MOMELOTINIB DIHYDROCHLORIDE MONOHYDRATE for VEXAS syndrome | Myelodysplastic syndrome

Inclusion criteria

• {"criterion_text":"- ECOG performance status 0-2 at the time of screening"}
• {"criterion_text":"- Adequate liver function (serum transaminases ≤ 3N, Bilirubin ≤ 1.5 x ULN (isolated bilirubin > 1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%))"}
• {"criterion_text":"- Adequate renal function (creatinine clearance with MDRD formula > 30 ml/min)"}
• {"criterion_text":"- Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically sterile) must: 1- Have a negative serum or urine pregnancy test within 24-hours prior to beginning treatment on this study. Lactating patients are excluded. 2- Agree to use, and to be able to comply with, effective contraception without interruption, 4 weeks before starting study drug throughout the entire duration study drug therapy (including doses interruptions) and for 12 weeks after the end of the study drug therapy. 3- Agree to learn about the procedures for preservation of egg before starting treatment."}
• {"criterion_text":"- Male patients must: 1- Agree the need for the use of a condom if engaged in sexual activity with a woman of childbearing potential during the entire period of treatment, even if disruption of treatment and during 12 weeks after end of treatment. 2- Agree to learn about the procedures for preservation of sperm before starting treatment."}
• {"criterion_text":"- Age ≥ 18 years"}
• {"criterion_text":"- Written informed consent"}
• {"criterion_text":"- Diagnosis of VEXAS syndrome with UBA1 mutation and clinically symptomatic disease requiring immunosuppressive treatment and at least 10 mg/d of glucocorticoids"}
• {"criterion_text":"- With uncontrolled symptoms related to VEXAS with prior treatment line(s) (including steroids)"}
• {"criterion_text":"- Patients refractory/dependent to steroids"}
• {"criterion_text":"- Single concomitant steroids therapy (e.g. prednisone or equivalent) at the time of inclusion is allowed"}
• {"criterion_text":"- For patients treated with other immunosuppressive/immuno-modulatory therapy than glucocorticoids, a wash out period of 28 days is required prior MMB onset"}
• {"criterion_text":"- Erythropoietin/luspatercept used as a growth factor is not allowed 28 days prior enrollment"}

Exclusion criteria

• {"criterion_text":"- Patients with MDS currently scheduled for allogeneic stem cell transplant or high risk MDS according to IWG 2023."}
• {"criterion_text":"- Active gastrointestinal conditions that may affect absorption"}
• {"criterion_text":"- No affiliation to a health insurance system."}
• {"criterion_text":"- Known hypersensitivity to the study investigational medicinal product, the metabolites, or formulation excipients."}
• {"criterion_text":"- Patients who are or have been already treated with JAK inhibitors for VEXAS syndrome or another indication."}
• {"criterion_text":"- Patients who are unable to receive a starting daily dose of MMB of at least 100 mg."}
• {"criterion_text":"- Subjects with any other active malignancies are not eligible, except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which subject has been disease-free for at least 3 years."}
• {"criterion_text":"- Uncontrolled congestive heart failure (New York Heart Association Classification 3 or 4), angina, myocardial infarction, cerebrovascular accident, coronary/peripheral artery bypass graft surgery, transient ischemic attack, or pulmonary embolism within 12 weeks prior to initiation of MMB."}
• {"criterion_text":"- Known infection with acute and chronic active HIV, HBV, HCV infections."}
• {"criterion_text":"- Any medical or psychiatric condition not allowing the informed consent of the subject"}
• {"criterion_text":"- Presence of clinically meaningful active bacterial, fungal, parasitic or viral infection which requires therapy"}
• {"criterion_text":"- Previous history of Progressive Multifocal Leuko-encephalopathy (PML)"}

Primary endpoints

• {"endpoint_text":"- For Safety run-in : Documentation of dose-limiting toxicities (DLTs) and identification of a maximal tolerated dose (MTD). DLTs will be defined during a safety observation period corresponding to the first 4-week cycle of MMB. Because of the addition of a 4-week period to observe recovery of adverse events of interest, the observation window for DLT will be up to 8 weeks.","definition_or_measurement_approach":"DLTs defined during safety observation period corresponding to the first 4-week cycle of MMB; observation window up to 8 weeks. Outcome: documentation of DLTs and identification of MTD."}
• {"endpoint_text":"- For phase II : Overall clinical response rate at 24 weeks after MMB initiation on VEXAS related symptoms (including complete (CR) or partial response (PR))","definition_or_measurement_approach":"Overall clinical response rate assessed at 24 weeks after MMB initiation on VEXAS-related symptoms; responses include complete response (CR) or partial response (PR)."}

