| 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 |
| To evaluate at 8 months the > Very Good Partial Response rate (as best response) in patients with newly diagnosed NTE multiple myeloma. |
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| E.2.2 | Secondary objectives of the trial |
- To determine Overall Survival (OS), Progression free survival (PFS), Time to Progression (TTP), Time to Next Therapy (TTNT) and Event Free survival (EFS)
- To determine duration of response (DOR) and time to response (TTR)
- To assess responses to the treatment according to IMWG*, ORR (Overall response rate) >PR, >CR (complete response), and best MRD 10-5 rate + sustained 12 and 24 months.
-To assess the safety and local tolerability of SC isatuximab + VRd according to CTCAE 5.0.
- To assess patient satisfaction with SC isatuximab
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
-Must be able to understand and voluntarily sign an informed consent form
-Must be able to adhere to the study visit schedule and other protocol requirements
-Life expectancy of > 6 months
-Subject, male or female, must be at least ≥ 65 years of age
-Must have a Newly diagnosed Multiple Myeloma requiring therapy (SLiM CRAB criteria) (see appendix 18.2)
1. Monoclonal plasma cells in the bone marrow ≥10% or presence of a biopsy proven plasmacytoma*
*Clonality should be established by showing κ/λ-light-chain restriction on flow cytometry, immunohistochemistry, or immunofluorescence. Bone marrow plasma cell percentage should preferably be estimated from a core biopsy specimen; in case of a disparity between the aspirate and core biopsy, the highest value should be used and any one or more of the following myeloma defining events:
2. Revised International Myeloma Working Group diagnostic criteria for multiple myeloma
Myeloma defining events:
○ 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)
†Measured or estimated by validated equations.
○ Anemia: hemoglobin value of ≥2g/dL below the lower limit of normal, or hemoglobin value ≤10 g/dL
○ Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT ‡
‡If bone marrow has less than 10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement.
○ 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
§These values are based on the serum Freelite assay (The Binding Site Group, Birmingham, UK).
The involved free light chain must be ≥100 mg/L.
1 focal lesion on MRI studies (¶Each focal lesion must be 5 mm or more in size.)
-Must have measurable disease as defined by any of the following:
○ Serum M-protein level ≥5 g/L or urine M- protein level ≥200 mg/24 hours; or
○ Light chain multiple myeloma: urine M- protein level ≥200 mg/24 hours or if not quantifiable in urines: Serum immunoglobulin free light chain ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio *
* Any laboratory method can be used. In such a case, the same method must be used along the study for the patient
-Must be non-transplant eligible
o Newly diagnosed and not considered candidate for high-dose chemotherapy with SCT.
o Subject must have Charlson comorbidity index ≤1
o ECOG ≤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), defined as:
o Absolute neutrophils ≥ 1 x109/L,
o Untransfused Platelet count ≥ 75 x109/L,
o Hemoglobin ≥ 8.5 g/dL.
-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).
-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:
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 5 months after the last dose of experimental treatments.
-All patients must understand and accept to comply with the conditions of the lenalidomide pregnancy prevention plan (see appendix 18.4).
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| E.4 | Principal 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. Smoldering multiple myeloma is defined as asymptomatic multiple myeloma with absence of related organ or tissue impairment end organ damage .
-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.
-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 ongoing malignancy (other than multiple myeloma) within 3 years (date of diagnosis of the malignancy) before the date of study treatment (exceptions are malignancies considered cured with minimal risk of recurrence within 3 years, eventhough the patient receives treatment).
-Subject has had radiation therapy/plasmapheresis within 7 days of study treatment
-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/hepatitis C active infection
-Subject has any clinically significant medical or psychiatric condition or 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, including: omyocardial infarction within 6 months before study treatment, or an unstable or uncontrolled disease/condition related to or affecting cardiac function ouncontrolled cardiac arrhythmia (NCI CTCAE Version 5 Grade ≥2) or clinically significant ECG abnormalities or LVEF < 40 %
-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 (refer to respective package inserts or Investigator's Brochure).
-Known hypersensitivity, allergy to one of the study product (isatuximab, lenalidomide, bortezomib), dexamethasone, boron or to one of the excipients. Allergy to bandages or adhesives (acrylic).
-Acute diffuse infiltrative pneumopathy, pericardial disease
-Subject has plasma cell leukemia (according to 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).
-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
-Subject has had major surgery within 2 weeks before study treatment 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 study treatment 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.
-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.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the VGPR rate or better (as best response) using IMWG criteria (see below). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
•To determine Survivals, Overall Survival (OS), Progression free survival (PFS), Time to Progression (TTP), Time to Next Therapy (TTNT) and Event Free survival (EFS)
•To determine duration of response (DOR) and time to response (TTR)
•To assess responses to the treatment according to IMWG*, ORR (Overall response rate) PR, CR (complete response), and best MRD 10-5 rate + sustained 12 and 24 months.
•To assess the safety, including infusions reactions, device deficiencies, and local tolerability (injections site reactions) of SC isatuximab + VRd according to CTCAE 5.0.
•Patient experience/satisfaction questionnaire with SC isatuximab using the patient experience and satisfaction questionnaire
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
For some points, this will be done throughout the study or until the patient dies
For other points, this will be done at 12 and 24 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| 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 | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 17 |
| 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 | Yes |
| 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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