IMROZ: Clinical Benefit of SAR650984, Bortezomib, Lenalidomide and Dexamethasone Combination in NDMM Patients Not Eligible for Transplant

Sponsor

Sanofi (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT03319667

Collaborator

(none)

475

Enrollment

104

Locations

Arms

114.7

Anticipated Duration (Months)

4.6

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Primary Objective:

-To demonstrate the benefit of isatuximab in combination with bortezomib, lenalidomide, and dexamethasone in the prolongation of progression free survival (PFS) as compared to bortezomib, lenalidomide, and dexamethasone, in patients with newly diagnosed multiple myeloma (NDMM) not eligible for transplant.

Secondary Objectives:

To evaluate in both randomized (isatuximab, bortezomib, lenalidomide and dexamethasone combination (IVRd) and bortezomib, lenalidomide and dexamethasone combination (VRd)) arms:
Complete response (CR) rate, as defined by the International Myeloma Working Group (IMWG) criteria.
Minimal residual disease (MRD) negativity rate in patients with CR.
Very good partial response or better rate, as defined by the IMWG criteria.
Overall survival (OS).
To evaluate the overall response rate (ORR) as per IMWG criteria.
To evaluate the time to progression (TTP) overall and by MRD status.
To evaluate PFS by MRD status.
To evaluate the duration of response (DOR) overall and by MRD status.
To evaluate time to first response (TT1R).
To evaluate time to best response (TTBR).
To evaluate progression-free survival on next line of therapy (PFS2).
To evaluate the sustained MRD negativity >12 months rate.
To evaluate safety.
To determine the pharmacokinetic (PK) profile of isatuximab in combination with bortezomib, lenalidomide, and dexamethasone (IVRd arm only).
To evaluate the immunogenicity of isatuximab in patients receiving isatuximab (IVRd and crossover arms).
To assess disease-specific and generic health-related quality of life (HRQL), disease and treatment-related symptoms, health state utility, and health status.

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

Detailed Description

The duration of the study for each patient will include a screening period of up to 4 weeks, an induction period of 24 weeks (4 cycles with a duration of 42 ± 3 days), a continuous treatment period and a crossover period (when applicable). The cycle duration is 28 ± 3 days during the continuous treatment and crossover periods.

Study Design

Study Type:

Interventional

Actual Enrollment :

475 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Parallel and crossoverParallel and crossover

Masking:

Single (Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

A Phase 3 Randomized, Open-label, Multicenter Study Assessing the Clinical Benefit of Isatuximab (SAR650984) in Combination With Bortezomib (Velcade®), Lenalidomide and Dexamethasone Versus Bortezomib, Lenalidomide and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma Not Eligible for Transplant

Actual Study Start Date :

Dec 7, 2017

Anticipated Primary Completion Date :

Dec 1, 2022

Anticipated Study Completion Date :

Jun 30, 2027

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Isatuximab/Bortezomib/Lenalidomide/Dexamethasone = IVRd arm Induction treatment with 4x6-week cycles with intravenous (IV) isatuximab + subcutaneous (SC) bortezomib + oral lenalidomide + IV or oral dexamethasone Continuous treatment with 4-week cycles with IV isatuximab + oral lenalidomide + IV or oral dexamethasone	Drug: Isatuximab SAR650984 Pharmaceutical form: Solution for infusion Route of administration: Intravenous (IV) Other Names: Sarclisa Drug: Bortezomib Pharmaceutical form: Lyophilized powder for injection Route of administration: Intravenous/Subcutaneous Other Names: Velcade® Drug: Lenalidomide Pharmaceutical form: Capsules Route of administration: Oral Drug: Dexamethasone Pharmaceutical form: Tablets, ampoules or vials for injection Route of administration: Oral/Intravenous
Active Comparator: Bortezomib/Lenalidomide/Dexamethasone = VRd arm Induction treatment with 4x6-week cycles with SC bortezomib + oral lenalidomide + IV or oral dexamethasone Continuous treatment with 4-week cycles with oral lenalidomide + IV or oral dexamethasone	Drug: Bortezomib Pharmaceutical form: Lyophilized powder for injection Route of administration: Intravenous/Subcutaneous Other Names: Velcade® Drug: Lenalidomide Pharmaceutical form: Capsules Route of administration: Oral Drug: Dexamethasone Pharmaceutical form: Tablets, ampoules or vials for injection Route of administration: Oral/Intravenous
Other: Isatuximab/Lenalidomide/Dexamethasone = IRd crossover arm 4-weeks cycles with IV isatuximab + oral lenalidomide + IV or oral dexamethasone	Drug: Isatuximab SAR650984 Pharmaceutical form: Solution for infusion Route of administration: Intravenous (IV) Other Names: Sarclisa Drug: Lenalidomide Pharmaceutical form: Capsules Route of administration: Oral Drug: Dexamethasone Pharmaceutical form: Tablets, ampoules or vials for injection Route of administration: Oral/Intravenous

