IFM2020-05-BENEFIT-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).

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Universitaire De Poitiers

Participant type

Patients

Age range

65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

11 Jun 2021 → ongoing

Decision date (initial)

2024-10-18

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

CHU de Poitiers · SANOFI

External identifiers

EU CT number

2024-517215-67-00

EudraCT number

2020-004602-59

ClinicalTrials.gov

NCT04751877

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy

To evaluate in both arms Minimal Residual Disease (MRD) rate at 10-5 at 18 months of IsRd + V vs IsRd in newly diagnosed NTE Multiple Myeloma in patients.

Secondary objectives 14

1. To determine safety in either arm
2. To determine the best response to the treatment at 6, 12, 18 and yearly in either arm according to the IMWG.
3. To evaluate the MRD rate at 10-5 at 12 months, and yearly (and at 10-6)
4. To determine the sustained MRD rate at 10-5
5. To determine the rate of loss of MRD at 10-5 at each time point
6. To determine the time to reach MRD negative rate at 10-5 and loss of MRD negative rate. at 10-5
7. To determine Overall Survival (OS), Progression free survival (PFS), Time to Progression (TTP), Time to Next Therapy (TTNT) and Event Free survival (EFS) in either arm
8. High Risk Multiple Myeloma
9. Comparison of efficacy of originator and generic bortezomib
10. Comparison of efficacy of originator and generic lenalidomid
11. To assess apixaban exposure
12. To determine correlation between apixaban plasma level and myeloma treatments
13. Evaluate the medico-economic impact of the different combinations of treatment IsaRd vs IsaVRd
14. To estimate the cost-effectiveness of the quadruple IsaVRd versus IsaRd in newly diagnosed NTE non frail Multiple Myeloma

Conditions and MedDRA coding

Newly diagnosed Non-Frail transplant Ineligible Multiple Myeloma elderly patients

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. 1) Must be able to understand and voluntarily sign an informed consent form
2. 2) Must be able to adhere to the study visit schedule and other protocol requirements
3. 3) Life expectancy of > 6 months
4. 4) Subject, male or female, must be at least ≥ 65 years of age and < 80 years of age
5. 5. Newly diagnosed multiple myeloma requiring therapy 5.1. Monoclonal plasma cells in bone marrow ≥ 10% or presence of biopsy-proven plasmacytoma 5.2. Revised International Myeloma Working Group diagnostic criteria for multiple myeloma
6. 6) Must have measurable disease o IgG myeloma: M-protein ≥1.0 g/dL or urine M- protein≥200 mg/24 hours; or o IgA, IgM, IgD, or IgE multiple myeloma: serum M-protein ≥0.5 g/dL or urine M- protein ≥200 mg/24 hours; or o Light chain multiple myeloma: urine M- protein ≥200 mg/24 hours or Serum immunoglobulin free light chain ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio
7. 7) Must be non-transplant eligible and not frail o Newly diagnosed and not considered candidate for high-dose chemotherapy with SCT. o Subject must be not frail
8. performance status ECOG ≤ 2
9. 9) 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), defined as: o Absolute neutrophils ≥ 1 x109/L, o Untransfused Platelet count ≥ 75 x109/L, o Hemoglobin ≥ 8.5 g/dL.
10. 10) Adequate organ function documented within one week prior to the first intake of investigational product (C1J1) defined as: o Serum total bilirubin < 2x upper limit of normal (ULN), o Creatinine clearance ≥ 30ml/min, calculated with MDRD formula, o Serum SGOT/AST or SGPT/ALT < 3x upper limit of normal (ULN).
11. 11) Subjects affiliated with an appropriate social security system
12. 12) 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 8 months after the last dose of treatment, even he has had a vasectomy
13. 13) 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 agree to continue abstinence from heterosexual intercourse or to use 2 reliable effective methods of contraception simultaneously without interruption: o For at least 28 days before starting experimental treatments, o Throughout the entire duration of experimental treatments, o During dose interruptions, o And for at least 8 months after the last dose of experimental treatments.
14. 14) All patients must understand and accept to comply with the conditions of the lenalidomide pregnancy prevention plan

