A Study of Momelotinib Versus Danazol in Symptomatic and Anemic Myelofibrosis Participants (MOMENTUM)
Condition: Primary Myelofibrosis; Post-polycythemia Vera Myelofibrosis; Post-essential Thrombocythemia Myelofibrosis
MeSH terms: Polycythemia Vera; Primary Myelofibrosis; Polycythemia; Thrombocytosis; Thrombocythemia, Essential
Intervention: Momelotinib; Placebo to match danazol; Danazol; Placebo to match momelotinib
Intervention description: Momelotinib tablets will be self-administered orally once daily; Danazol placebo capsules will be self-administered orally twice daily; Danazol capsules will be self-administered orally twice daily; Momelotinib placebo tablets will be self-administered orally once daily
Intervention MeSH terms: Danazol; N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
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, participants, investigators and sponsor and relevant vendor personnel (with the exception of specified unblinded personnel, for example clinical supply) will remain blinded to the participant's treatment assignment and to aggregate data that may lead to inadvertent unblinding. Participants who continue treatment with momelotinib or danazol after Week 24 in the extended treatment phase will receive unblinded treatment.
Enrollment: 195.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Myelofibrosis; JAK inhibitor; Danazol; Momelotinib; Functional Iron deficiency; Activin receptor type 1; Anemia; Transfusion; Hepcidin; Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases

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 participants 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, United Kingdom (UK) and
      United States (US).

      Participants must be symptomatic with a Myelofibrosis Symptom Assessment Form (MFSAF) version
      (v) 4.0 Total Symptom Score of >= 10 at screening, and be anemic with hemoglobin (Hgb) < 10
      gram/deciliter (g/dL). For participants 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.

      Participants will be randomized 2:1 to orally self-administer blinded treatment: MMB plus
      placebo or DAN plus placebo. Participants 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 participants tolerates and continues to benefit from MMB.

      Participants 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.
      Participants 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.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Age >= 18 years.

          -  Confirmed diagnosis of PMF in accordance with the World Health Organization (WHO) 2016
             criteria, or Post- polycythemia vera/essential thrombocythemia (PV/ET) MF in
             accordance with the International Working Group-Myeloproliferative Neoplasms Research
             and Treatment (IWG-MRT criteria).

          -  Symptomatic, defined as a TSS of >= 10 units assessed by a single MFSAF v4.0
             assessment during Screening prior to Baseline period (Day BL1).

          -  Anemic, defined as a Hgb < 10 g/dL in Screening/Baseline period.

          -  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.

          -  Baseline splenomegaly, defined as having a palpable spleen at >= 5 centimeter (cm),
             below the left costal margin, or with volume >= 450 cubic centimeter (cm^3) on imaging
             (ultrasound, magnetic resonance imaging [MRI] or computed tomography [CT] are
             acceptable), assessed during Screening at any point prior to Randomization.

          -  High risk, intermediate-2, or intermediate-1 risk MF as defined by Dynamic
             International Prognostic Scoring System (DIPSS), or DIPSS-plus.

          -  No allogeneic stem cell transplant planned.

          -  Acceptable laboratory assessments:

               1. Absolute neutrophil count (ANC) >= 0.75 × 10^9/Liter (L).

               2. Platelet count (PLT) >= 25 × 10^9/L (without requirement for platelet
                  transfusion).

               3. Peripheral blast count < 10%.

               4. Alanine aminotransferase/ glutamic-oxaloacetic transaminase (AST/SGOT) and
                  alanine aminotransferase/ serum glutamic-pyruvic transaminase (ALT/SGPT) <= 3 ×
                  Upper Limit Normal (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).

               5. Calculated creatinine clearance (CCr) >= 30 milliliter per minute (mL/min)
                  according to Cockcroft-Gault.

               6. Direct bilirubin <= 2.0 × ULN.

        Exclusion Criteria:

          -  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.

          -  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.

          -  Prostate specific antigen (PSA) > 4 nanograms per milliliter (ng/mL).

          -  Unsuitable for spleen volume measurements due to prior splenectomy or unwilling or
             unable to undergo an MRI scan or CT scan for spleen volume measurement per protocol
             requirements.

          -  Any of the following (criteria a - k):

               1. Uncontrolled intercurrent illness including, but not limited to: active
                  uncontrolled infection (participants 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. QT Interval Corrected Using Fridericia's Formula (QTcF) interval > 500
                  millisecond (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.

          -  Participants 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.

          -  Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies,
             or autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding or
             thalassemia.

          -  Known positive status for human immunodeficiency viruses (HIV).

          -  Chronic active or acute viral hepatitis A, B, or C infection, or hepatitis B or C
             carrier (testing required for hepatitis B and C).

          -  Unresolved non-hematologic toxicities from prior therapies that are > Grade 1 per
             CTCAE v5.0.

          -  Presence of peripheral neuropathy >= Grade 2 per CTCAE v5.0.

          -  Women who are already pregnant or lactating. Additional inclusion/exclusion criteria
             may apply.