| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| newly diagnosed patients with multiple myeloma and severe renal impairment |
|
| E.1.1.1 | Medical condition in easily understood language |
| Multiple Myeloma and renal impairment |
|
| 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 | 100000004864 |
|
| 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 |
| To assess the effect of induction treatment with isatuximab in combination with bortezomib, cyclophosphamide, and dexamethasone (VCd) on the renal function of newly diagnosed patients with multiple myeloma (NDMM) and severe renal impairment (RI). |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the effect of isatuximab in combination with VCd, followed by lenalidomide maintenance on:
Overall response rate (ORR)
Progression-Free Survival (PFS)
Time to Response (TTR)
Duration of Response (DoR)
Overall Survival (OS)
Minimal Residual Disease (MRD) negativity rate
Safety |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.The patient has signed an informed consent form (ICF), stating that he or she understands the purpose of the procedures required for the study and is willing to participate in the study. The patient must be willing and able to adhere to the prohibitions and restrictions specified in this protocol, as stated in the ICF.
2.Male or female patients aged 18 years or older at the time of the ICF signature.
3.Patients diagnosed with MM based on the International Myeloma Working Group (IMWG) criteria.
4.Patients with severe RI defined as estimated glomerular filtration rate (eGFR) <30 ml/min/1.73m2 (calculated with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula) or in need for dialysis.
5.Patients with current evidence of measurable disease defined as:
-Serum monoclonal protein (M-protein) level ≥0.5 g/dL, measured using serum protein electrophoresis (SPEP) and/or
-Urine M-protein level ≥200 mg/24 hours, measured using urine protein electrophoresis (UPEP), or
-Serum immunoglobulin free light chain (FLC) ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda FLC ratio.
6.Adequate bone marrow and hepatic function as defined by ALL the laboratory criteria:
-Absolute Neutrophil Count (ANC) ≥1.0 x 109/L (GCSF administration is not allowed to reach this level)
-Hemoglobin level ≥7.5 g/dL (≥4.65 mmol/L)
-Platelet count ≥75 x 109/L in patients in whom <50% of bone marrow nucleated cells are plasma cells OR Platelet count ≥50 x 109/L in patients in whom ≥ 50% of bone marrow nucleated cells are plasma cells (transfusions are not allowed to reach this level)
-Alanine aminotransferase (ALT) level ≤2.5 x the upper limit of normal (ULN)
-Aspartate aminotransferase (AST) level ≤2.5 x ULN
-Total bilirubin level ≤1.5 x ULN (except for Gilbert Syndrome: direct bilirubin ≤1.5 x ULN)
-Serum calcium corrected for albumin ≤14.0 mg/dL (≤3.5 mmol/L), or free ionized calcium ≤ 6.5 mg/dL (≤1.6 mmol/L)
7.Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤ 2 (see Appendix C)
8.For patients experiencing toxicities resulting from previous therapy, the toxicities must be resolved or stabilized to ≤ Grade 1 |
|
| E.4 | Principal exclusion criteria |
1.Prior or current systemic therapy or stem-cell transplantation for any plasma cell dyscrasia, with the exception of emergency use of a short course (the equivalent of dexamethasone 40 mg/day for a maximum of 4 days) of corticosteroids before treatment.
2.History of malignancy (other than MM) within three years before Cycle 1, Day 1 (exceptions are squamous and basal cell carcinomas of the skin, carcinoma in situ of the cervix or breast, or other non-invasive lesion that in the opinion of the Investigator, with concurrence with the Sponsor's medical monitor, are considered cured with minimal risk of recurrence within three years).
3.Clinical signs of meningeal involvement of MM.
4.Clinically significant cardiac disease, including:
-Myocardial infarction within six months before Cycle 1, Day 1, or unstable or uncontrolled condition (e.g., unstable angina, congestive heart failure, New York Heart Association Class III-IV).
-Cardiac arrhythmia (Common Terminology Criteria for Adverse Events Grade 3 or higher) or clinically significant electrocardiogram (ECG) abnormalities
-ECG showing a baseline QT interval as corrected QTc >470 msec.
5.Known:
-Active hepatitis A
-To be seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen). Patients with resolved infection (i.e., patients who are positive for antibodies to hepatitis B core antigen [antiHBc] and/or antibodies to hepatitis B surface antigen [antiHBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded
Exception: Patients with serologic findings suggestive of HBV vaccination (antiHBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR
-To be seropositive for hepatitis C (except in the setting of a sustained virologic response, defined as aviremia at least 12 weeks after completion of antiviral therapy)
-Known to be seropositive for human immunodeficiency virus.
