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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT04751877




Registration number
NCT04751877
Ethics application status
Date submitted
4/02/2021
Date registered
12/02/2021
Date last updated
7/09/2022

Titles & IDs
Public title
Multicenter Open Label Phase 3 Study of Isatuximab Plus Lenalidomide and Dexamethasone With/Without Bortezomib in the Treatment of Newly Diagnosed Non Frail Transplant Ineligible Multiple Myeloma Elderly Patients (= 65; < 80 Years).
Scientific title
Multicenter Open Label Phase 3 Study of Isatuximab Plus Lenalidomide and Dexamethasone With/Without Bortezomib in the Treatment of Newly Diagnosed Non Frail Transplant Ineligible Multiple Myeloma Elderly Patients (= 65; < 80 Years).
Secondary ID [1] 0 0
BENEFIT - IFM2020-05
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Multiple Myeloma 0 0
Myeloma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Other cancer types

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Isatuximab
Treatment: Drugs - Lenalidomide
Treatment: Drugs - Bortezomib
Treatment: Drugs - Dexamethasone

Experimental: Isatuximab/Lenalidomide/Dexamethasone/Bortezomib -

Active Comparator: Isatuximab/Lenalidomide/Dexamethasone -


Treatment: Drugs: Isatuximab
Isatuximab by IV route, per 28 days cycle - Cycle1: 10 mg/kg on days 1, 8, 15, and 22. Cycles 2 to 12: 10 mg/kg on days 1 and 15. From cycle 13: 10 mg/kg on day 1.

Treatment: Drugs: Lenalidomide
Lenalidomide by oral route, per 28 days cycle - 25 mg daily on days 1-21.

Treatment: Drugs: Bortezomib
Bortezomib sub-cutaneous, per 28 days cycle - Cycles 1 to 12: 1.3 mg/m2 on days 1, 8, 15. Cycles 13-18: 1.3 mg/m2 on days 1, 15.

Treatment: Drugs: Dexamethasone
Dexamethasone by oral route, per 28 days cycle - 20 mg daily on days 1, 8, 15 and 22.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Minimal Residual Disease (MRD) rate at 10-5 at 18 months
Timepoint [1] 0 0
at 18 months
Secondary outcome [1] 0 0
Safety of trial treatments
Timepoint [1] 0 0
Up to 5 years
Secondary outcome [2] 0 0
To determine the best response to the treatment
Timepoint [2] 0 0
Up to 5 years
Secondary outcome [3] 0 0
Progression Free survival
Timepoint [3] 0 0
Up to 5 years
Secondary outcome [4] 0 0
To determine the time to reach MRD negative rate at 10-5
Timepoint [4] 0 0
Up to 5 years
Secondary outcome [5] 0 0
To determine the time to loss of MRD negative rate at 10-5
Timepoint [5] 0 0
Up to 5 years
Secondary outcome [6] 0 0
To evaluate the MRD rate at 10-5 at 12 months, and yearly (and at 10-6)
Timepoint [6] 0 0
Up to 5 years
Secondary outcome [7] 0 0
To determine the rate of loss of MRD at 10-5 at each time point
Timepoint [7] 0 0
Up to 5 years
Secondary outcome [8] 0 0
To determine the sustained MRD rate at 10-5 (similar time points)
Timepoint [8] 0 0
Up to 5 years

Eligibility
Key inclusion criteria
Must be able to understand and voluntarily sign an informed consent form

- Life expectancy > 6 months

- Subject, male or female, must be at least = 65 years of age and < 80 years of age

- Must have a Newly diagnosed Multiple Myeloma requiring therapy (SLiM CRAB criteria)

- Must have measurable disease

- Must be Non Transplant Eligible Non Frail

- Newly diagnosed and not considered candidate for high-dose hemotherapy with SCT.

- Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2

- Adequate bone marrow function, documented within 72 hours and without transfusion 72
hours prior to the first intake of investigational product (C1J1) with no growth
factor support (one week),

- Adequate organ function defined as:

- Subjects affiliated with an appropriate social security system.

