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Trial record 1 of 10 for:    momelotinib | Myeloproliferative Neoplasm | United States
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A Study of Momelotinib Versus Danazol in Symptomatic and Anemic Myelofibrosis Patients (MOMENTUM)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04173494
Recruitment Status : Active, not recruiting
First Posted : November 22, 2019
Results First Posted : December 22, 2022
Last Update Posted : December 22, 2022
Sponsor:
Information provided by (Responsible Party):
Sierra Oncology, Inc.

Brief Summary:

MOMENTUM is a randomized, double-blind, active control Phase 3 trial intended to confirm the differentiated clinical benefits of the investigational drug momelotinib (MMB) versus danazol (DAN) in symptomatic and anemic subjects who have previously received an approved Janus kinase inhibitor (JAKi) therapy for myelofibrosis (MF). The purpose of this clinical study is to compare the effectiveness and safety of MMB to DAN in treating and reducing: 1) disease related symptoms, 2) the need for blood transfusions and 3) splenomegaly, in adults with primary MF, post-polycythemia vera MF or post-essential thrombocythemia MF. The study is planned in countries including, but not limited to: Australia, Austria, Belgium, Bulgaria, Canada, Czech Republic, Denmark, France, Germany, Hungary, Israel, Italy, New Zealand, Poland, Romania, Singapore, South Korea, Spain, Sweden, Taiwan, UK, and US.

Subjects must be symptomatic with a MFSAF v4.0 Total Symptom Score of ≥ 10 at screening, and be anemic with Hgb < 10 g/dL. For subjects with ongoing JAKi therapy at screening, JAKi therapy must be tapered over a period of at least 1 week, followed by a 2-week non-treatment washout interval prior to randomization.

Subjects will be randomized 2:1 to orally self-administer blinded treatment: MMB plus placebo or DAN plus placebo. Subjects randomized to receive MMB who complete the randomized treatment period to the end of Week 24 may continue to receive MMB in the open-label extended treatment period to the end of Week 204 (a total period of treatment of approximately 4 years) if the subject tolerates and continues to benefit from MMB.

Subjects randomized to receive DAN may cross-over to MMB open-label treatment in the following circumstances:

  • at the end of Week 24 if they complete the randomized treatment period; or
  • at the end of Week 24 if they discontinue treatment with DAN but continue study assessments and do not receive prohibited medications including alternative active anti-MF therapy; or
  • at any time during the randomized treatment period if they meet the protocol-defined criteria for radiographically-confirmed symptomatic splenic progression.

Subjects randomized to receive DAN who are receiving clinical benefit at the end of Week 24 may choose to continue DAN therapy up to Week 48. The comparator treatment, DAN, is an approved medication in the US and in some other countries and is recommended by national guidelines as a treatment for anemia in MF.


Condition or disease Intervention/treatment Phase
Primary Myelofibrosis Post-polycythemia Vera Myelofibrosis Post-essential Thrombocythemia Myelofibrosis Drug: Momelotinib Drug: Danazol Drug: Placebo to match momelotinib Drug: Placebo to match danazol Phase 3

Detailed Description:
MOMENTUM Contact Email: GSKClinicalSupportHD@gsk.com

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 195 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: During the 24 week randomized treatment phase of the study, subjects, investigators and sponsor and relevant vendor personnel (with the exception of specified unblinded personnel, for example clinical supply) will remain blinded to the subject's treatment assignment and to aggregate data that may lead to inadvertent unblinding. Subjects who continue treatment with momelotinib or danazol after Week 24 in the extended treatment phase will receive unblinded treatment.
Primary Purpose: Treatment
Official Title: A Randomized, Double-blind, Phase 3 Study to Evaluate the Activity of Momelotinib (MMB) Versus Danazol (DAN) in Symptomatic, Anemic Subjects With Primary Myelofibrosis (PMF), Post-polycythemia Vera (PV) Myelofibrosis, or Post-essential Thrombocythemia (ET) Myelofibrosis Who Were Previously Treated With JAK Inhibitor Therapy
Actual Study Start Date : February 7, 2020
Actual Primary Completion Date : December 3, 2021
Estimated Study Completion Date : April 2028


