Plasma Cell Myeloma
Conditions
Keywords
Anti-CD38 monoclonal antibody
Brief summary
Primary Objectives: * Safety run-in Part: To confirm the recommended dose of isatuximab when combined with lenalidomide and dexamethasone in participants with high-risk smoldering multiple myeloma (SMM) * Randomized Phase 3 Part: To demonstrate the clinical benefit of isatuximab in combination with lenalidomide and dexamethasone in the prolongation of progression-free survival when compared to lenalidomide and dexamethasone in subjects with high-risk SMM Secondary Objectives: Safety run-in Part: * To assess overall response rate (ORR) * To assess duration of response (DOR) * To assess minimal residual disease (MRD) negativity in participants achieving very good partial response (VGPR) or complete response (CR) * To assess time to diagnostic (SLiM CRAB) progression or death * To assess time to first-line treatment for multiple myeloma (MM) * To assess the potential immunogenicity of isatuximab * Impact of abnormal chromosomal subtype on participant outcome Randomized Phase 3 Part: Key Secondary Objectives: To compare between the arms * MRD negativity * Sustained MRD negativity * Second progression-free survival (PFS2) * Overall survival Other Secondary Objectives: To evaluate in both arms * CR rate * ORR * DOR * Time to diagnostic (SLiM CRAB) progression * Time to biochemical progression * Time to first-line treatment for MM * Impact of abnormal chromosomal subtype on participant outcome * Safety and tolerability * Pharmacokinetics (PK) * Potential of isatuximab immunogenicity * Clinical outcome assessments (COAs)
Detailed description
Study duration is expected to be approximately 12 years, including a 42-day screening period, followed by an up to 36-month treatment period, and a follow-up period of approximately 9 years.
Interventions
Pharmaceutical for: Solution for infusion Route of administration: Intravenous
DRUGLenalidomide
Pharmaceutical form: Capsules Route of administration: Oral
DRUGDexamethasone
Pharmaceutical form: Tablets and solution for injection Route of administration: Oral and intravenous
Auxiliary Medicinal Product (AxMP)/pre-medication; ATC code: R03DC03; Pharmaceutical form: tablet; Route of administration: Oral;
DRUGAcetaminophen
AxMP/pre-medication ATC code: N02BE01 Pharmaceutical form: tablet/ampule/capsule; Route of administration: Intravenous (IV) or per os (PO)
AxMP/pre-medication ATC code: R06AA02 Pharmaceutical form: ampule; Route of administration: Intravenous
AxMP/pre-medication; ATC code: H02AB04; Pharmaceutical form: vial; Route of administration: Intravenous
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Participants who are diagnosed within 5 years with SMM (per International Myeloma Working Group \[IMWG\] criteria), defined as serum M-protein ≥30 g/L or urinary M-protein ≥500 mg per 24 hour or both, and/or clonal bone marrow plasma cells (BMPCs) 10% to \<60%, and absence of myeloma defining events or other related conditions and with high-risk SMM * Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1 or 2 * Capable of giving voluntary written informed consent * Absolute neutrophil count (ANC) ≥1000/µL (1 × 10\^9/L) * Platelets ≥50,000/µL (50 × 10\^9/L) * Total bilirubin ≤3 mg/dL (except Gilbert syndrome, in which direct bilirubin should be -≤5 mg/dL). * Alanine aminotransferase ≤3× upper limit of normal (ULN), aspartate aminotransferase ≤ 3 × ULN.
