Participants | 140 Participants | 284 Participants |
| Platelet count <100 × 10^9 cells/L | 1 Participants | 2 Participants | 3 Participants |
| Platelet count 100-200 × 10^9 cells/L | 59 Participants | 57 Participants | 116 Participants |
| Platelet count >200 × 10^9 cells/L | 154 Participants | 157 Participants | 311 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 35 Participants | 42 Participants | 77 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 16 Participants | 11 Participants | 27 Participants |
| Race (NIH/OMB) White | 160 Participants | 163 Participants | 323 Participants |
| Sex: Female, Male Female | 85 Participants | 94 Participants | 179 Participants |
| Sex: Female, Male Male | 129 Participants | 122 Participants | 251 Participants |
| Spleen volume from central reads | 1522.43 cm^3 STANDARD_DEVIATION 950.18 | 1539.28 cm^3 STANDARD_DEVIATION 920.78 | 1530.90 cm^3 STANDARD_DEVIATION 934.47 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 11 / 212 | 10 / 214 |
| other Total, other adverse events | 201 / 212 | 204 / 214 |
| serious Total, serious adverse events | 63 / 212 | 63 / 214 |
Outcome results
Primary
Number of Participants With Splenic Response by Central Radiology Reads at Week 24
Splenic response was characterized by a reduction of at least 35% in spleen volume from baseline (SVR35), as determined by magnetic resonance imaging (MRI) or computerized tomography (CT), and evaluated through a blinded central radiology review at Week 24.
Time frame: Week 24
Population: Intent-to-Treat (ITT) Analysis Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pelabresib + Ruxolitinib (Experimental Arm) | Number of Participants With Splenic Response by Central Radiology Reads at Week 24 | 141 Participants |
| Placebo + Ruxolitinib (Control Arm) | Number of Participants With Splenic Response by Central Radiology Reads at Week 24 | 76 Participants |
Comparison: Splenic Response Rate at Week 24p-value: <0.00195% CI: [21.6, 39.3]Cochran-Mantel-Haenszel
Secondary
Absolute Change From Baseline in Total Symptom Score (TSS) at Week 48
The Total Symptom Score (TSS) at Week 48, compared to baseline, is measured using the Myelofibrosis Symptom Assessment Form v4.0. This score represents the sum of seven individual symptom items, each rated on a 0-10 scale, resulting in a possible total daily score ranging from 0 to 70. A higher TSS reflects a greater disease burden and therefore a worse outcome. The baseline TSS is calculated as the average of non-missing daily total symptom scores over the seven-day period preceding the day of randomization. The TSS for each treatment week is determined as the average of non-missing daily total symptom scores for that week. However, if fewer than four daily scores are available for a given week, the weekly TSS is considered missing.
Time frame: Baseline, Week 48
Secondary
Category Change From Baseline of Patient Global Impression of Change (PGIC) at Week 24
The Patient Global Impression of Change (PGIC) was a single-item measure of the patient's perceived change in MF symptoms since starting treatment. Patients responded to: Since beginning this study treatment, your myelofibrosis symptoms were: (1) Very much improved, (2) Much improved, (3) Minimally improved, (4) No change, (5) Minimally worse, (6) Much worse, (7) Very much worse.