Arm Intervention/treatment
Experimental: Momelotinib
Participants will receive momelotinib plus placebo to match danazol
Drug: Momelotinib
Momelotinib tablets will be self-administered orally once daily
Other Name: MMB, GS-0387, CYT387

Drug: Placebo to match danazol
Danazol placebo capsules will be self-administered orally twice daily

Active Comparator: Danazol
Participants will receive danazol plus placebo to match momelotinib
Drug: Danazol
Danazol capsules will be self-administered orally twice daily
Other Name: Danocrine

Drug: Placebo to match momelotinib
Momelotinib placebo tablets will be self-administered orally once daily




Primary Outcome Measures :
  1. Total Symptom Score (TSS) Response Rate at Week 24 [ Time Frame: Baseline and Week 24 ]

    TSS response rate was measured using the Myelofibrosis Symptom Assessment Form (MFSAF) v4.0. The MFSAF v4.0 comprises 7 domains representing the 7 most relevant symptoms of myelofibrosis (MF) identified through existing patient- and clinician-based evidence: fatigue, night sweats, pruritus, abdominal discomfort, pain under the left ribs, early satiety, and bone pain. Participants scored each symptom domain using an 11-point numeric rating scale ranging from 0 (absent) to 10 (worst imaginable). The MFSAF TSS was calculated as the sum of scores of the 7 domains for a possible range of scores of 0 to 70, with a higher TSS corresponding to more severe symptoms.

    MFSAF TSS v4.0 response rate was defined as the percentage of participants with a ≥ 50% reduction from baseline in mean MFSAF TSS over the consecutive 28-day period immediately before the end of Week 24. A reduction from baseline corresponded to a lessening of MF symptoms.



Secondary Outcome Measures :
  1. Number of Participants With Transfusion Independence (TI) at Week 24 [ Time Frame: Week 24 ]
    TI status was defined as not requiring red blood cell or whole blood transfusion (except in the case of clinically overt bleeding) for ≥12 weeks, with all hemoglobin levels during the terminal ≥ 12 week interval of ≥ 8 g/dL (except in the case of clinically overt bleeding).

  2. Splenic Response Rate (SRR) of ≥ 25% at Week 24 [ Time Frame: Baseline and Week 24 ]
    Measured as the percentage of participants who had splenic response at Week 24. A splenic response was defined as a reduction in spleen volume of ≥ 25% from baseline.

  3. SRR of ≥ 35% at Week 24 [ Time Frame: Baseline and Week 24 ]
    Measured as the percentage of participants who had splenic response at Week 24. A splenic response was defined as a reduction in spleen volume of ≥ 35% from baseline.

  4. Change in MFSAF TSS From Baseline at Week 24 [ Time Frame: Baseline and Week 24 ]
    Defined as the change from baseline in mean MFSAF TSS over the 28 days immediately before the end of Week 24. TSS was measured using the MFSAF v4.0. The MFSAF v4.0 comprises 7 domains representing the 7 most relevant symptoms of MF identified through existing patient- and clinician-based evidence: fatigue, night sweats, pruritus, abdominal discomfort, pain under the left ribs, early satiety, and bone pain. Participants scored each symptom domain using an 11-point numeric rating scale ranging from 0 (absent) to 10 (worst imaginable). The MFSAF TSS was calculated as the sum of scores of the 7 domains for a possible range of scores of 0 to 70, with a higher TSS corresponding to more severe symptoms. A reduction from baseline corresponded to a lessening of MF symptoms.

  5. Rate of No Transfusion at Week 24 [ Time Frame: Week 24 ]
    Defined as the percentage of participants with zero red blood cell or whole blood units transfused during the 24-week randomized treatment period.

  6. Duration of the End of Week 24 MFSAF TSS Response [ Time Frame: Week 48 ]
    For participants who achieved a Week 24 TSS response, the duration of response was defined as the number of days from the start of the initial 28-day period (during the 24-Week Randomized Treatment Period), in which the participant had a ≥ 50% reduction from baseline TSS to the first day of the 7-day assessment that determines the mean TSS for the 28-day period during which the participant's TSS equaled or exceeded their baseline value. TSS will be assessed during the last 7 days (± 7 days) of each month during the open label extended treatment period until Week 48.

