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

NCT05147493 | Unknown Phase 2

• 1 other identifier: EAE116
• Study Type: interventional
• Target: 51
• Locations: 1 country
• Sites: 6

Brief Summary

This is an Investigator-Initiated, phase 2, prospective, open-label study designed to be conducted in six hospitals in Greece. Eligible patients will initially receive an induction phase of six 28-day cycles of isatuximab in combination with bortezomib, cyclophosphamide, and dexamethasone (VCd), followed by a maintenance phase with isatuximab and lenalidomide until disease progression, death, unacceptable adverse events, lost to follow up, or consent withdrawal, whichever occurs first. The study will last for approximately 36 months (follow-up period), starting from the date of the first patient in, to the date of the last patient last visit. The primary objective is to assess the effect of induction treatment with isatuximab in combination with VCd on the renal function of newly diagnosed patients with multiple myeloma and severe renal impairment (RI). The secondary objectives are to evaluate the effect of isatuximab in combination with VCd, followed by lenalidomide maintenance on: Overall response rate, Progression-Free Survival, Time to Response, Duration of Response, Overall Survival, Minimal Residual Disease negativity rate, Safety

Conditions

Multiple Myeloma; Renal Impairment; Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases

Outcome Measures

Primary Outcomes (1)

• Renal Response Rate (RRR)

  The primary endpoint is the renal response rate (RRR) after 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

  After six months of treatment with isatuximab plus VCd

Secondary Outcomes (7)

• Overall response rate (ORR)

  From study treatment initiation to progressive disease (PD), or initiation of further anti-myeloma treatment, or death, whichever comes first. Maximum time period 36 months

• Progression-free survival (PFS)

  From study treatment initiation to progressive disease (PD), or initiation of further anti-myeloma treatment, or death, whichever comes first. Maximum time period 36 months

• Time to Response (TTR)

  From study treatment initiation to partial response (PR), or better. Maximum time period 36 months

• Duration of Response (DoR)

  From time response is achieved to progressive disease (PD), or death, whichever comes first. Maximum time period 36 months

• Overall Survival (OS)

  From study treatment initiation to death. Maximum time period 36 months

Study Arms (1)

Single-arm

EXPERIMENTAL

Eligible patients will initially receive an induction phase of six 28-day cycles of Isatuximab in combination with Bortezomib, Cyclophosphamide, and Dexamethasone, followed by a maintenance phase with isatuximab and lenalidomide until disease progression, death, unacceptable adverse events (AEs), lost to follow up, or consent withdrawal, whichever occurs first. Isatuximab will be given at a dose of 10 mg/kg once weekly (QW) on Days 1, 8, 15, and 22 in Cycle 1, on Days 1 and 15 during Cycles 2-6 and on Day 1 from Cycle 7 onwards. Bortezomib will be given at 1.3 mg/m2 on Days 1, 4, 8, 11 of Cycle 1 and days 1, 8, 15, 22 of Cycles 2-6. Cyclophosphamide will be given at 300 mg/m2 on Days 1, 8, 15 of Cycle 1 and days 1, 8, 15, 22 of Cycles 2-6. Dexamethasone will be given at 40 mg (20 mg for ≥75 years old) on Days 1-4 and 9-12 of Cycle 1 and Days 1, 8, 15 and 22 of Cycles 2-6. Lenalidomide will be given at 10 mg (or according to renal function) daily from Cycle 7 onwards.

Drug: Isatuximab; Drug: Bortezomib; Drug: Cyclophosphamide; Drug: Dexamethasone; Drug: Lenalidomide

Interventions

Isatuximab DRUG

Route of administration: Intravenous (IV). Dose regimen: Isatuximab will be given at a dose of 10 mg/kg once weekly (QW) on Days 1, 8, 15, and 22 in Cycle 1, on Days 1 and 15 during Cycles 2-6 and on Day 1 from Cycle 7 onwards.

