Primary Myelofibrosis, Post-polycythemia Vera Myelofibrosis, Post-essential Thrombocythemia Myelofibrosis
Conditions
Keywords
Myelofibrosis, JAK inhibitor, Danazol, Momelotinib, Functional Iron deficiency, Activin receptor type 1, Anemia, Transfusion, Hepcidin, Myeloproliferative Disorders, Bone Marrow Diseases, Hematologic Diseases
Brief summary
MOMENTUM is a randomized, double-blind, active control Phase 3 trial intended to confirm the differentiated clinical benefits of the investigational drug momelotinib (MMB) versus danazol (DAN) in symptomatic and anemic participants who have previously received an approved Janus kinase inhibitor (JAKi) therapy for myelofibrosis (MF). The purpose of this clinical study is to compare the effectiveness and safety of MMB to DAN in treating and reducing: 1) disease related symptoms, 2) the need for blood transfusions and 3) splenomegaly, in adults with primary MF, post-polycythemia vera MF or post-essential thrombocythemia MF. The study is planned in countries including, but not limited to: Australia, Austria, Belgium, Bulgaria, Canada, Czech Republic, Denmark, France, Germany, Hungary, Israel, Italy, New Zealand, Poland, Romania, Singapore, South Korea, Spain, Sweden, Taiwan, United Kingdom (UK) and United States (US). Participants must be symptomatic with a Myelofibrosis Symptom Assessment Form (MFSAF) version (v) 4.0 Total Symptom Score of \>= 10 at screening, and be anemic with hemoglobin (Hgb) \< 10 gram/deciliter (g/dL). For participants with ongoing JAKi therapy at screening, JAKi therapy must be tapered over a period of at least 1 week, followed by a 2-week non-treatment washout interval prior to randomization. Participants will be randomized 2:1 to orally self-administer blinded treatment: MMB plus placebo or DAN plus placebo. Participants randomized to receive MMB who complete the randomized treatment period to the end of Week 24 may continue to receive MMB in the open-label extended treatment period to the end of Week 204 (a total period of treatment of approximately 4 years) if the participants tolerates and continues to benefit from MMB. Participants randomized to receive DAN may cross-over to MMB open-label treatment in the following circumstances: at the end of Week 24 if they complete the randomized treatment period; or at the end of Week 24 if they discontinue treatment with DAN but continue study assessments and do not receive prohibited medications including alternative active anti-MF therapy; or at any time during the randomized treatment period if they meet the protocol-defined criteria for radiographically confirmed symptomatic splenic progression. Participants randomized to receive DAN who are receiving clinical benefit at the end of Week 24 may choose to continue DAN therapy up to Week 48. The comparator treatment, DAN, is an approved medication in the US and in some other countries and is recommended by national guidelines as a treatment for anemia in MF.
Detailed description
MOMENTUM Contact Email: GSKClinicalSupportHD@gsk.com
Interventions
DRUGMomelotinib
Momelotinib tablets will be self-administered orally once daily
DRUGPlacebo to match danazol
Danazol placebo capsules will be self-administered orally twice daily
DRUGDanazol
Danazol capsules will be self-administered orally twice daily
Momelotinib placebo tablets will be self-administered orally once daily
Sponsors
Sierra Oncology LLC - a GSK company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
During the 24 week randomized treatment phase of the study, participants, investigators and sponsor and relevant vendor personnel (with the exception of specified unblinded personnel, for example clinical supply) will remain blinded to the participant's treatment assignment and to aggregate data that may lead to inadvertent unblinding. Participants who continue treatment with momelotinib or danazol after Week 24 in the extended treatment phase will receive unblinded treatment.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age \>= 18 years. * Confirmed diagnosis of PMF in accordance with the World Health Organization (WHO) 2016 criteria, or Post- polycythemia vera/essential thrombocythemia (PV/ET) MF in accordance with the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT criteria). * Symptomatic, defined as a TSS of \>= 10 units assessed by a single MFSAF v4.0 assessment during Screening prior to Baseline period (Day BL1). * Anemic, defined as a Hgb \< 10 g/dL in Screening/Baseline period. * Previously treated with an approved JAK inhibitor for PMF or Post-PV/ET MF for \>= 90 days, or \>= 28 days if JAK inhibitor therapy is complicated by RBC transfusion requirement of \>= 4 units in 8 weeks, or Grade 3/4 AEs of thrombocytopenia, anemia, or hematoma. * Baseline splenomegaly, defined as having a palpable spleen at \>= 5 centimeter (cm), below the left costal margin, or with volume \>= 450 cubic centimeter (cm\^3) on imaging (ultrasound, magnetic resonance imaging \[MRI\] or computed tomography \[CT\] are acceptable), assessed during Screening at any point prior to Randomization. * High risk, intermediate-2, or intermediate-1 risk MF as defined by Dynamic International Prognostic Scoring System (DIPSS), or DIPSS-plus. * No allogeneic stem cell transplant planned. * Acceptable laboratory assessments: 1. Absolute neutrophil count (ANC) \>= 0.75 × 10\^9/Liter (L). 2. Platelet count (PLT) \>= 25 × 10\^9/L (without requirement for platelet transfusion). 3. Peripheral blast count \< 10%. 4. Alanine aminotransferase/ glutamic-oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase/ serum glutamic-pyruvic transaminase (ALT/SGPT) \<= 3 × Upper Limit Normal (ULN) (\<= 5 × ULN if liver is involved by extramedullary hematopoiesis as judged by the investigator or if related to iron chelator therapy that was started within the prior 60 days). 5. Calculated creatinine clearance (CCr) \>= 30 milliliter per minute (mL/min) according to Cockcroft-Gault. 6. Direct bilirubin \<= 2.0 × ULN.