Arm

Intervention/Treatment

Experimental: Isatuximab/Bortezomib/Lenalidomide/Dexamethasone = IVRd arm

Induction treatment with 4x6-week cycles with intravenous (IV) isatuximab + subcutaneous (SC) bortezomib + oral lenalidomide + IV or oral dexamethasone Continuous treatment with 4-week cycles with IV isatuximab + oral lenalidomide + IV or oral dexamethasone

Drug: Isatuximab SAR650984

Pharmaceutical form: Solution for infusion Route of administration: Intravenous (IV)

Other Names:

Sarclisa

Drug: Bortezomib

Pharmaceutical form: Lyophilized powder for injection Route of administration: Intravenous/Subcutaneous

Other Names:

Velcade®

Drug: Lenalidomide

Pharmaceutical form: Capsules Route of administration: Oral

Drug: Dexamethasone

Pharmaceutical form: Tablets, ampoules or vials for injection Route of administration: Oral/Intravenous

Active Comparator: Bortezomib/Lenalidomide/Dexamethasone = VRd arm

Induction treatment with 4x6-week cycles with SC bortezomib + oral lenalidomide + IV or oral dexamethasone Continuous treatment with 4-week cycles with oral lenalidomide + IV or oral dexamethasone

Drug: Bortezomib

Pharmaceutical form: Lyophilized powder for injection Route of administration: Intravenous/Subcutaneous

Other Names:

Velcade®

Drug: Lenalidomide

Pharmaceutical form: Capsules Route of administration: Oral

Drug: Dexamethasone

Pharmaceutical form: Tablets, ampoules or vials for injection Route of administration: Oral/Intravenous

Other: Isatuximab/Lenalidomide/Dexamethasone = IRd crossover arm

4-weeks cycles with IV isatuximab + oral lenalidomide + IV or oral dexamethasone

Drug: Isatuximab SAR650984

Pharmaceutical form: Solution for infusion Route of administration: Intravenous (IV)

Other Names:

Sarclisa

Drug: Lenalidomide

Pharmaceutical form: Capsules Route of administration: Oral

Drug: Dexamethasone

Pharmaceutical form: Tablets, ampoules or vials for injection Route of administration: Oral/Intravenous

Outcome Measures

Primary Outcome Measures

Progression free survival (PFS) [Up to approximately 60 months after the first patient in (FPI) or scheduled assessment]
defined as the time from the date of randomization to the date of first documentation of progression disease (PD) as determined by the independent review committee (IRC) or the date of death from any cause, whichever occurs first.

