Phase 2 Evaluation of Isatuximab with Bortezomib, Cyclophosphamide, and Dexamethasone in Newly Diagnosed Multiple Myeloma with Severe Renal Impairment
- Trial ID
- 2024-516061-36-00
- Protocol
- EAE116
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 2 study is 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 and severe renal impairment. This is clinically relevant as multiple myeloma often leads to renal complications, and improving renal function can significantly impact patient outcomes and treatment options.
Secondary objectives include evaluating the effect of isatuximab in combination with VCd, followed by lenalidomide maintenance, on several clinical endpoints: - 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
Participants
The clinical trial involves **newly diagnosed patients with multiple myeloma** and severe renal impairment. The study population includes both male and female participants aged 18 years or older. Participants are required to have a severe renal impairment, defined as an estimated glomerular filtration rate (eGFR) of less than 30 ml/min/1.73m² or the need for dialysis. The trial population was selected based on specific inclusion criteria, including adequate bone marrow and hepatic function, and an Eastern Cooperative Oncology Group Performance Status of 2 or less. Participants must have current evidence of measurable disease and meet laboratory criteria for bone marrow and hepatic function. The sponsor has not provided the total number of participants. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The study includes a vulnerable population, indicating that additional ethical considerations are in place to protect the participants.
Plans and Procedures
The clinical trial is designed to evaluate the effect of induction treatment with **isatuximab** in combination with **bortezomib**, **cyclophosphamide monohydrate**, and **dexamethasone** on the renal function of newly diagnosed patients with multiple myeloma and severe renal impairment. This is a Phase 2, randomized, double-blind, controlled study. The trial is expected to last until March 2025, with recruitment having commenced in March 2022. The study involves multiple visits, starting with an inclusion (screening) visit to assess eligibility based on specific criteria, including age, diagnosis, and renal function. Participants will undergo regular follow-up visits to monitor treatment response and safety, with the primary endpoint being the renal response rate at six months. Secondary endpoints include overall response rate, progression-free survival, and overall survival, among others. The end-of-study visit will conclude the participant's involvement, which is anticipated to last up to 36 months from the first patient enrollment. Conditions that may lead to early termination from the study include non-compliance with the protocol, adverse events, or disease progression. The trial aims to provide valuable insights into the treatment efficacy and safety for this patient population. Participants will receive treatment through various routes, including intravenous and oral administration, depending on the specific medication involved. The study's rigorous design ensures that data collected will contribute to understanding the therapeutic potential of the drug combination in improving renal function and overall outcomes in patients with multiple myeloma and severe renal impairment.
Treatment
The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **Cyclophosphamide Monohydrate** is provided as a powder for solution for injection or infusion. It is administered intravenously, with the dosage expressed in milligrams per square meter (mg/m²). The maximum treatment period for this medication is 168 days.
**Bortezomib** is supplied as a powder for solution for injection and is administered subcutaneously. The dosage is also measured in mg/m², and the treatment duration is up to 168 days. Bortezomib is a chemical origin proteasome inhibitor.
**Isatuximab** is available as a concentrate for solution for infusion and is administered intravenously. The dosage is calculated in milligrams per kilogram (mg/kg), with a maximum treatment period of 36 weeks. This medication is a protein of other origin, and commercial supplies are packaged and labeled specifically for clinical trial use.
**Lenalidomide** is provided in the form of hard capsules for oral use. The dosage is measured in milligrams (mg), and the treatment period is limited to 30 weeks. Lenalidomide is a chemical origin immunosuppressant.
**Dexamethasone** is available in two forms: an oral solution and a solution for injection. The oral solution is administered orally, while the injectable form is administered intravenously. Both forms have a dosage measured in mg and a maximum treatment period of 168 days. Dexamethasone is a chemical origin corticosteroid.
Throughout the trial, participant compliance with the dosing schedules is monitored to ensure adherence to the treatment protocols. The trial aims to assess the effect of these medications, particularly focusing on the renal function of newly diagnosed patients with multiple myeloma and severe renal impairment.
Efficacy
Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is the **renal response rate (RRR)** at six months of treatment with isatuximab in combination with bortezomib, cyclophosphamide, and dexamethasone (VCd). RRR is defined as the proportion of patients who achieve a partial renal response. Secondary endpoints include the overall response rate (ORR), progression-free survival (PFS), time to response (TTR), duration of response (DoR), overall survival (OS), and minimal residual disease (MRD) negativity rate. ORR is the proportion of patients achieving a partial response or better, assessed by the Investigator using the International Myeloma Working Group (IMWG) criteria. PFS is the time from study treatment initiation to the first documentation of disease progression or death from any cause. TTR is the time from study treatment initiation to the first objective response of partial response or better. DoR is the time from the first objective response to the first documented disease progression or death. OS is the time from study treatment initiation to death from any cause. MRD negativity rate is the proportion of patients achieving MRD-negative status, assessed at suspected complete response as per IMWG criteria.
Safety will also be evaluated by monitoring the incidence of adverse events (AEs), treatment-emergent adverse events (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. The efficacy assessments will be conducted at various timepoints throughout the study, with specific intervals for each parameter as per the study protocol. The analysis will be performed using validated scales and criteria, ensuring the reliability and accuracy of the results.
Inclusion and Exclusion Criteria
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 10^9/L (GCSF administration is not allowed to reach this level) -Hemoglobin level ≥7.5 g/dL (≥4.65 mmol/L) -Platelet count ≥75 x 10^9/L in patients in whom <50% of bone marrow nucleated cells are plasma cells OR Platelet count ≥50 x 10^9/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
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 × 10^9/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
- -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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Greece | Not Recruiting | 01 Mar 2022 | 51 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
CYCLOPHOSPHAMIDE MONOHYDRATE | Test | — | INTRAVENOUS USE | 00 | 168 | SUB16414MIG |
BORTEZOMIB | Test | — | SUBCUTANEOUS USE | 00 | 168 | SUB20020 |
ISATUXIMAB | Test | — | INTRAVENOUS USE | 00 | 36 | SUB187359 |
LENALIDOMIDE | Test | — | ORAL USE | 00 | 30 | SUB25389 |
DEXAMETHASONE | Test | — | ORAL USE | 00 | 168 | SUB07017MIG |
DEXAMETHASONE | Test | — | INTRAVENOUS USE | 00 | 168 | SUB07017MIG |