Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, Post-Essential Thrombocythemia Myelofibrosis
Conditions
Brief summary
This study is to determine the efficacy of momelotinib (MMB) versus ruxolitinib (RUX) in participants with primary myelofibrosis (PMF) or post-polycythemia vera or post-essential thrombocythemia myelofibrosis (post-PV/ET MF) who have not yet received treatment with a Janus kinase inhibitor (JAK inhibitor). Participants will be randomized to receive either MMB or ruxolitinib for 24 weeks during a double-blind treatment phase, after which they will be eligible to receive open-label MMB for up to an additional 216 weeks. After discontinuation of study medication, assessments will continue for 12 additional weeks, after which participants will be contacted for survival follow-up approximately every 6 months for up to 5 years from the date of enrollment or until study termination. For those participants planning to continue treatment with MMB following the end of the study, the Early Study Drug Discontinuation (ESDD), 30-day, 12-Week, and survival follow-up visits are not required.
Interventions
DRUGRuxolitinib
Ruxolitinib tablets administered orally twice daily
Placebo to match momelotinib tablets administered orally once daily
DRUGMomelotinib
Momelotinib tablet administered orally once daily
DRUGPlacebo to match ruxolitinib
Placebo to match ruxolitinib tablets administered orally twice 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)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Palpable splenomegaly at least 5 cm below the left costal margin * Confirmed diagnosis of PMF or post-PV/ET MF * Requires myelofibrosis therapy, in the opinion of the investigator * Classified as high risk OR intermediate-2 risk as defined by the International Prognostic Scoring System (IPSS) for PMF, or intermediate-1 risk (IPSS) associated with symptomatic splenomegaly, hepatomegaly, anemia (hemoglobin \< 10.0 g/dL), and/or unresponsive to available therapy * Acceptable laboratory assessment obtained within 14 days prior to the first dose of study drug: * Absolute neutrophil count (ANC) ≥ 0.75 x 10\^9/L in the absence of growth factor in the prior 7 days * Platelet Count ≥ 50 x 10\^9/L (≥ 100 x 10\^9/L if aspartate aminotransferase \[AST\] or alanine aminotransferase \[ALT\] is ≥ 2 x the upper limit of the normal range \[ULN\]) in the absence of platelet transfusion(s) or thrombopoietin mimetics in the prior 7 days * Peripheral blood blast count \< 10% * AST and ALT ≤ 3 x ULN (≤ 5 x 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) * Calculated creatinine clearance (CrCL) of ≥ 45 mL/min * Direct bilirubin ≤ 2.0 x ULN * Life expectancy of \> 24 weeks * Males and females of childbearing potential must agree to use protocol-specified method(s) of contraception * Females who are nursing must agree to discontinue nursing before the first dose of study drug * Able to understand and willing to sign the informed consent form Key
Exclusion criteria
* Prior splenectomy * Splenic irradiation within 3 months prior to the first dose of study drug * Eligible for allogeneic bone marrow or stem cell transplantation * Uncontrolled inter-current illness, per protocol. * Known positive status for human immunodeficiency virus (HIV) * Chronic active or acute viral hepatitis A, B, or C infection, or a hepatitis B or C carrier * Prior use of a JAK1 or JAK2 inhibitor * Use of chemotherapy, immunomodulating therapy, biologic therapy, radiation therapy, or investigational therapy within 4 weeks of the first dose of study drug * Presence of peripheral neuropathy ≥ Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 * Unwilling or unable to undergo a magnetic resonance imaging (MRI) or computed tomography (CT) scan Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Splenic Response Rate at Week 24 | Week 24 | Splenic response rate at Week 24 is defined as the percentage of participants who achieved a spleen volume reduction of ≥ 35% from baseline at the Week 24 assessment as measured by MRI or CT. