| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | |
| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028228 |
| E.1.2 | Term | Multiple myeloma |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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. |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives are in both arms:
- To assess the safety according to CTCAE 5.0.
- To assess response to the treatment according to IMWG*.
- To assess the survival according to IMWG*
*IMWG : see appendix 18.1 of the protocol :
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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:
oEvidence 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
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| E.4 | Principal exclusion criteria |
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.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| MRD 10-5 incidence rate obtained at 18 months of treatment as per IMWG criteria by NGS (centrally performed, Pr Avet Loiseau Toulouse Oncopole). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
• To determine best Overall Response rate (ORR, Partial Response and better), Very Good Partial Response (VGPR) and Complete Response (CR) incidence rate in either arm.
• To determine CR rate a 6, 12, 18 months then yearly
• To determine Time to response and Response duration to both regimens for responders. To determine the rate of primary refractory patients.
• 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.
• To determine safety in either arm
• To determine the MRD rate at 12 months, and yearly
• the sustained MRD rate (similar time points),
• the rate of loss of MRD at each time point
• the time to reach MRD negative rate and loss of negative rate.
• To determine Response, MRD rate and survival rate in either arm with regards to genomic abnormalities in the bone marrow tumor plasma cells (Pr Avet Loiseau, Oncopole Toulouse).
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
For some points, this will be done at each time point
For other points, this will be done at 6, 12, 18 months |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 60 |
| E.8.9.1 | In the Member State concerned days | |
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