Clinical trial NCT04270409: Isatuximab in Combination With Lenalidomide and Dexamethasone in High-risk Smoldering Multiple Myeloma
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Plasma Cell Myeloma
Keywords: Anti-CD38 monoclonal antibody
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2020-02-17
Enrollment: 337
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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
* 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.

Primary outcomes:
measure: Number of participants with Treatment-emergent adverse events (AEs) and serious adverse events- Safety Run-in Part
timeFrame: Up to approximately 63 months
measure: Plasma concentration of isatuximab during the treatment period - Safety Run-in Part
timeFrame: After first infusion from Cycle 1 Day 1 to Day 28 in safety run-in part
measure: Receptor density/receptor occupancy Safety Run-in Part
timeFrame: Baseline to Cycle 2 Day 1 (each cycle is 28 days)
measure: Progression-free survival (PFS) Randomized Phase 3 Part
timeFrame: Up to approximately 114 months
Secondary outcomes:
measure: Overall Response Rate (ORR)- Safety Run-in Part
timeFrame: Up to approximately 63 months
measure: Duration of Response (DOR) - Safety Run-in Part
timeFrame: Up to approximately 63 months
measure: Minimal residual disease (MRD) negativity -Safety Run-in Part
timeFrame: Up to approximately 36 months
measure: Time to diagnostic (SLiM CRAB) progression or death - Safety Run-in Part
timeFrame: Up to approximately 63 months
measure: Time to first-line treatment for multiple myeloma (MM) - Safety Run-in Part
timeFrame: Up to approximately 63 months
measure: Number of participants with anti-drug antibodies (ADA) against isatuximab- Safety Run-in Part
timeFrame: Up to approximately 63 months
measure: PFS in participants with chromosomal abnormalities - Safety Run-In Part
timeFrame: Up to approximately 63 months
measure: Overall Survival (OS) in participants with chromosomal abnormalities - Safety Run-In Part
timeFrame: Up to approximately 63 months
measure: Minimal residual disease (MRD) negativity - Randomized Phase 3 Part
timeFrame: Up to approximately 36 months
measure: Sustained MRD negativity - Randomized Phase 3 Part
timeFrame: Up to approximately 36 months
measure: Second PFS (PFS2) - Randomized Phase 3 Part
timeFrame: Up to approximately 144 months
measure: OS - Randomized Phase 3 Part
timeFrame: Up to approximately 114 months
measure: Complete response (CR) rate - Randomized Phase 3 Part
timeFrame: Up to approximately 114 months
measure: Overall Response Rate (ORR) - Randomized Phase 3 Part
timeFrame: Up to approximately 114 months
measure: Duration of response (DOR) - Randomized Phase 3 Part
timeFrame: Up to approximately 114 months
measure: Time to diagnostic (SLiM CRAB) progression - Randomized Phase 3 Part
timeFrame: Up to approximately 114 months
measure: Time to biochemical progression - Randomized Phase 3 Part
timeFrame: Up to approximately 114 months
measure: Time to first-line treatment for MM- Randomized Phase 3 Part
timeFrame: Up to approximately 144 months
measure: PFS in participants with chromosomal abnormalities - Randomized Phase 3 Part
timeFrame: Up to approximately 114 months
measure: OS in participants with chromosomal abnormalities - Randomized Phase 3 Part
timeFrame: Up to approximately 144 months
measure: Number of participants with Treatment-emergent adverse events (AEs) and serious adverse events - Randomized Phase 3 Part
timeFrame: Up to approximately 144 months
measure: Plasma concentration of isatuximab (Ctrough)- Safety Run-in and Randomized Phase 3 Part
timeFrame: Baseline to Cycle 2 Day 1 (each cycle is 28 days)
measure: Concentration observed at the end of intravenous infusion.(Ceoi)- Safety Run-in Part
timeFrame: Day 1 of Cycle 1 to 4
measure: Number of participants with Incidence of anti-drug antibodies (ADA) against isatuximab- Randomized Phase 3 Part
timeFrame: Up to approximately 144 months
measure: European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 - Randomized Phase 3 Part
timeFrame: Baseline to follow-up (up to approximately 114 months)
measure: EORTC QLQ-MY20 - Randomized Phase 3 Part
timeFrame: Baseline to follow-up (up to approximately 114 months)
measure: EQ-5D-5L - Randomized Phase 3 Part
timeFrame: Baseline to follow-up (up to approximately 114 months)
measure: Randomized Phase 3: HRUPQ - Randomized Phase 3 Part
timeFrame: Baseline to follow-up (up to approximately 114 months)
measure: Patient's Qualitative Assessment of Treatment Version 2 (PQAT-v2) - Randomized Phase 3 Part
timeFrame: End of treatment (up to approximately 3 year)