  7. Average Duration of TI at Week 24 [ Time Frame: Week 48 ]
    Measured in participants who achieved TI status at Week 24. TI status was defined as the number of days from the first day of a period of at least 12 weeks, during which a participant received no transfusions and had no hemoglobin < 8 g/dL (except in the case of clinically overt bleeding), to the first red blood cell or whole blood transfusion or hemoglobin level < 8 g/dL (again, except in the case of clinically overt bleeding) (assessed until the end of Week 48).

  8. Cumulative Transfusion Risk at Week 24 [ Time Frame: Week 24 ]
    Cumulative transfusion risk was calculated as the estimated mean cumulative number of red blood cell or whole blood units transfused during the randomized treatment period.

  9. Transfusion Dependence (TD) Rate at Week 24 [ Time Frame: Week 24 ]
    Defined as the percentage of participants with TD. Participants were defined as having TD if they met both of the following requirements in the 8 weeks immediately before the end of Week 24: ≥ 4 red blood cell or whole blood units were transfused (except in the case of clinically overt bleeding), each in response to a hemoglobin assessment of ≤ 9.5 g/dL; and there were ≥ 2 hemoglobin assessments with ≥ 28 days between the earliest and latest hemoglobin assessments.

  10. Number of Participants With a Hemoglobin Response [ Time Frame: Baseline and Week 24 ]
    Hemoglobin response was defined as increases of ≥1, ≥1.5, or ≥2 g/dL from baseline in hemoglobin over the 24-week randomized treatment period and the last 12 weeks of the period with any hemoglobin values within 4 weeks after a transfusion excluded. Assessed in all participants and in the subset of participants who were TI at baseline.

  11. Percentage of Baseline TD Participants With TI Status at Week 24 [ Time Frame: Baseline and Week 24 ]
    Participants were defined as having TD if they met both of the following requirements in the 8 weeks immediately before the end of Week 24: ≥ 4 red blood cell or whole blood units were transfused (except in the case of clinically overt bleeding), each in response to a hemoglobin assessment of ≤ 9.5 g/dL; and there were ≥ 2 hemoglobin assessments with ≥ 28 days between the earliest and latest hemoglobin assessments. TI status was defined as not requiring red blood cell transfusion (except in the case of clinically overt bleeding) for ≥ 12 weeks immediately prior to the end of Week 24, with hemoglobin levels ≥ 8 g/dL.

  12. Average Duration of TI at Week 24 in Baseline TD Participants [ Time Frame: Baseline and Week 48 ]
    Measured in participants who achieved TI status at Week 24 who were TD at baseline. TI status was defined as the number of days from the first day of a period of at least 12 weeks, during which a participant received no transfusions and had no hemoglobin < 8 g/dL (except in the case of clinically overt bleeding), to the first red blood cell or whole blood transfusion or hemoglobin level < 8 g/dL (again, except in the case of clinically overt bleeding) (assessed until the end of Week 48).

  13. Number of Participants Who Experienced an Adverse Event (AE) [ Time Frame: Day 1 to Week 204 ]
    An AE was defined as any untoward medical occurrence in a trial participant administered an investigational product(s), a comparator product, or an approved drug regardless of the causal relationship with treatment. A serious AE (SAE) was defined as an AE that resulted in death, was life-threatening, required hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability or incapacity, resulted in in a congenital anomaly/ birth defect in the offspring of an exposed female participant or offspring of a female partner of a male participant, or required medical or surgical intervention. AEs at Grade 3 (severe) or above based on Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, relationship of AEs to study drug, serious AEs and AEs leading to discontinuation of study drug were reported. Any clinically significant changes in laboratory tests and spleen measurements were also recorded as AEs.

  14. Overall Survival (OS) [ Time Frame: Day 1 to Week 204 ]
    Defined as the interval from the first study drug dosing date to death from any cause.

  15. Leukemia-free Survival (LFS) [ Time Frame: Day 1 to Week 204 ]
    Defined as the interval from the first study drug dosing date to any evidence of leukemic transformation and/or death.

