Etude : IFM2020-05 / BENEFIT



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Acronyme / Nom
Situation thérapeutique
Traitement
Cadre réglementaire
MÀJ
Présentation de l'étude
Acronyme / Nom : IFM2020-05 / BENEFIT

Situation thérapeutique : Induction

Traitement : Chimiothérapie / Immunothérapie / Thérapie ciblée

Cadre réglementaire : RIPH1

Dernière MÀJ : 23/12/2021
Titre
Spécialité(s)
CIM10 - Localisation(s)
Informations principales
Titre : Etude de phase III, en ouvert, randomisée, de l'association Isatuximab, Lénalidomide et Dexaméthasone avec ou sans Bortézomib chez les sujets âgés de 65 à 79 ans présentant un myélome multiple nouvellement diagnostiqué, non éligibles à l'autogreffe et non fragiles

Spécialité : Tissus lymphoïde, hématopoïétique et apparentés
Localisation : C90 - Myélome multiple et tumeurs malignes à plasmocytes
Schéma
Phase
Stade
Ligne(s)
Informations complémentaires
Schéma : 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.


Study arms:
- Experimental: Isatuximab/Lenalidomide/Dexamethasone/Bortezomib
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.
Lenalidomide by oral route, per 28 days cycle - 25 mg daily on days 1-21.
Dexamethasone by oral route, per 28 days cycle - 20 mg daily on days 1, 8, 15 and 22.
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.

- Active Comparator: Isatuximab/Lenalidomide/Dexamethasone


Main Objective:
The primary objective is to evaluate Minimal Residual disease (MRD) rate at 10-5 at 18 months in both arms of IsRd + V vs IsRd in newly diagnosed NTE non frail Multiple Myeloma.

Secondary Objectives:al
- To assess the safety according to CTCAE 5.0.
- To assess response to the treatment according to IMWG*. (*IMWG : see appendix 18.1 of the protocol)
- To assess the survival according to IMWG*

Phase : III

Stade : NA

1 (hémato)
Informations libres de droit
Critères d'inclusion
Critères de non-inclusion
Informations libres de droit
Critères d'inclusion et de non-inclusion
Critères d'inclusion : 1.Life expectancy > 6 months
2.Subject, male or female, must be at least ≥ 65 years of age and < 80 years of age
3.Must have a Newly diagnosed Multiple Myeloma requiring therapy (SLiM CRAB criteria)
3.1-Monoclonal plasma cells in the bone marrow ≥10% or presence of a biopsy proven plasmacytoma
3.2-Revised International Myeloma Working Group diagnostic criteria for multiple myeloma
Myeloma defining events:
o Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically:
• Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11 mg/dL)
• Renal insufficiency: creatinine clearance ≤40 mL per min† or serum creatinine ≥177 μmol/L (≥2 mg/dL)

o Anemia: hemoglobin value of ≥ 20 g/L below the lower limit of normal, or hemoglobin value ≤100 g/L

o Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT

o Any one or more of the following biomarkers of malignancy:Clonal bone marrow plasma cell percentage ≥60%/Involved/uninvolved serum free light chain ratio ≥100
•>1 focal lesion on MRI studies (Each focal lesion must be 5 mm or more in size.)

4.Must have measurable disease as defined by any of the following: IgG myeloma: Serum monoclonal paraprotein (M-protein) level ≥1.0 g/dL or urine M- protein level ≥200 mg/24 hours;or IgA, IgM, IgD, or IgE multiple myeloma: serum M-protein level ≥0.5 g/dL or urine M- protein level ≥200 mg/24 hours;or Light chain multiple myeloma: Serum immunoglobulin free light chain ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio
5.Must be NTE Non Frail
5.1. Newly diagnosed and not considered candidate for high-dose chemotherapy with SCT.
5.2. Subject must have a Frailty Score < 2
6.Eastern Cooperative Oncology Group performance status score of 0, 1, or 2
7.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: - Absolute neutrophils ≥ 1 x109/L, - Untransfused Platelet count ≥ 75 x109/L- Hemoglobine ≥8.5 g/L
8.Adequate organ function defined as:-Serum total bilirubin < 2.0 mg/dL-Creatinine clearance ≥ 30ml/min-Serum SGOT/AST or SGPT/ALT < 3x upper limit of normal
9.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. All men must also not donate sperm, spermatozoa during the study, for 5 months following treatment discontinuation.
10.A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
10.1.Not a female of childbearing potential Or 10.2.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.
10.2.1. For at least 28 days before starting experimental treatments, 10.2.2.Throughout the entire duration of experimental treatments, 10.2.3.During dose interruptions, 10.2.4.And for at least 5 months after the last dose of experimental treatments.
11. All patients must agree to not donate blood during the treatment period, interruptions of treatment and at least 5 months after the last dose of treatment
12. All patients must understand and accept to comply with the conditions of the Lenalidomide pregnancy prevention plan

Critères de non-inclusion : 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. Smoldering multiple myeloma is defined as asymptomatic multiple myeloma with absence of related organ or tissue impairment end organ damage .
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.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.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 sponsor's medical monitor, is considered cured with minimal risk of recurrence within 3 years).
5.Subject has had radiation therapy and plasmapheresis within 7 days of randomization
6.Subject is exhibiting clinical signs of meningeal involvement of multiple myeloma.
7.known to be seropositive for history of HIV or to have hepatitis A active infection.
8.Known to have hepatitis B active or uncontrolled infection (positive HBsAg and/or HBV DNA)
9.Known to have hepatitis C active infection (positive HCV RNA and negative anti-HCV)
10.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.
11.Subject has active systemic infection and severe infections requiring treatment with a parenteral administration of antibiotics.
12.Subject has clinically significant cardiac disease, including: myocardial infarction within 6 months before randomization, or an unstable or uncontrolled disease/condition related to or affecting cardiac function and uncontrolled cardiac arrhythmia or clinically significant ECG abnormalities
13.Subject has known allergies, hypersensitivity, or intolerance to steroids, mannitol, pregelatinized starch, sodium stearyl ,fumarate, histidine base , 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
14. Known hypersensitivity, allergy to one of the study product or to one of the excipients.
15.Acute diffuse infiltrative pneumopathy, pericardial disease
16..Subject has plasma cell leukemia 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).
17.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.
18.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.
19.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.
20.Subject has contraindications to required prophylaxis for deep vein thrombosis and pulmonary embolism
21.Incidence of gastrointestinal disease that may significantly alter the absorption of oral drugs.
NCT
Promoteur
Coordonnateur
Informations relatives au promoteur
NCT :
NCT04751877
Promoteur :
CHU de Poitiers
Type de sponsor : Institutionnel
2 Rue de la Milétrie, 86021 Poitiers
86000 POITIERS

Coordonnateur :
Centre investigateur
Investigateur
TEC / ARC / IDE
État
MÀJ
Informations relatives aux investigateurs
Centre investigateur :
Institut d'Hématologie Bas-Normand (IHBN) - Avenue de la Cote de Nacre - 14000 CAEN

Investigateur :
Margaret MACRO

TEC / ARC / IDE :
Véronique ABONNET
abonnet-v@
chu-caen.fr

Statut de l'essai : OUVERT

MAJ : 14/10/2021