Secondary endpoints

• {"endpoint_text":"- For safety run-in: Adverse events (AE), serious AE (SAE) and toxicity as measured by NCI CTCAE v5.0","definition_or_measurement_approach":"Safety assessed by recording AEs and SAEs and grading per NCI CTCAE v5.0 during safety run-in."}
• {"endpoint_text":"- For safety run-in phase : Plasma MMB/M21 pharmacokinetic parameters (i.e. AUC, Cmax) as data permits","definition_or_measurement_approach":"PK parameters of MMB/M21 in plasma (AUC, Cmax) measured during safety run-in."}
• {"endpoint_text":"- Overall clinical response rates (including CR or PR) and biological response rates (complete or partial) at 4, 12, 24 and 48 weeks after MMB initiation","definition_or_measurement_approach":"Clinical and biological response rates assessed at weeks 4, 12, 24 and 48 post-initiation; includes CR/PR."}
• {"endpoint_text":"- Erythroid hematological improvement (HI-E) evaluated at 16 weeks according to IWG 2018","definition_or_measurement_approach":"HI-E evaluated at 16 weeks according to IWG 2018 criteria."}
• {"endpoint_text":"- Steroids dose reduction compared to baseline and/or steroids withdrawal rates at 24 weeks","definition_or_measurement_approach":"Comparison of steroid dose to baseline and measurement of steroid withdrawal rates at 24 weeks."}
• {"endpoint_text":"- Overall survival at 12 months","definition_or_measurement_approach":"Overall survival assessed at 12 months."}
• {"endpoint_text":"- Changes in the underlying MDS from baseline, at 12 and 24 weeks, including MDS progression based on hematological, cytogenetic and molecular analysis","definition_or_measurement_approach":"Assessment of MDS changes/progression at 12 and 24 weeks using hematological, cytogenetic and molecular analyses."}
• {"endpoint_text":"- Responses: 1-Duration of Response (DoR) on VEXAS symptoms defined as the time from the date of initial documentation of a clinical response (CR or PR) to the date of first documented evidence of relapse or death ; 2-Time to first and best clinical response ; 3-Duration of RBC independency in patients with RBC dependency at time of inclusion, according to IWG 2018 criteria","definition_or_measurement_approach":"DoR measured from initial documented CR/PR to relapse or death; time to first/best response measured; duration of RBC independence per IWG 2018 in RBC-dependent patients."}
• {"endpoint_text":"- Evolution of UBA1 VAF on MMB","definition_or_measurement_approach":"Measurement of UBA1 variant allele fraction (VAF) changes during treatment with MMB."}
• {"endpoint_text":"- Adverse events (AE), serious AE (SAE) and toxicity as measured by NCI CTCAE v5.0","definition_or_measurement_approach":"Safety assessed by AE/SAE reporting and NCI CTCAE v5.0 grading (secondary endpoint duplicate of safety)."}
• {"endpoint_text":"- For ancillary study (biological end point): Evolution of UBA1 VAF from baseline to W4, W12 and W24","definition_or_measurement_approach":"Ancillary biological endpoint: UBA1 VAF measured at baseline, week 4, week 12 and week 24."}
• {"endpoint_text":"- For ancillary study (Clinical end point): Evolution of VPSS from baseline to W4, W12 and W24","definition_or_measurement_approach":"Ancillary clinical endpoint: VPSS (VEXAS personal scoring system) measured at baseline, week 4, week 12 and week 24."}

France

Earliest CTIS Part Ii Submission Date

01-09-2025

Latest Decision Or Authorization Date

08-10-2025

Processing Time Days

37

Number Of Sites

12

Number Of Participants

57

Primary sponsor

Full Name

Groupe Francophone Des Myelodysplasies

Organisation Type

Patient organisation/association

Country Of Registered Address

France