Brief Summary
This study will evaluate the transfusion independence response rate in transfusion-dependent adults with myelofibrosis after treatment with momelotinib (MMB).
Brief Title
Momelotinib in Transfusion-Dependent Adults With Primary Myelofibrosis (PMF) or Post-polycythemia Vera or Post-essential Thrombocythemia Myelofibrosis (Post-PV/ET MF)
Categories
Completion Date
Completion Date Type
Actual
Conditions
Primary Myelofibrosis (PMF)
Post-polycythemia Vera (Post-PV) Myelofibrosis
Postessential Thrombocythemia (Post-ET) Myelofibrosis
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.
* 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.
Inclusion Criteria
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
Inclusion/
* 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
Inclusion/
Gender
All
Gender Based
false
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT02515630
Org Class
Industry
Org Full Name
Sierra Oncology LLC - a GSK company
Org Study Id
GS-US-352-1672
Overall Status
Completed
Phases
Phase 2
Primary Completion Date
Primary Completion Date Type
Actual
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)
Primary Outcomes
Outcome 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.
Outcome Measure
Transfusion Independence Response by Week 24
Outcome Time Frame
From baseline to Week 24
Secondary Outcomes
Outcome 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.
Outcome Time Frame
From baseline to Week 24
Outcome Measure
Transfusion Response Rate by Week 24
Outcome Description
The percentage of subjects who achieved a ≥ 35% reduction in spleen volume from baseline as measured by MRI at Week 24.
Outcome Time Frame
Measured at Week 24
Outcome Measure
Splenic Response Rate at Week 24
Outcome 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.
Outcome Time Frame
Measured at Week 24
Outcome Measure
Response Rate in Total Symptom Score (TSS) at Week 24
Outcome 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.
Outcome Time Frame
At baseline, Day 1, Weeks 2, 4, 8, 12, 16, 20 and 24
Outcome Measure
Change in Markers of Iron Metabolism and Anemia - Change From Baseline in Hepcidin Daily Change
Outcome Description
Median hepcidin at trough was assessed predose at each study visit.
Outcome Time Frame
At baseline, Day 1, Weeks 2, 4, 8, 12, 16, 20 and 24
Outcome Measure
Change in Markers of Iron Metabolism and Anemia - Trough Hepcidin
Outcome 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).
Outcome Time Frame
At Weeks 2, 4, 8, 12, 16, 20 and 24
Outcome Measure
Change in Markers of Iron Metabolism and Anemia - Serum Iron
Outcome 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).
Outcome Time Frame
At Weeks 2, 4, 8, 12, 16, 20 and 24
Outcome Measure
Change in Markers of Iron Metabolism and Anemia - Hemoglobin
Outcome 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).
Outcome Time Frame
At Weeks 2, 4, 8, 12, 16, 20 and 24
Outcome Measure
Change in Markers of Iron Metabolism and Anemia - Total Iron Binding Capacity
Outcome 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).
Outcome Time Frame
At Weeks 2, 4, 8, 12, 16, 20 and 24
Outcome Measure
Change in Markers of Iron Metabolism and Anemia - Reticulocytes
Outcome 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).
Outcome Time Frame
At Weeks 2, 4, 8, 12, 16, 20 and 24
Outcome Measure
Change in Markers of Iron Metabolism and Anemia - Reticulocytes/Erythrocytes%
Outcome 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).
Outcome Time Frame
At Weeks 8 and 20
Outcome Measure
Change in Markers of Iron Metabolism and Anemia - Erythropoietin
Outcome 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).
Outcome Time Frame
At Weeks 2, 4, 8, 12, 16, 20 and 24
Outcome Measure
Change in Markers of Iron Metabolism and Anemia - Erythrocytes
Outcome 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).
Outcome Time Frame
At Weeks 2, 4, 8, 12, 16, 20 and 24
Outcome Measure
Change in Markers of Iron Metabolism and Anemia - Hematocrit
Outcome 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).
Outcome Time Frame
At Weeks 2, 4, 8, 12, 16, 20 and 24
Outcome Measure
Change in Markers of Iron Metabolism and Anemia - Ferritin
Outcome 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).
Outcome Time Frame
At Weeks 2, 4, 8, 12, 16, 20 and 24
Outcome Measure
Change in Markers of Iron Metabolism and Anemia - Soluble Transferrin Receptor
Outcome 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).
Outcome Time Frame
At Weeks 2, 4, 8, 12, 16, 20 and 24
Outcome Measure
Change in Markers of Iron Metabolism and Anemia - Transferrin Saturation
Outcome 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).
Outcome Time Frame
At Weeks 2, 4, 8, 12, 16, 20 and 24
Outcome Measure
Change in Markers of Iron Metabolism and Anemia - Unsaturated Iron Binding Capacity
Outcome 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).
Outcome Time Frame
At Weeks 2, 4, 8, 12, 16, 20 and 24
Outcome Measure
Change in Markers of Iron Metabolism and Anemia - Platelets
Outcome 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).
Outcome Time Frame
At Weeks 2, 4, 8, 12, 16, 20 and 24
Outcome Measure
Change in Markers of Iron Metabolism and Anemia - Leukocytes
Outcome 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).
Outcome Time Frame
At Weeks 2 and 4
Outcome Measure
Change in Markers of Iron Metabolism and Anemia - Blasts
Outcome 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).
Outcome Time Frame
Measured at Week 24
Outcome Measure
Change in Liver Iron Content
Outcome 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).
Outcome Time Frame
On Day 1 and at Weeks 4 and 24
Outcome Measure
Change in Pharmacodynamics Biomarker - pSTAT3
Outcome 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).
Outcome Time Frame
On Day 1 and at Weeks 4 and 24
Outcome Measure
Change in Pharmacodynamics Biomarker - pSTAT3/tSTAT3 Ratio
Outcome 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).
Outcome Time Frame
At Weeks 2, 12 and 24
Outcome Measure
Change in Inflammatory Markers - C-Reactive Protein (CRP)
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Swati Goel
Investigator Email
swgoel@montefiore.org
Investigator Phone
718-920-6310 / 718-920-4137
Categories Mesh Debug
Blood & Bone Marrow Cancers --- MYELOPROLIFERATIVE DISORDERS
Blood & Bone Marrow Cancers --- BONE MARROW DISEASES
Blood Disorders --- HEMATOLOGIC DISEASES
Blood & Bone Marrow Cancers --- HEMATOLOGIC DISEASES
MeSH Terms
PRIMARY MYELOFIBROSIS
MYELOPROLIFERATIVE DISORDERS
BONE MARROW DISEASES
HEMATOLOGIC DISEASES
HEMIC AND LYMPHATIC DISEASES
N-(CYANOMETHYL)-4-(2-((4-(4-MORPHOLINYL)PHENYL)AMINO)-4-PYRIMIDINYL)BENZAMIDE