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total Symptom Score (TSS) Response Rate at Week 24 | Week 24 | Total symptom score (TSS) is defined as the percentage of participants who achieved a ≥50% reduction in TSS at Week 24 versus baseline as measured by the modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) v2.0 diary. Response rate was calculated using the average of the daily TSS from a consecutive 28-day period prior to Week 24, which had ≥20 daily TSS available. The modified MPN-SAF patient-reported outcome instrument consisted of 8 items assessing worst daily incidence of tiredness, filling up quickly, abdominal discomfort, night sweats, itching, bone pain, pain under ribs on left side, and inactivity. Scoring of the Total Symptom Score (TSS), in this study was based on 7 of these items, (range of 0-70,), excluding inactivity. These items assess the impact experienced by the participant in the 24 hours prior to completing the questionnaire. All items are measured using a 0 to 10 Numeric Rating Scale, with 0 corresponding to Absent and 10 being the worse |
| Rate of Red Blood Cell (RBC) Transfusions in the Double-blind Phase, (the Average Number of RBC Units Transfused Per Month Not Associated With Overt Bleeding) | Baseline to Week 24 | Rate of RBC transfusion was defined as the average number of RBC units transfused not associated with clinically overt bleeding per subject-month during the double-blind phase. |
| RBC Transfusion Independence Rate at Week 24, (Defined as Absence of RBC Transfusions and no Hemoglobin Level Below 8 g/dL in the 12 Weeks Prior to Week 24, Excluding Cases Associated With Clinically Overt Bleeding) | Week 24 | RBC transfusion independence is the percentage of participants who are transfusion independent at Week 24, defined as absence of RBC transfusions and no hemoglobin level below 8 g/dL in the 12 weeks prior to Week 24, excluding cases associated with clinically overt bleeding. |
| RBC Transfusion Dependence Rate at Week 24. (Defined as Having Had at Least 4 Units of RBC Transfusions, or a Hemoglobin Level Below 8 g/dL in 8 Weeks Prior to Week 24 (Excluding Cases Associated With Clinically Overt Bleeding)). | Week 24 | RBC transfusion dependence is the percentage of participants who are transfusion dependent at Week 24, defined as having had at least 4 units of RBC transfusions, or a hemoglobin level below 8 g/dL in 8 weeks prior to Week 24 (excluding cases associated with clinically overt bleeding). Participants with the last double-blind phase participation date prior to Day 162 (ie. missing at Week 24) were considered transfusion dependent at Week 24. |
Countries
Australia, Austria, Belgium, Bulgaria, Canada, Czechia, Denmark, France, Germany, Hungary, Israel, Japan, Netherlands, Poland, Romania, Singapore, South Korea, Spain, Sweden, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
432 participants were randomized at 131 centers in 22 countries.
Pre-assignment details
Participants were screened within 35 days after signing the informed consent form to determine eligibility for participation in the study. Participants who were not randomized within the 35 day screening window were screen failed. At randomization, participants were randomly assigned 1:1 to MMB plus RUX-placebo or RUX plus MMB-placebo.
Participants by arm
| Arm | Count |
|---|---|
| Momelotinib (MMB) Participants received momelotinib plus placebo to match ruxolitinib.
Momelotinib: Momelotinib tablets were administered orally once daily at a starting dose of 200 mg. Additional available strengths included 100 mg and 150 mg.
Placebo to match ruxolitinib: Placebo to match ruxolitinib tablets were administered orally twice daily. | 215 |
| Ruxolitinib (RUX) Participants received ruxolitinib plus placebo to match momelotinib.
Ruxolitinib: Ruxolitinib tablets were administered orally twice daily. The dose ranged from 5 to 20 mg BID and was dependent on platelet count, creatinine clearance, and transaminase levels.
Placebo to match momelotinib: Placebo to match momelotinib tablets were administered orally once daily | 217 |
| Total | 432 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Double-blind Phase | Adverse Event | 10 | 4 | 0 | 0 |
| Double-blind Phase | Death | 5 | 2 | 0 | 0 |
| Double-blind Phase | Disease Progression | 2 | 0 | 0 | 0 |
| Double-blind Phase | Physician Decision | 5 | 1 | 0 | 0 |
| Double-blind Phase | Subject Decision | 4 | 2 | 0 | 0 |
| Double-blind Phase | Symptomatic Spleen Growth | 1 | 0 | 0 | 0 |
| Open-label Phase | Adverse Event | 0 | 0 | 37 | 49 |
| Open-label Phase | Death | 0 | 0 | 13 | 11 |
| Open-label Phase | Disease Progression | 0 | 0 | 26 | 27 |
| Open-label Phase | Lack of Efficacy | 0 | 0 | 17 | 19 |
| Open-label Phase | Non-compliance with Study Drug | 0 | 0 | 2 | 0 |
| Open-label Phase | Physician Decision | 0 | 0 | 9 | 14 |
