Isatuximab, Bortezomib, and Dexamethasone for the Treatment of Multiple Myeloma and Severe Kidney Impairment
This phase I clinical trial tests the safety, side effects, and best dose of isatuximab, bortezomib, and dexamethasone in treating patients with multiple myeloma who have severe kidney impairment. Isatuximab is monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Bortezomib is an antineoplastic agent that disrupts cell signaling pathways to delay tumor growth. Anti-inflammatory drugs like dexamethasone lower the body's immune response and are commonly used with other drugs in the treatment of some types of cancer. Giving isatuximab, bortezomib, and dexamethasone may kill more cancer cells in patients with multiple myeloma who also have kidney dysfunction.
Inclusion Criteria
- Newly diagnosed multiple myeloma diagnosis according to International Melanoma Working Group (IMWG) criteria. Patients eligible for autologous stem cell transplant may be enrolled if the intent is to proceed to transplant after 4 or more cycles of study treatment
- Severe renal impairment (estimated glomerular filtration rate [eGFR] < 30ml/min/1.73m^2 using the Modification of Diet in Renal Disease [MDRD] calculator) or on dialysis. The value at screening confirms eligibility (if eGFR improves prior to enrollment, this does not render a patient ineligible). The renal impairment may be acute or chronic and may be related to the underlying myeloma (e.g. multiple myeloma [MM] cast nephropathy, monoclonal immunoglobulin deposition disease [MIDD], myeloma cell infiltration) or another cause (e.g. diabetes, hypertension), however the acuity/chronicity and the underlying cause should be documented clearly. Those who have acute kidney injury from hypercalcemia should receive intravenous hydration and calcium-lowering therapy to see if this renal impairment is reversible
- At least 18 years of age
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- Absolute neutrophil count >= 1,000/mm^3 (growth factor to achieve this level is permissible)
- Platelets >= 50,000/mm^3 (transfusion to achieve this level is permissible)
- Bilirubin =< 2 mg/dL
- Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 3.5 x institutional upper limit of normal (IULN)
- The effects of isatuximab and bortezomib on the developing human fetus are unknown. For this reason, women of childbearing potential must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry, for the duration of study participation, and for 5 months after discontinuation of study treatment. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of the study, and 5 months after completion of the study
- Ability to understand and willingness to sign an Institutional Review Board (IRB) approved written informed consent document (or that of legally authorized representative, if applicable)
Exclusion Criteria
- Concomitant use of other anti-neoplastic medications or radiotherapy (except for localized disease) * Note: Participants are permitted to have received one dose of bortezomib or up to 80 mg of dexamethasone (or equivalent) prior to study treatment initiation if deemed clinically necessary for disease control
- Currently receiving any other investigational agents
- Evidence of myeloma within the central nervous system (CNS)
- Presence of amyloidosis without concomitant multiple myeloma. Patients with concomitant amyloidosis and multiple myeloma are eligible
- Prior refractoriness, intolerance, or hypersensitivity to bortezomib
- Prior treatment with an anti-CD38 monoclonal antibody
- A history of allergic reactions attributed to compounds of similar chemical or biologic composition to isatuximab, bortezomib, or dexamethasone or other agents used in the study
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia
- Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of study entry
- Active acute or chronic hepatitis B viral infection * Screening with serological tests for hepatitis B virus (HBV) with surface antigen and antibody (HBsAg and HBsAb) and HBV total core antibody (HBcAb IgG and IgM), and screening for hepatitis C virus (HCV) (HCV Ab and HCV ribonucleic acid [RNA] level) are required to have been performed within 1 year of screening, or should otherwise be performed as part of screening * Patients with uncontrolled or active HBV infection (patients with positive HBsAg and/or HBV deoxyribonucleic acid [DNA]), as well as patients with active HCV infection (positive HCV RNA and negative anti-HCV) are not eligible * In case HBcAb are positive, HBV DNA testing by polymerase chain reaction will also be done at baseline. For patients with positive anti-HBc IgG, negative HBsAg and undetectable (under limit of quantification) HBV DNA at study entry (HBV carriers: past resolved infection, resolving acute infection or receiving antiviral treatment with controlled infection), specialist advice may be requested, close monitoring of viral reactivation throughout and following the end of study treatment should be proposed (alanine aminotransferase, aspartate aminotransferase, and HBV DNA at least every 3 months, up to 6 months after treatment discontinuation or initiation of further anticancer therapy
- Patients with human immunodeficiency virus (HIV) are eligible unless their CD4+ T-cell counts are < 350 cells/mcL or they have a history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection within the 12 months prior to registration. Concurrent treatment with effective antiretroviral therapy (ART) according to Department of Health and Human Services (DHHS) treatment guidelines is recommended
- Baseline grade 2 or higher peripheral neuropathy
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT04912427.
PRIMARY OBJECTIVE:
I. To evaluate the safety and tolerability of isatuximab, bortezomib, and dexamethasone in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 ml/min/1.73m^2) and those on dialysis.
SECONDARY OBJECTIVES:
I. To evaluate for favorable impact on renal impairment.
II. To evaluate the preliminary anti-myeloma efficacy of the regimen in this population.
III. To evaluate impact on progression-free survival (PFS) of patients with severe renal impairment.
IV. To evaluate impact on overall survival (OS) of patients with severe renal impairment.
V. To assess duration of response.
VI. To evaluate safety and tolerability of each individual drug in the therapeutic regimen.
VII. To quantify and detail the specific adverse events related to therapy.
VIII. To evaluate the impact of therapy on health-related quality of life.
OUTLINE:
Patients receive isatuximab intravenously (IV) over 1 hour on days 1, 8, 15, and 22 of cycle 1 and on days 1 and 15 of subsequent cycles. Patients receive bortezomib subcutaneously (SC) on days 1, 8, 15, and 22 of cycles 1 through 8. Patients also receive dexamethasone IV over 15-60 minutes or orally (PO) on days 1, 8, 15, and 22 of cycles 1 through 8 and on days 1 and 15 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed at least annually for 5 years.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationSiteman Cancer Center at Washington University
Principal InvestigatorKeith E. Stockerl-Goldstein
- Primary ID202107134
- Secondary IDsNCI-2021-11057
- ClinicalTrials.gov IDNCT04912427