Primary Myelofibrosis (PMF), Post-polycythemia Vera (Post-PV), Post-essential Thrombocythemia Myelofibrosis (Post-ET MF)
Conditions
Brief summary
This study is to determine the efficacy of momelotinib (MMB) versus best available therapy (BAT) in anemic or thrombocytopenic adults with primary myelofibrosis (PMF), or post-polycythemia vera or post-essential thrombocythemia myelofibrosis (Post-PV/ET MF) who were treated with ruxolitinib as measured by splenic response rate at Week 24 (SRR24). Participants will be randomized to receive either MMB or BAT for 24 weeks during the randomized treatment phase, after which they will be eligible to receive MMB in an extended treatment phase for up to an additional 204 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 subjects planning to continue treatment with MMB following the end of the study, the End of Treatment, 30-day, 12-Week, and survival follow-up visits are not required.
Interventions
DRUGMomelotinib
Momelotinib tablet administered orally once daily
Regimens for BAT may include but are not limited to chemotherapy (eg hydroxyurea), anagrelide, corticosteroid, hematopoietic growth factor, immunomodulating agent, androgen, interferon, and may include no myelofibrosis treatment.
Sponsors
Sierra Oncology LLC - a GSK company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
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 left costal margin * Confirmed diagnosis of PMF in accordance, or Post-PV/ET MF * Currently or previously treated with ruxolitinib for PMF or Post-PV/ET MF for at least 28 days, and characterized by * Requirement for RBC transfusion while on ruxolitinib treatment, OR * Dose adjustment of ruxolitinib to \< 20 mg twice daily at start of or during ruxolitinib treatment AND at least one of the following while on ruxolitinib treatment: * ≥ Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 thrombocytopenia, OR * ≥ CTCAE Grade 3 anemia, OR * ≥ CTCAE Grade 3 hematoma (bleed) * High risk OR intermediate-2 risk as defined by Dynamic International Prognostic Scoring System (DIPSS), OR intermediate-1 risk as defined by DIPSS and associated with symptomatic splenomegaly, and/or hepatomegaly * If receiving myelofibrosis therapy, must be on a stable dose of the same regimen for at least 2 weeks prior to screen date and through the screening period * If not receiving myelofibrosis therapy, must remain off therapy for at least 2 weeks prior to screen date and through the screening period * Acceptable laboratory assessments obtained within 14 days prior to Randomization * Absolute neutrophil count (ANC) \> 0.75 x 10\^9/L in the absence of growth factor in the prior 7 days * Peripheral blood blast count \< 10% * Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 x the upper limit of the normal range (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 of ≥ 45 mL/min * Direct bilirubin ≤ 2.0 x ULN * Life expectancy \> 24 weeks * Negative serum pregnancy test for female subjects (unless surgically sterile or greater than two years post-menopausal) * 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 MMB * Able to understand and willing to sign informed consent form (ICF) Key
Exclusion criteria
* Prior splenectomy * Splenic irradiation within 3 months prior to Randomization * Use of investigational agent within 28 days prior to Randomization * Prior treatment with MMB * Hematopoietic growth factor (granulocyte growth factor, erythropoiesis stimulating agent, thrombopoietin mimetic) within 28 days prior to Randomization * 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 hepatitis B or C carrier * Presence of peripheral neuropathy ≥ CTCAE Grade 2 * Unwilling or unable to undergo a MRI or CT Scan per study protocol requirements 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 TSS in this study was based on 7 of these items, (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 corresponding to Worst Imaginable. |
| Rate of Red Blood Cell (RBC) Transfusion in the Randomized Treatment Phase, (the Average Number of RBC Units Transfused Per Month Not Associated With Overt Bleeding) | Baseline to Week 24 | Rate of RBC transfusion is defined as the average number of RBC units transfused not associated with clinically overt bleeding per subject-month during the randomized treatment 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 rate is the percentage of participants who achieved transfusion independence at Week 24 (responders). RBC transfusion independence is 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. Transfusion dependence, (non-responder) is defined as at least 4 units of RBC transfusion, or a Hgb level below 8 g/dL, in the 8 weeks prior to week 24. Methods used to assess this outcome measure include collection and recording of any instances of RBC transfusions and collection and recording of any local or central lab hemoglobin measurements |
| RBC Transfusion Dependence Rate at Week 24 | Week 24 | RBC transfusion dependence is the percentage of participants who are transfusion dependent at Week 24, defined as at least 4 units of RBC transfusions, or a hemoglobin level below 8 g/dL in the 8 weeks prior to Week 24, excluding cases associated with clinically overt bleeding. |
Countries
Canada, France, Germany, Israel, Italy, Spain, United Kingdom, United States
Participant flow
Recruitment details
156 participants were randomized at 52 centers in 8 countries.
Pre-assignment details
Participants were screened within 30 days before randomization to determine eligibility for participation in the study. Participants who were not randomized within the 30-day screening window were considered screen failures. At randomization, participants were randomly assigned 2:1 to MMB:BAT.
Participants by arm
| Arm | Count |
|---|---|
| Momelotinib (MMB) Participants received momelotinib orally once daily at a starting dose of 200 mg. Additional available strengths included 100 mg and 150 mg. | 104 |
| Best Available Therapy (BAT) Participants received treatment at doses and schedules determined by the investigator in accordance with standard of care. Therapy may have been changed at any time during the study except during the screening period. No active therapy was a permissible option. | 52 |
| Total | 156 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Extended Treatment Phase | Adverse Event | 0 | 0 | 14 | 18 |
| Extended Treatment Phase | Death | 0 | 0 | 5 | 1 |
| Extended Treatment Phase | Disease Progression | 0 | 0 | 13 | 6 |
| Extended Treatment Phase | Lack of Efficacy | 0 | 0 | 9 | 4 |
| Extended Treatment Phase | Physician Decision | 0 | 0 | 5 | 2 |
| Extended Treatment Phase | Subject Decision | 0 | 0 | 3 | 2 |
| Extended Treatment Phase | Transferred to Study SRA-MMB-4365 | 0 | 0 | 15 | 7 |
| Randomized Treatment Phase | Adverse Event | 6 | 0 | 0 | 0 |
| Randomized Treatment Phase | Death | 5 | 4 | 0 | 0 |
| Randomized Treatment Phase | Disease Progression | 4 | 1 | 0 | 0 |
| Randomized Treatment Phase | Physician Decision | 4 | 1 | 0 | 0 |
| Randomized Treatment Phase | Subject Decision | 8 | 4 | 0 | 0 |
| Randomized Treatment Phase | Symptomatic Spleen Growth | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Momelotinib (MMB) | Best Available Therapy (BAT) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 63 Participants | 38 Participants | 101 Participants |
| Age, Categorical Between 18 and 65 years | 41 Participants | 14 Participants | 55 Participants |
| Age, Continuous | 67.0 years | 69.5 years | 68.0 years |
| Body Mass Index | 25.9 kg/m^2 | 26.1 kg/m^2 | 26.0 kg/m^2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 4 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 81 Participants | 40 Participants | 121 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 18 Participants | 8 Participants | 26 Participants |
| Height | 170.0 cm | 168.0 cm | 170.0 cm |
| Hemoglobin | 9.0 g/dL | 9.2 g/dL | 9.0 g/dL |
| Race/Ethnicity, Customized Black or African American | 6 Participants | 0 Participants | 6 Participants |
| Race/Ethnicity, Customized Not Permitted | 15 Participants | 8 Participants | 23 Participants |
| Race/Ethnicity, Customized White | 83 Participants | 44 Participants | 127 Participants |
| Sex: Female, Male Female | 35 Participants | 28 Participants | 63 Participants |
| Sex: Female, Male Male | 69 Participants | 24 Participants | 93 Participants |
| Total Symptom Score (TSS) < 18 | 61 Participants | 28 Participants | 89 Participants |
| Total Symptom Score (TSS) >= 18 | 43 Participants | 24 Participants | 67 Participants |
| Transfusion Dependent No | 46 Participants | 25 Participants | 71 Participants |
| Transfusion Dependent Yes | 58 Participants | 27 Participants | 85 Participants |
| Weight | 75.4 kg | 74.0 kg | 75.0 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 / 104 | 5 / 52 | 29 / 64 | 18 / 40 |
| other Total, other adverse events | 99 / 104 | 46 / 52 | 63 / 64 | 40 / 40 |
| serious Total, serious adverse events | 37 / 104 | 12 / 52 | 33 / 64 | 19 / 40 |
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 | Responder | 7 Participants |
| Momelotinib (MMB) | Splenic Response Rate at Week 24 | Nonresponder | 97 Participants |
| Best Available Therapy (BAT) | Splenic Response Rate at Week 24 | Responder | 3 Participants |
| Best Available Therapy (BAT) | Splenic Response Rate at Week 24 | Nonresponder | 49 Participants |
p-value: 0.995% CI: [-0.09, 0.1]Cochran-Mantel-Haenszel
Secondary
Rate of Red Blood Cell (RBC) Transfusion in the Randomized Treatment Phase, (the Average Number of RBC Units Transfused Per Month Not Associated With Overt Bleeding)
Rate of RBC transfusion is defined as the average number of RBC units transfused not associated with clinically overt bleeding per subject-month during the randomized treatment Phase.
Time frame: Baseline to Week 24
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Momelotinib (MMB) | Rate of Red Blood Cell (RBC) Transfusion in the Randomized Treatment Phase, (the Average Number of RBC Units Transfused Per Month Not Associated With Overt Bleeding) | 0.5 units/month |
| Best Available Therapy (BAT) | Rate of Red Blood Cell (RBC) Transfusion in the Randomized Treatment Phase, (the Average Number of RBC Units Transfused Per Month Not Associated With Overt Bleeding) | 1.2 units/month |
p-value: 0.3895% CI: [0.49, 1.31]Negative Binomial Model, Adjusted
Secondary
RBC Transfusion Dependence Rate at Week 24
RBC transfusion dependence is the percentage of participants who are transfusion dependent at Week 24, defined as at least 4 units of RBC transfusions, or a hemoglobin level below 8 g/dL in the 8 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 Dependence Rate at Week 24 | Dependent | 52 Participants |
| Momelotinib (MMB) | RBC Transfusion Dependence Rate at Week 24 | Nondependent | 52 Participants |
| Best Available Therapy (BAT) | RBC Transfusion Dependence Rate at Week 24 | Dependent | 33 Participants |
| Best Available Therapy (BAT) | RBC Transfusion Dependence Rate at Week 24 | Nondependent | 19 Participants |
p-value: 0.195% CI: [-0.29, 0.03]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 rate is the percentage of participants who achieved transfusion independence at Week 24 (responders). RBC transfusion independence is 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. Transfusion dependence, (non-responder) is defined as at least 4 units of RBC transfusion, or a Hgb level below 8 g/dL, in the 8 weeks prior to week 24. Methods used to assess this outcome measure include collection and recording of any instances of RBC transfusions and collection and recording of any local or central lab hemoglobin measurements
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 | 45 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 | 59 Participants |
| Best Available Therapy (BAT) | 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 | 11 Participants |
| Best Available Therapy (BAT) | 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 | 41 Participants |
p-value: 0.00195% CI: [0.09, 0.37]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 TSS in this study was based on 7 of these items, (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 corresponding to Worst Imaginable.
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 | 27 Participants |
| Momelotinib (MMB) | Total Symptom Score (TSS) Response Rate at Week 24 | Nonresponder | 76 Participants |
| Best Available Therapy (BAT) | Total Symptom Score (TSS) Response Rate at Week 24 | Responder | 3 Participants |
| Best Available Therapy (BAT) | Total Symptom Score (TSS) Response Rate at Week 24 | Nonresponder | 48 Participants |
p-value: <0.00195% CI: [0.09, 0.32]Cochran-Mantel-Haenszel