- A man who is sexually active with a pregnant woman or a woman of childbearing
potential must agree to use a barrier method of birth control e.g., condom with
spermicidal foam/gel/film/cream/suppository during the study and for at least 5 months
after the last dose of treatment, even he has had a vasectomy.

- A female participant is eligible to participate if she is not pregnant, not
breastfeeding, and at least one of the following conditions applies:

Not a female of childbearing potential Or A FCBP who must have a negative serum or urine
pregnancy test with a sensitivity of at least 25 mIU/mL within 10 - 14 days prior to and
again within 24 hours prior to starting study medication and before each cycle of study
treatment.

A FCBP must understand and agree to continue abstinence from heterosexual intercourse or to
use 2 reliable effective methods of contraception (a very effective method and an effective
additional method) simultaneously without interruption

- All patients must understand and accept to comply with the conditions of the
lenalidomide pregnancy prevention plan
Minimum age
65 Years
Maximum age
79 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Subject has a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined
significance, or smoldering multiple myeloma. Monoclonal gammopathy of undetermined
significance is defined by presence of serum M-protein <3 g/dL; absence of lytic bone
lesions, anemia, hypercalcemia, and renal insufficiency related to the M-protein; and
(if determined) proportion of plasma cells in the bone marrow of 10% or less (Kyle
2003). Smoldering multiple myeloma is defined as asymptomatic multiple myeloma with
absence of related organ or tissue impairment end organ damage (Kyle 2003, Kyle 2007).

- Subject has a diagnosis of Waldenstro¨m's disease, or other conditions in which IgM
M-protein is present in the absence of a clonal plasma cell infiltration with lytic
bone lesions.

- Subject has prior or current systemic therapy or SCT for multiple myeloma, with the
exception of an emergency use of a short course (equivalent of dexamethasone 40 mg/day
for a maximum 4 days) of corticosteroids before treatment.

- Subject has a history of malignancy (other than multiple myeloma) within 3 years
before the date of randomization (exceptions are squamous and basal cell carcinomas of
the skin and carcinoma in situ of the cervix, or malignancy that in the opinion of the
investigator, with concurrence with the Coordinator Investigator, is considered cured
with minimal risk of recurrence within 3 years).

- Subject has had radiation therapy within 7 days of randomization.

- Subject has had plasmapheresis within 7 days of randomization.

- Subject is exhibiting clinical signs of meningeal involvement of multiple myeloma.

- Subject known to be seropositive for history of human immunodeficiency virus (HIV) or
to have hepatitis A active infection.

- Known to have hepatitis B active or uncontrolled infection (positive HBsAg and/or HBV
DNA)

- 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.

o • 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.

• Known to have hepatitis C active infection (positive HCV RNA and negative anti-HCV)
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.

- Subject has any clinically significant medical or psychiatric condition or disease
(e.g., uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) in the
investigator's opinion, would expose the patient to excessive risk or may interfere
with compliance or interpretation of the study results.

- Subject has active systemic infection and severe infections requiring treatment with a
parenteral administration of antibiotics.

- Subject has clinically significant cardiac disease,

- Subject has known allergies, hypersensitivity, or intolerance to steroids, mannitol,
pregelatinized starch, sodium stearyl fumarate, histidine (as base and hydrochloride
salt), arginine hydrochloride, poloxamer 188, sucrose or any of the other components
of study intervention that are not amenable to premedication with steroids and H2
blockers or would prohibit further treatment with these agents, monoclonal antibodies
or human proteins, or their excipients.

- Known hypersensitivity, allergy to one of the study product (isatuximab, lenalidomide,
bortezomib), dexamethasone or to one of the excipients

- Acute diffuse infiltrative pneumopathy, pericardial disease

- Subject has plasma cell leukemia.

- Subject has had major surgery within 2 weeks before randomization or has not fully
recovered from surgery, Kyphoplasty or vertebroplasty is not considered major surgery.