Time frame: Baseline, Week 24
Population: Intent-to-Treat (ITT) Analysis Set - Only participants with evaluable data at the pre-specified time points
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Pelabresib + Ruxolitinib (Experimental Arm) | Category Change From Baseline of Patient Global Impression of Change (PGIC) at Week 24 | Minimally improved | 63 Participants |
| Pelabresib + Ruxolitinib (Experimental Arm) | Category Change From Baseline of Patient Global Impression of Change (PGIC) at Week 24 | Minimally worse | 7 Participants |
| Pelabresib + Ruxolitinib (Experimental Arm) | Category Change From Baseline of Patient Global Impression of Change (PGIC) at Week 24 | Much improved | 63 Participants |
| Pelabresib + Ruxolitinib (Experimental Arm) | Category Change From Baseline of Patient Global Impression of Change (PGIC) at Week 24 | Much worse | 5 Participants |
| Pelabresib + Ruxolitinib (Experimental Arm) | Category Change From Baseline of Patient Global Impression of Change (PGIC) at Week 24 | No change | 14 Participants |
| Pelabresib + Ruxolitinib (Experimental Arm) | Category Change From Baseline of Patient Global Impression of Change (PGIC) at Week 24 | Very much worse | 1 Participants |
| Pelabresib + Ruxolitinib (Experimental Arm) | Category Change From Baseline of Patient Global Impression of Change (PGIC) at Week 24 | Very much improved | 24 Participants |
| Placebo + Ruxolitinib (Control Arm) | Category Change From Baseline of Patient Global Impression of Change (PGIC) at Week 24 | Very much worse | 0 Participants |
| Placebo + Ruxolitinib (Control Arm) | Category Change From Baseline of Patient Global Impression of Change (PGIC) at Week 24 | Very much improved | 26 Participants |
| Placebo + Ruxolitinib (Control Arm) | Category Change From Baseline of Patient Global Impression of Change (PGIC) at Week 24 | Much improved | 62 Participants |
| Placebo + Ruxolitinib (Control Arm) | Category Change From Baseline of Patient Global Impression of Change (PGIC) at Week 24 | Minimally improved | 79 Participants |
| Placebo + Ruxolitinib (Control Arm) | Category Change From Baseline of Patient Global Impression of Change (PGIC) at Week 24 | No change | 13 Participants |
| Placebo + Ruxolitinib (Control Arm) | Category Change From Baseline of Patient Global Impression of Change (PGIC) at Week 24 | Minimally worse | 14 Participants |
| Placebo + Ruxolitinib (Control Arm) | Category Change From Baseline of Patient Global Impression of Change (PGIC) at Week 24 | Much worse | 0 Participants |
Secondary
Duration of the Splenic Response
Duration of splenic response, defined as the time from onset of splenic response until the time at which the patient has a \<35% decrease from baseline in spleen volume and a \>25% increase from nadir, as confirmed by the central review) or death, whichever comes first
Time frame: Through study completion, an average of 6 years
Secondary
Duration of the TSS50 Response
Duration of TSS response, defined as the time from onset of TSS50 response until the time at which the patient has a \<50% reduction in TSS from baseline and an increase of ≥25% from nadir
Time frame: Through study completion, an average of 6 years
Secondary
Key Secondary: Absolute Change From Baseline in Total Symptom Score (TSS) at Week 24
The Total Symptom Score (TSS) at Week 24, compared to baseline, was measured using the Myelofibrosis Symptom Assessment Form v4.0. This score represented the sum of seven individual symptom items, each rated on a 0-10 scale, resulting in a possible total daily score ranging from 0 to 70. A higher TSS reflected a greater disease burden and therefore a worse outcome. The baseline TSS was calculated as the average of non-missing daily total symptom scores over the seven-day period preceding the day of randomization. The TSS for each treatment week was determined as the average of non-missing daily total symptom scores for that week. However, if fewer than four daily scores were available for a given week, the weekly TSS was considered missing.
Time frame: Baseline, Week 24
Population: Intent-to-Treat (ITT) Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pelabresib + Ruxolitinib (Experimental Arm) | Key Secondary: Absolute Change From Baseline in Total Symptom Score (TSS) at Week 24 | -15.99 score on a scale | Standard Error 1.028 |
| Placebo + Ruxolitinib (Control Arm) | Key Secondary: Absolute Change From Baseline in Total Symptom Score (TSS) at Week 24 | -14.05 score on a scale | Standard Error 0.986 |
Comparison: Absolute Change from Baseline in Total Symptom Score (TSS) at Week 24p-value: 0.054595% CI: [-3.92, 0.04]ANCOVA
Secondary
Key Secondary: Number of Participants With TSS50 Response at Week 24
The probability of a TSS response at Week 24 was estimated by calculating the TSS response rate, defined as the percentage of patients who achieved a TSS50 response at Week 24 in each of the two treatment groups. The Total Symptom Score (TSS) response was defined as a ≥50% reduction from baseline in TSS, as measured by the Myelofibrosis Symptom Assessment Form v4.0.