  16. Change From Baseline in Disease-related Fatigue as Assessed by MFSAF v4.0 [ Time Frame: Baseline to Week 48 ]
    The MFSAF v4.0 comprises 7 domains representing the 7 most relevant symptoms of MF identified through existing patient- and clinician-based evidence: fatigue, night sweats, pruritus, abdominal discomfort, pain under the left ribs, early satiety, and bone pain. Participants scored each symptom domain using an 11-point numeric rating scale ranging from 0 (absent) to 10 (worst imaginable). The total possible range of scores was 0 to 70, with higher scores corresponding to more severe MF symptoms. An increase in score from baseline indicated a worsening of MF symptoms, and a decrease in score from baseline indicated an improvement in MF symptoms.

  17. Change From Baseline in Cancer-related Fatigue as Assessed by European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) [ Time Frame: Baseline to Week 96 ]
    The EORTC QLQ-C30 is comprised of 5 functional scales (physical, role, emotional, social, cognitive), eight single item symptom scales (fatigue, pain, nausea/vomiting, appetite loss, constipation, diarrhea, insomnia, dyspnea), as well as sub-scales assessing global health/quality of life and financial impact. Most items use a 4-point Likert scale from "not at all" to "very much" and a one-week recall period with the exception of the final two items which use a 7 point scale response from "very poor" to "excellent". Raw scores were transformed to a 0-100 scale, with higher scores representing better functioning/quality of life. An increase in scores from baseline indicated an improved functioning/quality of life, and a decrease in scores from baseline indicated a worsened functioning/quality of life.

  18. Change From Baseline in Physical Function Score as Assessed by Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function Short Form 10b [ Time Frame: Baseline to Week 96 ]
    The PROMIS Physical Function Short Form 10b consists of 14 questions; each with a 5-point response. The PROMIS short form assesses the self-reported capability of a participant rather than actual performance of physical activities. This includes the functioning of one's upper extremities (dexterity), lower extremities (walking or mobility), and central regions (neck, back), as well as instrumental activities of daily living, such as running errands. Participants scored each response on a scale from 1 (unable to do) to 5 (without any difficulty, or not at all). The total possible range of scores was 14 to 70, with higher scores corresponding to a greater physical function ability. An increase in score from baseline indicated an improvement in physical function ability, and a decrease in score from baseline indicated a reduction in physical function ability.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age ≥ 18 years.
  2. Confirmed diagnosis of PMF in accordance with the World Health Organization (WHO) 2016 criteria, or Post-PV/ET MF in accordance with the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT criteria).
  3. Symptomatic, defined as a TSS of ≥ 10 units assessed by a single MFSAF v4.0 assessment during Screening prior to Day BL1.
  4. Anemic, defined as a Hgb < 10 g/dL in Screening/Baseline period.
  5. Previously treated with an approved JAK inhibitor for PMF or Post-PV/ET MF for ≥ 90 days, or ≥ 28 days if JAK inhibitor therapy is complicated by RBC transfusion requirement of ≥ 4 units in 8 weeks, or Grade 3/4 AEs of thrombocytopenia, anemia, or hematoma.
  6. Baseline splenomegaly, defined as having a palpable spleen at ≥ 5 cm, below the left costal margin, or with volume ≥ 450 cm³ on imaging (ultrasound, MRI or CT are acceptable), assessed during Screening at any point prior to Randomization.
  7. High risk, intermediate-2, or intermediate-1 risk MF as defined by DIPSS, or DIPSS-plus.
  8. No allogeneic stem cell transplant planned.
  9. Acceptable laboratory assessments:

    • Absolute neutrophil count (ANC) ≥ 0.75 × 10E9/L.
    • Platelet count (PLT) ≥ 25 × 10E9/L (without requirement for platelet transfusion).
    • Peripheral blast count < 10%.
    • Alanine aminotransferase/ glutamic-oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase/ serum glutamic-pyruvic transaminase (ALT/SGPT) ≤ 3 × ULN (≤ 5 × 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 (CCr) ≥ 30 mL/min according to Cockcroft-Gault.
    • Direct bilirubin ≤ 2.0 × ULN.