Exclusion criteria
* Use of the following treatments within the time periods noted: 1. Prior momelotinib treatment at any time. 2. Approved JAK inhibitor therapy (eg, fedratinib or ruxolitinib) within 1 week prior to the first day of Baseline. 3. Active anti-MF therapy within 1 week prior to the first day of Baseline. 4. Potent Cytochrome P450 3A4 (CYP3A4) inducers within 1 week prior to Randomization. 5. Investigational agent (including investigational JAK inhibitors) within 4 weeks prior to Randomization. 6. Erythropoiesis stimulating agent (ESA) within 4 weeks prior to Randomization. 7. Danazol within 3 months prior to Randomization. 8. Splenic irradiation within 3 months prior to Randomization. 9. Current treatment with simvastatin, atorvastatin, lovastatin or rosuvastatin. * History of prostate cancer, with the exception of localized prostate cancer that has been treated surgically or by radiotherapy with curative intent and presumed cured. * Prostate specific antigen (PSA) \> 4 nanograms per milliliter (ng/mL). * Unsuitable for spleen volume measurements due to prior splenectomy or unwilling or unable to undergo an MRI scan or CT scan for spleen volume measurement per protocol requirements. * Any of the following (criteria a - k): 1. Uncontrolled intercurrent illness including, but not limited to: active uncontrolled infection (participants receiving outpatient antibacterial and/or antiviral treatments for infection that is under control or as infection prophylaxis may be included in the trial). 2. Significant active or chronic bleeding event \>= Grade 2 per Common Terminology Criteria for Adverse Events (CTCAE) v5.0, within 4 weeks prior to Randomization. 3. Unstable angina pectoris within 6 months prior to Randomization. 4. Symptomatic congestive heart failure within 6 months prior to Randomization. 5. Uncontrolled cardiac arrhythmia within 6 months prior to Randomization. 6. QT Interval Corrected Using Fridericia's Formula (QTcF) interval \> 500 millisecond (msec), unless attributed to bundle branch block. 7. Current progressive thrombosis despite treatment. 8. History of porphyria. 9. Child-Pugh score \>= 10. 10. Psychiatric illness, social situation, or any other condition that would limit compliance with trial requirements or may interfere with the interpretation of study results, as judged by investigator or sponsor. 11. Inability or unwillingness to comply with the protocol restrictions on MF therapy and other medications prior to and during study treatment. * Participants with a prior or concurrent malignancy, whose natural history or treatment has a significant potential to interfere with the safety or efficacy assessment of the investigational regimen. * Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding or thalassemia. * Known positive status for human immunodeficiency viruses (HIV). * Chronic active or acute viral hepatitis A, B, or C infection, or hepatitis B or C carrier (testing required for hepatitis B and C). * Unresolved non-hematologic toxicities from prior therapies that are \> Grade 1 per CTCAE v5.0. * Presence of peripheral neuropathy \>= Grade 2 per CTCAE v5.0. * Women who are already pregnant or lactating. Additional inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Symptom Score (TSS) Response Rate at Week 24 | Baseline and Week 24 | Myelofibrosis Symptom Assessment Form (MFSAF) TSS version (v) 4.0 response rate was defined as percentage of participants with a \>= 50 percent (%) reduction from Baseline in mean MFSAF TSS over consecutive 28-day period immediately before end of Week 24. TSS response rate was measured using MFSAF v4.0. MFSAF v4.0 comprises 7 domains representing 7 most relevant symptoms of myelofibrosis (MF) identified through existing participant and clinician-based evidence: fatigue,night sweats,pruritus,abdominal discomfort,pain under left ribs,early satietyand bone pain. Participants scored each symptom domain using an 11-point numeric rating scale ranging from 0(absent) to 10(worst imaginable). The MFSAF TSS was calculated as sum of scores of 7 domains for a possible range of scores of 0 to 70, with a higher TSS corresponding to more severe symptoms. A reduction from Baseline corresponded to a lessening of MF symptoms. Baseline was the last assessment done before or on the day of first dose date. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Splenic Response Rate (SRR) of >=25% at Week 24 | Baseline and Week 24 | Splenic response rate (SRR) is defined as the percentage of participants who have reduction in spleen volume of \>=25% from Baseline at the end of Week 24. Baseline was the last assessment done before or on the day of first dose date. |
| Change From Baseline in MFSAF TSS at Week 24 | Baseline and Week 24 | TSS was measured using the MFSAF v4.0. The MFSAF v4.0 comprises 7 domains representing the 7 most relevant symptoms of MF identified through existing participant and clinician-based evidence: fatigue, night sweats, pruritus, abdominal discomfort, pain under the left ribs, early satiety, and bone pain. Participants scored each symptom domain using an 11-point numeric rating scale ranging from 0 (absent) to 10 (worst imaginable). The MFSAF TSS was calculated as the sum of scores of the 7 domains for a possible range of scores of 0 to 70, with a higher TSS corresponding to more severe symptoms. A reduction from Baseline corresponded to a lessening of MF symptoms. Baseline was the last assessment done before or on the day of first dose date. Change from Baseline was defined as the post-Baseline value minus Baseline value. |
| Splenic Response Rate (SRR) of >= 35% at Week 24 | Baseline and Week 24 | Splenic response rate (SRR) is defined as the percentage of participants who have reduction in spleen volume of \>=35 % from Baseline at the end of Week 24. Baseline was the last assessment done before or on the day of first dose date. |
