A Phase 2 Study of Isatuximab in combination with Bortezomib, Cyclophosphamide and Dexamethasone followed by isatuximab and lenalidomide maintenance in Newly Diagnosed Patients with Multiple Myeloma and severe Renal Impairment

Phase 1

• Conditions: newly diagnosed patients with multiple myeloma and severe renal impairment; Therapeutic area: Diseases [C] - Cancer [C04]; MedDRA version: 21.0Level: LLTClassification code 10028228Term: Multiple myelomaSystem Organ Class: 100000004864

• Registration Number: EUCTR2021-004895-32-GR
• Lead Sponsor: Hellenic Society of Hematology (EAE)

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2022-02-15
• Last Update Posted: 9 January 2023

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 51

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
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 20
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 31

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. -FCB

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: 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).;Secondary Objective: To evaluate the effect of isatuximab in combination with VCd, followed by lenalidomide maintenance on:<br>Overall response rate (ORR)<br>Progression-Free Survival (PFS)<br>Time to Response (TTR)<br>Duration of Response (DoR)<br>Overall Survival (OS)<br>Minimal Residual Disease (MRD) negativity rate <br>Safety;Primary end point(s): The renal response rate (RRR) at six months of treatment with isatuximab plus VCd.<br>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.;Timepoint(s) of evaluation of this end point: At six months of treatment with isatuximab plus VCd