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

Plasma Cell Myeloma Clinical Trial

Official 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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04270409
• Other study ID #: EFC15992
• Secondary ID: U1111-1222-70682
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: June 16, 2020
• Est. completion date: October 10, 2033

Study information

• Verified date: March 2024
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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 on participant outcome

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 biochemical progression

• Time to first-line treatment for MM

• Safety and tolerability

• Pharmacokinetics (PK)

• Potential of isatuximab immunogenicity

• Clinical outcome assessments (COAs)

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 337
• Est. completion date: October 10, 2033
• Est. primary completion date: November 11, 2030
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

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

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 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 potential participation in a clinical trial.

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell
• Plasma Cell Myeloma
• Smoldering Multiple Myeloma

Intervention

Drug:
• Isatuximab SAR650984
Pharmaceutical for: Solution for infusion Route of administration: Intravenous
• Lenalidomide
Pharmaceutical form: Capsules Route of administration: Oral
• Dexamethasone
Pharmaceutical form: Tablets and solution for injection Route of administration: Oral and intravenous
• Montelukast or equivalent
Auxiliary Medicinal Product (AxMP)/pre-medication; ATC code: R03DC03; Pharmaceutical form: As per local commercial product; Route of administration: Oral;
• Acetaminophen
AxMP/pre-medication ATC code: N02BE01 Pharmaceutical form: As per local commercial product; Route of administration: Oral
• Diphenhydramine or equivalent
AxMP/pre-medication ATC code: R06AA02 Pharmaceutical form: As per local commercial product; Route of administration: Intravenous
• Methylprednisolone or equivalent
AxMP/pre-medication; ATC code: H02AB04; Pharmaceutical form: As per local commercial product; Route of administration: Intravenous