| Percentage of Participants With Zero RBC Units Transfused Over 24-Weeks | Up to 24 weeks | Percentage of participants with zero RBC units transfused over 24-weeks were reported. |
| Percentage of Participants With <=4 RBC Units Transfused Over 24-weeks | Up to 24 weeks | Percentage of participants with \<=4 RBC units transfused over 24-weeks were reported. |
| Duration of MFSAF TSS Response | Up to a maximum of 151 weeks | Duration of MFSAF TSS response is defined as the number of days from the start of the initial 28-day period in which a participant had a \>= 50% reduction from Baseline TSS to the first day of the 7-day assessment that determines the mean TSS for the 28-day period during which the participants TSS equals or exceeds their Baseline value. |
| Duration of TI Response | Up to a maximum of 151 weeks | Duration of TI is defined as the number of days from (a) the first day of a 12-week period that satisfies the 12-week TI status definition, to (b) the first RBC transfusion or Hgb level \< 8 g/dL (except in the case of clinically overt bleeding). |
| Mean Cumulative Number of Whole Blood Units Transfused Over 24 Weeks | Up to Week 24 | Cumulative transfusion risk was calculated as the estimated mean cumulative number of whole blood units transfused during the study. |
| Percentage of Participants With Transfusion Dependence (TD) Status at Week 24 | Week 24 | TD status at Week 24 is defined as requirement of \>=4 RBC units in an 8-week period immediately prior to the end of Week 24. |
| Percentage of Participants With Transfusion Independence (TI) at Week 24 | Week 24 | TI status was defined as not receiving red blood cell (RBC) or whole blood transfusion for \>=12 weeks, with no hemoglobin (Hgb) level \< 8 grams per deciliter (g/dL) during the same interval. Percentage of participants with TI have been presented. |
| Number of Baseline TD Participants With TI Status at Week 24 | Week 24 | Participants were defined as having TD if they met both of the following requirements in the 8 weeks immediately before the end of Week 24: \>= 4 red blood cell or whole blood units were transfused (except in the case of clinically overt bleeding), each in response to a hemoglobin assessment of \<= 9.5 g/dL; and there were \>= 2 hemoglobin assessments with \>= 28 days between the earliest and latest hemoglobin assessments. TI status was defined as not requiring red blood cell transfusion (except in the case of clinically overt bleeding) for \>= 12 weeks immediately prior to the end of Week 24, with hemoglobin levels \>= 8 g/dL. |
| Duration of TI in Baseline TD Participants | Up to a maximum of 151 weeks | Duration of TI is defined as the number of days from (a) the first day of a 12-week period that satisfies the 12-week TI status definition, to (b) the first RBC transfusion or Hgb level \< 8 g/dL (except in the case of clinically overt bleeding). |
| Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs)- up to Week 24 | Up to Week 24 | An adverse event (AE) is any untoward medical occurrence in a trial participant administered an investigational product(s), a comparator product, or an approved drug regardless of the causal relationship with treatment. An SAE is an AE that Results in death, life threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, results in a congenital anomaly/birth defect or any important medical events as per medical or scientific judgment. Adverse events which were not Serious were considered as Non-Serious adverse events. |
| Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs)- From Week 24 to a Maximum of 151 Weeks | From Week 24 to a maximum of 151 weeks | An AE is any untoward medical occurrence in a trial participant administered an investigational product(s), a comparator product, or an approved drug regardless of the causal relationship with treatment. An SAE is an AE that Results in death, life threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, results in a congenital anomaly/birth defect or any important medical events as per medical or scientific judgment. Adverse events which were not Serious were considered as Non-Serious adverse events. |
| Overall Survival (OS) | Up to a maximum of 151 weeks | Overall survival is defined as the interval from the first study drug dosing date (or randomization date for participants who did not receive treatment) to death from any cause. |
| Leukemia-free Survival (LFS) | Up to a maximum of 151 weeks | LFS is defined as the interval from first study drug dosing date (or randomization date for participants who did not receive treatment) to any evidence of leukemic transformation and/or death (from any cause). |
| Change From Baseline in Disease-related Fatigue as Assessed by MFSAF TSS v4.0 at Week 24 | Baseline and Week 24 | The MFSAF v4.0 comprises 7 domains representing the 7 most relevant symptoms of MF identified through existing participant- and clinician-based evidence: fatigue, night sweats, pruritus, abdominal discomfort, pain under the left ribs, early satiety, and bone pain. Participants scored each symptom domain using an 11-point numeric rating scale ranging from 0 (absent) to 10 (worst imaginable). Data has been reported for Disease-related Fatigue domain measured using an 11-point numeric rating scale ranging from 0 (absent) to 10 (worst imaginable), higher score indicates worst outcome. An increase in score from Baseline indicated a worsening of fatigue and a decrease in score from Baseline indicated an improvement in fatigue. Baseline was the last assessment done before or on the day of first dose date. Change from Baseline was defined as the post-Baseline value minus Baseline value. |
