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
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 during Screening prior to 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 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 (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:
- Use of the following treatments within the time periods noted:
- Prior momelotinib treatment at any time.
- Approved JAK inhibitor therapy (eg, fedratinib or ruxolitinib) within 1 week prior to the first day of Baseline.
- Active anti-MF therapy within 1 week prior to the first day of Baseline.
- Potent Cytochrome P450 3A4 (CYP3A4) inducers within 1 week prior to Randomization.
- Investigational agent (including investigational JAK inhibitors) 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 or thalassemia.
- 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.