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: UCLA Site Number : 8400010
state: California
city: Denver
country: United States
facility: Colorado Blood Cancer Institute Site Number : 8400007
state: Colorado
city: Jacksonville
country: United States
facility: Cancer Specialist of North Florida Site Number : 8400011
state: Florida
city: Miami
country: United States
facility: University of Miami Site Number : 8400012
state: Florida
city: Boston
country: United States
facility: Dana Farber Cancer Institute Site Number : 8400001
state: Massachusetts
city: Charlotte
country: United States
facility: Presbyterian Hospital Site Number : 8400015
state: North Carolina
city: Winston-Salem
country: United States
facility: Novant Health Forsyth Medical Center Site Number : 8401015
state: North Carolina
city: Nashville
country: United States
facility: Tennessee Oncology Site Number : 8400006
state: Tennessee
city: Houston
country: United States
facility: ~University of Texas - MD Anderson Cancer Center Site Number : 8400002
state: Texas
city: Liverpool
country: Australia
facility: Investigational Site Number :0360008
state: New South Wales
city: Waratah
country: Australia
facility: Investigational Site Number :0360005
state: New South Wales
city: Wollongong
country: Australia
facility: Investigational Site Number :0360001
state: New South Wales
city: Fitzroy
country: Australia
facility: Investigational Site Number :0360002
state: Victoria
city: Heidelberg West
country: Australia
facility: Investigational Site Number :0360007
state: Victoria
city: Richmond
country: Australia
facility: Investigational Site Number :0360004
state: Victoria
city: Nedlands
country: Australia
facility: Investigational Site Number :0360006
state: Western Australia
city: Sao Paulo
country: Brazil
facility: Investigational Site Number :0760002
state: São Paulo
city: Edmonton
country: Canada
facility: Investigational Site Number :1240004
state: Alberta
city: Moncton
country: Canada
facility: Investigational Site Number :1240005
state: New Brunswick
city: Montreal
country: Canada
facility: Investigational Site Number :1240001
state: Quebec
city: Hangzhou
country: China
facility: Investigational Site Number :1560002
city: Hangzhou
country: China
facility: Investigational Site Number :1560003
city: Nanchang
country: China
facility: Investigational Site Number :1560006
city: Shanghai
country: China
facility: Investigational Site Number :1560004
city: Shenyang
country: China
facility: Investigational Site Number :1560005
city: Tianjin
country: China
facility: Investigational Site Number :1560001
city: Brno
country: Czechia
facility: Investigational Site Number : 2030004
city: Hradec Kralove
country: Czechia
facility: Investigational Site Number : 2030005
city: Olomouc
country: Czechia
facility: Investigational Site Number : 2030002
city: Ostrava - Poruba
country: Czechia
facility: Investigational Site Number : 2030003
city: Praha 2
country: Czechia
facility: Investigational Site Number : 2030001
city: Aalborg
country: Denmark
facility: Investigational Site Number :2080001
city: Aarhus N
country: Denmark
facility: Investigational Site Number :2080003
city: Copenhagen
country: Denmark
facility: Investigational Site Number :2080005
city: Roskilde
country: Denmark
facility: Investigational Site Number :2080002
city: Ars-Laquenexy
country: France
facility: Investigational Site Number :2500009
city: Bayonne
country: France
facility: Investigational Site Number :2500010
city: GRENOBLE Cedex 9
country: France
facility: Investigational Site Number :2500007
city: La Roche sur Yon
country: France
facility: Investigational Site Number :2500006
city: Lille
country: France
facility: Investigational Site Number :2500003
city: Paris
country: France
facility: Investigational Site Number :2500005
city: Paris
country: France
facility: Investigational Site Number :2500011
city: Poitiers Cedex
country: France
facility: Investigational Site Number :2500002
city: RENNES Cedex 09
country: France
facility: Investigational Site Number :2500001
city: Hamburg
country: Germany
facility: Investigational Site Number :2760001
city: Heidelberg
country: Germany
facility: Investigational Site Number :2760002
city: Athens
country: Greece
facility: Investigational Site Number :3000002
city: Athens
country: Greece
facility: Investigational Site Number :3000001
city: Thessaloniki
country: Greece
facility: Investigational Site Number :3000003
city: Budapest
country: Hungary
facility: Investigational Site Number :3480003
city: Budapest
country: Hungary
facility: Investigational Site Number :3480001
city: Debrecen
country: Hungary
facility: Investigational Site Number :3480002
city: Kaposvár
country: Hungary
