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

Phase 2

Completed

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

Interventions: Drug: MMB

Registration Number: NCT02515630

Lead Sponsor: Sierra Oncology LLC - a GSK company

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

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 41

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Momelotinib	MMB	MMB for 24 weeks (± 7 days)

Primary Outcome Measures

Name	Time	Method
Transfusion Independence Response by Week 24	From baseline to 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.

Secondary Outcome Measures

Name	Time	Method
Change in Markers of Iron Metabolism and Anemia - Erythrocytes	At Weeks 2, 4, 8, 12, 16, 20 and 24	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).
Change in Markers of Iron Metabolism and Anemia - Hematocrit	At Weeks 2, 4, 8, 12, 16, 20 and 24	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).
Change in Markers of Iron Metabolism and Anemia - Ferritin	At Weeks 2, 4, 8, 12, 16, 20 and 24	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).
Change in Markers of Iron Metabolism and Anemia - Soluble Transferrin Receptor	At Weeks 2, 4, 8, 12, 16, 20 and 24	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).
Change in Markers of Iron Metabolism and Anemia - Transferrin Saturation	At Weeks 2, 4, 8, 12, 16, 20 and 24	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).
Change in Markers of Iron Metabolism and Anemia - Unsaturated Iron Binding Capacity	At Weeks 2, 4, 8, 12, 16, 20 and 24	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).
Change in Pharmacodynamics Biomarker - pSTAT3/tSTAT3 Ratio	On Day 1 and at Weeks 4 and 24	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).
Transfusion Response Rate by Week 24	From baseline to 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.
Splenic Response Rate at Week 24	Measured at Week 24	The percentage of subjects who achieved a ≥ 35% reduction in spleen volume from baseline as measured by MRI at Week 24.
Response Rate in Total Symptom Score (TSS) at Week 24	Measured 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.
Change in Markers of Iron Metabolism and Anemia - Change From Baseline in Hepcidin Daily Change	At baseline, Day 1, Weeks 2, 4, 8, 12, 16, 20 and 24	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.
Change in Markers of Iron Metabolism and Anemia - Trough Hepcidin	At baseline, Day 1, Weeks 2, 4, 8, 12, 16, 20 and 24	Median hepcidin at trough was assessed predose at each study visit.
Change in Markers of Iron Metabolism and Anemia - Serum Iron	At Weeks 2, 4, 8, 12, 16, 20 and 24	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).
Change in Markers of Iron Metabolism and Anemia - Hemoglobin	At Weeks 2, 4, 8, 12, 16, 20 and 24	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).
Change in Markers of Iron Metabolism and Anemia - Total Iron Binding Capacity	At Weeks 2, 4, 8, 12, 16, 20 and 24	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).
Change in Markers of Iron Metabolism and Anemia - Reticulocytes	At Weeks 2, 4, 8, 12, 16, 20 and 24	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).
Change in Markers of Iron Metabolism and Anemia - Reticulocytes/Erythrocytes%	At Weeks 2, 4, 8, 12, 16, 20 and 24	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).
Change in Markers of Iron Metabolism and Anemia - Erythropoietin	At Weeks 8 and 20	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).
Change in Markers of Iron Metabolism and Anemia - Platelets	At Weeks 2, 4, 8, 12, 16, 20 and 24	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).
Change in Markers of Iron Metabolism and Anemia - Leukocytes	At Weeks 2, 4, 8, 12, 16, 20 and 24	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).
Change in Markers of Iron Metabolism and Anemia - Blasts	At Weeks 2 and 4	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).
Change in Liver Iron Content	Measured at Week 24	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).
Change in Pharmacodynamics Biomarker - pSTAT3	On Day 1 and at Weeks 4 and 24	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).
Change in Inflammatory Markers - C-Reactive Protein (CRP)	At Weeks 2, 12 and 24	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).