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

• Sponsor: Sanofi (Industry)
• Overall Status: Recruiting
• CT.gov ID: NCT04270409
• Collaborator: (none)
• Enrollment: 300
• Locations: 106
• Arms: 2
• Anticipated Duration (Months): 159.5
• Patients Per Site: 2.8
• Patients Per Site Per Month: 0

Study Details

Study Description

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)

Condition or Disease	Intervention/Treatment	Phase
Plasma Cell Myeloma	Drug: Isatuximab SAR650984; Drug: Lenalidomide; Drug: Dexamethasone	Phase 3

Detailed Description

Study duration is expected to be approximately 10 years, including a 28-day screening period, followed by an up to 36-month treatment period, and a follow-up period of approximately 7 years.

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 300 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: Jun 16, 2020
• Anticipated Primary Completion Date: Jun 1, 2028
• Anticipated Study Completion Date: Oct 1, 2033

Arms and Interventions

Arm	Intervention/Treatment
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	Drug: Isatuximab SAR650984; Pharmaceutical for: Solution for infusion Route of administration: Intravenous; Other Names: Sarclisa ; Drug: Lenalidomide; Pharmaceutical form: Capsules Route of administration: Oral; Drug: Dexamethasone; Pharmaceutical form: Tablets and solution for injection Route of administration: Oral and intravenous
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	Drug: Lenalidomide; Pharmaceutical form: Capsules Route of administration: Oral; Drug: Dexamethasone; Pharmaceutical form: Tablets and solution for injection Route of administration: Oral and intravenous

Outcome Measures

Primary Outcome Measures

1. Plasma concentration of isatuximab: Cmax [Up to approximately 24 months]

   Maximum concentration observed after the first infusion (Cmax)

2. Receptor density/receptor occupancy (safety run-in) [Baseline to Cycle 2 Day 1 (each cycle is 28 days)]

   Change in CD38 receptor occupancy from baseline

3. Progression-free survival (PFS) randomized Phase 3 [Up to approximately 85 months]

   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

Secondary Outcome Measures

1. Overall response rate (ORR) [Up to approximately 85 months]

   Proportion of participants with best overall response recorded as partial response or better according to 2016 IMWG criteria

2. Duration of response (DOR) [Up to approximately 85 months]

   Time from the date of the first response to date of progressive disease or death, whichever happens first

3. Minimal residual disease (MRD) negativity [Up to approximately 85 months]

   Number of participants for whom MRD is negative

4. Time to diagnostic (SLiM CRAB) progression or death [Up to approximately 85 months]

   Time from randomization to diagnosis of SLiM-CRAB or other related conditions, progression, or death from any cause

5. Time to first-line treatment for multiple myeloma (MM) [Up to approximately 85 months]

   Time from randomization to first-line treatment for MM

6. Immunogenicity: Incidence of anti-drug antibodies (ADA) [Up to approximately 24 months]

   Number of participants with anti-drug antibodies against isatuximab

7. Sustained MRD negativity [Up to approximately 85 months]

   Number of participants with sustained MRD negativity (sample is still negative at least 1 year after the first negativity assessment)

8. Second PFS (PFS2) [Up to approximately 120 months]

   Time from randomization to date of second objective progressive disease or death from any cause

9. Overall survival [Up to approximately 144 months]

   Time from date of randomization to death from any cause

10. Complete response rate [Up to approximately 85 months]

    Percentage of particpants with a CR as defined by 2016 IMWG response criteria

11. Safety assessment: adverse events (AEs) [Baseline to 30 days after last study treatment administration (up to approximately 100 months after first study treatment)]

    Number of participants with AEs

12. Plasma concentration of isatuximab [Up to approximately 24 months]

    Maximum concentration observed after the first infusion (Cmax)