Locations

Country	Name	City	State
Australia	Investigational Site Number :0360002	Fitzroy	Victoria
Australia	Investigational Site Number :0360007	Heidelberg West	Victoria
Australia	Investigational Site Number :0360008	Liverpool	New South Wales
Australia	Investigational Site Number :0360006	Nedlands	Western Australia
Australia	Investigational Site Number :0360004	Richmond	Victoria
Australia	Investigational Site Number :0360005	Waratah	New South Wales
Australia	Investigational Site Number :0360001	Wollongong	New South Wales
Brazil	Investigational Site Number :0760002	Sao Paulo	São Paulo
Canada	Investigational Site Number :1240004	Edmonton	Alberta
Canada	Investigational Site Number :1240005	Moncton	New Brunswick
Canada	Investigational Site Number :1240001	Montreal	Quebec
China	Investigational Site Number :1560002	Hangzhou
China	Investigational Site Number :1560003	Hangzhou
China	Investigational Site Number :1560006	Nanchang
China	Investigational Site Number :1560004	Shanghai
China	Investigational Site Number :1560005	Shenyang
China	Investigational Site Number :1560001	Tianjin
Czechia	Investigational Site Number : 2030004	Brno
Czechia	Investigational Site Number : 2030005	Hradec Kralove
Czechia	Investigational Site Number : 2030002	Olomouc
Czechia	Investigational Site Number : 2030003	Ostrava - Poruba
Czechia	Investigational Site Number : 2030001	Praha 2
Denmark	Investigational Site Number :2080001	Aalborg
Denmark	Investigational Site Number :2080003	Aarhus N
Denmark	Investigational Site Number :2080005	Copenhagen
Denmark	Investigational Site Number :2080002	Roskilde
France	Investigational Site Number :2500009	Ars-Laquenexy
France	Investigational Site Number :2500010	Bayonne
France	Investigational Site Number :2500007	GRENOBLE Cedex 9
France	Investigational Site Number :2500006	La Roche sur Yon
France	Investigational Site Number :2500003	Lille
France	Investigational Site Number :2500005	Paris
France	Investigational Site Number :2500011	Paris
France	Investigational Site Number :2500002	Poitiers Cedex
France	Investigational Site Number :2500001	RENNES Cedex 09
Germany	Investigational Site Number :2760001	Hamburg
Germany	Investigational Site Number :2760002	Heidelberg
Greece	Investigational Site Number :3000001	Athens
Greece	Investigational Site Number :3000002	Athens
Greece	Investigational Site Number :3000003	Thessaloniki
Hungary	Investigational Site Number :3480001	Budapest
Hungary	Investigational Site Number :3480003	Budapest
Hungary	Investigational Site Number :3480002	Debrecen
Hungary	Investigational Site Number :3480004	Kaposvár
Ireland	Investigational Site Number :3720003	Dublin 7	Dublin
Ireland	Investigational Site Number :3720002	Dublin 8	Dublin
Ireland	Investigational Site Number :3720001	Dublin 9	Dublin
Israel	Investigational Site Number :3760004	Ashdod
Israel	Investigational Site Number :3760001	Jerusalem
Israel	Investigational Site Number :3760002	Jerusalem
Israel	Investigational Site Number :3760005	Petah-Tikva
Israel	Investigational Site Number :3760006	Ramat Gan
Israel	Investigational Site Number :3760003	Tel Aviv
Italy	Investigational Site Number :3800005	Ancona
Italy	Investigational Site Number :3800003	Bologna
Italy	Investigational Site Number :3800006	Meldola	Forlì-Cesena
Italy	Investigational Site Number :3800001	Rozzano	Milano
Italy	Investigational Site Number :3800002	Terni
Japan	Investigational Site Number :3920005	Higashiibaraki-gun	Ibaraki
Japan	Investigational Site Number :3920006	Kamogawa-shi	Chiba
Japan	Investigational Site Number :3920008	Maebashi-shi	Gunma
Japan	Investigational Site Number :3920002	Nagoya-shi	Aichi
Japan	Investigational Site Number :3920003	Okayama-shi	Okayama
Japan	Investigational Site Number :3920001	Shibuya-ku	Tokyo
Japan	Investigational Site Number :3920009	Sunto-gun	Shizuoka
Korea, Republic of	Investigational Site Number :4100004	Gangnam-gu	Seoul-teukbyeolsi
Korea, Republic of	Investigational Site Number :4100001	Seoul	Seoul-teukbyeolsi
Korea, Republic of	Investigational Site Number :4100002	Seoul
Korea, Republic of	Investigational Site Number :4100003	Seoul	Seoul-teukbyeolsi
Lithuania	Investigational Site Number :4400001	Vilnius
New Zealand	Investigational Site Number :5540004	Christchurch	Canterbury
New Zealand	Investigational Site Number :5540001	Hamilton	Waikato
Norway	Investigational Site Number :5780002	Bergen
Norway	Investigational Site Number :5780001	Oslo
Poland	Investigational Site Number :6160006	Bydgoszcz	Kujawsko-pomorskie
Poland	Investigational Site Number :6160005	Chorzow	Slaskie
Poland	Investigational Site Number :6160008	Gdansk	Pomorskie
Poland	Investigational Site Number :6160002	Lodz	Lódzkie
Spain	Investigational Site Number :7240001	Barcelona	Barcelona [Barcelona]
Spain	Investigational Site Number :7240004	Barcelona	Barcelona [Barcelona]
Spain	Investigational Site Number :7240005	Madrid
Spain	Investigational Site Number :7240006	Pamplona	Navarra
Spain	Investigational Site Number :7240007	Salamanca
Spain	Investigational Site Number :7240002	Valencia	Valenciana, Comunidad
Spain	Investigational Site Number :7240003	Zaragoza
Sweden	Investigational Site Number :7520001	Göteborg
Sweden	Investigational Site Number :7520003	Helsingborg
Turkey	Investigational Site Number : 7920001	Ankara
Turkey	Investigational Site Number : 7920005	Ankara
Turkey	Investigational Site Number : 7920002	Istanbul
Turkey	Investigational Site Number : 7920004	Istanbul
Turkey	Investigational Site Number : 7920003	Izmir
United Kingdom	Investigational Site Number :8260002	Bournemouth	Hampshire
United Kingdom	Investigational Site Number :8260001	Leicester
United Kingdom	Investigational Site Number :8260003	London	London, City Of
United Kingdom	Investigational Site Number :8260004	Southampton
United States	Dana Farber Cancer Institute Site Number : 8400001	Boston	Massachusetts
United States	Presbyterian Hospital Site Number : 8400015	Charlotte	North Carolina
United States	Colorado Blood Cancer Institute Site Number : 8400007	Denver	Colorado
United States	~University of Texas - MD Anderson Cancer Center Site Number : 8400002	Houston	Texas
United States	Cancer Specialist of North Florida Site Number : 8400011	Jacksonville	Florida
United States	UCLA Site Number : 8400010	Los Angeles	California
United States	University of Miami Site Number : 8400012	Miami	Florida
United States	Tennessee Oncology Site Number : 8400006	Nashville	Tennessee
United States	Novant Health Forsyth Medical Center Site Number : 8401015	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Sanofi

