MOMELOTINIB DIHYDROCHLORIDE MONOHYDRATE for Primary myelofibrosis | Post-polycythaemia vera myelofibrosis | Post-essential thrombocythaemia myelofibrosis

Inclusion criteria

• {"criterion_text":"- 1. Is age ≥18 years at the time of signing the ICF, or the legal age of consent in the jurisdiction in which the study is taking place.\n- 10. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.\n- 11. Has adequate organ function.\n- 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 (IWGMRT) criteria.\n- 3. JAKi naïve or previously treated with either ruxolitinib or fedratinib 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.\n- 4. High risk, intermediate-2, or intermediate-1 risk as defined by DIPSS or DIPSS-plus.\n- 5. TD defined as requiring RBC transfusion ≥4 units or Hgb < 8 g/dL in the 8 weeks prior to the first dose of study treatment with no Hgb ≥8 g/dL during the Screening period. Only transfusions given when Hgb levels are ≤9.5 g/dL are counted towards TD. RBC transfusions given for clinically overt bleeding, or accident/injury (as assessed by the investigator) are not counted towards TD.\n- 6. Has no allogeneic stem cell transplant currently planned.\n- 7. Has a life expectancy > 24 weeks.\n- 8. A female participant is eligible to participate if she is not pregnant or breastfeeding and at least one of the following conditions applies: -Is a woman of childbearing potential (WOCBP) and using a contraceptive method that is highly effective (with a failure rate of <1% per year), consistent with local regulations and with low user dependency during the intervention period and for at least one week after the last dose of momelotinib (and for at least 3 months after the last dose of luspatercept) and per the instruction of the local prescribing information for the combination partner. • A WOCBP must have a negative highly sensitive pregnancy test (urine or serum, as required by local regulations) within 24 hours before the first dose of study intervention and monthly during study treatment. • The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. • Female participants who become pregnant after the start of study intervention must permanently discontinue study intervention.\n- 9. Is capable of giving signed informed consent, including compliance with the requirements and restrictions listed in the ICF and in this protocol."}

Exclusion criteria

• {"criterion_text":"- 1. History of intestinal disease, inflammatory bowel disease, major gastric surgery, or other gastrointestinal conditions (e.g., uncontrolled nausea, vomiting, malabsorption syndrome) likely to alter absorption of study intervention or result in inability to swallow oral medications.\n- 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.\n- 11. Presence of peripheral neuropathy ≥Grade 2 per CTCAE v5.0.\n- 12. Known contraindication or hypersensitivity to Momelotinib and its metabolites, to Luspatercept, or any of their excipients.\n- 13. Use of the following treatments within the time periods noted. NOTE: All active anti-MF therapy must discontinue at least 1 week prior to the start of baseline MFSAF recording (Study Day -7): a. Active anti-MF therapy as defined in within 28 days or 5 half-lives, whichever is shorter (exception is prior JAK inhibitor therapy; refer to IC3). b. Steroid use for the treatment of MF is prohibited within 14 days prior to the first dose of study treatment until discontinuation of study treatment. Supportive care including steroids for non-MF indications may be used. c. Potent cytochrome P450 3A4 (CYP3A4) inducers, except for rifampin and rifampicin, within 14 days prior to the first dose of study intervention. d. Any prior investigational agent for MF within 4 weeks prior to the first dose of study treatment. e. Erythropoiesis stimulating agent (ESA) within 4 weeks prior to the first dose of study treatment. f. Splenic irradiation within 3 months prior to the first dose of study treatment.\n- 14. Prior treatment with known ACVR1 (aka ALK2) inhibitors.\n- 15. Prior treatment with Momelotinib.\n- 16. Prior treatment with TGF-β pathway ligand traps (e.g., luspatercept, sotatercept, eritercept).\n- 17. Prior splenectomy.\n- 18. Inability or unwillingness to comply with the protocol restrictions on MF therapy and other medications prior to and during study treatment.\n- 19. Unresolved non-hematologic toxicities from prior therapies that are >Grade 1 per CTCAE v5.0 unless otherwise specified.\n- 2. Participants with an invasive malignancy or history of invasive malignancy other than the disease under study within the last 5 years, except as noted below: a. Participants may be enrolled in the study with a history of an invasive malignancy for which the participant was definitively treated, from which the participant has been disease free for at least 2 years, and which, in the opinion of the principal investigator and medical monitor, is not expected to affect the evaluation of the effects of the study intervention on the currently targeted malignancy b. Participants with curatively treated basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, in situ cervical cancer, and/or in situ breast cancer may be enrolled in the study.\n- 20. Known positive status for HIV.\n- 21. Hepatitis A, B, or C status as defined below: a. Chronic active or acute viral hepatitis A. b. Active Hepatitis B infection indicated by the presence of hepatitis B surface antigen (HBsAg) at screening or within 3 months prior to the first dose of study intervention. c. Positive hepatitis C antibody test result at screening or within 3 months before the first dose of study intervention. NOTE: Participants with positive hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative hepatitis C RNA test is obtained.\n- 22. Women who are already pregnant or lactating.\n- 3. Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, gastrointestinal bleeding, or thalassemia.\n- 4. Uncontrolled intercurrent illness including, but not limited to: a. 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); or b. Significant active or chronic bleeding event ≥Grade 2 per Common Terminology Criteria for Adverse Events (CTCAE) v5.0, within 4 weeks prior to the first dose of study treatment; or c. Uncontrolled acute and chronic liver disease (e.g., Child-Pugh score ≥10) OR has current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis. NOTE: Stable chronic liver disease (including Gilbert's syndrome or asymptomatic gallstones) is acceptable if participant otherwise meets entry criteria.\n- 5. Uncontrolled hypertension, defined as repeated elevations of systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg, that is not resolved at the time of the first dose of study treatment.\n- 6. Any of the following in conditions within 6 months prior to the first dose of study intervention: a. Unstable angina pectoris; or b. Symptomatic congestive heart failure; or c. Uncontrolled cardiac arrhythmia.\n- 7. QTc interval >450 msec or QTc >480 msec for participants with bundle branch block.\n- 8. Participants with stroke, deep venous thrombosis, pulmonary or arterial embolism within 6 months prior to the first dose of study intervention. Participants on anticoagulant therapy who are not under appropriate control or on a stable dose of anticoagulant therapy for a minimum of 3 months should be excluded.\n- 9. History of porphyria."}