6.Patient has plasma cell leukemia (>2.0 × 109/L circulating plasma cells by standard differential) or Waldenström’s macroglobulinemia or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) or amyloidosis.
7.Any concurrent medical or psychiatric condition or disease (e.g., active systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) that is likely to interfere with the study procedures or results or that, in the opinion of the investigator, would constitute a hazard for participating in this study.
8.Ongoing ≥Grade 2 peripheral neuropathy.
9.Patient has had major surgery within two weeks before C1D1, or has not fully recovered from an earlier surgery, or has a surgery planned during the time the patient is expected to participate in the study or within two weeks after the last dose of study drug administration. Note: patients with planned surgical procedures to be conducted under local anesthesia may participate.Kyphoplasty or vertebroplasty are not considered major surgery.
10.Patient has known allergies, hypersensitivity, or intolerance to any of the study drugs, monoclonal antibodies, human proteins, or their excipients (refer to isatuximab Investigator’s Brochure) or known sensitivity to mammalian-derived products.
11.Patient was vaccinated with live vaccines within four weeks prior to C1D1
12.Pregnant or nursing women
13. -FCBP unwilling to prevent pregnancy with the use of two reliable methods of contraception for ≥four weeks before the start of study treatment, during treatment (including dose interruptions), and up to five months following the last dose of isatuximab or three months following the last dose of the rest of the study treatment, whichever is longer. This includes one highly effective form of contraception (tubal ligation, intrauterine device, hormonal [birth control pills, injections, hormonal patches, vaginal rings or implants] or partner’s vasectomy) and one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap)
-FCBP who are unwilling or unable to be tested for pregnancy: a) before study treatment initiation, b) weekly during 1st month of treatment and then prior to each treatment cycle administration or c) every two weeks in case of irregular menstrual cycles, and d) up to five months following the last dose of isatuximab or three months following the last dose of the rest of the study treatment, whichever is longer
14.Male participants who refuse to practice abstinence or use a condom during sexual contact with a pregnant female or an FCBP while participating in the study, during dose interruptions and at least five months following the last dose of isatuximab or three months following the last dose of the rest of the study treatment, whichever is longer, even if they have undergone a successful vasectomy.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The renal response rate (RRR) at six months of treatment with isatuximab plus VCd.
RRR is defined as the proportion of patients who achieve a partial renal (PRrenal) or better response after six months of treatment with isatuximab plus VCd, using the eGFR cut-off values of the IMWG response criteria. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At six months of treatment with isatuximab plus VCd |
|
| E.5.2 | Secondary end point(s) |
1.Overall response rate (ORR): The proportion of patients who achieve a partial response (PR) or better, assessed by the Investigator using the IMWG criteria, from study treatment initiation to PD, or the initiation of further anti-myeloma treatment, or death, whichever comes first
2.Progression-free survival (PFS): The time from study treatment initiation to the date of first documentation of PD, assessed by the Investigator using the IMWG response criteria, or the initiation of further anti-myeloma treatment, or death from any cause, whichever comes first
3.Time to Response (TTR): The time from study treatment initiation to the date of the first objective response of partial response (PR) or better, assessed with the IMWG response criteria
4.Duration of Response (DoR):
- The time from the date of the first objective response to the date of first documented PD, assessed by the Investigator using the IMWG response criteria, or death, whichever occurs first.
-DoR will be assessed only for patients who have achieved ≥PR
5.Overall Survival (OS): The time from study treatment initiation to the date of death from any cause.
-OS will be assessed during the response follow-up visits, and for a maximum of 36 months from first patient enrolment.
6.Minimal Residual Disease (MRD) negativity rate: The proportion of patients achieving MRD-negative status, assessed by the Investigator at suspected CR as per IMWG criteria.
7.Safety: The incidence of AEs, TEAEs, and serious adverse events (SAEs) from study treatment initiation until 30 days after the last study treatment. AEs and laboratory parameters will be graded using the NCI-CTCAE version 4.03. Specific safety laboratory tests are planned in case of an infusion reaction
|
|
| 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 | 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.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 6 |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| 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 | 3 |
| 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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