Evaluation of Isatuximab and Dexamethasone in Autologous Hematopoietic Stem Cell Transplantation for Relapsed Multiple Myeloma Patients
- Trial ID
- 2024-513397-21-00
- Protocol
- ISABEL
Trial statistics
Diseases & Conditions
Objectives
The primary objective of the study is to evaluate the **efficacy** of isatuximab in combination with salvage autologous hematopoietic stem cell transplantation (ASCT) in patients with relapsed **Multiple Myeloma**. This evaluation is clinically relevant as it aims to determine the potential of this therapeutic approach to improve outcomes in a patient population with limited treatment options.
The secondary objectives include the assessment of additional efficacy parameters, safety, and response-related features of isatuximab and salvage ASCT. These objectives are crucial for understanding the broader impact of the treatment regimen on patient health and its potential side effects, thereby informing clinical decision-making and optimizing patient care strategies.
Participants
The clinical trial involves participants diagnosed with **Relapsed Multiple Myeloma**. The study population includes both male and female subjects, aged between 18 and 70 years. Participants are required to have a life expectancy of at least three months and must have previously undergone an autologous stem cell transplant (ASCT) in the first line of therapy, with a progression or relapse occurring after a minimum of 24 months. The trial population was selected based on specific inclusion criteria, including adequate platelet count, neutrophil count, and other laboratory values, as well as the ability to comply with study visits and procedures. Participants must not be pregnant or breastfeeding, and both male and female subjects are required to use effective contraception during the study and for a specified period afterward. The sponsor has not provided information regarding the total number of participants. The trial includes a vulnerable population, and lifestyle considerations such as diet and physical activity are not specified in the available data.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **isatuximab** in combination with autologous hematopoietic stem cell transplantation for patients with relapsed multiple myeloma. This is a phase II, randomized, double-blind, controlled trial. The trial is expected to last until January 2027, with recruitment having started in July 2021. Participants will be involved in the study for a maximum treatment period of 18 months, depending on the specific treatment arm they are assigned to.
The trial includes several key study visits. The initial visit is the inclusion (screening) visit, where eligibility criteria are assessed, including platelet count, absolute neutrophil count, serum calcium levels, and other laboratory values. Participants must provide informed consent and meet specific inclusion criteria, such as age between 18 and 70 years, a life expectancy of at least three months, and previous autologous stem cell transplantation. Following the screening, participants will undergo randomization and begin the treatment phase, which includes administration of the study drugs, **dexamethasone sodium phosphate** and isatuximab, via oral and intravenous routes, respectively.
Follow-up visits are scheduled to monitor the participants' response to treatment and assess any adverse events. These visits will include evaluations of response rates, progression-free survival, and overall survival, among other secondary endpoints. The primary endpoint is the rate of minimal residual disease (MRD) negativity within 12 months after transplantation. Participants will be classified as MRD positive if they do not achieve MRD negativity or do not undergo MRD assessment.
The end-of-study visit will occur at the conclusion of the treatment period or upon early termination. Conditions that may lead to early termination include disease progression, unacceptable toxicity, or withdrawal of consent. Participants who withdraw or are lost to follow-up will be censored at the time of their last complete disease assessment. The trial will adhere to the National Cancer Institute's Common Terminology Criteria for Adverse Events to evaluate safety and adverse events. The study aims to provide valuable insights into the treatment of relapsed multiple myeloma, with a focus on improving patient outcomes through innovative therapeutic strategies.
Treatment
The clinical trial involves the administration of several experimental medications, including **SOLDESAM 0.2%** oral drops, which contain the active substance **dexamethasone sodium phosphate**. This pharmaceutical form is an oral solution, and the medication is administered orally. The maximum daily dose is 40 mg, with a total maximum dose of 1360 mg over a treatment period of 17 days. The medication is classified as a corticosteroid and is produced by Laboratorio Farmacologico Milanese S.R.L. Compliance with the dosing schedule is monitored throughout the trial.
Another experimental medication used in the trial is **SARCLISA 20 mg/mL**, a concentrate for solution for infusion containing the active substance **isatuximab**. This medication is administered via intravenous infusion. The maximum daily dose is 10 mg/kg, with a total maximum dose of 380 mg/kg over a treatment period of 18 days. Isatuximab is a monoclonal antibody produced by Sanofi Winthrop Industrie. The administration schedule and participant compliance are closely monitored to ensure adherence to the protocol.