| Change From Baseline in Cancer-related Fatigue as Assessed by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) at Week 24 | Baseline and Week 24 | The EORTC QLQ-C30 is comprised of 5 functional scales (physical, role, emotional, social, cognitive), eight single item symptom scales (fatigue, pain, nausea/vomiting, appetite loss, constipation, diarrhea, insomnia, dyspnea), as well as sub-scales assessing global health/quality of life and financial impact. Most items use a 4-point Likert scale from not at all to very much and a one-week recall period with the exception of the final two items which use a 7 point scale response from very poor to excellent. Scores were averaged and transformed to a 0-100 scale, with higher scores representing better functioning/quality of life. An increase in scores from Baseline indicated an improved functioning/quality of life, and a decrease in scores from Baseline indicated a worsened functioning/quality of life. Baseline was the last assessment done before or on the day of first dose date. Change from Baseline was defined as the post-Baseline value minus Baseline value. |
| Change From Baseline in Physical Function Score as Assessed by Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function Short Form 10b at Week 24 | Baseline and Week 24 | PROMIS Physical Function Short Form 10b consists of 14 questions; each with a 5-point response. PROMIS short form assesses self-reported capability of a participant rather than actual performance of physical activities. This includes functioning of one's upper extremities (dexterity), lower extremities (walking or mobility), and central regions (neck, back) as well as instrumental activities of daily living, such as running errands. Participants scored each response on a scale from 1 (unable to do) to 5 (without any difficulty, or not at all). Total possible range of scores was 14 to 70, with higher scores corresponding to a greater physical function ability. An increase in score from Baseline indicated an improvement in physical function ability and a decrease in score from Baseline indicated a reduction in physical function ability. Baseline was last assessment done before or on the day of first dose date. Change from Baseline was defined as post-Baseline value minus Baseline value. |
| Percentage of Participants With a Hemoglobin Response | Baseline and Week 24 | Hemoglobin responses are defined as increases of \>= 1, \>= 1.5, or \>= 2 g/dL from Baseline in Hgb, as measured over a (rolling) period of at least 12 consecutive weeks falling entirely before the end of Week 24. Baseline was the last assessment done before or on the day of first dose date. Data has been reported for percentage of participants who had \>= 1, \>= 1.5, or \>= 2 g/dL increase from Baseline in hemoglobin. |
Countries
Australia, Austria, Belgium, Bulgaria, Canada, Czechia, Denmark, France, Germany, Hungary, Israel, Italy, New Zealand, Poland, Romania, Singapore, South Korea, Spain, Sweden, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
This study evaluated the activity of Momelotinib (MMB) versus Danazol (DAN) in Symptomatic, Anemic participants. This study consists of Randomized Double-blind (DB) Treatment Period (TP) and Open-label extended Treatment Period.
Pre-assignment details
A total of 195 participants were enrolled in the study.
Participants by arm
| Arm | Count |
|---|---|
| MMB 200 mg QD + Placebo Participants were randomized to receive 200 milligrams (mg) of MMB orally QD and a DAN-placebo orally twice daily (BID) during the randomized 24-week double-blind treatment period. Participants who completed the randomized treatment period or discontinued treatment early for other reasons but completed scheduled assessments through Week 24 were enrolled in an open-label extended treatment period. Participants continued to receive 200 mg of MMB orally QD during the open-label extended treatment period. Participants who discontinued treatment prior to Week 24 due to splenic progression or other reasons, but completed assessments, were unblinded. Participants who discontinued MMB during the randomized treatment period were not eligible to receive MMB in the open-label extended treatment period. Participants who were randomized to MMB during the randomized treatment period with confirmed splenic progression could not proceed to the open-label extended treatment period. | 130 |
| DAN 300 mg BID + Placebo Participants were randomized to receive 300 mg of DAN orally BID and MMB-placebo orally QD during the randomized 24-week double-blind treatment period. Participants who completed the randomized treatment period, discontinued treatment early due to splenic progression, or discontinued treatment early for other reasons but completed scheduled assessments through Week 24 were enrolled in an open-label extended treatment period. Participants who received DAN 300 mg BID during randomized period switched to receive 200 mg of MMB orally QD during open-label extended treatment period. | 65 |
| Total | 195 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Open-Label Extended TP(Weeks 24 to 151) | Adverse Event | 11 | 1 |
| Open-Label Extended TP(Weeks 24 to 151) | Continuing in MMB extension study | 61 | 27 |
| Open-Label Extended TP(Weeks 24 to 151) | Death | 6 | 3 |
| Open-Label Extended TP(Weeks 24 to 151) | Disease progression | 1 | 1 |
| Open-Label Extended TP(Weeks 24 to 151) | Lack of Efficacy | 6 | 2 |
| Open-Label Extended TP(Weeks 24 to 151) | Leukemic transformation | 0 | 1 |
| Open-Label Extended TP(Weeks 24 to 151) | Physician Decision | 4 | 3 |
| Open-Label Extended TP(Weeks 24 to 151) | Withdrawal by Subject | 4 | 3 |
| Randomized DB TP (Up to Week 24) | Adverse Event | 16 | 11 |
| Randomized DB TP (Up to Week 24) | Death | 4 | 3 |
| Randomized DB TP (Up to Week 24) | Disease Progression | 1 | 2 |
