Isatuximab in Combination With Lenalidomide and Dexamethasone in High-risk Smoldering Multiple Myeloma
- Conditions
- Plasma Cell Myeloma
- Interventions
- Registration Number
- NCT04270409
- Lead Sponsor
- Sanofi
- 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.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 337
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Isatuximab, lenalidomide, and dexamethasone (ILd) Montelukast or equivalent Participants will receive isatuximab \[intravenous (IV) administration\] in combination with lenalidomide \[per os (PO) administration\] and dexamethasone \[IV on Day 1 of Cycle 1 for participants receiving isatuximab IV only and PO otherwise for subsequent cycles\] for 24 cycles followed by isatuximab monotherapy for 12 cycles for a total duration of 36 cycles. 1 cycle = 28 days. Participants may receive other treatments as pre-medication. Isatuximab, lenalidomide, and dexamethasone (ILd) Dexamethasone Participants will receive isatuximab \[intravenous (IV) administration\] in combination with lenalidomide \[per os (PO) administration\] and dexamethasone \[IV on Day 1 of Cycle 1 for participants receiving isatuximab IV only and PO otherwise for subsequent cycles\] for 24 cycles followed by isatuximab monotherapy for 12 cycles for a total duration of 36 cycles. 1 cycle = 28 days. Participants may receive other treatments as pre-medication. Isatuximab, lenalidomide, and dexamethasone (ILd) Isatuximab SAR650984 Participants will receive isatuximab \[intravenous (IV) administration\] in combination with lenalidomide \[per os (PO) administration\] and dexamethasone \[IV on Day 1 of Cycle 1 for participants receiving isatuximab IV only and PO otherwise for subsequent cycles\] for 24 cycles followed by isatuximab monotherapy for 12 cycles for a total duration of 36 cycles. 1 cycle = 28 days. Participants may receive other treatments as pre-medication. Isatuximab, lenalidomide, and dexamethasone (ILd) Lenalidomide Participants will receive isatuximab \[intravenous (IV) administration\] in combination with lenalidomide \[per os (PO) administration\] and dexamethasone \[IV on Day 1 of Cycle 1 for participants receiving isatuximab IV only and PO otherwise for subsequent cycles\] for 24 cycles followed by isatuximab monotherapy for 12 cycles for a total duration of 36 cycles. 1 cycle = 28 days. Participants may receive other treatments as pre-medication. Isatuximab, lenalidomide, and dexamethasone (ILd) Acetaminophen Participants will receive isatuximab \[intravenous (IV) administration\] in combination with lenalidomide \[per os (PO) administration\] and dexamethasone \[IV on Day 1 of Cycle 1 for participants receiving isatuximab IV only and PO otherwise for subsequent cycles\] for 24 cycles followed by isatuximab monotherapy for 12 cycles for a total duration of 36 cycles. 1 cycle = 28 days. Participants may receive other treatments as pre-medication. Isatuximab, lenalidomide, and dexamethasone (ILd) Diphenhydramine or equivalent Participants will receive isatuximab \[intravenous (IV) administration\] in combination with lenalidomide \[per os (PO) administration\] and dexamethasone \[IV on Day 1 of Cycle 1 for participants receiving isatuximab IV only and PO otherwise for subsequent cycles\] for 24 cycles followed by isatuximab monotherapy for 12 cycles for a total duration of 36 cycles. 1 cycle = 28 days. Participants may receive other treatments as pre-medication. Isatuximab, lenalidomide, and dexamethasone (ILd) Methylprednisolone or equivalent Participants will receive isatuximab \[intravenous (IV) administration\] in combination with lenalidomide \[per os (PO) administration\] and dexamethasone \[IV on Day 1 of Cycle 1 for participants receiving isatuximab IV only and PO otherwise for subsequent cycles\] for 24 cycles followed by isatuximab monotherapy for 12 cycles for a total duration of 36 cycles. 1 cycle = 28 days. Participants may receive other treatments as pre-medication. Lenalidomide and dexamethasone (Ld) Lenalidomide Lenalidomide \[PO administration\] in combination with dexamethasone \[PO administration\] for 24 cycles. 1 cycle = 28 days Lenalidomide and dexamethasone (Ld) Dexamethasone Lenalidomide \[PO administration\] in combination with dexamethasone \[PO administration\] for 24 cycles. 1 cycle = 28 days
- Primary Outcome Measures
Name Time Method 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 Outcome Measures
Name Time Method 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
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.