Secondary Outcome Measures

Complete response rate (CR) [Up to approximately 60 months after the first patient in (FPI) or scheduled assessment]
defined as the proportion of patients with CR and stringent complete response (sCR) as assessed by the IRC using the IMWG criteria.
Minimal residual disease (MRD) negativity rate for patients with CR [Up to approximately 60 months after the first patient in (FPI) or scheduled assessment]
Proportion of patients with CR for whom MRD measurement is negative
Very good partial response (VGPR) or better rate [Up to approximately 60 months after the first patient in (FPI) or scheduled assessment]
Proportion of patients with sCR, CR and VGPR as assessed by the IRC using the International Myeloma Working Group (IMWG) criteria
Overall survival (OS) [Up to approximately 60 months after the first patient in (FPI) or scheduled assessment]
defined as the time from the date of randomization to death from any cause
Overall response rate (ORR) [Up to approximately 60 months after the first patient in (FPI) or scheduled assessment]
Proportion of patients with best overall response (BOR) recorded as sCR, CR, VGPR, or partial response (PR) as assessed by the IRC using the IMWG criteria
Time to progression (TTP) [Up to approximately 60 months after the first patient in (FPI) or scheduled assessment]
Defined as the time from randomization to date of first documentation of PD as assessed by the IRC using the IMWG criteria
Duration of response (DOR) [Up to approximately 60 months after the first patient in (FPI) or scheduled assessment]
Defined as the time from date of first IRC determined response to date of first IRC PD or death, whichever occurs first for patients achieving sCR, CR, VGPR, or PR
Time to first response (TT1R) [Up to approximately 60 months after the first patient in (FPI) or scheduled assessment]
Time from randomization to the first IRC determined response (PR or better) that is subsequently confirmed
Time to best response (TTBR) [Up to approximately 60 months after the FPI or scheduled assessment]
Defined as the time from randomization to the date of first occurrence of IRC determined best response (PR or better) that is subsequently confirmed
PFS on next line of therapy (PFS2) [At 4 years after cutoff for primary PFS analysis]
Defined as the time from randomization to the date of first documentation of disease progression (as assessed by investigator) after initiation of further anti-myeloma treatment, or death from any cause, whichever occurs first
PFS in MRD negative patients [Up to approximately 60 months after the FPI or scheduled assessment]
Defined as the time from the date of randomization to the date of first documentation of PD or the date of death from any cause, whichever comes first in MRD negative patients
Sustained MRD negativity ≥12 months rate [Up to approximately 60 months after the FPI or scheduled assessment]
defined as the proportion of patients with the maintenance of MRD negativity confirmed ≥12 months apart with no MRD positive test in between.
Adverse Events [Up to 30 days after end of treatment (EOT) visit]
Treatment-emergent adverse events/serious adverse events (TEAEs/SAEs) including infusion associated reactions (IARs), second primary malignancies, laboratory parameters, vital signs, weight, ECOG PS, and findings from physical examination
Assessment of PK parameter: Ctrough [Cycle 1 Day 8/Day 15/Day 29 (pre-dose) and Day 1 (pre-dose) of Cycle 2, 3, 4, 5, 6, 7, 8, 9 and 10 (Duration of each cycle for Cycles 1-4: 6 weeks; Duration of each cycle for Cycles 5-10: 4 weeks)]
Isatuximab: Pre-dose plasma isatuximab concentration (Ctrough)
Assessment of PK parameter: AUC [Cycle 1 Day 1 to Day 29]
Isatuximab: Cumulative area under the plasma isatuximab concentration versus time curve (AUC)
Assessment of PK parameter: CL [Cycle 1 Day 1 to Cycle 10 Day 1 (Duration of each cycle for Cycles 1-4: 6 weeks; Duration of each cycle for Cycles 5-10: 4 weeks)]
Isatuximab: Clearance (CL) for linear non-specific elimination pathway
Immunogenicity [Up to approximately 60 months after the FPI or scheduled assessment]
Levels of isatuximab anti-drug antibodies
Patient reported outcome (PRO): QLQ-C30 [Up to approximately 60 months after the FPI or scheduled assessment]
Disease-specific HRQL will be assessed using the European Organization for Research and Treatment of Cancer (EORTC) core quality of life questionnaire (QLQ-C30)
PRO: QLQ-MY20 [Up to approximately 60 months after the FPI or scheduled assessment]
Disease- and treatment-related quality of life will be assessed using the EORTC myeloma module (QLQ-MY20) questionnaire
PRO: EQ-5D-5L [Up to approximately 60 months after the FPI or scheduled assessment]
Health state utility and health status will be assessed using the European Quality of Life Group questionnaire with 5 dimensions and 5 levels per dimension (EQ-5D-5L)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Inclusion criteria :

Multiple myeloma (IMWG criteria).
Newly diagnosed multiple myeloma not eligible for transplant due to age (≥ 65 years) or patients < 65 years with comorbidities impacting possibility of transplant.
Evidence of measurable disease.
Written informed consent.

Exclusion Criteria:

Exclusion criteria:

Age < 18 years.
Prior treatment for multiple myeloma.
Any other prior or ongoing disease/health conditions incompatible with the study objectives.
Organ function values not met.
Eastern Cooperative Oncology Group (ECOG) Performance Status ( PS) > 2.
Hypersensitivity to the study medications.
Pregnant, breastfeeding, or woman of child bearing potential unwilling to use recommended contraception methods.
Male participants who disagree to follow the study contraceptive counseling.

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Investigational Site Number :8400006	Fort Myers	Florida	United States	33901
2	Investigational Site Number :8400004	Saint Petersburg	Florida	United States	33705
3	Investigational Site Number :8400007	Kansas City	Missouri	United States	64132
4	Investigational Site Number :8400005	Nashville	Tennessee	United States	37203
5	Investigational Site Number :8400001	Houston	Texas	United States	77030
6	Investigational Site Number :0360003	Liverpool	New South Wales	Australia	2170
7	Investigational Site Number :0360001	Waratah	New South Wales	Australia	2298
8	Investigational Site Number :0360002	Wollongong	New South Wales	Australia	2500
9	Investigational Site Number :0360007	South Brisbane	Queensland	Australia	4101
10	Investigational Site Number :0360005	Clayton	Victoria	Australia	3168
11	Investigational Site Number :0360004	Heidelberg West	Victoria	Australia	3081
12	Investigational Site Number :0360006	Nedlands	Western Australia	Australia	6009
13	Investigational Site Number :0360008	West Perth	Western Australia	Australia	6005
14	Investigational Site Number :0560001	Liège		Belgium	4000
15	Investigational Site Number :1560002	Beijing		China	100034
16	Investigational Site Number :1560003	Beijing		China	100191
17	Investigational Site Number :1560008	Changchun		China	130021
18	Investigational Site Number :1560007	Fuzhou		China	350001
19	Investigational Site Number :1560009	Guangzhou		China	510060
20	Investigational Site Number :1560006	Guangzhou		China	510080
21	Investigational Site Number :1560005	Hangzhou		China	310003
22	Investigational Site Number :1560014	Hangzhou		China	310003
23	Investigational Site Number :1560004	Nanjing		China	210029
24	Investigational Site Number :1560013	Shanghai		China	200025
25	Investigational Site Number :1560011	Shenyang		China	110022
26	Investigational Site Number :1560001	Tianjin		China	300020
27	Investigational Site Number :1560012	Wuhan		China	430022
28	Investigational Site Number :2030002	Brno		Czechia	62500
29	Investigational Site Number :2030007	Hradec Kralove		Czechia	50005
30	Investigational Site Number :2030004	Olomouc		Czechia	77900
31	Investigational Site Number :2030003	Ostrava - Poruba		Czechia	70852
32	Investigational Site Number :2030006	Plzen		Czechia	30599
33	Investigational Site Number :2030001	Praha 2		Czechia	12808
34	Investigational Site Number :2080002	Aalborg		Denmark	9000
35	Investigational Site Number :2080003	Aarhus N		Denmark	8200
36	Investigational Site Number :2080004	Odense C		Denmark	5000
37	Investigational Site Number :2500011	Bayonne		France	64100
38	Investigational Site Number :2500007	Caen		France	14033
39	Investigational Site Number :2500009	Dijon		France	21000
40	Investigational Site Number :2500008	La Roche Sur Yon		France	85925
41	Investigational Site Number :2500001	Lille		France	59037
42	Investigational Site Number :2500003	Nantes		France	44093
43	Investigational Site Number :2500012	Paris		France	75012
44	Investigational Site Number :2500002	Pessac		France	33600
45	Investigational Site Number :2500006	Pierre Benite		France	69495
46	Investigational Site Number :2500005	Poitiers Cedex		France	86021
47	Investigational Site Number :2500004	TOULOUSE Cedex 9		France	31059
48	Investigational Site Number :2500010	Vandoeuvre-les-nancy		France	54511