Exclusion Criteria:

  1. Use of the following treatments within the time periods noted:

    1. Prior momelotinib treatment at any time.
    2. Approved JAK inhibitor therapy (eg, fedratinib or ruxolitinib) within 1 week prior to the first day of Baseline.
    3. Active anti-MF therapy within 1 week prior to the first day of Baseline.
    4. Potent Cytochrome P450 3A4 (CYP3A4) inducers within 1 week prior to Randomization.
    5. Investigational agent (including investigational JAK inhibitors) within 4 weeks prior to Randomization.
    6. Erythropoiesis stimulating agent (ESA) within 4 weeks prior to Randomization.
    7. Danazol within 3 months prior to Randomization.
    8. Splenic irradiation within 3 months prior to Randomization.
    9. Current treatment with simvastatin, atorvastatin, lovastatin or rosuvastatin.
  2. History of prostate cancer, with the exception of localized prostate cancer that has been treated surgically or by radiotherapy with curative intent and presumed cured.
  3. Prostate specific antigen (PSA) > 4 ng/mL.
  4. Unsuitable for spleen volume measurements due to prior splenectomy or unwilling or unable to undergo an MRI or CT scan for spleen volume measurement per protocol requirements.
  5. Any of the following (criteria a - k):

    1. Uncontrolled intercurrent illness including, but not limited to: active uncontrolled infection (subjects receiving outpatient antibacterial and/or antiviral treatments for infection that is under control or as infection prophylaxis may be included in the trial).
    2. Significant active or chronic bleeding event ≥ Grade 2 per Common Terminology Criteria for Adverse Events (CTCAE) v5.0, within 4 weeks prior to Randomization.
    3. Unstable angina pectoris within 6 months prior to Randomization.
    4. Symptomatic congestive heart failure within 6 months prior to Randomization.
    5. Uncontrolled cardiac arrhythmia within 6 months prior to Randomization.
    6. QTcF interval > 500 msec, unless attributed to bundle branch block.
    7. Current progressive thrombosis despite treatment.
    8. History of porphyria.
    9. Child-Pugh score ≥ 10.
    10. Psychiatric illness, social situation, or any other condition that would limit compliance with trial requirements or may interfere with the interpretation of study results, as judged by investigator or sponsor.
    11. Inability or unwillingness to comply with the protocol restrictions on MF therapy and other medications prior to and during study treatment.
  6. Subjects with a prior or concurrent malignancy, whose natural history or treatment has a significant potential to interfere with the safety or efficacy assessment of the investigational regimen.
  7. Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding or thalassemia.
  8. Known positive status for HIV.
  9. Chronic active or acute viral hepatitis A, B, or C infection, or hepatitis B or C carrier (testing required for hepatitis B and C).
  10. Unresolved non-hematologic toxicities from prior therapies that are > Grade 1 per CTCAE v5.0.
  11. Presence of peripheral neuropathy ≥ Grade 2 per CTCAE v5.0.
  12. Women who are already pregnant or lactating.

Additional inclusion/exclusion criteria may apply.


Information from the National Library of Medicine

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): NCT04173494


Locations
Show Show 167 study locations
Sponsors and Collaborators
Sierra Oncology, Inc.
Investigators
Layout table for investigator information
Principal Investigator: Srdan Verstovsek, M.D., Ph.D. Department of Leukemia, The University of Texas MD Anderson Cancer Center
Principal Investigator: Ruben Mesa UT Health San Antonio Cancer Center, San Antonio, TX, USA
  Study Documents (Full-Text)

Documents provided by Sierra Oncology, Inc.:
Study Protocol  [PDF] December 18, 2020
Statistical Analysis Plan  [PDF] December 30, 2021

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Sierra Oncology, Inc.
ClinicalTrials.gov Identifier: NCT04173494    
Other Study ID Numbers: SRA-MMB-301
First Posted: November 22, 2019    Key Record Dates
Results First Posted: December 22, 2022
Last Update Posted: December 22, 2022
Last Verified: December 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Sierra Oncology, Inc.:
Momelotinib
Myeloproliferative Disorders
Myelofibrosis
JAK inhibitor
Danazol
Functional Iron deficiency
ACVR1
Anemia
Transfusion
Hepcidin
Bone Marrow Diseases
Hematologic Diseases
Additional relevant MeSH terms:
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Myeloproliferative Disorders
Bone Marrow Neoplasms
Hematologic Neoplasms
Neoplasms by Site
Neoplasms
Polycythemia Vera
Primary Myelofibrosis
Polycythemia
Thrombocytosis
Thrombocythemia, Essential
Bone Marrow Diseases
Hematologic Diseases
Blood Platelet Disorders
Blood Coagulation Disorders
Hemorrhagic Disorders
Danazol
N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action