Exclusion criteria 23

1. 1 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).
2. 2 Subject has a diagnosis of Waldenström’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.
3. 3 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.
4. 4 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).
5. 5 Subject has had radiation therapy within 7 days of randomization unless done for antalgic reason or in case of functional risk for the patient
6. 6 Subject has had plasmapheresis within 7 days of randomization unless patient disease is still measurable (inclusion criteria n° 6) after the plasmapheresis
7. 7 Subject is exhibiting clinical signs of meningeal involvement of multiple myeloma.
8. 8 Subject known to be seropositive for history of human immunodeficiency virus (HIV) or to have hepatitis A active infection.
9. 9 Known to have hepatitis B active or uncontrolled infection (positive HBsAg and/or HBV DNA) o 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.
10. 10 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.
11. 11 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.
12. 12 Subject has active systemic infection and severe infections requiring treatment with a parenteral administration of antibiotics.
13. 13 Subject has clinically significant cardiac disease, including: o myocardial infarction within 6 months before randomization, or an unstable or uncontrolled disease/condition related to or affecting cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association Class III-IV) o uncontrolled cardiac arrhythmia (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] Version 5 Grade ≥2) or clinically significant ECG abnormalities or LVEF < 40 %
14. 14 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
15. 15 Known hypersensitivity, allergy to one of the study products (isatuximab, lenalidomide, bortezomib), dexamethasone or to one of the excipients
16. Acute diffuse infiltrative pneumopathy, pericardial disease
17. 17 Subject has plasma cell leukemia (according to World Health Organization [WHO] criterion: ≥20% of cells in the peripheral blood with an absolute plasma cell count of more than 2 × 109/L) or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes).
18. 18 Subject is known or suspected of not being able to comply with the study protocol (e.g., because of alcoholism, drug dependency, or psychological disorder). Subject has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol- specified assessments. Subject is taking any prohibited medications
19. 19 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
20. 20 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. circulating plasma cell) delay could be shortened after agreement between sponsor and investigator, in absence of residual toxicities from previous therapy
21. 21 Refusal to consent or protected by legal regime (under judicial protection, guardianship, trusteeship)
22. 22 Subject has contraindications to required prophylaxis for deep vein thrombosis and pulmonary embolism
23. 23 Incidence of gastrointestinal disease that may significantly alter the absorption of oral drugs

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. MRD negative rate: defined as the proportion of patients with MRD negative in bone marrow aspirate (< 10-5) at 18 months

Secondary endpoints 13

1. Clinical and laboratory parameters, adverse events, and vital signs according to CTCAE 5.0
2. Overall Response rate defined as the proportion of patients with best overall response /VGPR or better rate defined as the proportion of patients with CR and VGPR /Duration of response defined as the time from first response to the date of first documentation of progression/Time to first response-time to best response defined as the time from randomization to the date of first documentation /Rate of primary refractory: defined as the proportion of patients with SD or DP
3. MRD rate: defined as the proportion of patients with MRD in bone marrow aspirate (< 10-5) at 12 months, and yearly
4. Sustained MRD rate: defined as the proportion of patients with sustained MRD in bone marrow aspirate (< 10-5) between 2 evaluations as determined in the protocol.
5. Rate of loss of MRD at 10-5: defined as the proportion of patients with MRD negative at 10-5 who lose the MRD negative status at the next evaluation.
6. Time to reach MRD negative rate at 10-5: defined as the time from randomization to the date of the first MRD negative rate at 10-5 Time to lose MRD negative rate at 10-5: defined as the time from randomization or from the date of MRD negative at 10-5 to the date of MRD positive at 10-5
7. OS=the time from the date of randomization to death TTP=the time from randomization to the date of 1er documentation of DP PFS= the time from randomization until the earliest date of documented DP or death TTNT= as time from discontinuation from treatment to the date of next myeloma therapy in patients that had progression and are alive. EFS=as permanent discontinuation of study treatment as a whole, death or progression .
8. To determine Response, MRD rate and survival rate in either arm with regards to genomic abnormalities in the bone marrow tumor plasma cells
9. All endpoints of efficacy of originator and generic bortezomib will be studying statistically
10. All endpoints of efficacy of originator and generic lenalidomid will be studying statistically
11. All endpoints of apixaban exposure will be studying statistically
12. All endpoints of correlation between apixaban plasma level and myeloma treatments will be studying statistically
13. The outcome measure are: - Adverse events (arm A vs B) - Overall management of the Velcade therapy within the frame of BENEFIT - Cost of the subsequent line of therapy (in both arms) - Progression in arm B of patients having relapsed before C19 (post C19 no more Velcade)Quality-adjusted life years (QALYs).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Auxiliary 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Universitaire De Poitiers

Sponsor organisation

Centre Hospitalier Universitaire De Poitiers

Address

2 Rue De La Miletrie

City

Poitiers

Postcode

86000

Country

France

Scientific contact point

Organisation

Centre Hospitalier Universitaire De Poitiers

Contact name

Dr Arthur BOBIN

Public contact point

Organisation

Centre Hospitalier Universitaire De Poitiers

Contact name

Dr Arthur BOBIN

Locations

1 EU/EEA country · 58 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 16 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications