Phase 1-2 UMBRELLA trial evaluating isatuximab with or without dexamethasone in combination with novel agents compared to isatuximab with pomalidomide and dexamethasone in relapsed or refractory multiple myeloma (RRMM)
Part 1 (dose finding, experimental substudies):
-To determine or confirm the recommended dose of novel agents when combined with isatuximab with or without dexamethasone in participants with RRMM.
Part 2 (expansion, experimental substudies):
To demonstrate the clinical benefit of novel agents combined with isatuximab with or without dexamethasone in terms of rate of very good partial response (VGPR) or better
Secondary Objectives:
-Master Protocol and Substudy 1-ACT16482-01 (Control Arm):
To assess the overall response rate (ORR) in each treatment arm.
To assess the clinical benefit rate (CBR) in each treatment arm.
To assess the duration of response (DOR) in each treatment arm.
To assess the time to first response (TT1R) in each treatment arm.
To assess the time to best response (TTBR) in each treatment arm.
To assess safety and tolerability in each treatment arm.
To assess progression free survival (PFS) in each treatment arm.
To assess overall survival (OS) in each treatment arm.
To evaluate the potential immunogenicity of isatuximab and novel agents when applicable.
To characterize the PK of isatuximab and novel agents.
To assess disease and treatment related symptoms, cancer and disease specific health-related quality of life, global impact of side effects and confirm/establish clinically meaningful change scores for clinical outcome assessments (COAs)/domain scores.
-Substudy 3-ACT16482-03:
To assess patient-reported visual functioning.
Eligibility: Inclusion Criteria
• Participant must be 18 years of age inclusive or older
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
• Participants with relapsed or refractory MM who have received at least 3 prior lines of therapy for MM, including PIs and IMiDs or at least 2 prior lines if at least one of these lines consisted of 2 or more multiagent regimens (eg, Induction regimen with autologous stem cell transplant followed by maintenance).
• RRMM with measurable disease:
• Serum M protein >=0.5 g/dL measured using serum protein immunoelectrophoresis and/or
• Urine M protein >=200 mg/24 hours measured using urine protein immunoelectrophoresis and/or
• Serum free light chain (sFLC) MM without measurable M protein in serum or urine per previous criteria (serum Ig free light chain >=10 mg/dL and abnormal serum Ig kappa lambda free light chain ratio 0.26 or >1.65).
• Men or woman or childbearing potential should agree to use contraception.
• Substudy 01-03:
• Anti-CD38 therapy naïve or prior exposure to such drugs without being refractory but with a wash out of at least 6 months after the last dose. "Refractory" is defined as progressing within 60 days of last dose of anti-CD38 targeting therapy.
Exclusion Criteria
• Primary systemic amyloid light chain amyloidosis, plasma cell leukemia, monoclonal gammopathy of undetermined significance, or smoldering myeloma.
• Uncontrolled infection within 14 days prior to randomization.
• Clinically significant cardiac (including valvular) or vascular disease within 3 months prior to randomization, eg, myocardial infarction, unstable angina, coronary (eg, coronary artery bypass graft, percutaneous coronary intervention) or peripheral artery revascularization, left ventricular ejection fraction 40%, heart failure New York Heart Association Classes III and IV, stroke, transient ischemic attack, pulmonary embolism, other thromboembolic event, or cardiac arrhythmia (Grade 3 or higher by NCI CTCAE Version 5.0).
• Known acquired immunodeficiency syndrome-related illness or known human immunodeficiency virus (HIV) disease requiring antiviral treatment or active hepatitis A.
• Uncontrolled or active hepatitis B virus (HBV) infection.
• Active hepatitis C virus (HCV) infection.
• Any of the following within 3 months prior to randomization: treatment resistant peptic ulcer disease, erosive esophagitis or gastritis, infectious or inflammatory bowel disease.
• Second malignancy other than basal cell or squamous cell carcinoma of the skin or in situ carcinoma, unless they are successfully treated with curative intent for more than 3 years before randomization.
• Any anti-MM drug treatment within 14 days before randomization, including dexamethasone.
• Participants with a contraindication to treatment.
• Vaccination with a live vaccine 4 weeks before the start of the study.
• Hemoglobin 8 g/dL.
• Platelets 50 × 109/L.
• Absolute neutrophil count 1.5 × 109/L.
• Creatinine clearance 30 mL/min.
• Total bilirubin >1.5 × ULN, except for known Gilbert syndrome in which direct bilirubin should be =2.5 × ULN.
• Aspartate aminotransferase and/or alanine aminotransferase >3 × ULN.
• Patients with grade 3 or 4 hypercalcemia.
• Substudy 01:
• Malabsorption syndrome or any condition that can significantly impact the absorption of pomalidomide.
• For the first 10 participants: Body weight =70 kg
• Substudy 03:
• Current corneal epithelial disease except mild punctate keratopathy
• Patients who have received prior therapy with belantamab mafodotin
• The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.