49	Investigational Site Number :2760003	Berlin		Germany	13125
50	Investigational Site Number :2760004	Frankfurt am Main		Germany	60590
51	Investigational Site Number :2760001	Heidelberg		Germany	69120
52	Investigational Site Number :2760005	Tübingen		Germany	72076
53	Investigational Site Number :3000003	Athens		Greece	10676
54	Investigational Site Number :3000001	Athens		Greece	11528
55	Investigational Site Number :3000002	Thessaloniki		Greece	57010
56	Investigational Site Number :3800005	Ancona		Italy	60032
57	Investigational Site Number :3800003	Bergamo		Italy	24127
58	Investigational Site Number :3800001	Bologna		Italy	40138
59	Investigational Site Number :3800004	Brescia		Italy	25123
60	Investigational Site Number :3800002	Torino		Italy	10126
61	Investigational Site Number :3920007	Nagoya-shi	Aichi	Japan	467-8602
62	Investigational Site Number :3920004	Higashiibaraki-gun	Ibaraki	Japan	311-3193
63	Investigational Site Number :3920008	Konan-ku, Yokohama-shi	Kanagawa	Japan	234-0054
64	Investigational Site Number :3920003	Kumamoto-shi	Kumamoto	Japan	860-8556
65	Investigational Site Number :3920009	Sendai-shi	Miyagi	Japan	983-8520
66	Investigational Site Number :3920005	Okayama-shi	Okayama	Japan	701-1192
67	Investigational Site Number :3920006	Sunto-gun	Shizuoka	Japan	411-8777
68	Investigational Site Number :3920001	Shibuya-ku	Tokyo	Japan	150-8935
69	Investigational Site Number :3920002	Shinjuku-ku	Tokyo	Japan	162-8666
70	Investigational Site Number :3920010	Yamagata-shi		Japan	990-9585
71	Investigational Site Number :4400002	Klaipeda		Lithuania	LT-92288
72	Investigational Site Number :4400001	Vilnius		Lithuania	08661
73	Investigational Site Number :4840001	Monterrey	Nuevo León	Mexico	64460
74	Investigational Site Number :5540002	Takapuna	Auckland	New Zealand	1309
75	Investigational Site Number :5540003	Hamilton	Waikato	New Zealand	3204
76	Investigational Site Number :5540001	Auckland		New Zealand	2025
77	Investigational Site Number :6160003	Lodz	Lódzkie	Poland	93-510
78	Investigational Site Number :6160001	Warszawa	Mazowieckie	Poland	02-781
79	Investigational Site Number :6160002	Gdansk	Pomorskie	Poland	80-952
80	Investigational Site Number :6160004	Poznan	Wielkopolskie	Poland	60-631
81	Investigational Site Number :6200002	Braga		Portugal	4710-243
82	Investigational Site Number :6200006	Coimbra		Portugal	3000-075
83	Investigational Site Number :6200001	Lisboa		Portugal	1070
84	Investigational Site Number :6200005	Porto		Portugal	4200-319
85	Investigational Site Number :6200003	Porto		Portugal	4200
86	Investigational Site Number :6430001	Moscow		Russian Federation	125284
87	Investigational Site Number :6430002	Moscow		Russian Federation	129301
88	Investigational Site Number :7240005	Barcelona	Barcelona [Barcelona]	Spain	08035
89	Investigational Site Number :7240004	Barcelona	Barcelona [Barcelona]	Spain	08041
90	Investigational Site Number :7240003	Madrid		Spain	28034
91	Investigational Site Number :7240001	Murcia		Spain	30008
92	Investigational Site Number :7520002	Lund		Sweden	221 85
93	Investigational Site Number :7520001	Stockholm		Sweden	14186
94	Investigational Site Number :1580003	Changhua		Taiwan	500
95	Investigational Site Number :1580002	Taichung		Taiwan	40447
96	Investigational Site Number :1580001	Taipei		Taiwan	100
97	Investigational Site Number :7920006	Adana		Turkey	01250
98	Investigational Site Number :7920007	Ankara		Turkey	06500
99	Investigational Site Number :7920001	Ankara		Turkey
100	Investigational Site Number :7920002	Istanbul		Turkey	34390
101	Investigational Site Number :7920004	Izmir		Turkey	35040
102	Investigational Site Number :7920003	Izmir		Turkey	35340
103	Investigational Site Number :7920005	Kayseri		Turkey	38039
104	Investigational Site Number :7920008	Samsun		Turkey	55139