Momelotinib Versus Ruxolitinib in Subjects With Myelofibrosis (Simplify 1)
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| ClinicalTrials.gov Identifier: NCT01969838 |
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Recruitment Status :
Completed
First Posted : October 25, 2013
Results First Posted : May 12, 2023
Last Update Posted : May 12, 2023
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This study is to determine the efficacy of momelotinib (MMB) versus ruxolitinib (RUX) in participants with primary myelofibrosis (PMF) or post-polycythemia vera or post-essential thrombocythemia myelofibrosis (post-PV/ET MF) who have not yet received treatment with a Janus kinase inhibitor (JAK inhibitor).
Participants will be randomized to receive either MMB or ruxolitinib for 24 weeks during a double-blind treatment phase, after which they will be eligible to receive open-label MMB for up to an additional 216 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 participants planning to continue treatment with MMB following the end of the study, the Early Study Drug Discontinuation (ESDD), 30-day, 12-Week, and survival follow-up visits are not required.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Primary Myelofibrosis Post-Polycythemia Vera Myelofibrosis Post-Essential Thrombocythemia Myelofibrosis | Drug: Momelotinib Drug: Ruxolitinib Drug: Placebo to match momelotinib Drug: Placebo to match ruxolitinib | Phase 3 |
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 432 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) |
| Primary Purpose: | Treatment |
| Official Title: | A Phase 3, Randomized, Double-blind Active-controlled Study Evaluating Momelotinib vs. Ruxolitinib in Subjects With Primary Myelofibrosis (PMF) or Post-Polycythemia Vera or Post-Essential Thrombocythemia Myelofibrosis (Post-PV/ET MF) |
| Actual Study Start Date : | December 6, 2013 |
| Actual Primary Completion Date : | September 12, 2016 |
| Actual Study Completion Date : | May 2, 2019 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Momelotinib
Participants will receive momelotinib plus placebo to match ruxolitinib.
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Drug: Momelotinib
Momelotinib tablet administered orally once daily
Other Names:
Drug: Placebo to match ruxolitinib Placebo to match ruxolitinib tablets administered orally twice daily |
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Active Comparator: Ruxolitinib
Participants will receive ruxolitinib plus placebo to match momelotinib.
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Drug: Ruxolitinib
Ruxolitinib tablets administered orally twice daily Drug: Placebo to match momelotinib Placebo to match momelotinib tablets administered orally once daily |
- Splenic Response Rate at Week 24 [ Time Frame: 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.
- Total Symptom Score (TSS) Response Rate at Week 24 [ Time Frame: 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 the Total Symptom Score (TSS), in this study was based on 7 of these items, (range of 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 being the worse
- Rate of Red Blood Cell (RBC) Transfusions in the Double-blind Phase, (the Average Number of RBC Units Transfused Per Month Not Associated With Overt Bleeding) [ Time Frame: Baseline to Week 24 ]Rate of RBC transfusion was defined as the average number of RBC units transfused not associated with clinically overt bleeding per subject-month during the double-blind phase.
- 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) [ Time Frame: Week 24 ]RBC transfusion independence is the percentage of participants who are transfusion independent 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 Dependence Rate at Week 24. (Defined as Having Had at Least 4 Units of RBC Transfusions, or a Hemoglobin Level Below 8 g/dL in 8 Weeks Prior to Week 24 (Excluding Cases Associated With Clinically Overt Bleeding)). [ Time Frame: Week 24 ]RBC transfusion dependence is the percentage of participants who are transfusion dependent at Week 24, defined as having had at least 4 units of RBC transfusions, or a hemoglobin level below 8 g/dL in 8 weeks prior to Week 24 (excluding cases associated with clinically overt bleeding). Participants with the last double-blind phase participation date prior to Day 162 (ie. missing at Week 24) were considered transfusion dependent at Week 24.
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Key Inclusion Criteria:
- Palpable splenomegaly at least 5 cm below the left costal margin
- Confirmed diagnosis of PMF or post-PV/ET MF
- Requires myelofibrosis therapy, in the opinion of the investigator
- Classified as high risk OR intermediate-2 risk as defined by the International Prognostic Scoring System (IPSS) for PMF, or intermediate-1 risk (IPSS) associated with symptomatic splenomegaly, hepatomegaly, anemia (hemoglobin < 10.0 g/dL), and/or unresponsive to available therapy
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Acceptable laboratory assessment obtained within 14 days prior to the first dose of study drug:
- Absolute neutrophil count (ANC) ≥ 0.75 x 10^9/L in the absence of growth factor in the prior 7 days
- Platelet Count ≥ 50 x 10^9/L (≥ 100 x 10^9/L if aspartate aminotransferase [AST] or alanine aminotransferase [ALT] is ≥ 2 x the upper limit of the normal range [ULN]) in the absence of platelet transfusion(s) or thrombopoietin mimetics in the prior 7 days
- Peripheral blood blast count < 10%
- AST and ALT ≤ 3 x 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 (CrCL) of ≥ 45 mL/min
- Direct bilirubin ≤ 2.0 x ULN
- Life expectancy of > 24 weeks
- 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 study drug
- 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 study drug
- Eligible for allogeneic bone marrow or stem cell transplantation
- 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 a hepatitis B or C carrier
- Prior use of a JAK1 or JAK2 inhibitor
- Use of chemotherapy, immunomodulating therapy, biologic therapy, radiation therapy, or investigational therapy within 4 weeks of the first dose of study drug
- Presence of peripheral neuropathy ≥ Common Terminology Criteria for Adverse Events (CTCAE) Grade 2
- Unwilling or unable to undergo a magnetic resonance imaging (MRI) or computed tomography (CT) scan
Note: Other protocol defined Inclusion/Exclusion criteria may apply.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01969838
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| Study Director: | Gilead Study Director | Gilead Sciences |
| Responsible Party: | Sierra Oncology LLC - a GSK company |
| ClinicalTrials.gov Identifier: | NCT01969838 |
| Other Study ID Numbers: |
GS-US-352-0101 2013-002707-33 ( EudraCT Number ) |
| First Posted: | October 25, 2013 Key Record Dates |
| Results First Posted: | May 12, 2023 |
| Last Update Posted: | May 12, 2023 |
| Last Verified: | May 2023 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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Polycythemia Vera Primary Myelofibrosis Polycythemia Thrombocytosis Thrombocythemia, Essential Myeloproliferative Disorders Bone Marrow Diseases Hematologic Diseases Bone Marrow Neoplasms Hematologic Neoplasms |
Neoplasms by Site Neoplasms Blood Platelet Disorders Blood Coagulation Disorders Hemorrhagic Disorders N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide Protein Kinase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action |