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.
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.
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
Trial Locations
- Locations (105)
Investigational Site Number :0360008
🇦🇺Liverpool, New South Wales, Australia
Investigational Site Number :3920001
🇯🇵Shibuya-ku, Tokyo, Japan
Investigational Site Number :4400001
🇱🇹Vilnius, Lithuania
Investigational Site Number :3720001
🇮🇪Dublin 9, Dublin, Ireland
Investigational Site Number :2080002
🇩🇰Roskilde, Denmark
Investigational Site Number :3800003
🇮🇹Bologna, Italy
Investigational Site Number :3760006
🇮🇱Ramat Gan, Israel
Investigational Site Number :0360007
🇦🇺Heidelberg West, Victoria, Australia
Investigational Site Number : 7920005
🇹🇷Ankara, Turkey
Investigational Site Number : 7920001
🇹🇷Ankara, Turkey
Investigational Site Number : 7920004
🇹🇷Istanbul, Turkey
Investigational Site Number :8260003
🇬🇧London, London, City Of, United Kingdom
Investigational Site Number :8260001
🇬🇧Leicester, United Kingdom
Investigational Site Number :1560001
🇨🇳Tianjin, China
Investigational Site Number :1240004
🇨🇦Edmonton, Alberta, Canada
Investigational Site Number :1240001
🇨🇦Montreal, Quebec, Canada
Investigational Site Number :1240005
🇨🇦Moncton, New Brunswick, Canada
~University of Texas - MD Anderson Cancer Center Site Number : 8400002
🇺🇸Houston, Texas, United States
Investigational Site Number :1560005
🇨🇳Shenyang, China
Investigational Site Number :0360006
🇦🇺Nedlands, Western Australia, Australia
Investigational Site Number :2080003
🇩🇰Aarhus N, Denmark
Investigational Site Number :0760002
🇧🇷Sao Paulo, São Paulo, Brazil
Investigational Site Number :3720003
🇮🇪Dublin 7, Dublin, Ireland
Investigational Site Number :3480002
🇭🇺Debrecen, Hungary
Investigational Site Number :3000001
🇬🇷Athens, Greece
Investigational Site Number :1560006
🇨🇳Nanchang, China
Investigational Site Number :3800002
🇮🇹Terni, Italy
Investigational Site Number :2500005
🇫🇷Paris, France
Investigational Site Number :2760001
🇩🇪Hamburg, Germany
Investigational Site Number : 2030004
🇨🇿Brno, Czechia
Investigational Site Number :3760004
🇮🇱Ashdod, Israel
Investigational Site Number :3920002
🇯🇵Nagoya-shi, Aichi, Japan
Investigational Site Number :1560002
🇨🇳Hangzhou, China
Investigational Site Number :0360004
🇦🇺Richmond, Victoria, Australia
Investigational Site Number :2500009
🇫🇷Ars-Laquenexy, France
Investigational Site Number : 2030005
🇨🇿Hradec Kralove, Czechia
Investigational Site Number : 2030001
🇨🇿Praha 2, Czechia
Investigational Site Number :3480004
🇭🇺Kaposvár, Hungary
Investigational Site Number :1560003
🇨🇳Hangzhou, China
Investigational Site Number :3920003
🇯🇵Okayama-shi, Okayama, Japan
Investigational Site Number :3480001
🇭🇺Budapest, Hungary
Investigational Site Number :2500007
🇫🇷GRENOBLE Cedex 9, France
Investigational Site Number :2080001
🇩🇰Aalborg, Denmark
Investigational Site Number :4100002
🇰🇷Seoul, Korea, Republic of
Investigational Site Number : 2030003
🇨🇿Ostrava - Poruba, Czechia
Investigational Site Number :2500002
🇫🇷Poitiers Cedex, France
Investigational Site Number :3760001
🇮🇱Jerusalem, Israel
Investigational Site Number :2080005
🇩🇰Copenhagen, Denmark
Investigational Site Number :3760002
🇮🇱Jerusalem, Israel
Investigational Site Number :3800005
🇮🇹Ancona, Italy
Investigational Site Number :3720002
🇮🇪Dublin 8, Dublin, Ireland
Investigational Site Number :3800006
🇮🇹Meldola, Forlì-Cesena, Italy