Primary endpoints

• {"endpoint_text":"- Proportion of participants with TI by the end of Week 24; defined as not requiring RBC transfusion (except in the case of clinically overt bleeding) for any ≥12-week interval.","definition_or_measurement_approach":"TI defined as not requiring RBC transfusion (except in the case of clinically overt bleeding) for any ≥12-week interval; measured by transfusion records and haemoglobin values over the period up to Week 24."}

Secondary endpoints

• {"endpoint_text":"- Incidences of AEs, SAEs, and AEs leading to discontinuation.","definition_or_measurement_approach":"Adverse events collected and categorized according to standard safety reporting (e.g., CTCAE); counts/incidence of AEs, SAEs, and AEs causing discontinuation."}
• {"endpoint_text":"- Clinically important changes in laboratory parameters (hematology, chemistry), vital signs, and ECOG performance status.","definition_or_measurement_approach":"Laboratory parameters, vital signs and ECOG performance status measured at scheduled visits and assessed for clinically important changes."}
• {"endpoint_text":"- Proportion of participants with TI at the end of Week 24; defined as not requiring RBC transfusion (except in the case of clinically overt bleeding) for ≥12 weeks preceding week 24, with all Hgb levels during the ≥12-week interval of ≥8 g/dL (except in the case of clinically overt bleeding).","definition_or_measurement_approach":"TI defined as no RBC transfusions during the ≥12-week interval preceding week 24 and all Hgb values during that interval ≥8 g/dL (except in case of clinically overt bleeding); assessed from transfusion records and Hb measurements."}
• {"endpoint_text":"- Plasma concentration of Momelotinib and M21.","definition_or_measurement_approach":"Pharmacokinetic measurement of plasma momelotinib and metabolite M21 concentrations at specified PK sampling times."}

Methods

• Recruitment arrangements documents submitted (titles include: K1_Recruit ICF Process, K2_Infographic, K2_Recruitment material_ePRO FACT-An, K2_Recruitment material_PGI-C-Cancer_StudyStart_Paper, K2_Recruitment Material Infographic, GSK_eCOA Handheld_PrivacyPolicy).
• Use of study informational infographics and recruitment material (country-specific K2 documents present for France, Germany, Italy, Spain).
• Provision of subject information and informed consent forms (multiple L1_SIS-ICF documents and appendices for participating countries).

Spain

Earliest CTIS Part Ii Submission Date

28-02-2025

Latest Decision Or Authorization Date

19-11-2025

Processing Time Days

264

Number Of Sites

7

Number Of Participants

12

Germany

Earliest CTIS Part Ii Submission Date

24-02-2025

Latest Decision Or Authorization Date

18-11-2025

Processing Time Days

267

Number Of Sites

5

Number Of Participants

15

Italy

Earliest CTIS Part Ii Submission Date

26-02-2025

Latest Decision Or Authorization Date

17-11-2025

Processing Time Days

264

Number Of Sites

6

Number Of Participants

12

France

Earliest CTIS Part Ii Submission Date

28-02-2025

Latest Decision Or Authorization Date

01-12-2025

Processing Time Days

276

Number Of Sites

7

Number Of Participants

12

Primary sponsor

Full Name

Glaxosmithkline Research & Development Limited

Organisation Type

Pharmaceutical company

Country Of Registered Address

United Kingdom

Contract research organisations

Name

Icon Clinical Research Limited

Responsibilities

Sample management and vendor management; additional duty codes: 1,11,12,14,2,5,6,7,8,9

Third parties

• {"country":"Belgium","full_name":"PPD Global Central Labs","duties_or_roles":"collect and hold; (additional duty code 4)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Frontage Laboratories Inc.","duties_or_roles":"hold; (additional duty code 4)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"FACIT.Org Inc.","duties_or_roles":"PRO licencing","organisation_type":"Pharmaceutical company"}
• {"country":"India","full_name":"Tata Consultancy Services Limited","duties_or_roles":"duty codes: 5, 8","organisation_type":"Pharmaceutical company"}
• {"country":"Ireland","full_name":"Icon Clinical Research Limited","duties_or_roles":"Sample management and vendor management; additional duty codes: 1,11,12,14,2,5,6,7,8,9","organisation_type":"Pharmaceutical company"}