| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Newly diagnosed symptomatic multiple myeloma |
| Symptomatisches Multiples Myelom, Primärtherapie |
|
| E.1.1.1 | Medical condition in easily understood language |
| Symptomatic, newly diagnosed (previously untreated) multiple myeloma |
| Bisher unbehandeltes, symptomatisches Multiples Myelom |
|
| 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 | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
(1) to compare induction therapy without isatuximab (arm IA) versus induction therapy with isatuximab (arm IB) regarding the MRD negativity after induction (assessed by flow cytometry).
(2) to compare maintenance therapy without isatuximab (arm IIA) with maintenance therapy with isatuximab (arm IIB) regarding the progression-free survival (PFS), defined as time from 2nd randomization (prior to maintenance therapy) to progression or death from any cause whichever occurs first. |
|
| E.2.2 | Secondary objectives of the trial |
Key Sec Objective:
- to assess and compare the four treatment arms (IA-IIA, IA-IIB, IB-IIA, IB-IIB) regarding PFS, defined as time from 1st randomization to progression or death from any cause whichever occurs first
Further Sec Objectives:
- To assess the treatment effect of the induction phase regarding PFS from 1st randomization
- Overall survival (OS) from 1st/2nd randomization
- Complete response (CR) rates after induction therapy, high dose therapy and during/after maintenance therapy
- MRD negativity after high dose therapy, during and after 3 years of maintenance treatment (flow cytometry)
- Sustained MRD negativity for ≥6 months / ≥12 months
- Best response to treatment during the trial
- PFS 2 (PFS after next line of therapy) from 2nd randomization
- Toxicity during induction and maintenance: adverse events of CTC grade ≥ 3 (and specific AE of CTC grade ≥ 2) and serious AE
- Quality of life assessment
- Pharmacokinetics of isatuximab in combination with RVd or Rd
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Confirmed diagnosis of untreated multiple myeloma requiring systemic therapy (diagnostic criteria (IMWG updated criteria (2014)). For some patients systemic therapy may be required though these diagnostic criteria are not fulfilled. In this case the GMMG study office has to be consulted prior to inclusion.
- Patient is eligible for high dose therapy and autologous stem cell transplantation.
- Measurable disease, defined as any quantifiable monoclonal protein value, defined by at least one of the following three measurements:
• Serum M-protein ≥ 10g/l (for IgA ≥ 5g/l)
• Urine light-chain (M-protein) of ≥ 200 mg/24 hours
• Serum FLC assay: involved FLC level ≥ 10 mg/dl and abnormal sFLC ratio
- Age 18 - 70 years inclusive
- WHO performance status 0-2
- Negative pregnancy test at inclusion (women of childbearing potential)
- For all men and women of childbearing potential: patients must be willing and capable to use adequate contraception during the complete therapy. Patients must agree on the requirements regarding the lenalidomide pregnancy prevention programme
- All patients must:
• agree to abstain from donating blood while taking lenalidomide and for 28 days following discontinuation of lenalidomide therapy
• agree not to share study drug lenalidomide with another person and to return all unused study drug to the investigator or pharmacist
- Ability of patient to understand character and individual consequences of the clinical trial
- Provide written informed consent (must be available before enrolment in the trial)
|
|
| E.4 | Principal exclusion criteria |
- Patient has known hypersensitivity (or contraindication) to dexamethasone, sucrose histidine (as base and hydrochloride salt), boron, mannitol, and polysorbate 80 or any of the components of study therapy that are not amenable to premedication with steroids or H2 blockers that would prohibit further treatment with these agents.
- Systemic AL amyloidosis (except for AL amyloidosis of the skin or the bone marrow)
- Plasma cell leukemia
- Previous chemotherapy or radiotherapy during the past 5 years except local radiotherapy in case of local myeloma Progression or benign diseases, such as non-malignant thyroid diseases. (Note: patients may have received a cumulative dose of up to 160 mg of dexamethasone or equivalent as emergency therapy.) Previous therapy due to smouldering myeloma may be acceptable. In this case the GMMG study office has to be consulted prior to inclusion.
- Severe cardiac dysfunction (NYHA classification III-IV)
- Significant hepatic dysfunction (ASAT and/or ALAT ≥ 3 times normal level and/or serum bilirubin ≥ 1.5 times normal level if not due to hereditary abnormalities as Gilbert’s disease), unless related to myeloma.