13. European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 [Baseline to follow-up (up to approximately 10 years)]

    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

14. EORTC QLQ-MY20 [Baseline to follow-up (up to approximately 10 years)]

    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

15. EQ-5D-5L [Baseline to follow-up (up to approximately 10 years)]

    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

16. Economic questionnaire [Baseline to follow-up (up to approximately 10 years)]

    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

17. Patient's Qualitative Assessment of Treatment Version 2 (PQAT-v2) [End of treatment (up to approximately 10 years)]

    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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 (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 potential participation in a clinical trial.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Investigational Site Number :8400007	Denver	Colorado	United States	80218
2	Investigational Site Number :8400011	Jacksonville	Florida	United States	32256
3	Investigational Site Number :8400012	Miami	Florida	United States	33136
4	Investigational Site Number :8400001	Boston	Massachusetts	United States	02115
5	Investigational Site Number :8400008	Boston	Massachusetts	United States	02215
6	Investigational Site Number :8400015	Charlotte	North Carolina	United States	28204
7	Investigational Site Number :8400006	Nashville	Tennessee	United States	37203
8	Investigational Site Number :8400002	Houston	Texas	United States	77030
9	Investigational Site Number :0360008	Liverpool	New South Wales	Australia	2170
10	Investigational Site Number :0360005	Waratah	New South Wales	Australia	2298
11	Investigational Site Number :0360001	Wollongong	New South Wales	Australia	2500
12	Investigational Site Number :0360002	Fitzroy	Victoria	Australia	3065
13	Investigational Site Number :0360007	Heidelberg West	Victoria	Australia	3081
14	Investigational Site Number :0360004	Richmond	Victoria	Australia	3121
15	Investigational Site Number :0360006	Nedlands	Western Australia	Australia	6009
16	Investigational Site Number :0760002	Sao Paulo	São Paulo	Brazil	04537-081
17	Investigational Site Number :1240004	Edmonton	Alberta	Canada	T6G 1Z2
18	Investigational Site Number :1240005	Moncton	New Brunswick	Canada	E1C 6Z8
19	Investigational Site Number :1240001	Montreal	Quebec	Canada	H1T 2M4
20	Investigational Site Number :1560002	Hangzhou		China	310003
21	Investigational Site Number :1560003	Hangzhou		China	310003
22	Investigational Site Number :1560006	Nanchang		China	330006
23	Investigational Site Number :1560004	Shanghai		China	200032
24	Investigational Site Number :1560005	Shenyang		China	110022
25	Investigational Site Number :1560001	Tianjin		China	300020
26	Investigational Site Number :2030004	Brno		Czechia	62500
27	Investigational Site Number :2030005	Hradec Kralove		Czechia	50005
28	Investigational Site Number :2030002	Olomouc		Czechia	77900
29	Investigational Site Number :2030003	Ostrava - Poruba		Czechia	70852
30	Investigational Site Number :2030001	Praha 2		Czechia	12808
31	Investigational Site Number :2080001	Aalborg		Denmark	9000
32	Investigational Site Number :2080003	Aarhus N		Denmark	8200
33	Investigational Site Number :2080005	Hellerup		Denmark	2900
34	Investigational Site Number :2080002	Roskilde		Denmark	4000
35	Investigational Site Number :2500009	Ars-Laquenexy		France	57085
36	Investigational Site Number :2500010	Bayonne Cedec		France	64109
37	Investigational Site Number :2500007	GRENOBLE Cedex 9		France	38043
38	Investigational Site Number :2500006	La Roche sur Yon		France	85925
39	Investigational Site Number :2500003	Lille		France	59037
40	Investigational Site Number :2500005	Paris		France	75012
41	Investigational Site Number :2500011	Paris		France	75013
42	Investigational Site Number :2500002	Poitiers Cedex		France	86021
43	Investigational Site Number :2500001	RENNES Cedex 09		France	35033
44	Investigational Site Number :2760001	Hamburg		Germany	20246
45	Investigational Site Number :2760002	Heidelberg		Germany	69120
46	Investigational Site Number :3000002	Athens		Greece	10676
47	Investigational Site Number :3000001	Athens		Greece	11528
48	Investigational Site Number :3000003	Thessaloniki		Greece	PC 54007
49	Investigational Site Number :3480003	Budapest		Hungary	1083
50	Investigational Site Number :3480001	Budapest		Hungary	1097
51	Investigational Site Number :3480002	Debrecen		Hungary	4032