facility: Investigational Site Number :3480004
city: Dublin 7
country: Ireland
facility: Investigational Site Number :3720003
state: Dublin
city: Dublin 8
country: Ireland
facility: Investigational Site Number :3720002
state: Dublin
city: Dublin 9
country: Ireland
facility: Investigational Site Number :3720001
state: Dublin
city: Ashdod
country: Israel
facility: Investigational Site Number :3760004
city: Jerusalem
country: Israel
facility: Investigational Site Number :3760001
city: Jerusalem
country: Israel
facility: Investigational Site Number :3760002
city: Petah-Tikva
country: Israel
facility: Investigational Site Number :3760005
city: Ramat Gan
country: Israel
facility: Investigational Site Number :3760006
city: Tel Aviv
country: Israel
facility: Investigational Site Number :3760003
city: Meldola
country: Italy
facility: Investigational Site Number :3800006
state: Forlì-Cesena
city: Rozzano
country: Italy
facility: Investigational Site Number :3800001
state: Milano
city: Ancona
country: Italy
facility: Investigational Site Number :3800005
city: Bologna
country: Italy
facility: Investigational Site Number :3800003
city: Terni
country: Italy
facility: Investigational Site Number :3800002
city: Nagoya-shi
country: Japan
facility: Investigational Site Number :3920002
state: Aichi
city: Kamogawa-shi
country: Japan
facility: Investigational Site Number :3920006
state: Chiba
city: Maebashi-shi
country: Japan
facility: Investigational Site Number :3920008
state: Gunma
city: Higashiibaraki-gun
country: Japan
facility: Investigational Site Number :3920005
state: Ibaraki
city: Okayama-shi
country: Japan
facility: Investigational Site Number :3920003
state: Okayama
city: Sunto-gun
country: Japan
facility: Investigational Site Number :3920009
state: Shizuoka
city: Shibuya-ku
country: Japan
facility: Investigational Site Number :3920001
state: Tokyo
city: Gangnam-gu
country: Korea, Republic of
facility: Investigational Site Number :4100004
state: Seoul-teukbyeolsi
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number :4100003
state: Seoul-teukbyeolsi
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number :4100001
state: Seoul-teukbyeolsi
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number :4100002
city: Vilnius
country: Lithuania
facility: Investigational Site Number :4400001
city: Christchurch
country: New Zealand
facility: Investigational Site Number :5540004
state: Canterbury
city: Hamilton
country: New Zealand
facility: Investigational Site Number :5540001
state: Waikato
city: Bergen
country: Norway
facility: Investigational Site Number :5780002
city: Oslo
country: Norway
facility: Investigational Site Number :5780001
city: Bydgoszcz
country: Poland
facility: Investigational Site Number :6160006
state: Kujawsko-pomorskie
city: Lodz
country: Poland
facility: Investigational Site Number :6160002
state: Lódzkie
city: Gdansk
country: Poland
facility: Investigational Site Number :6160008
state: Pomorskie
city: Chorzow
country: Poland
facility: Investigational Site Number :6160005
state: Slaskie
city: Barcelona
country: Spain
facility: Investigational Site Number :7240004
state: Barcelona [Barcelona]
city: Barcelona
country: Spain
facility: Investigational Site Number :7240001
state: Barcelona [Barcelona]
city: Pamplona
country: Spain
facility: Investigational Site Number :7240006
state: Navarra
city: Valencia
country: Spain
facility: Investigational Site Number :7240002
state: Valenciana, Comunidad
city: Madrid
country: Spain
facility: Investigational Site Number :7240005
city: Salamanca
country: Spain
facility: Investigational Site Number :7240007
city: Zaragoza
country: Spain
facility: Investigational Site Number :7240003
city: Göteborg
country: Sweden
facility: Investigational Site Number :7520001
city: Helsingborg
country: Sweden
facility: Investigational Site Number :7520003
city: Ankara
country: Turkey
facility: Investigational Site Number : 7920005
city: Ankara
country: Turkey
facility: Investigational Site Number : 7920001
city: Istanbul
country: Turkey
facility: Investigational Site Number : 7920004
city: Istanbul
country: Turkey
facility: Investigational Site Number : 7920002
city: Izmir
country: Turkey
facility: Investigational Site Number : 7920003
city: Bournemouth
country: United Kingdom
facility: Investigational Site Number :8260002
state: Hampshire
city: London
country: United Kingdom
facility: Investigational Site Number :8260003
state: London, City Of
city: Leicester
country: United Kingdom
facility: Investigational Site Number :8260001
city: Southampton
country: United Kingdom
facility: Investigational Site Number :8260004
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References: