Phase 2 Study of Momelotinib in Combination with Luspatercept in Participants with Transfusion Dependent Myelofibrosis.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Glaxosmithkline Research & Development Limited

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Decision date (initial)

2025-03-31

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

GlaxoSmithKline Research & Development Limited

External identifiers

EU CT number

2024-518225-15-00

ClinicalTrials.gov

NCT06517875

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

Assess the effect of Momelotinib in combination with Luspatercept on TI response by Week 24 (Rolling TI response).

Secondary objectives 3

1. To characterize the safety and tolerability profile of Momelotinib in combination with Luspatercept.
2. To assess the effect of Momelotinib in combination with Luspatercept on TI status at Week 24 (Terminal TI response).
3. To describe the exposure of Momelotinib and M21, when Momelotinib is administered in combination with Luspatercept.

Conditions and MedDRA coding

Myelofibrosis

Study design 1 period

Regulatory references

Plan to share IPD

No

IPD plan description

GSK will assess requests from qualified researchers for anonymized individual patient-level data and related study documents (e.g., Protocol, Statistical Analysis Plan, Clinical Study Report). Data sharing is subject to certain criteria, conditions, and exceptions. For further information, refer to ‘Sharing Clinical Trial Data’ on the GSK Study Register (www.gsk-studyregister.com).

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. 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.
2. 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.
3. 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.
4. 4. High risk, intermediate-2, or intermediate-1 risk as defined by DIPSS or DIPSS-plus.
5. 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 (NOTE: 2 consecutive Hgb < 8 g/dL, at least 1 week apart are required; Hgb values impacted by transfusions are excluded). 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.
6. 6. Has no allogeneic stem cell transplant currently planned.
7. 7. Has a life expectancy > 24 weeks.
8. 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.
9. 9. Is capable of giving signed informed consent, including compliance with the requirements and restrictions listed in the ICF and in this protocol.
10. 10. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
11. 11. Has adequate organ function.

Exclusion criteria 22

1. 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.
2. 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.
3. 3. Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, gastrointestinal bleeding, or thalassemia.
4. 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.
5. 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.
6. 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.
7. 7. QTc interval >450 msec or QTc >480 msec for participants with bundle branch block.
8. 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.
9. 9. History of porphyria.
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. 11. Presence of peripheral neuropathy ≥Grade 2 per CTCAE v5.0.
12. 12. Known contraindication or hypersensitivity to Momelotinib and its metabolites, to Luspatercept, or any of their excipients.
13. 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.
14. 14. Prior treatment with known ACVR1 (aka ALK2) inhibitors.
15. 15. Prior treatment with Momelotinib.
16. 16. Prior treatment with TGF-β pathway ligand traps (e.g., luspatercept, sotatercept, eritercept).
17. 17. Prior splenectomy.
18. 18. Inability or unwillingness to comply with the protocol restrictions on MF therapy and other medications prior to and during study treatment.
19. 19. Unresolved non-hematologic toxicities from prior therapies that are >Grade 1 per CTCAE v5.0 unless otherwise specified.
20. 20. Known positive status for HIV.
21. 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.
22. 22. Women who are already pregnant or lactating.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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.

Secondary endpoints 4

1. Incidences of AEs, SAEs, and AEs leading to discontinuation.
2. Clinically important changes in laboratory parameters (hematology, chemistry), vital signs, and ECOG performance status.
3. 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).
4. Plasma concentration of Momelotinib and M21.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Glaxosmithkline Research & Development Limited

Sponsor organisation

Glaxosmithkline Research & Development Limited

Address

79 New Oxford Street

City

London

Postcode

WC1A 1DG

Country

United Kingdom

Scientific contact point

Organisation

Glaxosmithkline Research & Development Limited

Contact name

EU GSK Clinical Trials Call Center

Public contact point

Organisation

Glaxosmithkline Research & Development Limited

Contact name

EU GSK Clinical Trials Call Center

Third parties 5

Locations

4 EU/EEA countries · 25 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 40 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications