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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT04270409




Registration number
NCT04270409
Ethics application status
Date submitted
13/02/2020
Date registered
17/02/2020
Date last updated
25/11/2020

Titles & IDs
Public title
Isatuximab in Combination With Lenalidomide and Dexamethasone in High-risk Smoldering Multiple Myeloma
Scientific title
A Phase 3 Randomized, Open Label, Multicenter Study of Isatuximab (SAR650984) in Combination With Lenalidomide and Dexamethasone Versus Lenalidomide and Dexamethasone in Patients With High-risk Smoldering Multiple Myeloma
Secondary ID [1] 0 0
2019-003139-47
Secondary ID [2] 0 0
EFC15992
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Plasma Cell Myeloma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Other cancer types
Cancer 0 0 0 0
Myeloma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Isatuximab SAR650984
Treatment: Drugs - Lenalidomide
Treatment: Drugs - Dexamethasone

Experimental: Isatuximab, lenalidomide, and dexamethasone (ILd) - Isatuximab intravenous (IV) administration on Days 1, 8, 15, and 22 during Cycle 1 (28 days per cycle), and Days 1 and 15 during Cycles 2-12, and Day 1 during subsequent cycles; lenalidomide per os (PO) administration on Days 1 to 21; and dexamethasone IV administration only on Day 1 during Cycle 1 and PO on Days 8, 15 and 22 of Cycle 1 and Days 1, 8, 15, and 22 of subsequent cycles

Active Comparator: Lenalidomide and dexamethasone (Ld) - Lenalidomide PO administration on Days 1 to 21 and dexamethasone PO administration on Days 1, 8, 15, and 22 of every 28-day cycle


Treatment: Drugs: Isatuximab SAR650984
Pharmaceutical for: Solution for infusion Route of administration: Intravenous

Treatment: Drugs: Lenalidomide
Pharmaceutical form: Capsules Route of administration: Oral

Treatment: Drugs: Dexamethasone
Pharmaceutical form: Tablets and solution for injection Route of administration: Oral and intravenous

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Safety assessment: adverse events (AEs) - Number of participants with AEs
Timepoint [1] 0 0
Baseline to 30 days after last study treatment administration (up to approximately 100 months after first study treatment)
Primary outcome [2] 0 0
Plasma concentration of isatuximab: Cmax - Maximum concentration observed after the first infusion (Cmax)
Timepoint [2] 0 0
Up to approximately 24 months
Primary outcome [3] 0 0
Receptor density/receptor occupancy (safety run-in) - Change in CD38 receptor occupancy from baseline
Timepoint [3] 0 0
Baseline to Cycle 2 Day 1 (each cycle is 28 days)
Primary outcome [4] 0 0
Progression-free survival (PFS) randomized Phase 3 - Time from randomization to MM (SLiM CRAB criteria) or other related conditions based on independent review committee assessment according to 2014 International Myeloma Working Group (IMWG) criteria or death from any cause, whichever happens first
Timepoint [4] 0 0
Up to approximately 85 months
Secondary outcome [1] 0 0
Overall response rate (ORR) - Proportion of participants with best overall response recorded as partial response or better according to 2016 IMWG criteria
Timepoint [1] 0 0
Up to approximately 85 months
Secondary outcome [2] 0 0
Duration of response (DOR) - Time from the date of the first response to date of progressive disease or death, whichever happens first
Timepoint [2] 0 0
Up to approximately 85 months
Secondary outcome [3] 0 0
Minimal residual disease (MRD) negativity - Number of participants for whom MRD is negative
Timepoint [3] 0 0
Up to approximately 85 months
Secondary outcome [4] 0 0
Time to diagnostic (SLiM CRAB) progression or death - Time from randomization to diagnosis of SLiM-CRAB or other related conditions, progression, or death from any cause
Timepoint [4] 0 0
Up to approximately 85 months
Secondary outcome [5] 0 0
Time to first-line treatment for multiple myeloma (MM) - Time from randomization to first-line treatment for MM
Timepoint [5] 0 0
Up to approximately 85 months
Secondary outcome [6] 0 0
Immunogenicity: Incidence of anti-drug antibodies (ADA) - Number of participants with anti-drug antibodies against isatuximab
Timepoint [6] 0 0
Up to approximately 24 months
Secondary outcome [7] 0 0
Sustained MRD negativity - Number of participants with sustained MRD negativity (sample is still negative at least 1 year after the first negativity assessment)
Timepoint [7] 0 0
Up to approximately 85 months
Secondary outcome [8] 0 0
Second PFS (PFS2) - Time from randomization to date of second objective progressive disease or death from any cause
Timepoint [8] 0 0
Up to approximately 120 months
Secondary outcome [9] 0 0
Overall survival - Time from date of randomization to death from any cause
Timepoint [9] 0 0
Up to approximately 144 months
Secondary outcome [10] 0 0
Complete response rate - Percentage of particpants with a CR as defined by 2016 IMWG response criteria
Timepoint [10] 0 0
Up to approximately 85 months
Secondary outcome [11] 0 0
Safety assessment: adverse events (AEs) - Number of participants with AEs
Timepoint [11] 0 0
Baseline to 30 days after last study treatment administration (up to approximately 100 months after first study treatment)
Secondary outcome [12] 0 0
Plasma concentration of isatuximab - Maximum concentration observed after the first infusion (Cmax)
Timepoint [12] 0 0
Up to approximately 24 months
Secondary outcome [13] 0 0
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 - 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
Timepoint [13] 0 0
Baseline to follow-up (up to approximately 10 years)
Secondary outcome [14] 0 0
EORTC QLQ-MY20 - 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
Timepoint [14] 0 0
Baseline to follow-up (up to approximately 10 years)
Secondary outcome [15] 0 0
EQ-5D-5L - 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
Timepoint [15] 0 0
Baseline to follow-up (up to approximately 10 years)
Secondary outcome [16] 0 0
Economic questionnaire - Mean change from baseline scores will assess work productivity, resource utilization and working days missed by a caregiver; higher scores represent greater impact on work/productivity and resources
Timepoint [16] 0 0
Baseline to follow-up (up to approximately 10 years)
Secondary outcome [17] 0 0
Patient's Qualitative Assessment of Treatment Version 2 (PQAT-v2) - Patient's qualitative assessment of treatment will be assessed using a 10 point visual analogue/numeric rating scale with response anchors of 'not beneficial at all' to 'extremely beneficial'; higher scores represent greater patient-perceived benefits of treatment
Timepoint [17] 0 0
End of treatment (up to approximately 10 years)

