Efficacy of Momelotinib Versus Best Available Therapy in Anemic or Thrombocytopenic Subjects With Primary Myelofibrosis (MF), Post-polycythemia Vera MF, or Post-essential Thrombocythemia MF

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 3, Randomized Study To Evaluate the Efficacy of Momelotinib Versus Best Available Therapy in Anemic or Thrombocytopenic Subjects With Primary Myelofibrosis, Post-polycythemia Vera Myelofibrosis, or Post-essential Thrombocythemia Myelofibrosis Who Were Treated With Ruxolitinib

Conditions
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Primary Myelofibrosis (PMF), Post-polycythemia Vera (Post-PV), Post-essential Thrombocythemia Myelofibrosis (Post-ET MF)

Intervention / Treatment
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* Drug: Momelotinib
* Drug: Best Available Therapy (BAT)


Participation Criteria
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Eligibility Criteria
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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/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: Momelotinib<br>Participants will receive open-label momelotinib for 24 weeks during the randomized treatment phase, after which they will be eligible to receive momelotinib in an extended treatment phase for up to an additional 204 weeks. | Drug: Momelotinib<br>* Momelotinib tablet administered orally once daily<br>* Other names: CYT387;|
| Active Comparator: Arm 2: Best Available Therapy (BAT)<br>Participants in the BAT treatment arm will receive open-label treatment at doses and schedules determined by the investigator in accordance with standard of care. Therapy may be changed at any time during the study except during the screening period. After completion of the randomized treatment phase, participants will be eligible to receive momelotinib for the duration of the study during the extended treatment phase for up to 204 weeks. | Drug: Best Available Therapy (BAT)<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Week 24 | 
| 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. | Baseline to Week 24 | 
| 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 | Week 24 | 
| 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. | Week 24 |