Additionally, the trial includes the use of **SOLDESAM 8 mg/2 mL** and **SOLDESAM 4 mg/1 mL** solutions for injection, both containing **dexamethasone sodium phosphate**. These solutions are administered intravenously. Each formulation has a maximum daily dose of 40 mg and a total maximum dose of 1360 mg over a 17-day treatment period. These corticosteroid formulations are also produced by Laboratorio Farmacologico Milanese S.R.L. The administration and dosing schedules are strictly followed, with compliance monitoring in place.
No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial data provided. The focus remains on the evaluation of the efficacy of the experimental medications in the context of the study's primary objective.
Efficacy
The efficacy of the clinical trial titled "Isatuximab and Autologous Hematopoietic Stem Cell Transplantation for Relapsed Multiple Myeloma Patients (Isabel study)" will be assessed using several primary and secondary endpoints. The primary endpoint is the rate of **Minimal Residual Disease (MRD)** negativity, determined as the proportion of patients achieving MRD negativity at a sensitivity level of 10-5 within 12 months after Autologous Stem Cell Transplantation (ASCT). This will be evaluated using the intention-to-treat principle, and patients who withdraw or are lost to follow-up will have their best MRD assessment considered. Patients will be classified as MRD positive if they have only MRD positive test results or do not undergo MRD assessment.
Secondary endpoints include various response rates such as stringent Complete Response (sCR), Complete Response (CR), Very Good Partial Response (VGPR), Partial Response (PR), and Overall Response Rate (ORR), evaluated according to the International Myeloma Working Group (IMWG) Response criteria after induction, transplant, and maintenance. Additional secondary endpoints include Time to Progression (TTP), Progression-Free Survival (PFS), Time to Next Treatment (TNT), PFS2, Overall Survival (OS), Duration of Response (DOR), and time to achieve PR, VGPR, CR, and sCR. These will be measured from specific timepoints such as the date of informed consent form (ICF) to the date of first observation of progression, death, or next anti-myeloma therapy, with appropriate censoring for subjects who withdraw, are lost to follow-up, or are still alive at the cut-off date of final analysis.
The efficacy assessments will be conducted using validated criteria and methodologies, ensuring that the data collected is robust and reliable for determining the efficacy of the treatment regimen in patients with relapsed multiple myeloma. The trial is designed to provide comprehensive insights into the therapeutic potential of isatuximab in combination with ASCT, with a focus on achieving sustained MRD negativity and improving patient outcomes.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patient has given voluntary written informed consent
- Patient is willing and able to comply with the study visits and procedures required per protocol
- Subject must have at least 18 and ≤ 70 years of age
- Patient has a life-expectancy ≥ 3 months
- Subject has received an ASCT in the first line of therapy with a progression/relapse after at least 24 months
- Subject must have received any cytoreductive treatment, excluding anti-CD38 antibodies containing regimens, as per local practice for the first relapse, according to local guidelines. Carfilzomib-based combinations are recommended (eg. carfilzomib-lenalidomide-dexamethasone or carfilzomib-dexamethasone). After the salvage duration phase (reinduction therapy), subject has achieved at least a PR according to IMWG Response criteria.