Countries where clinical trial is conducted

United States,  Australia,  Brazil,  Canada,  China,  Czechia,  Denmark,  France,  Germany,  Greece,  Hungary,  Ireland,  Israel,  Italy,  Japan,  Korea, Republic of,  Lithuania,  New Zealand,  Norway,  Poland,  Spain,  Sweden,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety assessment: adverse events (AEs)- Safety Run-in Part	Number of participants with AEs	Up to approximately 63 months
Primary	Plasma concentration of isatuximab: Cmax- Safety Run-in Part	Maximum concentration observed after the first infusion (Cmax)	After first infusion in Cycle 1 in safety run-in part. 1 cycle = 28 days
Primary	Receptor density/receptor occupancy Safety Run-in Part	Change in CD38 receptor occupancy from baseline	Baseline to Cycle 2 Day 1 (each cycle is 28 days)
Primary	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	Up to approximately 114 months
Secondary	Overall response rate (ORR)- Safety Run-in Part and Randomized Phase 3	Proportion of participants with best overall response recorded as partial response or better according to 2016 IMWG criteria	Up to approximately 63 and 114 months for Safety Run-in Part and Randomized Phase 3, respectively
Secondary	Duration of response (DOR)-Safety Run-in Part and Randomized Phase 3	Time from the date of the first response to date of progressive disease or death, whichever happens first	Up to approximately 63 and 114 months for Safety Run-in Part and Randomized Phase 3, respectively
Secondary	Minimal residual disease (MRD) negativity-Safety Run-in Part and Randomized Phase 3	Number of participants for whom MRD is negative	Up to approximately 65 months
Secondary	Time to diagnostic (SLiM CRAB) progression or death -Safety Run-in Part and Randomized Phase 3	Time from randomization to diagnosis of SLiM-CRAB or other related conditions, progression, or death from any cause	Up to approximately 63 and 114 months for Safety Run-in Part and Randomized Phase 3, respectively
Secondary	Time to first-line treatment for multiple myeloma (MM)- Safety Run-in Part and Randomized Phase 3	Time from randomization to first-line treatment for MM	Up to approximately 63 and 114 months for Safety Run-in Part and Randomized Phase 3, respectively
Secondary	Immunogenicity: Incidence of anti-drug antibodies (ADA)- Safety Run-in Part	Number of participants with anti-drug antibodies against isatuximab	Up to approximately 27 months
Secondary	Sustained MRD negativity- Randomized Phase 3	Number of participants with sustained MRD negativity (sample is still negative at least 1 year after the first negativity assessment)	Up to approximately 65 months
Secondary	Second PFS (PFS2) Randomized Phase 3	Time from randomization to date of second objective progressive disease or death from any cause	Up to approximately 144 months
Secondary	Overall survival- Randomized Phase 3	Time from date of randomization to death from any cause	Up to approximately 144 months
Secondary	PFS and OS in participants with cytogenetic abnormalities- Safety Run-In and Randomized Part	Association of cytogenetic abnormalities with survival outcomes	Up to approximately 63 and 114 months for Safety Run-in Part and Randomized Phase 3, respectively
Secondary	Complete response rate - Randomized Phase 3	Percentage of particpants with a CR as defined by 2016 IMWG response criteria	Up to approximately 114 months
Secondary	Time to biochemical progression - Randomized Phase 3	Time to biochemical progression is defined as the time from randomization to the date of biochemical progression based on IRC assessment.	Up to approximately 114 months
Secondary	Safety assessment: adverse events (AEs)- Randomized Phase 3	Number of participants with AEs	Up to approximately 144 months
Secondary	Plasma concentration of isatuximab- Randomized Phase 3	Concentration observed just before treatment administration during repeated dosing (Ctrough) after IV administration	At predose of Cycle 2 Day 1 and Cycle 6 Day 1
Secondary	European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30-Randomized Phase 3	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	Baseline to follow-up (up to approximately 7 years)
Secondary	EORTC QLQ-MY20 - Randomized Phase 3	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	Baseline to follow-up (up to approximately 7 years)
Secondary	EQ-5D-5L Randomized Phase 3	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	Baseline to follow-up (up to approximately 7 years)
Secondary	Randomized Phase 3: HRUPQ - Randomized Phase 3	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 HRSM on employment/work higher scores = greater impact on work/productivity, resources	Baseline to follow-up (up to approximately 7 years)
Secondary	Patient's Qualitative Assessment of Treatment Version 2 (PQAT-v2) Randomized Phase 3	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	End of treatment (up to approximately 5 years)