A Study of Momelotinib in Participants With Low-risk Myelodysplastic Syndrome

Official title

A Phase 2, Randomized, Open-label, Study of Momelotinib in Participants With Anemia Due to Low-risk Myelodysplastic Syndrome

Overview

The goal of this clinical trial is to determine if momelotinib is safe and effective for people with low-risk myelodysplastic syndromes (LR-MDS). The trial will also examine how the body processes the drug. Participants will receive different doses of momelotinib to find the best dose by evaluating effectiveness in improving red blood cell transfusion requirements and safety.

Interventions

• Drug Momelotinib
  Momelotinib will be administered.

Primary outcome measures

• Percentage of participants with Red Blood Cells - transfusion independence (RBC-TI) for at least 12 weeks, rolling over 24 weeks [Time frame: Up to 24 weeks]
• Number of participants with Grade 3 Adverse events (AEs), AE leading to treatment discontinuation and AEs leading to dose modifications [Time frame: Up to approximately 109 weeks]
• Maximum plasma concentration (Cmax) of momelotinib and major metabolite of momelotinib (M21) [Time frame: Up to 24 weeks]
• Area under the plasma concentration versus time curve (AUC) of momelotinib and M21 [Time frame: Up to 24 weeks]

Secondary outcome measures (10)

• Percentage of participants with ≥16 weeks of RBC-TI by the end of Week 24 [Time frame: At week 24]
• Percentage of participants with ≥1.5 grams per deciliter (g/dL) increase in hemoglobin [Time frame: Up to 24 weeks]
• Percentage of participants with ≥24 weeks of RBC-TI by the end of Week 48 [Time frame: At week 48]
• Number of participants with hematologic improvement (HI-E) response per International Working Group (IWG) 2018 criteria [Time frame: Up to 24 weeks]
• Time to RBC-TI by Weeks 24 and 48 [Time frame: Up to Weeks 24 and 48]
• Number of participants with AEs, Serious adverse events (SAEs), AEs leading to treatment discontinuation, and AEs leading to dose modifications [Time frame: Up to approximately 133 weeks]
• Number of participants with AEs, SAEs, AEs leading to treatment discontinuation, and AEs leading to dose modifications by Severity [Time frame: Up to approximately 133 weeks]
• Number of participants with clinically significant changes in laboratory parameters [Time frame: Up to approximately 133 weeks]
• Number of participants with clinically significant changes in vital signs [Time frame: Up to approximately 133 weeks]
• Plasma concentration of momelotinib and M21 [Time frame: Up to 24 weeks]

Eligibility criteria

Inclusion criteria

• Age ≥18 years or of legal age of consent in the jurisdiction in which the study is taking place, at the time of signing the informed consent form (ICF).
• Documented diagnosis of MDS according to the World Health Organization classifications with an Revised International Prognostic Scoring System (IPSS-R) classification of very low, low, or intermediate risk disease, with an overall risk score ≤3.5 and bone marrow blasts < 5%.
• Received only one prior line of treatment with either Erythropoiesis-stimulating agent (ESA) or luspatercept for LR-MDS-related anemia that is relapsed/refractory to therapy. Participants intolerant OR ineligible to prior ESA or luspatercept will fulfill this inclusion criterion provided the definition below is met.

• Refractory to prior treatment: documentation of loss of erythroid (E) response or never achieved HI-E response as defined by the IWG 2018 criteria.
• Intolerant to prior treatment: documentation of reasons for discontinuation of prior ESA containing regimen, either as single agent or combination (e.g., G-CSF) or luspatercept due to intolerance or adverse event.
• ESA ineligible: low chance of response to ESA based on endogenous serum erythropoietin level > 200 U/L for participants not previously treated with ESAs.
• Red blood cell transfusion dependence, defined as requiring ≥3 units of Packed red blood cells (pRBC) transfused over 16-week period in at least 2 transfusions episodes during the 16 weeks preceding randomization. Documentation of a participant's transfusion policy during this 16-week period is required.
• A female participant is eligible to participate if she is not pregnant or breastfeeding and one of the following conditions applies:
• Is a woman of non-childbearing potential (WONCBP). OR
• Is a woman of childbearing potential (WOCBP) and using a contraceptive method.
• Is capable of giving signed informed consent.
• Eastern Cooperative Oncology Group performance status ≤2.
• Adequate organ function.

