Plasma Cell Myeloma Refractory Clinical Trial
Official title:
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) - Master Protocol
The purpose of this umbrella study is to evaluate isatuximab when combined with novel agents with or without dexamethasone in participants with relapsed or refractory myeloma. Substudies 02, 03, and 06 are controlled experimental substudies. Substudies 04 and 05 are independent experimental substudies.
| Status | Recruiting |
| Enrollment | 197 |
| Est. completion date | March 2, 2028 |
| Est. primary completion date | June 30, 2027 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | 18 Years and older |
| 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, 06: Anti-CD38 therapy naïve or prior exposure to such drugs with a wash out of at least 6 months after the last dose. "Exposure" is defined as at least 2 cycles of therapy. - Substudies 02, 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. - Substudy 04: Anti-CD38 and anti-B cell maturation antigen (BCMA) therapy prior exposed participants with RRMM. - Substudy 05: Participants with RRMM with at least 2 cycles of prior exposure to anti-CD38 therapy. For participants to whom BCMA targeted therapy is available (ie, approved in their region and can be reimbursed), at least 2 cycles of prior exposure to a BCMA targeted agent is mandatory. 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 first study intervention administration. - Clinically significant cardiac (including valvular) or vascular disease within 3 months prior to first study intervention administration., 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 first study intervention administration: 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 first study intervention administration. - Any anti-MM drug treatment within 14 days before first study intervention administration, including dexamethasone. - Participants with a contraindication to treatment. - Vaccination with a live vaccine 4 weeks before the start of the study. - Seasonal flu and COVID-19 vaccines that do not contain live virus are permitted. - Hemoglobin <8 g/dL. - Platelets <50 × 10^9/L. - Absolute neutrophil count <1.5 × 10^9/L. - Creatinine clearance <30 mL/min/1.73m2. - 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. Substudy 02: - History of resected/ablated basal or squamous cell carcinoma (SCC) of the skin or carcinoma in situ of the cervix, or other local tumors, even if considered cured by local treatment. - Therapeutic doses of anticoagulants or antiplatelet agents within 7 days prior to the first dose of SAR439459. - Prothrombin time or INR >1.5 × upper limit of normal (ULN). Substudy 03: - Current corneal epithelial disease except mild punctate keratopathy - Patients who have received prior therapy with belantamab mafodotin Substudy 04: - Central nervous system or leptomeningeal disease. - Medical history of seizure. - Participants currently receiving hepatically metabolized narrow therapeutic index drugs (eg, digoxin, warfarin) if cannot be closely monitored. Substudy 05: - Participant unable to swallow tablets Substudy 06: - History of active autoimmune disorders - History of autoimmune hemolytic anemia or autoimmune thrombocytopenia - Active graft versus host disease (GVHD) or ongoing immunosuppression for GVHD - Prior allogenic hematopoietic stem cell transplant (allo-HSCT) - Hemoglobin < 9g/dL - Prior therapy with any anti-CD47 or anti signal regulatory protein alpha agent The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial. |
| Country | Name | City | State |
|---|---|---|---|
| Australia | Investigational Site Number : 0360002 | Fitzroy | Victoria |
| Australia | Investigational Site Number : 0360001 | Richmond | Victoria |
| Australia | Investigational Site Number : 0360006 | Wollongong | New South Wales |
| France | Investigational Site Number : 2500002 | Lille | |
| France | Investigational Site Number : 2500001 | Nantes | |
| France | Investigational Site Number : 2500003 | Paris | |
| France | Investigational Site Number : 2500004 | Paris | |
| Germany | Investigational Site Number : 2760006 | Frankfurt am Main | |
| Greece | Investigational Site Number : 3000001 | Athens | |
| Greece | Investigational Site Number : 3000002 | Athens | |
| Italy | Investigational Site Number : 3800002 | Bologna | |
| Italy | Investigational Site Number : 3800001 | Meldola | Forlì-Cesena |
| Norway | Investigational Site Number : 5780001 | Oslo | |
| Portugal | Investigational Site Number : 6200001 | Coimbra | |
| Portugal | Investigational Site Number : 6200002 | Vila Nova Gaia | |
| Puerto Rico | Puerto Rico Medical Research Center, LLC Site Number : 8400005 | Hato Rey | |
| United States | University of Michigan Site Number : 8400004 | Ann Arbor | Michigan |
| United States | Roswell Park Cancer Institute Site Number : 8400008 | Buffalo | New York |
| United States | University of Illinois Site Number : 8400007 | Chicago | Illinois |
| Lead Sponsor | Collaborator |
