| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with multiple myeloma, newly diagnosed and eligible for autologous stem cell transplantation |
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| E.1.1.1 | Medical condition in easily understood language |
| patients under 66 years of age, with multiple myeloma, newly diagnosed and eligible for Autologous Stem Cells transplantation |
| patients de moins de 66 ans, atteints de myélome multiple, nouvellement diagnostiqués et éligibles à la greffe |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| 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 | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| For patients MRD negative after induct°(NGS,10-5) -Principal object:increase by 15% the rate of MRD negativity (NGS, 10-6)beforemaintenance with high-dose therapy and ASCT (Arm B) vs addit cycles of Isa-KRD (Arm A), i.e.,85% MRD negativity in Arm B vs 70% in Arm A. Secondary objectives: MRD postinduction,MRD post consolidat°, responses rate according to IMWG criteria, PFS,OS, safety (ongoing basis), sustained MRD negativity(every year since the start of maintenance phase).For patients MRD positive after induction (NGS, 10-5)- Principal objective: increase by 20% the rate of MRD negativity (NGS, 10-6) before maintenance with tandem ASCT (Arm D) vs single ASCT (Arm C), i.e., 45% MRD negativity in Arm D vs 25% in Arm C. Secondary object:MRD post induction,MRD post consolidat°, responses rate according to IMWG criteria, PFS, OS, safety (ongoing basis), sustained MRD negativity (every year since the start of mainte- nance phase), PRO for arms C&D (every year since the start of maintenance) |
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| E.2.2 | Secondary objectives of the trial |
| PFS , OS, sustained MRD negativity and safety . |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Male or female subjects, 18 years of age or older, younger than 66 years (< 66 years)
2) Voluntary written informed consent must be given before performance of any study-related procedure not part of normal medical care, with the understanding that the subject may withdraw consent at any time without prejudice to future medical care.
3) Subject must have documented multiple myeloma satisfying the CRAB and measurable disease as defined by:
• Monoclonal plasma cells in the bone marrow ≥ 10% or presence of a biopsy proven plasmacytoma AND any one or more of the following myeloma defining events:
- Hypercalcemia: serum calcium > 0.25 mmol/L (> 1 mg/dL) higher than ULN or > 2.75 mmol/L (> 11 mg/dL)
- Renal insufficiency: creatinine clearance < 40mL/min or serum creatinine > 177 μmol/L (> 2 mg/dL)
- Anemia: hemoglobin > 2 g/dL below the lower limit of normal or hemoglobin < 10 g/dL
- Bone lesions: one or more osteolytic lesions on skeletal radiography, CT or PET-CT
- Clonal bone marrow plasma cell percentage ≥ 60%
- Involved: uninvolved serum free light chain ratio ≥ 100
- Superior 1 focal lesion on MRI studies
• Measurable disease as defined by the following:
M-component ≥ 5g/l, and/or urine M-component ≥ 200 mg/24h and/or serum FLC ≥ 100 mg/l between screening and C1D1.
4) Newly diagnosed subjects eligible for high dose therapy and autologous stem cell transplantation
5) Karnofsky performance status score ≥ 50% (eastern cooperative oncology group performance status ECOG score ≤ 2)
6) Subject must have pretreatment clinical laboratory values meeting the following criteria during the Screening Phase (Lab tests should be repeated if done more than 15 days before C1D1):
a- Hemoglobin ≥ 7.5 g/dL (≥ 5mmol/L). Prior red blood cell [RBC] transfusion or recombinant human erythropoietin use is permitted;
b- Absolute neutrophil count (ANC) ≥ 1.0 Giga/l (GCSF use is permitted);
c- ASAT ≤ 3 x ULN;
d- ALAT ≤ 3 x ULN;
e- Total bilirubin ≤ 3 x ULN (except in subjects with congenital bilirubinemia, such as Gilbert syndrome, direct bilirubin ≤ 1.5 x ULN);
f- Calculated creatinine clearance ≥ 40 mL/min/1.73 m²;
g- Corrected serum calcium ≤ 14 mg/dL (< 3.5 mmol/L); or free ionized calcium ≤6.5 mg/dL (≤ 1.6 mmol/L);
h- Platelet count ≥ 50 Giga/l for subjects in whom < 50% of bone marrow nucleated cells are plasma cells; otherwise platelet count > 50 Giga/l (transfusions are not permitted to achieve this minimum platelet count).
7) Women of childbearing potential must have a negative serum or urine pregnancy test within 10 to 14 days prior to therapy and repeated within 24 hours before starting study drug. They must commit to continued abstinence from heterosexual intercourse or begin 2 acceptable methods of birth control (One highly effective method and one additional effective method) used at the same time, beginning at least 4 weeks before initiation of lenalidomide treatment and continuing for at least 30 days after the last dose of Lenalidomide, Iberdomide and 5 months after last dose of Isatuximab. Women must also agree to notify pregnancy during the study.
8) Men must agree to not father a child and agree to use a latex condom during therapy and for and during dose interruptions and for at least 90 days after the last dose of study drug including Lenalidomide and Iberdomide and 5 months after last dose of Isatuximab, even if they have had a successful vasectomy, if their partner is of childbearing potential. Patient must also refrain from donating sperm during this period.
