Isatuximab for Relapsed Multiple Myeloma

Inclusion criteria

• {"criterion_text":"- Patient has given voluntary written informed consent"}
• {"criterion_text":"- 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)"}
• {"criterion_text":"- 1.2 Absolute neutrophil count (ANC) ≥ 1 x 10^9/L without the use of growth factors"}
• {"criterion_text":"- 1.3 Corrected serum calcium ≤14 mg/dL (3.5 mmol/L)"}
• {"criterion_text":"- 1.4 Alanine transaminase (ALT): ≤ 3 x the ULN"}
• {"criterion_text":"- 1.5 Total bilirubin: ≤ 2 x the ULN"}
• {"criterion_text":"- 1.6 Calculated or measured creatinine clearance: ≥ 30 mL/minute"}
• {"criterion_text":"- 2. Female subjects are eligible to participate if they are not pregnant, not breastfeeding, and at least one of the following conditions applies:"}
• {"criterion_text":"- 2.1 They are not females of childbearing potential (FCBP)"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- Patient is willing and able to comply with the study visits and procedures required per protocol"}
• {"criterion_text":"- Subject must have at least 18 and ≤ 70 years of age"}
• {"criterion_text":"- Patient has a life-expectancy ≥ 3 months"}
• {"criterion_text":"- Subject has received an ASCT in the first line of therapy with a progression/relapse after at least 24 months"}
• {"criterion_text":"- 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."}
• {"criterion_text":"- Subject must have at least 2.0 x 10^6 CD34+/Kg cryopreserved autologous stem cells"}
• {"criterion_text":"- Subject must have an ECOG Performance Status score of 0, 1"}
• {"criterion_text":"- 1.Subject must have the following laboratory values:"}

Exclusion criteria

• {"criterion_text":"- Previous therapy with daratumumab, isatuximab or any other anti-CD38 monoclonal antibody"}
• {"criterion_text":"- 2. Active HCV infection: positive HCV RNA and negative anti-HCV. Of note:"}
• {"criterion_text":"- 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."}
• {"criterion_text":"- 2.2 Patients with positive anti-HCV and undetectable HCV RNA without antiviral therapy for HCV are eligible."}
• {"criterion_text":"- 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"}
• {"criterion_text":"- Subject with active tuberculosis and systemic or severe infections requiring treatment with an antibiotic parenteral administration"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- Subject with pulmonary deficit, defined as FEV1 <65% and/or DLCO <65%"}
• {"criterion_text":"- 3. Subject with clinically significant cardiac disease, including:"}
• {"criterion_text":"- 3.1 LVEF <50%"}
• {"criterion_text":"- 3.2 Myocardial infarction within 6 months before eligibility confirmation, or unstable"}
• {"criterion_text":"- 2. MM localization to the central nervous system"}
• {"criterion_text":"- 3.3 Uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure, New York Heart Association Class III-IV)"}
• {"criterion_text":"- 3.4 Cardiac arrhythmia (Common Terminology Criteria for Adverse Events [CTCAE] Version 5 Grade 2 or higher) or clinically significant ECG abnormalities"}
• {"criterion_text":"- 3.5 Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s formula (QTcF) >500 msec"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- Subjects who have received an allogeneic stem cell transplant"}
• {"criterion_text":"- 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)"}
• {"criterion_text":"- 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."}
• {"criterion_text":"- 1. Uncontrolled or active HBV infection: patients with positive HBsAg and/or HBV DNA. Of note:"}
• {"criterion_text":"- 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."}
• {"criterion_text":"- 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."}

Primary endpoints

• {"endpoint_text":"- The rate of MRD negativity is determined as the proportion of patients with NGF MRD negativity (10-5 sensitivity level) within 12 months after ASCT using the intention-to-treat principle. For patients who withdraw from the study or are lost to follow up before this timepoint, the best MRD assessment will be considered. Patients will be classified as MRD positive if they have only MRD positive test results or do not undergo MRD assessment.","definition_or_measurement_approach":"Defined as the proportion of patients with NGF MRD negativity at the 10^-5 sensitivity level within 12 months after ASCT using the intention-to-treat principle. For withdrawals or lost to follow-up before 12 months, the best MRD assessment is considered. Patients with only MRD positive results or without MRD assessment are classified as MRD positive."}