Investigational Site Number :3760005
🇮🇱Petah-Tikva, Israel
Investigational Site Number :2500003
🇫🇷Lille, France
UCLA Site Number : 8400010
🇺🇸Los Angeles, California, United States
Colorado Blood Cancer Institute Site Number : 8400007
🇺🇸Denver, Colorado, United States
University of Miami Site Number : 8400012
🇺🇸Miami, Florida, United States
Cancer Specialist of North Florida Site Number : 8400011
🇺🇸Jacksonville, Florida, United States
Novant Health Forsyth Medical Center Site Number : 8401015
🇺🇸Winston-Salem, North Carolina, United States
Tennessee Oncology Site Number : 8400006
🇺🇸Nashville, Tennessee, United States
Dana Farber Cancer Institute Site Number : 8400001
🇺🇸Boston, Massachusetts, United States
Presbyterian Hospital Site Number : 8400015
🇺🇸Charlotte, North Carolina, United States
Investigational Site Number :0360005
🇦🇺Waratah, New South Wales, Australia
Investigational Site Number :0360002
🇦🇺Fitzroy, Victoria, Australia
Investigational Site Number :0360001
🇦🇺Wollongong, New South Wales, Australia
Investigational Site Number :1560004
🇨🇳Shanghai, China
Investigational Site Number :2500006
🇫🇷La Roche sur Yon, France
Investigational Site Number :2500001
🇫🇷RENNES Cedex 09, France
Investigational Site Number :2500011
🇫🇷Paris, France
Investigational Site Number :2760002
🇩🇪Heidelberg, Germany
Investigational Site Number :3000002
🇬🇷Athens, Greece
Investigational Site Number :3480003
🇭🇺Budapest, Hungary
Investigational Site Number :3000003
🇬🇷Thessaloniki, Greece
Investigational Site Number :3800001
🇮🇹Rozzano, Milano, Italy
Investigational Site Number :3920006
🇯🇵Kamogawa-shi, Chiba, Japan
Investigational Site Number :3920008
🇯🇵Maebashi-shi, Gunma, Japan
Investigational Site Number :3920009
🇯🇵Sunto-gun, Shizuoka, Japan
Investigational Site Number :3920005
🇯🇵Higashiibaraki-gun, Ibaraki, Japan
Investigational Site Number :4100003
🇰🇷Seoul, Seoul-teukbyeolsi, 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 :5780001
🇳🇴Oslo, Norway
Investigational Site Number :5540004
🇳🇿Christchurch, Canterbury, New Zealand
Investigational Site Number :5780002
🇳🇴Bergen, Norway
Investigational Site Number :5540001
🇳🇿Hamilton, Waikato, New Zealand
Investigational Site Number :6160002
🇵🇱Lodz, Lódzkie, Poland
Investigational Site Number :6160008
🇵🇱Gdansk, Pomorskie, Poland
Investigational Site Number :6160006
🇵🇱Bydgoszcz, Kujawsko-pomorskie, Poland
Investigational Site Number :6160005
🇵🇱Chorzow, Slaskie, Poland
Investigational Site Number :7240004
🇪🇸Barcelona, Barcelona [Barcelona], Spain
Investigational Site Number :7240001
🇪🇸Barcelona, Barcelona [Barcelona], Spain
Investigational Site Number :7240006
🇪🇸Pamplona, Navarra, Spain
Investigational Site Number :7240005
🇪🇸Madrid, Spain
Investigational Site Number :7240002
🇪🇸Valencia, Valenciana, Comunidad, Spain
Investigational Site Number :7520001
🇸🇪Göteborg, Sweden
Investigational Site Number :7240003
🇪🇸Zaragoza, Spain
Investigational Site Number :7240007
🇪🇸Salamanca, Spain
Investigational Site Number :7520003
🇸🇪Helsingborg, Sweden
Investigational Site Number : 7920002
🇹🇷Istanbul, Turkey
Investigational Site Number : 7920003
🇹🇷Izmir, Turkey
Investigational Site Number :8260002
🇬🇧Bournemouth, Hampshire, United Kingdom
Investigational Site Number :8260004
🇬🇧Southampton, United Kingdom
Investigational Site Number : 2030002
🇨🇿Olomouc, Czechia
Investigational Site Number :2500010
🇫🇷Bayonne, France
Investigational Site Number :3760003
🇮🇱Tel Aviv, Israel