| Randomized DB TP (Up to Week 24) | Lack of Efficacy | 6 | 3 |
| Randomized DB TP (Up to Week 24) | Leukemic Transformation | 2 | 2 |
| Randomized DB TP (Up to Week 24) | Lost to Follow-up | 1 | 0 |
| Randomized DB TP (Up to Week 24) | Physician Decision | 0 | 1 |
| Randomized DB TP (Up to Week 24) | Withdrawal by Subject | 6 | 5 |
Baseline characteristics
| Characteristic | DAN 300 mg BID + Placebo | Total | MMB 200 mg QD + Placebo |
|---|---|---|---|
| Age, Continuous | 71.46 Years STANDARD_DEVIATION 6.99 | 70.38 Years STANDARD_DEVIATION 7.86 | 69.85 Years STANDARD_DEVIATION 8.24 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 11 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 54 Participants | 169 Participants | 115 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 15 Participants | 10 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 6 Participants | 18 Participants | 12 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 4 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 | 7 Participants | 16 Participants | 9 Participants |
| Race (NIH/OMB) White | 50 Participants | 157 Participants | 107 Participants |
| Sex: Female, Male Female | 21 Participants | 72 Participants | 51 Participants |
| Sex: Female, Male Male | 44 Participants | 123 Participants | 79 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 25 / 130 | 16 / 65 | 23 / 93 | 8 / 41 |
| other Total, other adverse events | 108 / 130 | 55 / 65 | 57 / 93 | 28 / 41 |
| serious Total, serious adverse events | 45 / 130 | 26 / 65 | 30 / 93 | 12 / 41 |
Outcome results
Primary
Total Symptom Score (TSS) Response Rate at Week 24
Myelofibrosis Symptom Assessment Form (MFSAF) TSS version (v) 4.0 response rate was defined as percentage of participants with a \>= 50 percent (%) reduction from Baseline in mean MFSAF TSS over consecutive 28-day period immediately before end of Week 24. TSS response rate was measured using MFSAF v4.0. MFSAF v4.0 comprises 7 domains representing 7 most relevant symptoms of myelofibrosis (MF) identified through existing participant and clinician-based evidence: fatigue,night sweats,pruritus,abdominal discomfort,pain under left ribs,early satietyand bone pain. Participants scored each symptom domain using an 11-point numeric rating scale ranging from 0(absent) to 10(worst imaginable). The MFSAF TSS was calculated as sum of scores of 7 domains for a possible range of scores of 0 to 70, with a higher TSS corresponding to more severe symptoms. A reduction from Baseline corresponded to a lessening of MF symptoms. Baseline was the last assessment done before or on the day of first dose date.
Time frame: Baseline and Week 24
Population: Measured in the Intent-To-Treat (ITT) Analysis Set, which included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MMB 200 mg QD + Placebo | Total Symptom Score (TSS) Response Rate at Week 24 | 24.62 Percentage of participants |
| DAN 300 mg BID + Placebo | Total Symptom Score (TSS) Response Rate at Week 24 | 9.23 Percentage of participants |
p-value: 0.009595% CI: [5.54, 25.81]Cochran-Mantel-Haenszel
Secondary
Change From Baseline in Cancer-related Fatigue as Assessed by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) at Week 24
The EORTC QLQ-C30 is comprised of 5 functional scales (physical, role, emotional, social, cognitive), eight single item symptom scales (fatigue, pain, nausea/vomiting, appetite loss, constipation, diarrhea, insomnia, dyspnea), as well as sub-scales assessing global health/quality of life and financial impact. Most items use a 4-point Likert scale from not at all to very much and a one-week recall period with the exception of the final two items which use a 7 point scale response from very poor to excellent. Scores were averaged and transformed to a 0-100 scale, with higher scores representing better functioning/quality of life. An increase in scores from Baseline indicated an improved functioning/quality of life, and a decrease in scores from Baseline indicated a worsened functioning/quality of life. Baseline was the last assessment done before or on the day of first dose date. Change from Baseline was defined as the post-Baseline value minus Baseline value.
Time frame: Baseline and Week 24
Population: ITT Analysis Set. Only those participants with data available at specified time points were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MMB 200 mg QD + Placebo | Change From Baseline in Cancer-related Fatigue as Assessed by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) at Week 24 | -14.34 Scores on a scale | Standard Error 2.35 |
| DAN 300 mg BID + Placebo | Change From Baseline in Cancer-related Fatigue as Assessed by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) at Week 24 | -3.52 Scores on a scale | Standard Error 3.65 |
p-value: 0.011395% CI: [-19.15, -2.48]MMRM
Secondary
Change From Baseline in Disease-related Fatigue as Assessed by MFSAF TSS v4.0 at Week 24
The MFSAF v4.0 comprises 7 domains representing the 7 most relevant symptoms of MF identified through existing participant- and clinician-based evidence: fatigue, night sweats, pruritus, abdominal discomfort, pain under the left ribs, early satiety, and bone pain. Participants scored each symptom domain using an 11-point numeric rating scale ranging from 0 (absent) to 10 (worst imaginable). Data has been reported for Disease-related Fatigue domain measured using an 11-point numeric rating scale ranging from 0 (absent) to 10 (worst imaginable), higher score indicates worst outcome. An increase in score from Baseline indicated a worsening of fatigue and a decrease in score from Baseline indicated an improvement in fatigue. Baseline was the last assessment done before or on the day of first dose date. Change from Baseline was defined as the post-Baseline value minus Baseline value.
