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

Primary Purpose

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

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
MMB
Sponsored by
Sierra Oncology LLC - a GSK company
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Primary Myelofibrosis (PMF)

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Momelotinib

Arm Description

MMB for 24 weeks (± 7 days)

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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.
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.
Change in Markers of Iron Metabolism and Anemia - Trough Hepcidin
Median hepcidin at trough was assessed predose at each study visit.
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).

Full Information

First Posted
August 3, 2015
Last Updated
June 14, 2023
Sponsor
Sierra Oncology LLC - a GSK company
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1. Study Identification

Unique Protocol Identification Number
NCT02515630
Brief Title
Momelotinib in Transfusion-Dependent Adults With Primary Myelofibrosis (PMF) or Post-polycythemia Vera or Post-essential Thrombocythemia Myelofibrosis (Post-PV/ET MF)
Official Title
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)
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Completed
Study Start Date
January 29, 2016 (Actual)
Primary Completion Date
July 18, 2017 (Actual)
Study Completion Date
August 15, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Sierra Oncology LLC - a GSK company

4. Oversight

Data Monitoring Committee
No

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Primary Myelofibrosis (PMF), Post-polycythemia Vera (Post-PV) Myelofibrosis, Postessential Thrombocythemia (Post-ET) Myelofibrosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
41 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Momelotinib
Arm Type
Experimental
Arm Description
MMB for 24 weeks (± 7 days)
Intervention Type
Drug
Intervention Name(s)
MMB
Other Intervention Name(s)
GS-0387, CYT387
Intervention Description
Momelotinib (MMB) tablet administered orally once daily
Primary Outcome Measure Information:
Title
Transfusion Independence Response by Week 24
Description
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.
Time Frame
From baseline to Week 24
Secondary Outcome Measure Information:
Title
Transfusion Response Rate by Week 24
Description
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.
Time Frame
From baseline to Week 24
Title
Splenic Response Rate at Week 24
Description
The percentage of subjects who achieved a ≥ 35% reduction in spleen volume from baseline as measured by MRI at Week 24.
Time Frame
Measured at Week 24
Title
Response Rate in Total Symptom Score (TSS) at Week 24
Description
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.
Time Frame
Measured at Week 24
Title
Change in Markers of Iron Metabolism and Anemia - Change From Baseline in Hepcidin Daily Change
Description
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.
Time Frame
At baseline, Day 1, Weeks 2, 4, 8, 12, 16, 20 and 24
Title
Change in Markers of Iron Metabolism and Anemia - Trough Hepcidin
Description
Median hepcidin at trough was assessed predose at each study visit.
Time Frame
At baseline, Day 1, Weeks 2, 4, 8, 12, 16, 20 and 24
Title
Change in Markers of Iron Metabolism and Anemia - Serum Iron
Description
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).
Time Frame
At Weeks 2, 4, 8, 12, 16, 20 and 24
Title
Change in Markers of Iron Metabolism and Anemia - Hemoglobin
Description
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).
Time Frame
At Weeks 2, 4, 8, 12, 16, 20 and 24
Title
Change in Markers of Iron Metabolism and Anemia - Total Iron Binding Capacity
Description
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).
Time Frame
At Weeks 2, 4, 8, 12, 16, 20 and 24
Title
Change in Markers of Iron Metabolism and Anemia - Reticulocytes
Description
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).
Time Frame
At Weeks 2, 4, 8, 12, 16, 20 and 24
Title
Change in Markers of Iron Metabolism and Anemia - Reticulocytes/Erythrocytes%
Description
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).
Time Frame
At Weeks 2, 4, 8, 12, 16, 20 and 24
Title
Change in Markers of Iron Metabolism and Anemia - Erythropoietin
Description
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).
Time Frame
At Weeks 8 and 20
Title
Change in Markers of Iron Metabolism and Anemia - Erythrocytes
Description
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).
Time Frame
At Weeks 2, 4, 8, 12, 16, 20 and 24
Title
Change in Markers of Iron Metabolism and Anemia - Hematocrit
Description
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).
Time Frame
At Weeks 2, 4, 8, 12, 16, 20 and 24
Title
Change in Markers of Iron Metabolism and Anemia - Ferritin
Description
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).
Time Frame
At Weeks 2, 4, 8, 12, 16, 20 and 24
Title
Change in Markers of Iron Metabolism and Anemia - Soluble Transferrin Receptor
Description
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).
Time Frame
At Weeks 2, 4, 8, 12, 16, 20 and 24
Title
Change in Markers of Iron Metabolism and Anemia - Transferrin Saturation
Description
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).
Time Frame
At Weeks 2, 4, 8, 12, 16, 20 and 24
Title
Change in Markers of Iron Metabolism and Anemia - Unsaturated Iron Binding Capacity
Description
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).
Time Frame
At Weeks 2, 4, 8, 12, 16, 20 and 24
Title
Change in Markers of Iron Metabolism and Anemia - Platelets
Description
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).
Time Frame
At Weeks 2, 4, 8, 12, 16, 20 and 24
Title
Change in Markers of Iron Metabolism and Anemia - Leukocytes
Description
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).
Time Frame
At Weeks 2, 4, 8, 12, 16, 20 and 24
Title
Change in Markers of Iron Metabolism and Anemia - Blasts
Description
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).
Time Frame
At Weeks 2 and 4
Title
Change in Liver Iron Content
Description
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).
Time Frame
Measured at Week 24
Title
Change in Pharmacodynamics Biomarker - pSTAT3
Description
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).
Time Frame
On Day 1 and at Weeks 4 and 24
Title
Change in Pharmacodynamics Biomarker - pSTAT3/tSTAT3 Ratio
Description
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).
Time Frame
On Day 1 and at Weeks 4 and 24
Title
Change in Inflammatory Markers - C-Reactive Protein (CRP)
Description
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).
Time Frame
At Weeks 2, 12 and 24

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Gilead Study Director
Organizational Affiliation
Gilead Sciences
Official's Role
Study Director
Facility Information:
City
Phoenix
State/Province
Arizona
Country
United States
City
Los Angeles
State/Province
California
Country
United States
City
Orange
State/Province
California
Country
United States
City
Jacksonville
State/Province
Florida
Country
United States
City
Baltimore
State/Province
Maryland
Country
United States
City
Ann Arbor
State/Province
Michigan
Country
United States
City
Saint Louis
State/Province
Missouri
Country
United States
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Bronx
State/Province
New York
Country
United States
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New York
State/Province
New York
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United States
City
Durham
State/Province
North Carolina
Country
United States
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Cleveland
State/Province
Ohio
Country
United States
City
Houston
State/Province
Texas
Country
United States
City
Toronto
State/Province
Ontario
Country
Canada

12. IPD Sharing Statement

Learn more about this trial

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

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