- Subject must have at least 2.0 x 10^6 CD34+/Kg cryopreserved autologous stem cells
- Subject must have an ECOG Performance Status score of 0, 1
- 1.Subject must have the following laboratory values:
- 1.1 Platelet count ≥50 x 10^9/L (≥30 x 10^9 /L if myeloma involvement in the bone marrow is > 50%) within 14 days prior to drug administration)
- 1.2 Absolute neutrophil count (ANC) ≥ 1 x 10^9/L without the use of growth factors
- 1.3 Corrected serum calcium ≤14 mg/dL (3.5 mmol/L)
- 1.4 Alanine transaminase (ALT): ≤ 3 x the ULN
- 1.5 Total bilirubin: ≤ 2 x the ULN
- 1.6 Calculated or measured creatinine clearance: ≥ 30 mL/minute
- Female subjects are eligible to participate if they are not pregnant, not breastfeeding, and at least one of the following conditions applies:
- 2.1 They are not females of childbearing potential (FCBP)
- 2.2 They are FCBP who 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 of starting study medication and before each cycle of study treatment and must either commit to continue abstinence from heterosexual intercourse or apply a highly effective method of birth control during the intervention period and for at least 5 months after the last dose of study treatment. Of note: contraception duration should take also into consideration any backbone therapy
- Male subjects must agree to use contraception on this protocol during the intervention period and for at least 5 months after the last dose of study treatment and refrain from donating sperm during this period
Exclusion Criteria
- Previous therapy with daratumumab, isatuximab or any other anti-CD38 monoclonal antibody
- MM localization to the central nervous system
- Subjects who have received any investigational drug within 14 days or 5 half-lives of the investigational drug from eligibility confirmation, whichever is longer. In case of very aggressive disease, delay could be shortened after agreement between Sponsor and Investigator, in absence of residual toxicities from previous therapy
- Subjects who have received an allogeneic stem cell transplant
- Subject with a history of malignancy (other than multiple myeloma) within 3 years before the date of eligibility confirmation (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy that in the opinion of the investigator, in agreement with the medical monitor, is considered cured with minimal risk of recurrence within 3 years)
- Subject is known to be seropositive for human immunodeficiency virus (HIV) or with an active hepatitis A, B and C infection, defined as a positive test for hepatitis B surface antigen [HBsAg] and a positivity for HAV-RNA, HBV-DNA or HCV-RNA.
- Uncontrolled or active HBV infection: patients with positive HBsAg and/or HBV DNA. Of note:
- 1.1 Subjects can be eligible if: anti-HBc IgG is positive (with or without positive anti-HBs) but HBsAg and HBV DNA are negative. If anti-HBV therapy in relation with prior infection was started before initiation of study treatment, the anti-HBV therapy and monitoring should continue throughout the study treatment period.
- 1.2 Subjects with negative HBsAg and positive HBV DNA observed during screening period will be evaluated by a specialist for start of anti-viral treatment: study treatment could be proposed if HBV DNA becomes negative and all the other study criteria are still met.
- Active HCV infection: positive HCV RNA and negative anti-HCV. Of note:
- 2.1 Subjects with antiviral therapy for HCV started before initiation of study treatment and positive HCV antibodies are eligible. The antiviral therapy for HCV should continue throughout the treatment period until seroconversion.
- 2.2 Patients with positive anti-HCV and undetectable HCV RNA without antiviral therapy for HCV are eligible.
- Subject with any concurrent, clinically significant, uncontrolled medical condition or disease (eg, active systemic infection) that is likely to interfere with study procedures or results, or that in the opinion of the investigator would constitute a hazard for participating in this study
- Subject with active tuberculosis and systemic or severe infections requiring treatment with an antibiotic parenteral administration
- Subject with hypersensitivity or history of 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 therapy that are not amenable to premedication with steroids and H1 blockers or would prohibit further treatment with these agents
- Subject with pulmonary deficit, defined as FEV1 <65% and/or DLCO <65%
- Subject with clinically significant cardiac disease, including:
- 3.1 LVEF <50%
- 3.2 Myocardial infarction within 6 months before eligibility confirmation, or unstable
- 3.3 Uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure, New York Heart Association Class III-IV)
- 3.4 Cardiac arrhythmia (Common Terminology Criteria for Adverse Events [CTCAE] Version 5 Grade 2 or higher) or clinically significant ECG abnormalities
- 3.5 Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s formula (QTcF) >500 msec
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Not Recruiting | 02 Jul 2021 | 25 |
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 |
|---|---|---|---|---|---|---|
SOLDESAM 4 mg/1 ml soluzione iniettabile | Test | SOLUZIONE INIETTABILE | INTRAVENOUS USE | 40 | 17 | PRD353040 |
SARCLISA 20mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 10 | 18 | PRD8132765 |
SOLDESAM 0,2% gocce orali, soluzione | Test | GOCCE ORALI, SOLUZIONE | ORAL | 40 | 17 | PRD362173 |
SARCLISA 20mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 10 | 18 | PRD8132767 |
SOLDESAM 8 mg/2 ml soluzione iniettabile | Test | SOLUZIONE INIETTABILE | INTRAVENOUS USE | 40 | 17 | PRD354313 |