- Subject has received an investigational drug (including investigational vaccines)
within 14 days or 5 half-lives of the investigational drug prior to initiation of
study intervention, whichever is longer, or used an invasive investigational medical
device within 4 weeks before randomization or is currently enrolled in an
interventional investigational study.

In case of very aggressive disease (i.e acute leukemia) delay could be shortened after
agreement between sponsor and investigator, in absence of residual toxicities from previous
therapy.

- Refusal to consent or protected by legal regime (under judicial protection,
guardianship, trusteeship)

- Subject has contraindications to required prophylaxis for deep vein thrombosis and
pulmonary embolism

- Incidence of gastrointestinal disease that may significantly alter the absorption of
oral drugs.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
17/07/2021
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
17/08/2027
Actual
Sample size
Target
Accrual to date
Final
270
Recruitment in Australia
Recruitment state(s)
Recruitment outside Australia
Country [1] 0 0
France
State/province [1] 0 0
Poitiers

Funding & Sponsors
Primary sponsor type
Other
Name
Poitiers University Hospital
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
Intergroupe Francophone du Myelome
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Commercial sector/Industry
Name [2] 0 0
Sanofi
Address [2] 0 0
Country [2] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
Overall the issue of patients above 65-70 years of age being that it is impossible for most
of them to undergo an intensive treatment like autologous stem cell transplant with little
prospect of debulking effectively the bone marrow with chemotherapy, and also few
possibilities to harass the bone microenvironment in the tumoral niche.

If, advanced age in frail patients is predictive of an increased risk of treatment-related
toxicity, there is a growing number of elderly patients in regards to transplantation, but
still fit if one considers the objectives of life characterized with prolonged survival.
These patients might have the same treatment as to the transplant eligible, but without the
transplant procedure. The development of immunotherapy has transformed the treatment
landscape of cancer, particularly in MM, increasing the treatment possibilities with possibly
fewer adverse events.

The therapeutic strategy and treatment options for NTE patients moved from melphalan-based
induction regimens to lenalidomide-based associations, which is now the backbone of most
treatment for NTE patients. Even though the latest melphalan, bortezomib and prednisone (MPV)
association was considered somewhat effective it was not so well tolerated. Furthermore, MPV
hardly prolonged PFS beyond 2 years. It was recently improved with the addition of
Daratumumab, first in class anti CD38 Mab in the phase III ALCYONE.

The association lenalidomide and dexamethasone (Rd) has significantly improved the easiness
of treating the NTE population and all drugs seem to be possible to combine to Rd. In that
extent, proteasome inhibitors have always been one of the most impactful family of agents in
MM, and as expected Bortezomib plus Rd has become a very relevant and commonly used regimen
in NTE NDMM. These groundbreaking results have favored the development of 2 randomized phase
3 studies for registration of combination of antiCD38Mab (Daratumumab (Cepheus, NCT03652064),
Isatuximab (Imroz, NCT03319667) +Rd +Velcade in comparison to VRd. Both studies have used as
a comparator the VRd regimen which is today one of the safest, active and popular triplet
based Rd regimen, approved, and therefore the best control arm possibly for these studies.

However, as much as there has been no direct head to head comparison of VRd to Dara Rd, when
looking at the data from Maia it is anticipated that DRd will become a standard of care, and
might challenge strongly VRd. Yet, multiple questions remain still, anticipating the change
in backbone from VRd to antiCD38 +Rd becoming the new standard of care for NTE NDMM patients.
The investigators have therefore planned to answer the critical question of the role of
proteasome inhibitors in NTE non frail NDMM when considering anti CD38 +Rd as the backbone.
Trial website
https://clinicaltrials.gov/ct2/show/NCT04751877
Trial related presentations / publications
Public notes
This record is viewable in the ANZCTR as it had previously listed Australia and/or New Zealand as a recruitment site, however these sites have since been removed

Contacts
Principal investigator
Name 0 0
LELEU Xavier, Prof.
Address 0 0
Poitiers University Hospital
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT04751877