Exclusion criteria

• Prior treatment with the following with noted time periods:

• Janus kinase (JAK)1/2 inhibitors;
• ACVR1 inhibitors,
• ACTRII receptor ligand trap other than luspatercept
• Hypomethylating agents or other disease modifying agents (i.e., IMiDs) and immunosuppressive therapy for MDS
• ESA within 4 weeks, or 8 weeks for long-acting ESA.
• Growth factors (i.e., G-CSF, GM-CSF) within 4 weeks.
• Luspatercept within 8 weeks.
• Investigational agents within 4 weeks or 5 half-lives, whichever is longer.
• Corticosteroids for treatment of the underlying disease within 28 days. Supportive care use of steroids for non-MDS indications may be used provided participant is on a stable dose equivalent to ≤10 mg prednisone per day.
• Other active anti-MDS therapy not otherwise listed within 28 days or 5 half-lives whichever is longer.
• Potent cytochrome P450 3A4 (CYP3A4) inducers, except for rifampin and rifampicin, within 14 days prior to the first dose of momelotinib.
• Has received a live vaccine within 30 days.
• Prior allogeneic or autologous stem cell transplant.
• Has had any major surgery within 28 days prior to randomization.
• Ongoing adverse reaction(s) from prior therapy that have not recovered to ≤Grade 1 or to the baseline status preceding prior therapy, except if the investigator, with the agreement of the sponsor, considers to be not clinically relevant for the tolerability of study intervention in the current clinical study.
• MDS associated with del 5q cytogenetic abnormality.
• MDS/ Myeloproliferative neoplasm (MPN) overlap disorders (e.g., Chronic Myelomonocytic Leukemia \[CMML\]).
• Secondary MDS (i.e., MDS that is known to have arisen as the result of chemical injury, treatment with chemotherapy, and/or radiation for other diseases).
• Known history of diagnosis of acute myeloid leukemia.
• Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, gastrointestinal bleeding, or thalassemia.
• Diagnosis of invasive malignancy or history of invasive malignancy other than the disease under study within the last 5 years, except as noted below:

• History of an invasive malignancy for which the participant was definitively treated, and in 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 disease under study.
• 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.
• Incidental histologic finding of prostate cancer (T1a or T1b using the Tumor, nodes, metastasis \[TNM\] clinical staging system).
• Uncontrolled intercurrent illness including, but not limited to:

• 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
• Significant active or chronic bleeding event ≥Grade 2 per Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) within 4 weeks prior randomization.
• 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.
• Any of the following conditions within 6 months prior to randomization:

• Unstable angina pectoris.
• Symptomatic congestive heart failure.
• Uncontrolled cardiac arrhythmia.
• QTc interval >480 milliseconds (msec) (corrected using Fridericia formula).
• 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.
• Presence of peripheral neuropathy ≥Grade 2 per CTCAE v5.0.
• Known positive status for human immunodeficiency virus (HIV).
• Hepatitis B or C status as defined below:

• 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.
• Positive hepatitis C antibody test result at screening or within 3 months before the first dose of study intervention. Has any clinically significant gastrointestinal conditions or abnormalities that may alter absorption, e.g., uncontrolled nausea, vomiting, malabsorption syndrome or major resection of the stomach and/or bowels.
• Is unable to swallow and/or retain oral medications.
• Known contraindication or hypersensitivity to momelotinib and its metabolites, or any of their excipients.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Spain · 8 centers

• GSK Investigational Site — Barcelona
• GSK Investigational Site — Barcelona
• GSK Investigational Site — Madrid
• GSK Investigational Site — Málaga
• GSK Investigational Site — Ourense
• GSK Investigational Site — PamplonaNavarra
• GSK Investigational Site — Salamanca
• GSK Investigational Site — Valencia

United States · 6 centers

• GSK Investigational Site — Goodyear
• GSK Investigational Site — Duarte
• GSK Investigational Site — Irvine
• GSK Investigational Site — New Haven
• GSK Investigational Site — Canton
• GSK Investigational Site — Houston

Italy · 6 centers

• GSK Investigational Site — Udine
• GSK Investigational Site — Catania
• GSK Investigational Site — Florence
• GSK Investigational Site — Milan
• GSK Investigational Site — Orbassano to
• GSK Investigational Site — Rozzano MI

France · 5 centers

• GSK Investigational Site — Le Mans
• GSK Investigational Site — Nice
• GSK Investigational Site — Paris
• GSK Investigational Site — Poitiers
• GSK Investigational Site — Toulouse

South Korea · 4 centers

• GSK Investigational Site — Seongnam-si Gyeonggi-do
• GSK Investigational Site — Seoul
• GSK Investigational Site — Seoul
• GSK Investigational Site — Seoul

Germany · 3 centers

• GSK Investigational Site — Münster
• GSK Investigational Site — Dresden
• GSK Investigational Site — Leipzig

United Kingdom · 3 centers

• GSK Investigational Site — Boston
• GSK Investigational Site — London
• GSK Investigational Site — Manchester

Canada · 2 centers

• GSK Investigational Site — Calgary
• GSK Investigational Site — Toronto

Poland · 2 centers

• GSK Investigational Site — Chorzów
• GSK Investigational Site — Warsaw

Identifiers

NCT: NCT06847867 · 223584 · 2024-519928-24

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