Time frame: Week 24
Population: Intent-to-Treat (ITT) Analysis Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pelabresib + Ruxolitinib (Experimental Arm) | Key Secondary: Number of Participants With TSS50 Response at Week 24 | 112 Participants |
| Placebo + Ruxolitinib (Control Arm) | Key Secondary: Number of Participants With TSS50 Response at Week 24 | 100 Participants |
Comparison: Percentage of TSS50 at Week 24p-value: 0.21695% CI: [-3.4, 15.5]Cochran-Mantel-Haenszel
Secondary
Number of Participants Who Transitioned From Red Blood Cell (RBC) Transfusion Dependence to Transfusion Independence
Transfusion dependence (TD) was defined as having received ≥6 units of RBCs during the 12-week baseline period prior to dosing and Transfusion independence (TI) was defined as the absence of RBC transfusions during any continuous 12-week period of the double-blind treatment phase. The conversion from TD to TI was evaluated and defined as the proportion of patients who transitioned from transfusion dependence to transfusion independence. Patients who remained in the double-blind treatment period and had not received any RBC transfusions during the most recent 12 weeks were considered responders. Patients who discontinued from the double-blind treatment before Week 12 were classified as non-responders.
Time frame: From 12-week baseline period prior to dosing to any 12-week period post baseline, up to 24 weeks
Population: Intent-to-Treat (ITT) Analysis Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pelabresib + Ruxolitinib (Experimental Arm) | Number of Participants Who Transitioned From Red Blood Cell (RBC) Transfusion Dependence to Transfusion Independence | 0 Participants |
| Placebo + Ruxolitinib (Control Arm) | Number of Participants Who Transitioned From Red Blood Cell (RBC) Transfusion Dependence to Transfusion Independence | 0 Participants |
Secondary
Number of Participants With Improvement From Baseline in Bone Marrow Fibrosis of at Least 1 Grade at Week 24
Improvement in bone marrow fibrosis by at least 1 grade, as assessed by central read compared to baseline, was analyzed by treatment group and overall. The improvement in bone marrow fibrosis grade was defined as a decrease by at least 1 grade in bone marrow fibrosis grade when compared to baseline, where a grade of MF-3 was the most severe, and MF-0 was the least severe.
Time frame: Baseline, Week 24
Population: Intent-to-Treat (ITT) Analysis Set: Only participants with available data at the specified time point were included in the analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pelabresib + Ruxolitinib (Experimental Arm) | Number of Participants With Improvement From Baseline in Bone Marrow Fibrosis of at Least 1 Grade at Week 24 | 36 Participants |
| Placebo + Ruxolitinib (Control Arm) | Number of Participants With Improvement From Baseline in Bone Marrow Fibrosis of at Least 1 Grade at Week 24 | 21 Participants |
Comparison: ≥1 Grade improvement From Baseline in Bone Marrow Fibrosis at Week 24p-value: 0.03795% CI: [0.52, 14.73]Cochran-Mantel-Haenszel
Secondary
Number of Participants With Modified Total Symptom Score (mTSS) Response at Week 24
The modified TSS (mTSS) was defined as TSS without the fatigue sub-domain and with a total scale of 60 points versus 70 points for TSS. Patients were classified as responders if the percentage of change from baseline in mTSS was ≤ -50% at Week 24.
Time frame: Week 24
Population: Intent-to-Treat (ITT) Analysis Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pelabresib + Ruxolitinib (Experimental Arm) | Number of Participants With Modified Total Symptom Score (mTSS) Response at Week 24 | 120 Participants |
| Placebo + Ruxolitinib (Control Arm) | Number of Participants With Modified Total Symptom Score (mTSS) Response at Week 24 | 104 Participants |
Comparison: Modified Total Symptom Score (mTSS) Response at Week 24p-value: 0.10795% CI: [-1.7, 17.2]Cochran-Mantel-Haenszel
Secondary
Number of Participants With Splenic Response by Central Radiology Reads at Week 48
Splenic response is characterized by a reduction of at least 35% in spleen volume from baseline (SVR35), as determined by magnetic resonance imaging (MRI) or computerized tomography (CT), and evaluated through a blinded central radiology review at Week 48.