| Open-label Phase | Subject Decision | 0 | 0 | 14 | 15 |
| Open-label Phase | Transferred to study SRA-MMB-4365 | 0 | 0 | 52 | 62 |
Baseline characteristics
| Characteristic | Momelotinib (MMB) | Ruxolitinib (RUX) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 125 Participants | 122 Participants | 247 Participants |
| Age, Categorical Between 18 and 65 years | 90 Participants | 95 Participants | 185 Participants |
| Age, Continuous | 67 years | 66 years | 66 years |
| BMI | 24.6 kg/m^2 | 24.9 kg/m^2 | 24.6 kg/m^2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 4 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 191 Participants | 194 Participants | 385 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 18 Participants | 19 Participants | 37 Participants |
| Height | 170.0 cm | 170.0 cm | 170.0 cm |
| Hemoglobin | 10.5 g/dL | 10.3 g/dL | 10.4 g/dL |
| Platelet Count (10^9/L) < 100 | 18 Participants | 23 Participants | 41 Participants |
| Platelet Count (10^9/L) >= 100 and <= 200 | 66 Participants | 63 Participants | 129 Participants |
| Platelet Count (10^9/L) > 200 | 131 Participants | 131 Participants | 262 Participants |
| Race/Ethnicity, Customized Asian | 17 Participants | 20 Participants | 37 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized Not Permitted | 15 Participants | 16 Participants | 31 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 179 Participants | 178 Participants | 357 Participants |
| Sex: Female, Male Female | 91 Participants | 97 Participants | 188 Participants |
| Sex: Female, Male Male | 124 Participants | 120 Participants | 244 Participants |
| Transfusion Dependent No | 162 Participants | 165 Participants | 327 Participants |
| Transfusion Dependent Yes | 53 Participants | 52 Participants | 105 Participants |
| Weight | 69.3 kg | 71.4 kg | 70.0 kg |
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 | 8 / 214 | 6 / 216 | 44 / 171 | 54 / 197 |
| other Total, other adverse events | 197 / 214 | 206 / 216 | 153 / 171 | 188 / 197 |
| serious Total, serious adverse events | 49 / 214 | 39 / 216 | 79 / 171 | 79 / 197 |
Outcome results
Primary
Splenic Response Rate at Week 24
Splenic response rate at Week 24 is defined as the percentage of participants who achieved a spleen volume reduction of ≥ 35% from baseline at the Week 24 assessment as measured by MRI or CT.
Time frame: Week 24
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Momelotinib (MMB) | Splenic Response Rate at Week 24 | Nonresponder | 158 Participants |
| Momelotinib (MMB) | Splenic Response Rate at Week 24 | Responder | 57 Participants |
| Ruxolitinib (RUX) | Splenic Response Rate at Week 24 | Nonresponder | 153 Participants |
| Ruxolitinib (RUX) | Splenic Response Rate at Week 24 | Responder | 64 Participants |
p-value: 0.01495% CI: [0.02, 0.16]Cochran-Mantel-Haenszel
Secondary
Rate of Red Blood Cell (RBC) Transfusions in the Double-blind Phase, (the Average Number of RBC Units Transfused Per Month Not Associated With Overt Bleeding)
Rate of RBC transfusion was defined as the average number of RBC units transfused not associated with clinically overt bleeding per subject-month during the double-blind phase.
Time frame: Baseline to Week 24
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Momelotinib (MMB) | Rate of Red Blood Cell (RBC) Transfusions in the Double-blind Phase, (the Average Number of RBC Units Transfused Per Month Not Associated With Overt Bleeding) | 0.0 units/month |
| Ruxolitinib (RUX) | Rate of Red Blood Cell (RBC) Transfusions in the Double-blind Phase, (the Average Number of RBC Units Transfused Per Month Not Associated With Overt Bleeding) | 0.4 units/month |
p-value: <0.00195% CI: [0.19, 0.43]Negative Binomial Model, Adjusted
Secondary
RBC Transfusion Dependence Rate at Week 24. (Defined as Having Had at Least 4 Units of RBC Transfusions, or a Hemoglobin Level Below 8 g/dL in 8 Weeks Prior to Week 24 (Excluding Cases Associated With Clinically Overt Bleeding)).
RBC transfusion dependence is the percentage of participants who are transfusion dependent at Week 24, defined as having had at least 4 units of RBC transfusions, or a hemoglobin level below 8 g/dL in 8 weeks prior to Week 24 (excluding cases associated with clinically overt bleeding). Participants with the last double-blind phase participation date prior to Day 162 (ie. missing at Week 24) were considered transfusion dependent at Week 24.