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| E.4 | Principal exclusion criteria |
-Subjects must not have been treated previously with any systemic therapy for multiple myeloma. Prior treatment with corticosteroids or radiation therapy does not disqualify the subject (the maximum dose of corticosteroids should not exceed the equivalent of 160 mg of dexamethasone over a period of 14 calendar days. Two weeks must have elapsed since the date of the last radiotherapy treatment. Enrolment of subjects who require concurrent radiotherapy (which must be localized in its field size) should be deferred until the radiotherapy is completed and 2 weeks have elapsed since the last date of therapy
-Subject has a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, or solitary plasmacytoma.
3) Subject has a diagnosis of Waldenström’s macroglobulinemia, or other conditions in which IgM M-protein is present in the absence of a clonal plasma cell infiltration with lytic bone lesions.
4) Subject has had plasmapheresis within 14 days of C1D1.
5) Subject is exhibiting clinical signs of meningeal involvement of multiple myeloma.
6) Myocardial infarction within 4 months prior to enrolment according to NYHA Class III or IV heart failure, uncontrolled angina, PAH, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities
7) Uncontrolled hypertension
8) Subjects with a history of moderate or severe persistent asthma within the past 2 years, or with uncontrolled asthma of any classification at the time of screening (Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study).
9) Intolerance to hydration due to pre-existing pulmonary or cardiac impairment.
10) 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).
11) Any clinically significant, uncontrolled medical conditions that, in the Investigator's opinion, would expose the patient to excessive risk or may interfere with compliance or interpretation of the study results.
12) Systemic treatment with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin), strong inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John’s wort within 14 days before the first dose of study treatment.
13) Known intolerance to steroid therapy, mannitol, pregelatinized starch, odium 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.
14) History of allergy to any of the study medications, their analogues, or excipients in the various formulations
15) Subject has had major surgery within 2 weeks before study inclusion (informed consent signature) or will not have fully recovered from surgery, or has surgery planned during the time the subject is expected to participate in the study. Kyphoplasty or Vertebroplasty are not considered major surgery.
16) Clinically relevant active infection or serious co-morbid medical conditions
17) Subject has had an prior or concurrent invasive malignancy (other than multiple myeloma, and adequately treated basal cell or squamous cell carcinoma in the skin) within 5 years of study start, except breast ductal carcinoma in situ, carcinoma in situ of the cervix, localized prostate adenocarcinoma diagnosed for more than 3 years and without evidence of disease
18) Female subject who is pregnant or breast-feeding
19) Serious medical or psychiatric illness likely to interfere with participation in study
20) Uncontrolled diabetes mellitus
21) Known HIV infection; Known active hepatitis A, B or C viral infection
22) Uncontrolled or active HBV infection: Patients with positive HBsAg and/or HBV DNA
23) Active HCV infection: positive HCV RNA and negative anti-HCV
24) Active systemic infection and severe infections requiring treatment with a parenteral
administration of antibiotics.
25) Incidence of gastrointestinal disease that may significantly alter the absorption of oral drugs
26) Subjects unable or unwilling to undergo antithrombotic prophylactic treatment
27) Person under guardianship, trusteeship or deprived of freedom by a judicial or administrative decision
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| E.5 End points |
| E.5.1 | Primary end point(s) |
For both parts of the trial (A vs B and C vs D), the primary comparison of the 2 strategies will be made with respect to negative MRD rate (10-6 NGS) before maintenance using the chi square test in the ITT population. The observed MRD negative rate will be provided along with its 2-sided 95% Confidence interval (CI). Treatment effect will be described by an Odds Ratio, along with its 2-sided 95% confidence interval, by fitting a logistic regression model adjusted on stratification variables (with high risk cytogenetics and MRD negative rate (10-5 NGS) after induction as fixed effects and center as random effects for A vs B comparison, and high risk cytogenetics as fixed effects and center as random effects for C vs D comparison).
In case of missing MRD, data will be imputed as positive in all arms. Sensitivity analyses will be performed using best-worst and worst-best case to check for robustness of the results.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
end of induction phase
end of consolidation phase
end of maintenance phase
end of the study |
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| E.5.2 | Secondary end point(s) |
Secondary endpoints
• Sustained MRD rate at year 2, 3, 4 post inclusion will be analyzed similarly to the primary endpoint.
• For Overall Survival (OS), the distribution of OS since randomization will be estimated using Kaplan Meier method. The comparison of the 2 arms will be made by log-rank test. Treatment effect will be described by Hazard Ratio and its 2-sided 95% confidence intervals are will be estimated using a Cox regression model adjusted on stratification variables (with high risk cytogenetics and MRD negative rate (10-5 NGS) after induction as fixed effects and center as random effects for A vs B comparison, and high risk cytogenetics as fixed effects and center as random effects for C vs D comparison).
• Progression Free survival, defined as time from randomization to either progression or death will be analyzed similarly.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
end of induction phase
end of consolidation phase
end of maintenance phase
end of the study |
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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 | Yes |
| E.6.5 | Efficacy | Yes |
| 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 | 4 |
| 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 | 70 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 70 |
| 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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| 1 year after last maintenance dose administred for last patient on treatment (not died) |
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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 | 7 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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