Exclusion criteria
* Evidence of any of the following calcium, renal failure, anemia, bone lesions (CRAB) criteria or Myeloma Defining Events (SLiM CRAB) detailed below (attributable to the participants SMM involvement): * Increased calcium levels: Corrected serum calcium \>1 mg/dL above the ULN or \>11 mg/dL * Renal insufficiency: Determined by glomerular filtration rate (GFR) \<40 mL/min/1.73 m² (Modification of Diet in Renal Disease \[MDRD\] Formula) or serum creatinine \>2 mg/dL * Anemia (hemoglobin 2 g/dL below lower limit of normal or \<10 g/dL or both) transfusion support or concurrent treatment with erythropoietin stimulating agents is not permitted * ≥ 1 bone lytic lesion * BMPCs ≥60% * Serum involved/uninvolved FLC ratio ≥100 and an involved FLC ≥100mg/L * Whole body magnetic resonance imaging (WB-MRI) or positron emission tomography-computed tomography (PET-CT) with more than 1 bone focal lesion (≥5 mm in diameter by MRI) * Primary systemic amyloid light-chain (AL) amyloidosis, monoclonal gammopathy of undetermined significance (MGUS), standard risk smoldering myeloma, soft tissue plasmacytoma, symptomatic myeloma * Uncontrolled infection within 28 days prior to randomization in Phase 3 or first study intervention administration in safety run-in * Clinically significant cardiac or vascular disease within 3 months prior to randomization, e.g. Myocardial Infarction; Unstable Angina; Coronary (e.g. Coronary Artery Bypass Graft, Percutaneous Coronary Intervention) or peripheral artery revascularization, Left Ventricular Ejection Fraction \<40%, Heart Failure NYHA III-IV, Stroke, Transient Ischemic Attack, Pulmonary Embolism, other thromboembolic event, cardiac arrhythmia (Grade 3 or higher by NCI-CTCAE Version 5.0) * Known acquired immunodeficiency syndrome (AIDS)-related illness or known human immunodeficiency virus (HIV) disease requiring antiviral treatment or active hepatitis A (defined as positive hepatitis A antigen or positive IgM). HIV serology at screening will be tested for German participants and any other country where required as per local regulations and serology hepatitis B and C at screening will be tested for all participants * Uncontrolled or active hepatitis B virus (HBV) infection: Patients with positive Hepatitis B surface antigen (HBsAg) and/or HBV Deoxyribonucleic acid (DNA) Of note: * Patient can be eligible if anti-HBc Immunoglobulin G (IgG) positive (with or without positive anti-HBs) but HBsAg and HBV DNA are negative. If anti-HBV therapy in relation with prior infection was started before initiation of IMP, the anti-HBV therapy and monitoring should continue throughout the study treatment period. * Patients with negative HBsAg and positive HBV DNA observed during screening period will be evaluated by a specialist for start of anti-viral treatment: study treatment could be proposed if HBV DNA becomes negative and all the other study criteria are still met. * Active hepatitis C virus (HCV) infection: positive HCV ribonucleic acid (RNA) and negative anti-HCV Of note: * Patients with antiviral therapy for HCV started before initiation of IMP and positive HCV antibodies are eligible. The antiviral therapy for HCV should continue throughout the treatment period until seroconversion. * Patients with positive anti-HCV and undetectable HCV RNA without antiviral therapy for HCV are eligible * Malabsorption syndrome or any condition that can significantly impact the absorption of lenalidomide * Any of the following within 3 months prior to randomization (or first study intervention administration in safety run-in cohort): treatment resistant peptic ulcer disease, erosive esophagitis or gastritis, infectious or inflammatory bowel disease, diverticulitis, pulmonary embolism, or other uncontrolled thromboembolic event * Received treatment (eg surgery, radiotherapy, medication) for a malignancy within 3 years of randomization (or first study intervention administration in safety run-in cohort) * Prior exposure to approved or investigational treatments for SMM or multiple myeloma (MM) (including but not limited to conventional chemotherapies, immunomodulatory imid drugs, or Proteasome inhibitors); concurrent use of bisphosphonates or receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor denosumab is not permitted; however, prior bisphosphonates or once-a-year intravenous bisphosphonate given for the treatment of osteoporosis is permitted * Ongoing treatment with corticosteroids with a dose \>10 mg prednisone or equivalent per day at the time of randomization (or first study intervention administration in safety run-in cohort) * Women of childbearing potential or male participant with women of childbearing potential who do not agree to use a highly effective method of birth control * Vaccination with a live vaccine 4 weeks before the start of the study drug. Seasonal flu vaccines that do not contain live virus are permitted The above information is not intended to contain all considerations relevant to a potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of participants with Treatment-emergent adverse events (AEs) and serious adverse events- Safety Run-in Part | Up to approximately 63 months | — |