Time frame: Week 24
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Momelotinib (MMB) | RBC Transfusion Dependence Rate at Week 24. (Defined as Having Had at Least 4 Units of RBC Transfusions, or a Hemoglobin Level Below 8 g/dL in 8 Weeks Prior to Week 24 (Excluding Cases Associated With Clinically Overt Bleeding)). | Dependent | 65 Participants |
| Momelotinib (MMB) | RBC Transfusion Dependence Rate at Week 24. (Defined as Having Had at Least 4 Units of RBC Transfusions, or a Hemoglobin Level Below 8 g/dL in 8 Weeks Prior to Week 24 (Excluding Cases Associated With Clinically Overt Bleeding)). | Nondependent | 150 Participants |
| Ruxolitinib (RUX) | RBC Transfusion Dependence Rate at Week 24. (Defined as Having Had at Least 4 Units of RBC Transfusions, or a Hemoglobin Level Below 8 g/dL in 8 Weeks Prior to Week 24 (Excluding Cases Associated With Clinically Overt Bleeding)). | Dependent | 87 Participants |
| Ruxolitinib (RUX) | RBC Transfusion Dependence Rate at Week 24. (Defined as Having Had at Least 4 Units of RBC Transfusions, or a Hemoglobin Level Below 8 g/dL in 8 Weeks Prior to Week 24 (Excluding Cases Associated With Clinically Overt Bleeding)). | Nondependent | 130 Participants |
p-value: 0.01995% CI: [-0.19, -0.02]Cochran-Mantel-Haenszel
Secondary
RBC Transfusion Independence Rate at Week 24, (Defined as Absence of RBC Transfusions and no Hemoglobin Level Below 8 g/dL in the 12 Weeks Prior to Week 24, Excluding Cases Associated With Clinically Overt Bleeding)
RBC transfusion independence is the percentage of participants who are transfusion independent at Week 24, defined as absence of RBC transfusions and no hemoglobin level below 8 g/dL in the 12 weeks prior to Week 24, excluding cases associated with clinically overt bleeding.
Time frame: Week 24
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Momelotinib (MMB) | RBC Transfusion Independence Rate at Week 24, (Defined as Absence of RBC Transfusions and no Hemoglobin Level Below 8 g/dL in the 12 Weeks Prior to Week 24, Excluding Cases Associated With Clinically Overt Bleeding) | Responder | 143 Participants |
| Momelotinib (MMB) | RBC Transfusion Independence Rate at Week 24, (Defined as Absence of RBC Transfusions and no Hemoglobin Level Below 8 g/dL in the 12 Weeks Prior to Week 24, Excluding Cases Associated With Clinically Overt Bleeding) | Nonresponder | 72 Participants |
| Ruxolitinib (RUX) | RBC Transfusion Independence Rate at Week 24, (Defined as Absence of RBC Transfusions and no Hemoglobin Level Below 8 g/dL in the 12 Weeks Prior to Week 24, Excluding Cases Associated With Clinically Overt Bleeding) | Responder | 107 Participants |
| Ruxolitinib (RUX) | RBC Transfusion Independence Rate at Week 24, (Defined as Absence of RBC Transfusions and no Hemoglobin Level Below 8 g/dL in the 12 Weeks Prior to Week 24, Excluding Cases Associated With Clinically Overt Bleeding) | Nonresponder | 110 Participants |
p-value: <0.00195% CI: [0.09, 0.26]Cochran-Mantel-Haenszel
Secondary
Total Symptom Score (TSS) Response Rate at Week 24
Total symptom score (TSS) is defined as the percentage of participants who achieved a ≥50% reduction in TSS at Week 24 versus baseline as measured by the modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) v2.0 diary. Response rate was calculated using the average of the daily TSS from a consecutive 28-day period prior to Week 24, which had ≥20 daily TSS available. The modified MPN-SAF patient-reported outcome instrument consisted of 8 items assessing worst daily incidence of tiredness, filling up quickly, abdominal discomfort, night sweats, itching, bone pain, pain under ribs on left side, and inactivity. Scoring of the Total Symptom Score (TSS), in this study was based on 7 of these items, (range of 0-70,), excluding inactivity. These items assess the impact experienced by the participant in the 24 hours prior to completing the questionnaire. All items are measured using a 0 to 10 Numeric Rating Scale, with 0 corresponding to Absent and 10 being the worse
Time frame: Week 24
Population: TSS rate analysis at Week 24 only included participants with TSS \> 0 at baseline or with TSS = 0 at baseline but with TSS \> 0 or missing at Week 24.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Momelotinib (MMB) | Total Symptom Score (TSS) Response Rate at Week 24 | Responder | 60 Participants |
| Momelotinib (MMB) | Total Symptom Score (TSS) Response Rate at Week 24 | Nonresponder | 151 Participants |
| Ruxolitinib (RUX) | Total Symptom Score (TSS) Response Rate at Week 24 | Responder | 89 Participants |
| Ruxolitinib (RUX) | Total Symptom Score (TSS) Response Rate at Week 24 | Nonresponder | 122 Participants |
p-value: 0.9895% CI: [-0.08, 0.08]Cochran-Mantel-Haenszel