A Randomized, Double-Blind, Phase 3 Study of Momelotinib vs Danazol in Symptomatic, Anemic Subjects With Previously JAKi Treated Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post Essential Thrombocythemia Myelofibrosis
Brief SummaryMOMENTUM 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.
Inclusion and Exclusion Criteria
- Inclusion Criteria:
- Age ≥ 18 years.
- 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).
- Symptomatic, defined as a TSS of ≥ 10 units assessed by a single MFSAF v4.0 assessment at a Screening visit.
- 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 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.
- High risk, intermediate-2, or intermediate-1 risk MF as defined by DIPSS, or DIPSS-plus.
- No allogeneic stem cell transplant planned.
- Acceptable laboratory assessments: - Absolute neutrophil count (ANC) ≥ 0.75 × 10⁹/L. - Platelet count (PLT) ≥ 25 × 10⁹/L. - 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:
- Use of the following treatments within the time periods noted:
- Prior momelotinib treatment at any time.
- JAK inhibitor therapy within 2 weeks prior to Randomization.
- Active anti-MF therapy within 2 weeks prior to Randomization.
- Potent Cytochrome P450 3A4 (CYP3A4) inducers within 1 week prior to Randomization.
- Investigational agent within 4 weeks prior to Randomization.
- Erythropoiesis stimulating agent (ESA) within 4 weeks prior to Randomization.
- Danazol within 3 months prior to Randomization.
- Splenic irradiation within 3 months prior to Randomization.
- 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 ng/mL.
- 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.
- Any of the following (criteria a - k):
- 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).
- Significant active or chronic bleeding event ≥ Grade 2 per Common Terminology Criteria for Adverse Events (CTCAE) v5.0, within 4 weeks prior to Randomization.
- Unstable angina pectoris within 6 months prior to Randomization.
- Symptomatic congestive heart failure within 6 months prior to Randomization.
- Uncontrolled cardiac arrhythmia within 6 months prior to Randomization.
- QTcF interval > 500 msec, unless attributed to bundle branch block.
- Current progressive thrombosis despite treatment.
- History of porphyria.
- Child-Pugh score ≥ 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.
- Inability or unwillingness to comply with the protocol restrictions on MF therapy and other medications prior to and during study treatment.
- 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.
- Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding.
- Known positive status for 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.
Please contact the trial administrator to learn more about where you can participate in this trial. Please use the contact form on the right side.