A Single-arm Phase II With safety-run-in Multicenter Study of Momelotinib in Patients With VEXAS Syndrome With or Without Associated Myelodysplastic Syndrome
Multicenter, phase II trial with safety run-in to evaluate the efficacy and safety of momelotinib in patients with VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory and Somatic) syndrome with or without associated myelodysplastic syndrome (MDS). The study will consist of two consecutive steps, a dose-finding safety run-in and a single-arm prospective phase II. During safety run-in phase, three fixed dose levels will be tested according to a 3+3 design, using cohorts of size 3 in order to establish the maximum tolerated dose. After this safety run-in phase, patients included in phase II will be treated with momelotinib at the maximum tolerated dose preliminary fixed. Patients included in the phase II will receive momelotinib continuously until disease progression or loss of response, at physician's discretion. All patients included in the study will receive glucocorticoids (prednisone/prednisolone equivalent) at baseline (at least \> 10mg/day). Response assessment regarding VEXAS related symptoms will be evaluated after 4, 12, 24 and 48 weeks. Response assessment regarding MDS features will be evaluated at 12 and 24 weeks.
• ECOG (Eastern Cooperative Oncology Group) performance status 0-2 at the time of screening
• Age ≥ 18 years
• Written informed consent
• Diagnosis of VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory and Somatic) syndrome with UBA1 (Ubiquitin Like Modifier Activating Enzyme 1) mutation and clinically symptomatic disease requiring immunosuppressive treatment and at least 10mg/d of glucocorticoids
• Patients with uncontrolled symptoms related to VEXAS with prior treatment line(s) (including steroids)
• Patients refractory/dependent to steroids
• Single concomitant steroids therapy (e.g., prednisone or equivalent) at the time of inclusion is allowed
• For patients treated with other immunosuppressive/immunomodulatory therapy than glucocorticoids, a wash out period of 28 days is required prior momelotinib onset
• Erythropoietin/luspatercept used as a growth factor treatment is not allowed 28 days prior enrollment
• Adequate liver function (serum transaminases ≤ 3 x ULN (Upper Limits of Normal), Bilirubin ≤ 1.5 x ULN (isolated bilirubin \> 1.5 x ULN is acceptable if bilirubin fractionated and direct bilirubin \< 35%)
• Adequate renal function (creatinine clearance with MDRD (Modification of Diet in Renal Disease) formula \> 30 ml/min)
• Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically sterile) must:
‣ Have a negative serum or urine pregnancy test within 24 hours prior to beginning treatment on this study. Lactating patients are excluded.
⁃ 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.
⁃ Agree to learn about the procedures for preservation of egg before starting treatment.
• Male patients must:
‣ 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.
⁃ Agree to learn about the procedures for preservation of sperm before starting treatment.