Momelotinib in Transfusion-Dependent Adults With Primary Myelofibrosis (PMF) or Post-polycythemia Vera or Post-essential Thrombocythemia Myelofibrosis (Post-PV/ET MF)

Study Overview
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Brief Summary
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This study will evaluate the transfusion independence response rate in transfusion-dependent adults with myelofibrosis after treatment with momelotinib (MMB).

Official Title
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A Phase 2, Open-label, Translational Biology Study of Momelotinib in Transfusion-Dependent Subjects With Primary Myelofibrosis (PMF) or Post-polycythemia Vera or Post-essential Thrombocythemia Myelofibrosis (Post-PV/ET MF)

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

Intervention / Treatment
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* Drug: MMB


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Diagnosis of PMF or Post PV/ET-MF Requires myelofibrosis therapy, in the opinion of the investigator High risk OR intermediate-2 risk defined by dynamic international prognostic scoring system (DIPSS) OR intermediate-1 risk defined by DIPSS and associated with symptomatic splenomegaly and/or hepatomegaly Transfusion dependent at baseline, defined as ≥ 4 U red blood cell (RBC) transfusion in the 8 weeks prior to first dose of MMB Acceptable organ function as evidenced by the following: Platelet Count ≥ 50 x 10^9/L Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤ 3 x upper limit of normal (ULN) or AST or ALT ≤ 5 x ULN if liver is involved by disease process as judged by the investigator Serum creatinine ≤ 2.0 mg/dL or calculated creatinine clearance of ≥ 60 mL/min Direct bilirubin ≤ 2.0 x ULN Life expectancy of > 24 weeks Males and females of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception Lactating females must agree to discontinue nursing before MMB administration 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 MMB Prior treatment with MMB Known positive status of human immunodeficiency virus (HIV) Chronic active or acute viral hepatitis A, B, or C infection (testing required for hepatitis B and C), or hepatitis B or C carrier Use of strong cytochrome P450 3A4 (CYP3A4) inducer within 2 weeks prior to the first dose of MMB Uncontrolled intercurrent illness per protocol Treatment with a Janus kinase (JAK) inhibitor within 21 days of the planned first dose of MMB Presence of peripheral neuropathy ≥ Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 Unwilling or unable to undergo a MRI per requirements in the study protocol Unwilling to consent to genomics sampling 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Momelotinib<br>MMB for 24 weeks (± 7 days) | Drug: MMB<br>* Momelotinib (MMB) tablet administered orally once daily<br>* Other names: CYT387;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Transfusion Independence Response by Week 24 | The percentage of subjects who became transfusion independent for ≥ 12 weeks at any time on study. A subject was considered transfusion independent on study if no RBC transfusion occurred in any 12-week period during the 24-week treatment period. | From baseline to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Transfusion Response Rate by Week 24 | The percentage of subjects who became transfusion independent for ≥ 8 weeks, defined as no RBC transfusions for at least an 8-week period at any time on study. | From baseline to Week 24 | 
| Splenic Response Rate at Week 24 | The percentage of subjects who achieved a ≥ 35% reduction in spleen volume from baseline as measured by MRI at Week 24. | Measured at Week 24 | 
| Response Rate in Total Symptom Score (TSS) at Week 24 | The percentage of subjects achieving a ≥ 50% reduction from baseline in TSS at Week 24, as measured by the modified Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPNSAF TSS) diary. Total symptom score was assessed using the modified MPN-SAF TSS Version 2, an 8-item questionnaire developed to assess symptom burden and quality of life in patients with MPN. The modified MPN-SAF TSS contained 8 questions, 7 of which were summed to generate the score (the included questions related to tiredness, early satiety, abdominal discomfort, night sweats, itching, bone pain, and pain under the ribs on the left side). Each question is scored on a scale of 0-10, where higher numbers indicate more severe symptoms. For this study, the TSS scale ranges from 0 to 70. The questionnaire was completed daily on an electronic diary device. | Measured at Week 24 | 
| Change in Markers of Iron Metabolism and Anemia - Change From Baseline in Hepcidin Daily Change | Hepcidin daily change (in nM) was calculated as the predose value subtracted from the 6 hours postdose value at each study visit. Daily hepcidin change at the baseline visit was the difference between 2 values obtained 6 hours apart. No momelotinib was administered on that day. | At baseline, Day 1, Weeks 2, 4, 8, 12, 16, 20 and 24 | 
| Change in Markers of Iron Metabolism and Anemia - Trough Hepcidin | Median hepcidin at trough was assessed predose at each study visit. | At baseline, Day 1, Weeks 2, 4, 8, 12, 16, 20 and 24 | 
| Change in Markers of Iron Metabolism and Anemia - Serum Iron | Percent change from baseline in serum iron, where the baseline value is defined as the last value from the baseline period prior to or on the date of first dose of momelotinib administration (Baseline visit). | At Weeks 2, 4, 8, 12, 16, 20 and 24 | 
| Change in Markers of Iron Metabolism and Anemia - Hemoglobin | Percent change from baseline in hemoglobin, where the baseline value is defined as the last value from the baseline period prior to or on the date of first dose of momelotinib administration (Baseline visit). | At Weeks 2, 4, 8, 12, 16, 20 and 24 | 