| Plasma concentration of isatuximab during the treatment period - Safety Run-in Part | After first infusion from Cycle 1 Day 1 to Day 28 in safety run-in part | — |
| Receptor density/receptor occupancy Safety Run-in Part | Baseline to Cycle 2 Day 1 (each cycle is 28 days) | Change in CD38 receptor occupancy from baseline |
| Progression-free survival (PFS) Randomized Phase 3 Part | Up to approximately 114 months | PFS defined as the time from randomization to MM (SLiM CRAB criteria) or other related conditions based on independent review committee (IRC) assessment according to 2014 International Myeloma Working Group (IMWG) criteria or death from any cause, whichever happens first |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to first-line treatment for multiple myeloma (MM) - Safety Run-in Part | Up to approximately 63 months | Time to first-line treatment for MM defined as the time from the date of the first study intervention administration to first-line treatment for MM. |
| Number of participants with anti-drug antibodies (ADA) against isatuximab- Safety Run-in Part | Up to approximately 63 months | — |
| PFS in participants with chromosomal abnormalities - Safety Run-In Part | Up to approximately 63 months | Association of chromosomal abnormalities with survival outcomes |
| Overall Survival (OS) in participants with chromosomal abnormalities - Safety Run-In Part | Up to approximately 63 months | Association of chromosomal abnormalities with survival outcomes |
| Minimal residual disease (MRD) negativity - Randomized Phase 3 Part | Up to approximately 36 months | MRD negativity defined as the proportion Number of participants for whom MRD is negative in participants achieving VGPR or above. |
| Sustained MRD negativity - Randomized Phase 3 Part | Up to approximately 36 months | Sustained MRD negativity defined as the proportion of participants for whom MRD is negative during a minimum period of one year. |
| Second PFS (PFS2) - Randomized Phase 3 Part | Up to approximately 144 months | PFS2 defined as the time from the date of randomization to the date of first documentation of PD (as reported by the Investigator) after initiation of further treatment for MM or the date of death from any cause, whichever happens first |
| OS - Randomized Phase 3 Part | Up to approximately 114 months | OS defined as the time from date of randomization to death from any cause. |
| Complete response (CR) rate - Randomized Phase 3 Part | Up to approximately 114 months | Percentage of participants with a CR (or better \[stringent CR (sCR)\]) as defined by 2016 IMWG response criteria, assessed by an IRC based on central laboratory values. |
| Overall Response Rate (ORR) - Randomized Phase 3 Part | Up to approximately 114 months | ORR is defined as the proportion of participants with BOR recorded as PR or better according to the 2016 IMWG criteria, assessed by an IRC based on central laboratory values. |
| Duration of response (DOR) - Randomized Phase 3 Part | Up to approximately 114 months | DOR is defined as the time from the date of the first IRC determined response to the date of first IRC PD, or death, whichever happens first. |
| Time to diagnostic (SLiM CRAB) progression - Randomized Phase 3 Part | Up to approximately 114 months | Time to diagnostic (SLiM CRAB) progression defined as the time from randomization to the date of diagnosis of SLiM CRAB progression based on IRC assessment. |
| Overall Response Rate (ORR)- Safety Run-in Part | Up to approximately 63 months | ORR defined as the proportion of participants with best overall response (BOR) recorded as partial response (PR) or better according to 2016 IMWG criteria |
| Time to first-line treatment for MM- Randomized Phase 3 Part | Up to approximately 144 months | Time to first-line treatment for MM defined as the time from randomization to first-line treatment for MM |
| PFS in participants with chromosomal abnormalities - Randomized Phase 3 Part | Up to approximately 114 months | Association of chromosomal abnormalities with survival outcomes. |
