NCT04270409 - Isatuximab in Combination With Lenalidomide and Dexamethasone in High-risk Smoldering Multiple Myeloma | Crick

Eligibility

Sex: ALLMin age: 18 YearsHealthy volunteers:

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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.

Outcomes

Primary Outcomes

Number of participants with Treatment-emergent adverse events (AEs) and serious adverse events- Safety Run-in Part

Time frame: Up to approximately 63 months

Plasma concentration of isatuximab during the treatment period - Safety Run-in Part

Time frame: After first infusion from Cycle 1 Day 1 to Day 28 in safety run-in part

Receptor density/receptor occupancy Safety Run-in Part

Change in CD38 receptor occupancy from baseline

Time frame: Baseline to Cycle 2 Day 1 (each cycle is 28 days)

Progression-free survival (PFS) Randomized Phase 3 Part

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

Time frame: Up to approximately 114 months

Secondary Outcomes

Overall Response Rate (ORR)- Safety Run-in Part

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 frame: Up to approximately 63 months

Duration of Response (DOR) - Safety Run-in Part

DOR defined as the time from the date of the first response to date of first progressive disease (PD) or death, whichever happens first.

Time frame: Up to approximately 63 months

Minimal residual disease (MRD) negativity -Safety Run-in Part

MRD negativity defined as the proportion of participants for whom MRD is negative in participants achieving very good partial response (VGPR) or above.

Time frame: Up to approximately 36 months

Time to diagnostic (SLiM CRAB) progression or death - Safety Run-in Part

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.

Time frame: Up to approximately 63 months

Time to first-line treatment for multiple myeloma (MM) - Safety Run-in Part

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.

Time frame: Up to approximately 63 months

Number of participants with anti-drug antibodies (ADA) against isatuximab- Safety Run-in Part

Time frame: Up to approximately 63 months

PFS in participants with chromosomal abnormalities - Safety Run-In Part

Association of chromosomal abnormalities with survival outcomes

Time frame: Up to approximately 63 months

Overall Survival (OS) in participants with chromosomal abnormalities - Safety Run-In Part

Association of chromosomal abnormalities with survival outcomes

Time frame: Up to approximately 63 months

Minimal residual disease (MRD) negativity - Randomized Phase 3 Part

MRD negativity defined as the proportion Number of participants for whom MRD is negative in participants achieving VGPR or above.

Time frame: Up to approximately 36 months

Sustained MRD negativity - Randomized Phase 3 Part

Sustained MRD negativity defined as the proportion of participants for whom MRD is negative during a minimum period of one year.

Time frame: Up to approximately 36 months

Second PFS (PFS2) - Randomized Phase 3 Part

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

Time frame: Up to approximately 144 months

OS - Randomized Phase 3 Part

OS defined as the time from date of randomization to death from any cause.

Time frame: Up to approximately 114 months

Complete response (CR) rate - Randomized Phase 3 Part

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.

Time frame: Up to approximately 114 months

Overall Response Rate (ORR) - Randomized Phase 3 Part

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.

Time frame: Up to approximately 114 months

Duration of response (DOR) - Randomized Phase 3 Part

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 frame: Up to approximately 114 months

Time to diagnostic (SLiM CRAB) progression - Randomized Phase 3 Part

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.

Time frame: Up to approximately 114 months

Time to biochemical progression - Randomized Phase 3 Part

Time to biochemical progression defined as the time from randomization to the date of biochemical progression based on IRC assessment.

Time frame: Up to approximately 114 months

Time to first-line treatment for MM- Randomized Phase 3 Part

Time to first-line treatment for MM defined as the time from randomization to first-line treatment for MM

Time frame: Up to approximately 144 months

PFS in participants with chromosomal abnormalities - Randomized Phase 3 Part

Association of chromosomal abnormalities with survival outcomes.

Time frame: Up to approximately 114 months

OS in participants with chromosomal abnormalities - Randomized Phase 3 Part

Association of chromosomal abnormalities with survival outcomes.

Time frame: Up to approximately 144 months

Number of participants with Treatment-emergent adverse events (AEs) and serious adverse events - Randomized Phase 3 Part

Time frame: Up to approximately 144 months

Plasma concentration of isatuximab (Ctrough)- Safety Run-in and Randomized Phase 3 Part

Ctrough defined as concentration observed just before treatment administration during repeated dosing after IV administration

Time frame: Baseline to Cycle 2 Day 1 (each cycle is 28 days)

Concentration observed at the end of intravenous infusion.(Ceoi)- Safety Run-in Part

Time frame: Day 1 of Cycle 1 to 4

Number of participants with Incidence of anti-drug antibodies (ADA) against isatuximab- Randomized Phase 3 Part

Time frame: Up to approximately 144 months

European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 - Randomized Phase 3 Part

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

Time frame: Baseline to follow-up (up to approximately 114 months)

EORTC QLQ-MY20 - Randomized Phase 3 Part

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

Time frame: Baseline to follow-up (up to approximately 114 months)

EQ-5D-5L - Randomized Phase 3 Part

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

Time frame: Baseline to follow-up (up to approximately 114 months)

Randomized Phase 3: HRUPQ - Randomized Phase 3 Part

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.

Time frame: Baseline to follow-up (up to approximately 114 months)

Patient's Qualitative Assessment of Treatment Version 2 (PQAT-v2) - Randomized Phase 3 Part

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 frame: End of treatment (up to approximately 3 year)

Isatuximab in Combination With Lenalidomide and Dexamethasone in High-risk Smoldering Multiple Myeloma

Overview

Conditions

Interventions

Eligibility

Locations (105)

Outcomes

Primary Outcomes

Secondary Outcomes