|---|---|
| Sanofi |
United States, Australia, France, Germany, Greece, Italy, Norway, Portugal, Puerto Rico,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | Part 1 (dose finding, experimental substudies): Determination of recommended dose of novel agents in combination with isatuximab | Determination or confirmation of the dose will be based on: safety and tolerability in terms of TEAEs/SAEs, dose-limiting toxicity occurrence, and laboratory parameters available information on PK (if appropriate) and biomarkers. | Through the end of cycle 1 (approximately 6 weeks) | |
| Primary | Part 2 (expansion, controlled experimental substudies): VGPR Rate (Rate of Very Good Partial Response Rate or Better) | VGPR or better rate is defined as the percentage of participants with a VGPR or better as defined by the 2016 IMWG response criteria, assessed by Investigator based on central laboratory values and local imaging. | Up to approximately 28 months after the First patient in or scheduled assessment | |
| Primary | Part 2 (expansion, independent experimental substudies): Overall Response Rate (ORR) in independent experimental substudies | ORR, defined as the proportion of participants with stringent complete response (sCR), complete response (CR), VGPR, or partial response (PR), according to the 2016 IMWG criteria assessed by Investigator based on central laboratory values and local imaging. | Up to approximately 28 months after the First patient in or scheduled assessment | |
| Secondary | Part 1 (dose finding, experimental substudies): ORR | ORR, defined as the proportion of participants with stringent complete response (sCR), complete response (CR), VGPR, or partial response (PR), according to the 2016 IMWG criteria assessed by Investigator based on central laboratory values and local imaging. | Up to approximately 28 months after the First patient in or scheduled assessment | |
| Secondary | Part 2 (expansion, controlled experimental substudies): ORR | ORR, defined as the proportion of participants with stringent complete response (sCR), complete response (CR), VGPR, or partial response (PR), according to the 2016 IMWG criteria assessed by Investigator based on central laboratory values and local imaging. | Up to approximately 28 months after the First patient in or scheduled assessment | |
| Secondary | Part 1 (dose finding, experimental substudies): VGPR or better | VGPR or better rate is defined as the percentage of participants with a VGPR or better as defined by the 2016 IMWG response criteria, assessed by Investigator based on central laboratory values and local imaging. | Up to approximately 28 months after the First patient in or scheduled assessment | |
| Secondary | Part 2 (expansion, independent experimental substudies): VGPR or better | VGPR or better rate is defined as the percentage of participants with a VGPR or better as defined by the 2016 IMWG response criteria, assessed by Investigator based on central laboratory values and local imaging. | Up to approximately 28 months after the First patient in or scheduled assessment | |
| Secondary | Clinical benefit rate (CBR) in each treatment arm | CBR, defined as the proportion of participants with sCR, CR, VGPR, PR, or minimal response, according to the 2016 IMWG criteria assessed by Investigator based on central laboratory values and local imaging. | Up to approximately 28 months after the First patient in or scheduled assessment | |
| Secondary | Duration of Response (DOR) in each treatment arm | DOR, defined as the time from the date of the first response that is subsequently confirmed for patients achieving PR or better to the date of first documented PD or death, whichever happens first. | Up to approximately 28 months after the First patient in or scheduled assessment | |
| Secondary | Time to First Response (TT1R) in each treatment arm | TT1R, defined as the time from the date of first treatment to the date of first response (PR or better) that is subsequently confirmed. | Up to approximately 28 months after the First patient in or scheduled assessment | |
| Secondary | Time to Best Response (TTBR) in each treatment arm | TTBR, defined as the time from the date of first treatment to the date of first occurrence of best overall response (PR or better) that is subsequently confirmed. | Up to approximately 28 months after the First patient in or scheduled assessment | |
| Secondary | Number of participants with treatment emergent adverse events and serious adverse events in each treatment arm | Safety and tolerability assessed in terms of adverse events/SAEs, including second primary malignancies, laboratory parameters, vital signs, and findings from physical examination. | Up to approximately 28 months after the First patient in or scheduled assessment | |
| Secondary | Progression-free survival (PFS) in each treatment arm | PFS is defined as the time from the date of first treatment to disease progression based on the Investigator assessment according to 2016 IMWG criteria or death from any cause, whichever happens first. | Up to approximately 28 months after the First patient in or scheduled assessment | |