52	Investigational Site Number :3480004	Kaposvár		Hungary	7400
53	Investigational Site Number :3720003	Dublin 7	Dublin	Ireland
54	Investigational Site Number :3720002	Dublin 8	Dublin	Ireland
55	Investigational Site Number :3720001	Dublin 9	Dublin	Ireland
56	Investigational Site Number :3760004	Ashdod		Israel	7747629
57	Investigational Site Number :3760001	Jerusalem		Israel	91031
58	Investigational Site Number :3760002	Jerusalem		Israel	91120
59	Investigational Site Number :3760005	Petah-Tikva		Israel	49100
60	Investigational Site Number :3760003	Tel Aviv		Israel	64239
61	Investigational Site Number :3800006	Meldola	Forlì-Cesena	Italy	47014
62	Investigational Site Number :3800001	Rozzano	Milano	Italy	20089
63	Investigational Site Number :3800005	Ancona		Italy	60032
64	Investigational Site Number :3800003	Bologna		Italy	40138
65	Investigational Site Number :3800002	Terni		Italy	05100
66	Investigational Site Number :3920002	Nagoya-shi	Aichi	Japan	467-8602
67	Investigational Site Number :3920006	Kamogawa-shi	Chiba	Japan	296-8602
68	Investigational Site Number :3920008	Maebashi-shi	Gunma	Japan	371-8511
69	Investigational Site Number :3920010	Sapporo-shi	Hokkaido	Japan	060-8543
70	Investigational Site Number :3920005	Higashiibaraki-gun	Ibaraki	Japan	311-3193
71	Investigational Site Number :3920004	Konan-ku, Yokohama-shi	Kanagawa	Japan	234-0054
72	Investigational Site Number :3920003	Okayama-shi	Okayama	Japan	701-1192
73	Investigational Site Number :3920007	Osaka-shi	Osaka	Japan	543-8555
74	Investigational Site Number :3920009	Sunto-gun	Shizuoka	Japan	411-8777
75	Investigational Site Number :3920001	Shibuya-ku	Tokyo	Japan	150-8935
76	Investigational Site Number :4100004	Gangnam-gu	Seoul-teukbyeolsi	Korea, Republic of	06351
77	Investigational Site Number :4100001	Seoul	Seoul-teukbyeolsi	Korea, Republic of	03722
78	Investigational Site Number :4100003	Seoul	Seoul-teukbyeolsi	Korea, Republic of	110-744
79	Investigational Site Number :4100002	Seoul		Korea, Republic of	06591
80	Investigational Site Number :4400001	Vilnius		Lithuania	08661
81	Investigational Site Number :5540004	Christchurch	Canterbury	New Zealand
82	Investigational Site Number :5540001	Hamilton	Waikato	New Zealand	3204
83	Investigational Site Number :5540003	Auckland		New Zealand	1023
84	Investigational Site Number :5780002	Bergen		Norway	5021
85	Investigational Site Number :5780001	Oslo		Norway	0450
86	Investigational Site Number :6160006	Bydgoszcz	Kujawsko-pomorskie	Poland	85-168
87	Investigational Site Number :6160002	Lodz	Lódzkie	Poland	93-510
88	Investigational Site Number :6160008	Gdansk	Pomorskie	Poland	80-214
89	Investigational Site Number :6160005	Chorzow	Slaskie	Poland	41-500
90	Investigational Site Number :7240004	Barcelona	Barcelona [Barcelona]	Spain	08036
91	Investigational Site Number :7240001	Barcelona	Barcelona [Barcelona]	Spain	08041
92	Investigational Site Number :7240005	Madrid	Madrid, Comunidad De	Spain	28041
93	Investigational Site Number :7240006	Pamplona	Navarra	Spain	31008
94	Investigational Site Number :7240002	Valencia	Valenciana, Comunidad	Spain	46017
95	Investigational Site Number :7240007	Salamanca		Spain	37007
96	Investigational Site Number :7240003	Zaragoza		Spain	50009
97	Investigational Site Number :7520001	Göteborg		Sweden	413 45
98	Investigational Site Number :7520003	Helsingborg		Sweden	251 87
99	Investigational Site Number :7920005	Ankara		Turkey	06010
100	Investigational Site Number :7920001	Ankara		Turkey
101	Investigational Site Number :7920004	Istanbul		Turkey	34214
102	Investigational Site Number :7920002	Istanbul		Turkey	34390
103	Investigational Site Number :7920003	Izmir		Turkey	35040
104	Investigational Site Number :8260002	Bournemouth	Hampshire	United Kingdom	BH7 7DW
105	Investigational Site Number :8260003	London	London, City Of	United Kingdom	SE1 7EH
106	Investigational Site Number :8260001	Leicester		United Kingdom	LE15WW

Sponsors and Collaborators

• Sanofi

Investigators

• Study Director: Clinical Sciences & Operations, Sanofi

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT04270409
• Other Study ID Numbers: EFC15992; 2019-003139-47; U1111-1222-7068
• First Posted: Feb 17, 2020
• Last Update Posted: Jul 6, 2022
• Last Verified: Jul 4, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Sanofi: Anti-CD38 monoclonal antibody
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Smoldering Multiple Myeloma; Dexamethasone; Lenalidomide

Study Results

No Results Posted as of Jul 6, 2022