Secondary endpoints

• {"endpoint_text":"- Response rate (sCR, CR, VGPR, PR, ORR) will be evaluated according to IMWG Response criteria after induction, transplant and maintenance.","definition_or_measurement_approach":"Response evaluated using IMWG Response criteria after induction, transplant and maintenance (measures: sCR, CR, VGPR, PR, ORR)."}
• {"endpoint_text":"- TTP will be measured from the date of ICF to the date of first observation of PD, or deaths for PD. Subjects who have not progressed or who withdraw from the study or die from causes other than PD will be censored at the time of the last complete disease assessment. Subjects lost to follow-up will also be censored at the time of last complete disease assessment","definition_or_measurement_approach":"Time to progression measured from informed consent (ICF) to first observation of progressive disease (PD) or deaths due to PD; censoring rules specified for non-PD deaths, withdrawals, and loss to follow-up."}
• {"endpoint_text":"- PFS will be measured from the date of ICF to the date of first observation of PD, or death from any cause as an event. Subjects who have not progressed or who withdraw from the study or who were lost to follow-up will be censored at the time of the last complete disease assessment.","definition_or_measurement_approach":"Progression-free survival from ICF to PD or death from any cause; censoring at last complete disease assessment for withdrawals or lost to follow-up."}
• {"endpoint_text":"- TNT will be measured from the date of eligibility confirmation to the date of next anti-myeloma therapy. Death due to any cause before starting therapy will be considered an event. Subjects who have not progressed or who withdraw from the study will be censored at the time of the last complete disease assessment. Subjects lost to FU will also be censored at the time of last contact.","definition_or_measurement_approach":"Time to next therapy from eligibility confirmation to start of next anti-myeloma therapy; death before therapy considered event; censoring rules provided."}
• {"endpoint_text":"- PFS2 will be measured from the date of ICF to the date of observation of second disease progression or death to any cause as an event. In case of date of second progression is not available, date of start of third line treatment can be used. Subjects who have not progressed or who withdraw from the study will be censored at the time of the last complete disease assessment. All subjects who were lost to follow-up prior to the end of the study, h","definition_or_measurement_approach":"PFS2 measured from ICF to second progression or death; if second progression date unavailable, start of third-line treatment may be used; censoring rules apply."}
• {"endpoint_text":"- OS is defined as the time between ICF date and death, regardless cause of death. Subjects who withdraw consent will be censored at the time of withdrawal. Subjects who are still alive at the cut-off date of final analysis will be censored at the cut-off date. Subjects lost to FU will also be censored at the time of last contact","definition_or_measurement_approach":"Overall survival from ICF to death from any cause; censoring at withdrawal or cut-off date; last contact censoring for lost to follow-up."}
• {"endpoint_text":"- DOR is defined as time between first documentation of response (achievement of at least a PR) and PD with deaths owning to causes other than progression not counted, but censored. Responders without disease progression at the cut-off date of final analysis will be censored either at the time of lost to follow-up, at the time of death due to other cause than PD, or at the time of last contact.","definition_or_measurement_approach":"Duration of response from first documented response (≥PR) to PD; non-progression deaths are censored; censoring rules specified."}
• {"endpoint_text":"- Time to PR will be measured from the date of ICF to the date of first observation of PR Subjects who achieved response better than PR will be consider that PR is achieved. Subjects who withdraw from the study will be censored at the time of the last complete disease assessment. Subjects have not achieved a PR, and are still alive at the cut-off date of final analysis will be censored at the cut-off date. All subjects who were lost to FU will also be censored at the time of last contact.","definition_or_measurement_approach":"Time from ICF to first observation of PR; achieving better response counts as PR; censoring rules provided."}
• {"endpoint_text":"- Time to VGPR will be measured from the date of ICF to the date of first observation of VGPR (Very Good Partial Response). Subjects who achieved response better than VGPR will be consider that VGPR is achieved. Subjects who withdraw from the study will be censored at the time of the last complete disease assessment. Subjects have not achieved a VGPR, and are still alive at the cut-off date of final analysis will be censored at the cut-off date. All subjects who were lost to FU will also be censor","definition_or_measurement_approach":"Time from ICF to first observation of VGPR; better responses count as achieving VGPR; censoring rules provided."}