Eligibility
Key inclusion criteria
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
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
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

- Whole body magnetic resonance imaging (WB-MRI) or positron emission
tomography-computed tomography (PET-CT) with more than 1 focal lesion (=5 mm in
diameter by MRI)

- Primary systemic amyloid light-chain (immunoglobulin light chain) 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 disease, including:

- Myocardial infarction within 6 months with left ventricular dysfunction or
uncontrolled ischemic cardiac disease before Cycle 1 Day 1, or unstable or
uncontrolled disease/condition related to or affecting cardiac function (eg,
unstable angina, congestive heart failure, New York Heart Association Class
III-IV)

- Uncontrolled cardiac arrhythmia (Grade 2 or higher by NCI-CTCAE Version 5.0) or
clinically significant electrocardiogram (ECG) abnormalities

- 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 HBV infection: Patients with positive HBsAg and/or HBV DNA

Of note:

Patient can be eligible if anti-HBc 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 HCV infection: positive HCV 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 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 patient's
potential participation in a clinical trial.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Investigational Site Number 0360002 - Fitzroy
Recruitment hospital [2] 0 0
Investigational Site Number 0360007 - Heidelberg West
Recruitment hospital [3] 0 0
Investigational Site Number 0360006 - Nedlands
Recruitment hospital [4] 0 0
Investigational Site Number 0360004 - Richmond
Recruitment hospital [5] 0 0
Investigational Site Number 0360001 - Wollongong
Recruitment postcode(s) [1] 0 0
3065 - Fitzroy
Recruitment postcode(s) [2] 0 0
3081 - Heidelberg West
Recruitment postcode(s) [3] 0 0
6009 - Nedlands
Recruitment postcode(s) [4] 0 0
3121 - Richmond
Recruitment postcode(s) [5] 0 0
2500 - Wollongong
Recruitment outside Australia
Country [1] 0 0
Brazil
State/province [1] 0 0
Sao Paulo
Country [2] 0 0
Denmark
State/province [2] 0 0
Roskilde
Country [3] 0 0
France
State/province [3] 0 0
Grenoble Cedex 9
Country [4] 0 0
France
State/province [4] 0 0
La Roche Sur Yon Cedex 9
Country [5] 0 0
France
State/province [5] 0 0
Metz Cedex 03
Country [6] 0 0
France
State/province [6] 0 0
Paris
Country [7] 0 0
France
State/province [7] 0 0
Poitiers Cedex
Country [8] 0 0
Hungary
State/province [8] 0 0
Budapest
Country [9] 0 0
Israel
State/province [9] 0 0
Jerusalem
Country [10] 0 0
Korea, Republic of
State/province [10] 0 0
Gangnam-Gu
Country [11] 0 0
Korea, Republic of
State/province [11] 0 0
Seoul
Country [12] 0 0
Lithuania
State/province [12] 0 0
Vilnius
Country [13] 0 0
Norway
State/province [13] 0 0
Bergen
Country [14] 0 0
Norway
State/province [14] 0 0
Oslo
Country [15] 0 0
Spain
State/province [15] 0 0
Barcelona
Country [16] 0 0
Spain
State/province [16] 0 0
Madrid
Country [17] 0 0
Spain
State/province [17] 0 0
Pamplona
Country [18] 0 0
Spain
State/province [18] 0 0
Salamanca
Country [19] 0 0
Spain
State/province [19] 0 0
Valencia
Country [20] 0 0
Turkey
State/province [20] 0 0
Ankara
Country [21] 0 0
Turkey
State/province [21] 0 0
Istanbul

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Sanofi
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Primary Objectives:

- Safety run-in: 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: 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

- 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 cytogenetic subtype

Randomized Phase 3 - 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 first-line treatment for MM

- Safety and tolerability

- Pharmacokinetics (PK)

- Potential of isatuximab immunogenicity

- Clinical outcome assessments (COAs)
Trial website
https://clinicaltrials.gov/show/NCT04270409
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Clinical Sciences & Operations
Address 0 0
Sanofi
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Trial Transparency email recommended (Toll free number for US & Canada)
Address 0 0
Country 0 0
Phone 0 0
800-633-1610
Fax 0 0
Email 0 0
Contact-US@sanofi.com
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT04270409