Time frame: Baseline and Week 24
Population: ITT Analysis Set. Only those participants with data available at specified time points were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MMB 200 mg QD + Placebo | Change From Baseline in Disease-related Fatigue as Assessed by MFSAF TSS v4.0 at Week 24 | -1.53 Scores on a scale | Standard Error 0.2 |
| DAN 300 mg BID + Placebo | Change From Baseline in Disease-related Fatigue as Assessed by MFSAF TSS v4.0 at Week 24 | -0.82 Scores on a scale | Standard Error 0.31 |
p-value: 0.051395% CI: [-1.42, 0]MMRM
Secondary
Change From Baseline in MFSAF TSS at Week 24
TSS was measured using the MFSAF v4.0. The MFSAF v4.0 comprises 7 domains representing the 7 most relevant symptoms of MF identified through existing participant and clinician-based evidence: fatigue, night sweats, pruritus, abdominal discomfort, pain under the left ribs, early satiety, and bone pain. Participants scored each symptom domain using an 11-point numeric rating scale ranging from 0 (absent) to 10 (worst imaginable). The MFSAF TSS was calculated as the sum of scores of the 7 domains for a possible range of scores of 0 to 70, with a higher TSS corresponding to more severe symptoms. A reduction from Baseline corresponded to a lessening of MF symptoms. Baseline was the last assessment done before or on the day of first dose date. Change from Baseline was defined as the post-Baseline value minus Baseline value.
Time frame: Baseline and Week 24
Population: ITT Analysis Set. Only those participants with data available at specified time points were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MMB 200 mg QD + Placebo | Change From Baseline in MFSAF TSS at Week 24 | -9.36 Scores on a scale | Standard Error 1.08 |
| DAN 300 mg BID + Placebo | Change From Baseline in MFSAF TSS at Week 24 | -3.13 Scores on a scale | Standard Error 1.62 |
p-value: 0.001495% CI: [-10, -2.43]mixed model for repeated measures (MMRM)
Secondary
Change From Baseline in Physical Function Score as Assessed by Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function Short Form 10b at Week 24
PROMIS Physical Function Short Form 10b consists of 14 questions; each with a 5-point response. PROMIS short form assesses self-reported capability of a participant rather than actual performance of physical activities. This includes functioning of one's upper extremities (dexterity), lower extremities (walking or mobility), and central regions (neck, back) as well as instrumental activities of daily living, such as running errands. Participants scored each response on a scale from 1 (unable to do) to 5 (without any difficulty, or not at all). Total possible range of scores was 14 to 70, with higher scores corresponding to a greater physical function ability. An increase in score from Baseline indicated an improvement in physical function ability and a decrease in score from Baseline indicated a reduction in physical function ability. Baseline was last assessment done before or on the day of first dose date. Change from Baseline was defined as post-Baseline value minus Baseline value.
Time frame: Baseline and Week 24
Population: ITT Analysis Set. Only those participants with data available at specified time points were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MMB 200 mg QD + Placebo | Change From Baseline in Physical Function Score as Assessed by Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function Short Form 10b at Week 24 | 1.19 Scores on a scale | Standard Error 0.77 |
| DAN 300 mg BID + Placebo | Change From Baseline in Physical Function Score as Assessed by Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function Short Form 10b at Week 24 | -0.11 Scores on a scale | Standard Error 1.21 |
p-value: 0.35795% CI: [-1.49, 4.11]MMRM
Secondary
Duration of MFSAF TSS Response
Duration of MFSAF TSS response is defined as the number of days from the start of the initial 28-day period in which a participant had a \>= 50% reduction from Baseline TSS to the first day of the 7-day assessment that determines the mean TSS for the 28-day period during which the participants TSS equals or exceeds their Baseline value.
Time frame: Up to a maximum of 151 weeks
Population: ITT Analysis Set. Only those participants with data available at specified time point were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MMB 200 mg QD + Placebo | Duration of MFSAF TSS Response | 286.00 Days |
| DAN 300 mg BID + Placebo | Duration of MFSAF TSS Response | NA Days |
Secondary
Duration of TI in Baseline TD Participants
Duration of TI is defined as the number of days from (a) the first day of a 12-week period that satisfies the 12-week TI status definition, to (b) the first RBC transfusion or Hgb level \< 8 g/dL (except in the case of clinically overt bleeding).
Time frame: Up to a maximum of 151 weeks
Population: ITT Analysis Set. Only those participants with data available at specified time points were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MMB 200 mg QD + Placebo | Duration of TI in Baseline TD Participants | NA Days |
| DAN 300 mg BID + Placebo | Duration of TI in Baseline TD Participants | NA Days |
Secondary
Duration of TI Response
Duration of TI is defined as the number of days from (a) the first day of a 12-week period that satisfies the 12-week TI status definition, to (b) the first RBC transfusion or Hgb level \< 8 g/dL (except in the case of clinically overt bleeding).