• {"endpoint_text":"- Time to CR will be measured from the date of ICF to the date of first observation of CR.Subjects who achieved response better than CR will be consider that CR is achieved. Subjects who withdraw from the study will be censored at the time of the last complete disease assessment. Subjects have not achieved a CR, and are still alive at the cut-off date of final analysis will be censored at the cut-off date. All subjects who were lost to FU will also be censored at the t","definition_or_measurement_approach":"Time from ICF to first CR; better responses count as CR; censoring rules provided."}
• {"endpoint_text":"- Time to sCR will be measured from the date of ICF to the date of first observation of sCR (stringent Complete Partial Response). Subjects who withdraw from the study will be censored at the time of the last complete disease assessment. Subjects have not achieved a sCR, and are still alive at the cut-off date of final analysis will be censored at the cut-off date. All subjects who were lost to FU will also be censored at the time of last contact. Difference will be calculated in 30-day months.","definition_or_measurement_approach":"Time from ICF to first sCR; censoring rules; differences calculated in 30-day months."}
• {"endpoint_text":"- Rate of 1 year sustained MRD negativity by NGF will be also evaluated, and correlated with PFS and OS.","definition_or_measurement_approach":"Proportion of patients with sustained MRD negativity at 1 year by NGF; correlation analyses with PFS and OS planned."}
• {"endpoint_text":"- The rate of MRD negativity is determined as the proportion of patients with NGF MRD negativity (10-5 sensitivity level) within 12 months after ASCT using the intention-to-treat principle. For patients who withdraw from the study or are lost to follow up before this timepoint, the best MRD assessment will be considered. Patients will be classified as MRD positive if they have only MRD positive test results or do not undergo MRD assessment.","definition_or_measurement_approach":"Same definition as primary endpoint (MRD negativity by NGF at 10^-5 within 12 months after ASCT, ITT principle); classification and handling of missing assessments specified."}
• {"endpoint_text":"- The 24 months MRD negativity rate is determined as the proportion of patients with MRD negativity (≥10-5 sensitivity level, NGF) after 12 months using ITT principle. Patients will be classified as MRD positive if they have only MRD positive test results or do not undergo MRD assessment/sample not adequate.","definition_or_measurement_approach":"Proportion with MRD negativity at 24 months (≥10^-5 NGF) using ITT; classification rules for MRD positive or inadequate samples specified."}
• {"endpoint_text":"- The analysis of safety as defined by type, frequency and severity will be done primarily by tabulation of the incidence of Adverse Events as defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. In the by-subject analysis, a subject having the same event more than once will be counted only once. Adverse Events will be summarized by worst CTCAE grade.","definition_or_measurement_approach":"Safety analysed by tabulating incidence, type, frequency and severity of adverse events per NCI CTCAE v5.0; by-subject analysis counts event once and summarizes worst grade."}
• {"endpoint_text":"- Dose reduction will be done primarily by tabulation of the incidence of dose reduction and causes.","definition_or_measurement_approach":"Tabulation of incidence of dose reductions and reasons."}
• {"endpoint_text":"- Time to discontinuation will be measured from the date of first dose of study drugs to the date of discontinuation due to AE or Death for AE/SPM. Subjects who discontinued drugs due to PD, or death for cause other than AE/SPM will be considered a competitive event. Subjects has not discontinued, and are still alive and on treatment at the cut-off date of final analysis will be censored at the cut-off date. All subjects who were lost to FU will also be censored at the time of last contact.","definition_or_measurement_approach":"Time from first dose to discontinuation due to AE or death from AE/SPM; competing events and censoring rules specified."}
• {"endpoint_text":"- Relative dose will be evaluated consider the ration between the administered and the planned dose. Relative dose will be estimated for each study drugs.","definition_or_measurement_approach":"Relative dose calculated as ratio between administered and planned dose for each study drug."}

Italy

Earliest CTIS Part Ii Submission Date

22-07-2024

Latest Decision Or Authorization Date

08-05-2026

Processing Time Days

655

Number Of Sites

6

Number Of Participants

25

Primary sponsor

Full Name

Emn Trial Office S.r.l. Impresa Sociale

Organisation Type

Laboratory/Research/Testing facility

Country Of Registered Address

Italy

Third parties

• {"country":"Italy","full_name":"Sanofi S.r.l.","duties_or_roles":"[{\"id\":979395,\"code\":\"14\"}]","organisation_type":"Pharmaceutical company"}
• {"country":"Italy","full_name":"Mipharm S.p.A.","duties_or_roles":"[{\"id\":979394,\"code\":\"14\"}]","organisation_type":"Pharmaceutical company"}
• {"country":"Italy","full_name":"University Hospital Consorziale Policlinico","duties_or_roles":"[{\"id\":979396,\"code\":\"4\"}]","organisation_type":"Health care"}