Single-arm

Bortezomib DRUG

Route of administration: Subcutaneous (SC). Dose regimen: Bortezomib will be given at 1.3 mg/m2 on Days 1, 4, 8, 11 of Cycle 1 and days 1, 8, 15, 22 of Cycles 2-6.

Single-arm

Cyclophosphamide DRUG

Route of administration: Intravenous (IV). Dose regimen: Cyclophosphamide will be given at 300 mg/m2on Days 1, 8, 15 of Cycle 1 and days 1, 8, 15, 22 of Cycles 2-6.

Single-arm

Dexamethasone DRUG

Route of administration: per os (PO)/Intravenous (IV). Dose regimen: Dexamethasone will be given at 40 mg (20 mg for ≥75 years old) on Days 1-4 and 9-12 of Cycle 1 and Days 1, 8, 15 and 22 of Cycles 2-6.

Single-arm

Lenalidomide DRUG

Route of administration: per os (PO). Dose regimen: Lenalidomide will be given at 10 mg (or according to renal function) daily from Cycle 7 onwards.

Single-arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Male or female patients aged 18 years or older at the time of the ICF signature.
• Patients diagnosed with MM based on the International Myeloma Working Group (IMWG) criteria (see Appendix H).
• 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 (see Appendix E).
• Patients with current evidence of measurable disease defined as:
• Serum monoclonal protein (M-protein) levels ≥0.5 g/dL, measured using serum protein electrophoresis (SPEP) and/or
• Urine M-protein levels ≥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.
• Adequate bone marrow and hepatic function as defined by ALL the laboratory criteria:
• Absolute Neutrophil Count (ANC) ≥1.0 x 109/L (Granulocyte colony-stimulating factor (GCSF) administration is not allowed to reach this level)
• Hemoglobin levels ≥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) levels ≤2.5 x the upper limit of normal (ULN)
• Aspartate aminotransferase (AST) levels ≤2.5 x ULN
• Total bilirubin levels ≤1.5 x ULN (except for Gilbert Syndrome: direct bilirubin ≤1.5 x ULN)

You may not qualify if:

• 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.
• 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).
• Clinical signs of meningeal involvement of MM.
• 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
• 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 \[anti-HBc\] and/or antibodies to hepatitis B surface antigen \[anti-HBs\]) 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 (anti-HBs 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 the completion of the antiviral therapy).
• Known to be seropositive for human immunodeficiency virus.
• 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.
• 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.

Sponsors & Collaborators

• Hellenic Society of Hematology: lead
• Sanofi: collaborator

Study Sites (6)

General Hospital of Athens "Evangelismos"

Athens, 106 76, Greece

Location

Anticancer Oncology Hospital of Athens "Agios Savvas"

Athens, 115 22, Greece

Location

General Hospital of Athens "Alexandra"

Athens, 115 28, Greece

Location

University General Hospital of Ioannina

Ioannina, 455 00, Greece

Location

University General Hospital of Patra

Pátrai, 265 04, Greece

Location

Anticancer Hospital of Thessaloniki "Theageneio"

Thessaloniki, 546 39, Greece

Location

MeSH Terms

Conditions

Multiple Myeloma; Renal Insufficiency; Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases

Interventions

isatuximab; Bortezomib; Cyclophosphamide; Dexamethasone; Lenalidomide

Condition Hierarchy (Ancestors)

Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Organic Chemicals; Pyrazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Phosphoramides; Organophosphorus Compounds; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Phthalimides; Phthalic Acids; Acids, Carbocyclic; Carboxylic Acids; Piperidones; Piperidines; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Evangelos Terpos, Prof

  Department of Clinical Therapeutics, School of Medicine, National Kapodistrian University of Athens (NKUA)

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Maria Pagoni, Prof

CONTACT

+302107211806; info@eae.gr

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 5, 2021
• First Posted: December 7, 2021
• Study Start: April 1, 2022
• Primary Completion: December 1, 2024
• Study Completion: February 1, 2025
• Last Updated: March 29, 2022

Record last verified: 2022-03

Data Sharing

• IPD Sharing: Will not share

Locations

GR (6)