Time frame: Week 48
Secondary
Number of Participants With TSS50 Response at Week 48
The probability of a TSS response at Week 48 is estimated by calculating the TSS response rate, defined as the percentage of patients who achieve a TSS50 response at Week 48 in each of the two treatment groups. The Total Symptom Score (TSS) response is defined as a ≥50% reduction from baseline in TSS, as measured by the Myelofibrosis Symptom Assessment Form v4.0.
Time frame: Week 48
Secondary
Overall Survival (OS)
OS, defined as the time from randomization until death from any cause
Time frame: Through study completion, an average of 6 years
Secondary
Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
A treatment-emergent adverse event (TEAE) for the double-blind treatment period is defined as an AE that has a start date on or after the first dose of the pelabresib/placebo and before 30 days after the last dose of pelabresib/placebo or before the start of alternative (off-study) treatment for MF, whichever occurs first. If the AE has a start date before the date of first dose but increases in severity after first dose and before 30 days post last dose will be considered a TEAE as well. An AE that occurs after the administration of the first dose of open-label pelabresib treatment will be considered treatment-emergent for the crossover treatment period. However, a TEAE for the crossover treatment period that occurs within 30 days after the last dose of pelabresib/placebo will be considered treatment emergent for the double-blind treatment period as well.
Time frame: Through study completion, an average of 6 years
Secondary
Percent Change From Baseline in Total Symptom Score (TSS) at Week 24
Percent Change From Baseline in Total Symptom Score (TSS) at Week 24 measured the change in a patient's symptoms after 24 weeks of treatment, relative to baseline. A negative value indicates symptom improvement, and a reduction of ≥50% is typically considered a meaningful clinical response.
Time frame: Baseline, Week 24
Population: Intent-to-Treat (ITT) Analysis Set
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Pelabresib + Ruxolitinib (Experimental Arm) | Percent Change From Baseline in Total Symptom Score (TSS) at Week 24 | -50.3 Percent change from baseline to Week 24 |
| Placebo + Ruxolitinib (Control Arm) | Percent Change From Baseline in Total Symptom Score (TSS) at Week 24 | -45.9 Percent change from baseline to Week 24 |
Secondary
Pharmacokinetic (PK) Parameters for Pelabresib: Apparent Total Clearance of the Drug From Plasma After Oral Administration (CL/F)
Pharmacokinetic (PK) parameters will be calculated based on Pelabresib plasma concentrations and actual sampling time points. CL/F will be listed and summarized using descriptive statistics.
Time frame: Cycle 1 Day 1, Cycle 1 Day 14 and Cycle 9 Day 1: Predose, 30 minutes to 1 hour post-dose, 3 to 4.5 hours post-dose. Cycle 3 and Cycle 7 Day 1: Predose, 5 minutes post ECG assessment. 1 Cycle = 21 days
Secondary
Pharmacokinetic (PK) Parameters for Pelabresib: Apparent Volume of Distribution After Non-intravenous Administration (Vd/F)
Pharmacokinetic (PK) parameters will be calculated based on Pelabresib plasma concentrations and actual sampling time points. Vd/F will be listed and summarized using descriptive statistics.
Time frame: Cycle 1 Day 1, Cycle 1 Day 14 and Cycle 9 Day 1: Predose, 30 minutes to 1 hour post-dose, 3 to 4.5 hours post-dose. Cycle 3 and Cycle 7 Day 1: Predose, 5 minutes post ECG assessment. 1 Cycle = 21 days
Secondary
Pharmacokinetic (PK) Parameters for Pelabresib: Area Under the Plasma Concentration-time Curve From Time Zero to Time t (AUC0-t)
Pharmacokinetic (PK) parameters will be calculated based on Pelabresib plasma concentrations and actual sampling time points. AUC0-t will be listed and summarized using descriptive statistics.