| Change in Markers of Iron Metabolism and Anemia - Total Iron Binding Capacity | Percent change from baseline in total iron binding capacity, where the baseline value is defined as the last value from the baseline period prior to or on the date of first dose of momelotinib administration (Baseline visit). | At Weeks 2, 4, 8, 12, 16, 20 and 24 | 
| Change in Markers of Iron Metabolism and Anemia - Reticulocytes | Percent change from baseline in reticulocytes, where the baseline value is defined as the last value from the baseline period prior to or on the date of first dose of momelotinib administration (Baseline visit). | At Weeks 2, 4, 8, 12, 16, 20 and 24 | 
| Change in Markers of Iron Metabolism and Anemia - Reticulocytes/Erythrocytes% | Percent change from baseline in reticulocytes/erythrocytes%, where the baseline value is defined as the last value from the baseline period prior to or on the date of first dose of momelotinib administration (Baseline visit). | At Weeks 2, 4, 8, 12, 16, 20 and 24 | 
| Change in Markers of Iron Metabolism and Anemia - Erythropoietin | Percent change in erythropoietin at Weeks 8 and 20. The baseline erythropoietin value is defined as the last value from the baseline period prior to or on the date of first dose of momelotinib administration (Baseline visit). | At Weeks 8 and 20 | 
| Change in Markers of Iron Metabolism and Anemia - Erythrocytes | Percent change from baseline in erythrocytes, where the baseline value is defined as the last value from the baseline period prior to or on the date of first dose of momelotinib administration (Baseline visit). | At Weeks 2, 4, 8, 12, 16, 20 and 24 | 
| Change in Markers of Iron Metabolism and Anemia - Hematocrit | Percent change from baseline in hematocrit, where the baseline value is defined as the last value from the baseline period prior to or on the date of first dose of momelotinib administration (Baseline visit). | At Weeks 2, 4, 8, 12, 16, 20 and 24 | 
| Change in Markers of Iron Metabolism and Anemia - Ferritin | Percent change from baseline in ferritin, where the baseline value is defined as the last value from the baseline period prior to or on the date of first dose of momelotinib administration (Baseline visit). | At Weeks 2, 4, 8, 12, 16, 20 and 24 | 
| Change in Markers of Iron Metabolism and Anemia - Soluble Transferrin Receptor | Percent change from baseline in soluble transferrin receptor, where the baseline value is defined as the last value from the baseline period prior to or on the date of first dose of momelotinib administration (Baseline visit). | At Weeks 2, 4, 8, 12, 16, 20 and 24 | 
| Change in Markers of Iron Metabolism and Anemia - Transferrin Saturation | Percent change from baseline in transferrin saturation, where the baseline value is defined as the last value from the baseline period prior to or on the date of first dose of momelotinib administration (Baseline visit). | At Weeks 2, 4, 8, 12, 16, 20 and 24 | 
| Change in Markers of Iron Metabolism and Anemia - Unsaturated Iron Binding Capacity | Percent change from baseline in unsaturated iron binding capacity, where the baseline value is defined as the last value from the baseline period prior to or on the date of first dose of momelotinib administration (Baseline visit). | At Weeks 2, 4, 8, 12, 16, 20 and 24 | 
| Change in Markers of Iron Metabolism and Anemia - Platelets | Percent change from baseline in platelets, where the baseline value is defined as the last value from the baseline period prior to or on the date of first dose of momelotinib administration (Baseline visit). | At Weeks 2, 4, 8, 12, 16, 20 and 24 | 
| Change in Markers of Iron Metabolism and Anemia - Leukocytes | Percent change from baseline in leukocytes, where the baseline value is defined as the last value from the baseline period prior to or on the date of first dose of momelotinib administration (Baseline visit). | At Weeks 2, 4, 8, 12, 16, 20 and 24 | 
| Change in Markers of Iron Metabolism and Anemia - Blasts | Change from baseline in % blasts at Weeks 2 and 4. The baseline % blasts value is defined as the last value from the baseline period prior to or on the date of first dose of momelotinib administration (Baseline visit). | At Weeks 2 and 4 | 
| Change in Liver Iron Content | Percent change from baseline in liver iron content assessed by MRI. The baseline value is defined as the last value from the baseline period prior to or on the date of first dose of momelotinib administration (Baseline visit). | Measured at Week 24 | 
| Change in Pharmacodynamics Biomarker - pSTAT3 | Percent change in %pSTAT stimulated CD3+/4+ T cell at Day 1 (postdose), Week 4 and Week 24. The baseline value is defined as the last predose value from the baseline period prior to or on the date of first dose of momelotinib administration (Day 1 predose). | On Day 1 and at Weeks 4 and 24 | 
| Change in Pharmacodynamics Biomarker - pSTAT3/tSTAT3 Ratio | Percent change in %pSTAT/%tSTAT Stimulated CD3+/4+ T cell ratio at Day 1 (postdose), Week 4 and Week 24. The baseline value is defined as the last predose value from the baseline period prior to or on the date of first dose of momelotinib administration (Day 1 predose). | On Day 1 and at Weeks 4 and 24 | 
| Change in Inflammatory Markers - C-Reactive Protein (CRP) | Percent change in C-reactive protein at Weeks 2, 12 and 24. The baseline C-reactive protein value is defined as the last value from the baseline period prior to or on the date of first dose of momelotinib administration (Baseline visit). | At Weeks 2, 12 and 24 |