| Secondary | Overall Survival (OS) in each treatment arm | OS is defined as the time from the date of first treatment to death from any cause. | Up to approximately 28 months after the First patient in or scheduled assessment | |
| Secondary | Immunogenicity of isatuximab and novel agents | Incidence of anti-drug antibodies (ADAs) for novel agents (experimental arms) and isatuximab. | Multiple timepoints up to approximately 28 months after the First patient in or scheduled assessment | |
| Secondary | Pharmacokinetics (PK) Parameters for Novel agents and isatuximab | Concentration of novel agents (experimental arms) and isatuximab | Multiple timepoints up to approximately 28 months after the First patient in or scheduled assessment | |
| Secondary | Disease-specific HRQL will be assessed using the European Organization for Research and Treatment of Cancer (EORTC) core quality of life questionnaire (QLQ-C30) | The EORTC QLQ-C30 will be used to assess cancer-specific HRQL, disease and treatment-related symptoms and impact of symptoms. | On Day1 Cycle 1, then every 2 cycles for the first year; then every 3 cycles thereafter, at end of treatment and at first follow-up visit. The cycle is 28 days. | |
| Secondary | Disease- and treatment-related quality of life will be assessed using the EORTC multiple myeloma module (QLQ-MY20) questionnaire | The EORTC QLQ-MY20 will be used to measure myeloma-specific HRQL, disease and treatment-related symptoms and impact of symptoms. | On Day1 Cycle 1, then every 2 cycles for the first year; then every 3 cycles thereafter, at end of treatment and at first follow-up visit. The cycle is 28 days. | |
| Secondary | Global impact of side effects will be assessed using the Functional Assessment of Cancer Therapy (FACT-G) (GP5) | A single item from the FACT-G GP5 will be used to assess the global impact of side effects. | On Day1 Cycle 1, then every 2 cycles for the first year; then every 3 cycles thereafter, at end of treatment and at first follow-up visit. The cycle is 28 days. | |
| Secondary | Estimate/Confirm established clinically meaningful change scores for clinical outcome assessments (COAs)/domain scores using the Patient Global Impression of Severity (PGIS) and Patient Global Impression of Change (PGIC) scales | Patient Global Impression of Severity (PGIS) and Patient Global Impression of Change (PGIC) scales will be utilized as anchors to estimate/confirm established clinically meaningful change scores for clinical outcome assessments (COAs)/domain scores. | On Day1 Cycle 1, then every 2 cycles for the first year; then every 3 cycles thereafter, at end of treatment and at first follow-up visit. The cycle is 28 days. | |
| Secondary | The intensity of skeletal-related events (SRE)- related bone pain will be assessed using the skeletal-related bone pain numeric rating scale (SRE-BP-NRS) for control and experimental arms (Substudy 02) | The SRE-BP-NRS) will be used to assess the intensity of SRE-related bone pain (on average and at its worst) for control arm only | On Day1 Cycle 1, then every 2 cycles for the first year; then every 3 cycles thereafter, at end of treatment and at first follow-up visit. The cycle is 28 days. | |
| Secondary | SRE Incidence for control and experimental arms (Substudy 02) | SRE incidence, defined as the proportion of participants who experienced pathological fracture, radiation to bone, spinal cord compression, or surgery to bone as a first bone event. | Continuous throughout study assessment (up to approximately 28 months) | |
| Secondary | Time to First Occurrence of SRE Assessment for control and experimental arms (Substudy 02) | Time to first occurrence of SRE is defined as time from the date of randomization to the occurrence of first SRE. | Continuous throughout study assessment (up to approximately 28 months) | |
| Secondary | Assessment of Health care resource utilization related with SREs for control and experimental arms (Substudy 02) | The Health Care Resource Use-SREs questionnaire (HCRU-SREs) will be used to assess the use of health care resources associated with these events. | On Day1 Cycle 1, then every 2 cycles for the first year; then every 3 cycles thereafter, at End of treatment and at first follow-up visit. The cycle is 28 days. | |
| Secondary | To assess patient-reported visual functioning for experimental arm only (Substudy 03) | An NEI VFQ-25 will be used to assess patient-reported visual functioning. | On Day1 Cycle 1, End of treatment and at first follow-up visit. The cycle is 28 days. |
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Not yet recruiting |
NCT06356571 -
A Study to Investigate Subcutaneous Isatuximab in Combination With Weekly Carfilzomib and Dexamethasone in Adult Participants With Relapsed and/or Refractory Multiple Myeloma
|
Phase 2 |