Time frame: Cycle 1 Day 1, Cycle 1 Day 14 and Cycle 9 Day 1: Predose, 30 minutes to 1 hour post-dose, 3 to 4.5 hours post-dose. Cycle 3 and Cycle 7 Day 1: Predose, 5 minutes post ECG assessment. 1 Cycle = 21 days
Secondary
Pharmacokinetic (PK) Parameters for Pelabresib: Effective Half-Life (T1/2)
Pharmacokinetic (PK) parameters will be calculated based on Pelabresib plasma concentrations and actual sampling time points. T1/2 will be listed and summarized using descriptive statistics.
Time frame: Cycle 1 Day 1, Cycle 1 Day 14 and Cycle 9 Day 1: Predose, 30 minutes to 1 hour post-dose, 3 to 4.5 hours post-dose. Cycle 3 and Cycle 7 Day 1: Predose, 5 minutes post ECG assessment. 1 Cycle = 21 days
Secondary
Pharmacokinetic (PK) Parameters for Pelabresib: Maximum (Peak) Plasma Drug Concentration (Cmax)
Pharmacokinetic (PK) parameters will be calculated based on Pelabresib plasma concentrations and actual sampling time points. AUC0-t will be listed and summarized using descriptive statistics. Cmax will be listed and summarized using descriptive statistics.
Time frame: Cycle 1 Day 1, Cycle 1 Day 14 and Cycle 9 Day 1: Predose, 30 minutes to 1 hour post-dose, 3 to 4.5 hours post-dose. Cycle 3 and Cycle 7 Day 1: Predose, 5 minutes post ECG assessment. 1 Cycle = 21 days
Secondary
Pharmacokinetic (PK) Parameters for Pelabresib: Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax)
Pharmacokinetic (PK) parameters will be calculated based on Pelabresib plasma concentrations and actual sampling time points. AUC0-t will be listed and summarized using descriptive statistics. Tmax will be listed and summarized using descriptive statistics.
Time frame: Cycle 1 Day 1, Cycle 1 Day 14 and Cycle 9 Day 1: Predose, 30 minutes to 1 hour post-dose, 3 to 4.5 hours post-dose. Cycle 3 and Cycle 7 Day 1: Predose, 5 minutes post ECG assessment. 1 Cycle = 21 days
Secondary
Progression-Free Survival (PFS)
Progression-Free Survival (PFS), defined as the time from randomization until documented progression, or until death from any cause for patients without documented progression
Time frame: Through study completion, an average of 6 years
Secondary
Proportion of Patients With Transformation to Blast Phase (AML)
Patients are categorized as having transformed to Acute Myelogenous Leukemia (AML) when the peripheral blood blast percentage increases to ≥20% and this elevation persists for at least two weeks, or when leukemic transformation is confirmed through disease status assessment.
Time frame: Through study completion, an average of 6 years
Secondary
Rate of Red Blood Cell (RBC) Transfusion Over First 24 Weeks of Treatment
The rate of RBC transfusions was defined as the average number of RBC units transfused per patient month (4 weeks) during the first 24 weeks of treatment. The average number of RBC units per patient-month was calculated by dividing the total (ie, for all patients) number of RBC units in the whole exposure time by the sum of patient-months.
Time frame: Week 24
Population: Intent-to-Treat (ITT) Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pelabresib + Ruxolitinib (Experimental Arm) | Rate of Red Blood Cell (RBC) Transfusion Over First 24 Weeks of Treatment | 1.359 RBC units transfused/patient-months |
| Placebo + Ruxolitinib (Control Arm) | Rate of Red Blood Cell (RBC) Transfusion Over First 24 Weeks of Treatment | 1.014 RBC units transfused/patient-months |
Secondary
Ruxolitinib Plasma Concentrations in the Presence or Absence of Pelabresib
Blood samples (approximately 4 mL each) will be collected at the time points specified in the Schedule of Assessments (SOA) to determine plasma concentrations of Ruxolitinib plasma concentrations in the presence or absence of Pelabresib
Time frame: Cycle 1 Day 1, Cycle 1 Day 14 and Cycle 9 Day 1: Predose, 30 minutes to 1 hour post-dose, 3 to 4.5 hours post-dose. Cycle 3 and Cycle 7 Day 1: Predose, 5 minutes post ECG assessment. 1 Cycle = 21 days