| OS in participants with chromosomal abnormalities - Randomized Phase 3 Part | Up to approximately 144 months | Association of chromosomal abnormalities with survival outcomes. |
| Number of participants with Treatment-emergent adverse events (AEs) and serious adverse events - Randomized Phase 3 Part | Up to approximately 144 months | — |
| Plasma concentration of isatuximab (Ctrough)- Safety Run-in and Randomized Phase 3 Part | Baseline to Cycle 2 Day 1 (each cycle is 28 days) | Ctrough defined as concentration observed just before treatment administration during repeated dosing after IV administration |
| Concentration observed at the end of intravenous infusion.(Ceoi)- Safety Run-in Part | Day 1 of Cycle 1 to 4 | — |
| Number of participants with Incidence of anti-drug antibodies (ADA) against isatuximab- Randomized Phase 3 Part | Up to approximately 144 months | — |
| European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 - Randomized Phase 3 Part | Baseline to follow-up (up to approximately 114 months) | The EORTC Multiple Myeloma Module (QLQ-C30) will be used to assess cancer-specific health related quality of life (HRQL), disease and treatment related symptoms and impact of symptoms. Mean change from baseline scores will be assessed, with responses ranging from 1=not at all to 4=very much or 1=very poor to 7=excellent; higher scores represent a better level of physical functioning |
| EORTC QLQ-MY20 - Randomized Phase 3 Part | Baseline to follow-up (up to approximately 114 months) | The EORTC Multiple Myeloma Module (QLQ-MY20) will be used to measure myeloma-specific HRQL, disease and treatment related symptoms and impact of symptoms. Mean change from baseline in scores will be assessed using a 4-point scale, with responses ranging from 1=not at all to 4=very much; higher scores represent better perspectives of the future and higher level of symptomatology |
| EQ-5D-5L - Randomized Phase 3 Part | Baseline to follow-up (up to approximately 114 months) | The EQ-5D-5L will be used to assess health status and health utility. Mean change from baseline scores will be assessed from 5 items, with responses ranging from 'no' to 'extreme problems'; health state utility values (HSUVs) are generated by multiplying the item scores by country specific value sets; health status is assessed via a VAS; higher scores = higher HSUV/health status |
| Randomized Phase 3: HRUPQ - Randomized Phase 3 Part | Baseline to follow-up (up to approximately 114 months) | Mean change from baseline in Health resource utilization and productivity questionnaire (HRUPQ) scores. HRUPQ will assess health care resource utilization of HRSM and the impact of high risk smoldering multiple myeloma (HRSMM) on employment/work; higher scores = greater impact on work/productivity, resources. |
| Patient's Qualitative Assessment of Treatment Version 2 (PQAT-v2) - Randomized Phase 3 Part | End of treatment (up to approximately 3 year) | PQAT-v2 will be used to assess participant-perceived advantages and disadvantages of treatment. Patient's qualitative assessment of treatment will be assessed using a 10 point VAS/NRS scale with response anchors of 'not beneficial at all' to 'extremely beneficial'; higher scores represent greater patient-perceived benefits of treatment |
| Time to biochemical progression - Randomized Phase 3 Part | Up to approximately 114 months | Time to biochemical progression defined as the time from randomization to the date of biochemical progression based on IRC assessment. |
| Duration of Response (DOR) - Safety Run-in Part | Up to approximately 63 months | DOR defined as the time from the date of the first response to date of first progressive disease (PD) or death, whichever happens first. |
| Minimal residual disease (MRD) negativity -Safety Run-in Part | Up to approximately 36 months | MRD negativity defined as the proportion of participants for whom MRD is negative in participants achieving very good partial response (VGPR) or above. |
| Time to diagnostic (SLiM CRAB) progression or death - Safety Run-in Part | Up to approximately 63 months | Time to diagnostic (SLiM CRAB) progression or death defined as the time from the date of the first study intervention administration to diagnosis of SLiM CRAB or other related conditions progression or death from any cause, whichever happens first. |
Countries
Australia, Brazil, Canada, China, Czechia, Denmark, France, Germany, Greece, Hungary, Ireland, Israel, Italy, Japan, Lithuania, New Zealand, Norway, Poland, South Korea, Spain, Sweden, Turkey (Türkiye), United Kingdom, United States
Outcome results
None listed