Time frame: Up to a maximum of 151 weeks
Population: ITT Analysis Set. Only those participants with data available at specified time point were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MMB 200 mg QD + Placebo | Duration of TI Response | NA Days |
| DAN 300 mg BID + Placebo | Duration of TI Response | NA Days |
Secondary
Leukemia-free Survival (LFS)
LFS is defined as the interval from first study drug dosing date (or randomization date for participants who did not receive treatment) to any evidence of leukemic transformation and/or death (from any cause).
Time frame: Up to a maximum of 151 weeks
Population: ITT Analysis Set. Values are presented based on the Kaplan-Meier analysis. All participants (overall population) were included in analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MMB 200 mg QD + Placebo | Leukemia-free Survival (LFS) | 624.0 Days |
| DAN 300 mg BID + Placebo | Leukemia-free Survival (LFS) | NA Days |
p-value: 0.43295% CI: [0.466, 1.386]Log Rank
Secondary
Mean Cumulative Number of Whole Blood Units Transfused Over 24 Weeks
Cumulative transfusion risk was calculated as the estimated mean cumulative number of whole blood units transfused during the study.
Time frame: Up to Week 24
Population: ITT Analysis Set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MMB 200 mg QD + Placebo | Mean Cumulative Number of Whole Blood Units Transfused Over 24 Weeks | 6.55 Whole blood units | Standard Deviation 8.413 |
| DAN 300 mg BID + Placebo | Mean Cumulative Number of Whole Blood Units Transfused Over 24 Weeks | 10.86 Whole blood units | Standard Deviation 13.203 |
p-value: 0.000695% CI: [0.397, 0.778]Anderson & Gill proportional means model
Secondary
Number of Baseline TD Participants With TI Status at Week 24
Participants were defined as having TD if they met both of the following requirements in the 8 weeks immediately before the end of Week 24: \>= 4 red blood cell or whole blood units were transfused (except in the case of clinically overt bleeding), each in response to a hemoglobin assessment of \<= 9.5 g/dL; and there were \>= 2 hemoglobin assessments with \>= 28 days between the earliest and latest hemoglobin assessments. TI status was defined as not requiring red blood cell transfusion (except in the case of clinically overt bleeding) for \>= 12 weeks immediately prior to the end of Week 24, with hemoglobin levels \>= 8 g/dL.
Time frame: Week 24
Population: ITT Analysis Set. Only those participants with data available at specified time points were analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MMB 200 mg QD + Placebo | Number of Baseline TD Participants With TI Status at Week 24 | 9 Participants |
| DAN 300 mg BID + Placebo | Number of Baseline TD Participants With TI Status at Week 24 | 3 Participants |
Secondary
Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs)- From Week 24 to a Maximum of 151 Weeks
An AE is any untoward medical occurrence in a trial participant administered an investigational product(s), a comparator product, or an approved drug regardless of the causal relationship with treatment. An SAE is an AE that Results in death, life threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, results in a congenital anomaly/birth defect or any important medical events as per medical or scientific judgment. Adverse events which were not Serious were considered as Non-Serious adverse events.
Time frame: From Week 24 to a maximum of 151 weeks
Population: Safety analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| MMB 200 mg QD + Placebo | Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs)- From Week 24 to a Maximum of 151 Weeks | Any non-SAEs | 57 Participants |
| MMB 200 mg QD + Placebo | Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs)- From Week 24 to a Maximum of 151 Weeks | Any SAEs | 30 Participants |
| DAN 300 mg BID + Placebo | Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs)- From Week 24 to a Maximum of 151 Weeks | Any non-SAEs | 28 Participants |
| DAN 300 mg BID + Placebo | Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs)- From Week 24 to a Maximum of 151 Weeks | Any SAEs | 12 Participants |
Secondary
Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs)- up to Week 24
An adverse event (AE) is any untoward medical occurrence in a trial participant administered an investigational product(s), a comparator product, or an approved drug regardless of the causal relationship with treatment. An SAE is an AE that Results in death, life threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, results in a congenital anomaly/birth defect or any important medical events as per medical or scientific judgment. Adverse events which were not Serious were considered as Non-Serious adverse events.
Time frame: Up to Week 24
Population: Safety analysis set included all participants in the ITT Analysis set who received at least one dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| MMB 200 mg QD + Placebo | Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs)- up to Week 24 | Any non-SAEs | 108 Participants |
| MMB 200 mg QD + Placebo | Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs)- up to Week 24 | Any SAEs | 45 Participants |
| DAN 300 mg BID + Placebo | Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs)- up to Week 24 | Any non-SAEs | 55 Participants |
| DAN 300 mg BID + Placebo | Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs)- up to Week 24 | Any SAEs | 26 Participants |
Secondary
Overall Survival (OS)
Overall survival is defined as the interval from the first study drug dosing date (or randomization date for participants who did not receive treatment) to death from any cause.
Time frame: Up to a maximum of 151 weeks
Population: ITT Analysis Set. Values are presented based on the Kaplan-Meier analysis. All participants (overall population) were included in analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MMB 200 mg QD + Placebo | Overall Survival (OS) | 624.0 Days |
| DAN 300 mg BID + Placebo | Overall Survival (OS) | NA Days |
p-value: 0.687995% CI: [0.504, 1.572]Log Rank
Secondary
Percentage of Participants With <=4 RBC Units Transfused Over 24-weeks
Percentage of participants with \<=4 RBC units transfused over 24-weeks were reported.