- Patients with active or history of hepatitis B or C (Prior hepatitis B may be acceptable if an adequate prophylaxis is being implemented during the course of the study.)
- HIV positivity
- Patients with active, uncontrolled infections
- Patients with severe renal insufficiency (Creatinine Clearance < 30ml/min)
- Patients with peripheral neuropathy or neuropathic pain, CTC grade 2 or higher (as defined by the NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0)
- Patients with a history of active malignancy during the past 5 years with the exception of the following malignancies after curative therapy: basal cell carcinoma of the skin, squamous cell skin carcinoma, stage 0 cervical carcinoma or any in situ malignancy (A history of an early stage malignancy during the past 5 years may be acceptable. In this case the GMMG study office has to be consulted prior to study inclusion.)
- Patients with acute diffuse infiltrative pulmonary and/or pericardial disease
- Autoimmune hemolytic anemia with positive Coombs test or immune thrombocytopenia
- Platelet count < 75 x 10^9/l (Platelet transfusions are not permitted to improve platelet count prior to study inclusion.)
- Haemoglobin ≤ 8.0 g/dl, unless related to myeloma
- Absolute neutrophil count (ANC) < 1.0 x 10^9/l (the use of colony stimulating factors within 14 days before the test is not allowed)
- Corrected serum calcium > 14 mg/dl (> 3.5 mmol/l)
- Unable or unwilling to undergo thromboprophylaxis
- Pregnancy and lactation
- Participation in other clinical trials. This does not include long-term follow-up periods without active drug treatment of previous studies during the last 6 months.
- Prisoners or subjects who are legally institutionalized, or those unwilling or unable to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions.
No patients will be allowed to enrol in this trial more than once.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
(1) minimal residual disease (MRD) negativity after induction (assessed by flow cytometry; sensitivity 1e-5), defined as proportion of patients with negative MRD after induction.
(2) progression-free survival (PFS), defined as time from 2nd randomization (prior to maintenance) to progression or death from any cause whichever occurs first. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Key Secondary Endpoint:
- PFS, defined as time from 1st randomization (at study inclusion) to progression or death from any cause whichever occurs first.
Further Secondary Endpoints:
- To assess the treatment effect of the induction phase regarding PFS from 1st randomization. Induction treatment effect will be assessed by comparing a) the overall IA to IB (independently on 2nd randomization) and additionally by comparing the treatment arms IA-IIA to IB-IIA (induction treatment followed by lenalidomide maintenance). To assess the treatment effect of the induction phase regarding overall survival from 1st randomization. Comparisons will be done analogously to PFS from 1st randomization.
- OS defined as time from 1st randomization and from 2nd randomization to time of death from any cause. Patients still being alive at the time of the analysis will be censored at the date last known to be alive.
- Complete response (CR) rates. The analysis will be based on the CR rate which is the proportion of patients achieving complete response (CR) to treatment adjusted after removal of isatuximab interference in the relevant patient subpopulations.
- MRD negativity after high dose therapy, during and after 3 years of maintenance treatment (flow cytometry) defined as the proportion of patients with negative MRD after high dose therapy, during and after 3 years of maintenance treatment (flow cytometry), respectively.
- Sustained MRD-negativity, defined as the maintenance of MRD-negativity (assessed by NGF at a sensitivity of 1e-5) >=6 / >=12 months apart (after first occurrence of MRD negativity)
- Best response to treatment during the trial (adjusted after removal of isatuximab interference in the relevant patient subpopulations)
- PFS 2 (PFS after next line of therapy) from 2nd randomization
- Quality of life
Safety will be analysed including:
- Toxicity (CTC grade ≥ 3) during induction and maintenance therapy, respectively, measured by CTC-AE (v5.0). For some specific adverse events toxicity of CTC grade ≥ 2 will be analysed.
- Immunogenicity (related to Isatuximab)
- Pharmacokinetic Parameters of isatuximab will be estimated using a population PK model |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Background treatment with or without isatuximab |
|
| 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 | 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
|
End of the trial is defined as the last visit of the last subject undergoing
the Trial (Last Patient Out, LPO) |
|
| 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 |
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