Time frame: Up to 24 weeks
Population: ITT Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MMB 200 mg QD + Placebo | Percentage of Participants With <=4 RBC Units Transfused Over 24-weeks | 55.38 Percentage of participants |
| DAN 300 mg BID + Placebo | Percentage of Participants With <=4 RBC Units Transfused Over 24-weeks | 44.62 Percentage of participants |
p-value: 0.113395% CI: [-2.4, 23.64]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With a Hemoglobin Response
Hemoglobin responses are defined as increases of \>= 1, \>= 1.5, or \>= 2 g/dL from Baseline in Hgb, as measured over a (rolling) period of at least 12 consecutive weeks falling entirely before the end of Week 24. Baseline was the last assessment done before or on the day of first dose date. Data has been reported for percentage of participants who had \>= 1, \>= 1.5, or \>= 2 g/dL increase from Baseline in hemoglobin.
Time frame: Baseline and Week 24
Population: ITT Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MMB 200 mg QD + Placebo | Percentage of Participants With a Hemoglobin Response | >=1g/dL Increase | 53.08 Percentage of participants |
| MMB 200 mg QD + Placebo | Percentage of Participants With a Hemoglobin Response | >=1.5g/dL Increase | 40.00 Percentage of participants |
| MMB 200 mg QD + Placebo | Percentage of Participants With a Hemoglobin Response | >=2g/dL Increase | 29.23 Percentage of participants |
| DAN 300 mg BID + Placebo | Percentage of Participants With a Hemoglobin Response | >=1g/dL Increase | 33.85 Percentage of participants |
| DAN 300 mg BID + Placebo | Percentage of Participants With a Hemoglobin Response | >=1.5g/dL Increase | 23.08 Percentage of participants |
| DAN 300 mg BID + Placebo | Percentage of Participants With a Hemoglobin Response | >=2g/dL Increase | 20.00 Percentage of participants |
p-value: 0.012495% CI: [4.68, 33.32]Cochran-Mantel-Haenszel
p-value: 0.028295% CI: [2.47, 28.9]Cochran-Mantel-Haenszel
p-value: 0.284495% CI: [-5.41, 19.35]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Transfusion Dependence (TD) Status at Week 24
TD status at Week 24 is defined as requirement of \>=4 RBC units in an 8-week period immediately prior to the end of Week 24.
Time frame: Week 24
Population: ITT Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MMB 200 mg QD + Placebo | Percentage of Participants With Transfusion Dependence (TD) Status at Week 24 | 15.38 Percentage of participants |
| DAN 300 mg BID + Placebo | Percentage of Participants With Transfusion Dependence (TD) Status at Week 24 | 24.62 Percentage of participants |
p-value: 0.160295% CI: [-20.18, 3.66]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Transfusion Independence (TI) at Week 24
TI status was defined as not receiving red blood cell (RBC) or whole blood transfusion for \>=12 weeks, with no hemoglobin (Hgb) level \< 8 grams per deciliter (g/dL) during the same interval. Percentage of participants with TI have been presented.
Time frame: Week 24
Population: ITT Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MMB 200 mg QD + Placebo | Percentage of Participants With Transfusion Independence (TI) at Week 24 | 30.0 Percentage of Participants |
| DAN 300 mg BID + Placebo | Percentage of Participants With Transfusion Independence (TI) at Week 24 | 20.00 Percentage of Participants |
p-value: 0.011695% CI: [1.86, 25.3]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Zero RBC Units Transfused Over 24-Weeks
Percentage of participants with zero RBC units transfused over 24-weeks were reported.
Time frame: Up to 24 weeks
Population: ITT Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MMB 200 mg QD + Placebo | Percentage of Participants With Zero RBC Units Transfused Over 24-Weeks | 35.38 Percentage of participants |
| DAN 300 mg BID + Placebo | Percentage of Participants With Zero RBC Units Transfused Over 24-Weeks | 16.92 Percentage of participants |
p-value: 0.001295% CI: [7.99, 26.4]Cochran-Mantel-Haenszel
Secondary
Splenic Response Rate (SRR) of >=25% at Week 24
Splenic response rate (SRR) is defined as the percentage of participants who have reduction in spleen volume of \>=25% from Baseline at the end of Week 24. Baseline was the last assessment done before or on the day of first dose date.
Time frame: Baseline and Week 24
Population: ITT Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MMB 200 mg QD + Placebo | Splenic Response Rate (SRR) of >=25% at Week 24 | 39.23 Percentage of Participants |
| DAN 300 mg BID + Placebo | Splenic Response Rate (SRR) of >=25% at Week 24 | 6.15 Percentage of Participants |
p-value: <0.000195% CI: [22.59, 43.51]Cochran-Mantel-Haenszel
Secondary
Splenic Response Rate (SRR) of >= 35% at Week 24
Splenic response rate (SRR) is defined as the percentage of participants who have reduction in spleen volume of \>=35 % from Baseline at the end of Week 24. Baseline was the last assessment done before or on the day of first dose date.
Time frame: Baseline and Week 24
Population: ITT Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MMB 200 mg QD + Placebo | Splenic Response Rate (SRR) of >= 35% at Week 24 | 22.31 Percentage of Participants |
| DAN 300 mg BID + Placebo | Splenic Response Rate (SRR) of >= 35% at Week 24 | 3.08 Percentage of Participants |
p-value: 0.001195% CI: [9.77, 26.59]Cochran-Mantel-Haenszel