Isatuximab as Upfront Therapy for the Treatment of High Risk AL Amyloidosis

NCT04754945 | Active Not Recruiting Phase 1 DMC FDA Drug

• 4 other identifiers: STUDY00001440NCI-2020-06548Winship5086-20P30CA138292
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 6

Brief Summary

This phase I trial studies the side effects of isatuximab and to see how well it works in treating patients with high risk immunoglobulin light chain amyloidosis (AL amyloidosis). Isatuximab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread.

Conditions

AL Amyloidosis

Outcome Measures

Primary Outcomes (1)

• Event-free proportion

  An event is defined as going off study due to toxicity, death or progression of disease. The events include off-study due to toxicity, death, or progression. The rate will be calculated with an exact 95% confidence interval using the efficacy evaluable population.

  At 3 months

Secondary Outcomes (1)

• Complete hematologic response proportion

  Up to 19 months

Study Arms (1)

Treatment (isatuximab, chemotherapy)

EXPERIMENTAL

All patients will receive Isatuximab plus dexamethasone 4 mg PO/IV days weekly. Based on tolerance, patients will add to their treatment subcutaneous Velcade (earliest time to add Velcade is cycle 1 day 15) and intravenous cyclophosphamide (earliest time to add cyclophosphamide is cycle 4 day 1) Patients then receive dexamethasone and isatuximab as maintenance treatment twice per month for 12 months in the absence of disease progression or unacceptable toxicity.

Drug: Bortezomib; Drug: Cyclophosphamide; Drug: Dexamethasone; Biological: Isatuximab

Interventions

Bortezomib DRUG

Given SC

Also known as: [(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic Acid, LDP 341, MLN341, PS-341, PS341, Velcade

Treatment (isatuximab, chemotherapy)

Cyclophosphamide DRUG

Given IV or PO

Also known as: (-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamide Monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719

Treatment (isatuximab, chemotherapy)

Dexamethasone DRUG

Given IV or PO

Also known as: Aacidexam, Adexone, Aknichthol Dexa, Alba-Dex, Alin, Alin Depot, Alin Oftalmico, Amplidermis, Anemul mono, Auricularum, Auxiloson, Baycadron, Baycuten, Baycuten N, Cortidexason, Cortisumman, Decacort, Decadrol, Decadron, Decadron DP, Decalix, Decameth, Decasone R.p., Dectancyl, Dekacort, Deltafluorene, Deronil, Desamethasone, Desameton, Dexa-Mamallet, Dexa-Rhinosan, Dexa-Scheroson, Dexa-sine, Dexacortal, Dexacortin, Dexafarma, Dexafluorene, Dexalocal, Dexamecortin, Dexameth, Dexamethasone Intensol, Dexamethasonum, Dexamonozon, Dexapos, Dexinoral, Dexone, Dinormon, Fluorodelta, Fortecortin, Gammacorten, Hexadecadrol, Hexadrol, Lokalison-F, Loverine, Methylfluorprednisolone, Millicorten, Mymethasone, Orgadrone, Spersadex, TaperDex, Visumetazone, ZoDex

Treatment (isatuximab, chemotherapy)

Isatuximab BIOLOGICAL

Given IV

Also known as: Hu 38SB19, Isatuximab-irfc, SAR 650984, SAR650984, Sarclisa

Treatment (isatuximab, chemotherapy)

Eligibility Criteria

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

You may qualify if:

• Histopathological diagnosis of amyloidosis based on detection by immunohistochemistry (IHC) and polarizing light microscopy of green birefringent material in Congo red-stained tissue specimens in an organ other than bone marrow, characteristic electron microscopy appearance, or mass spectrometry. Specifically for male subjects 70 years of age or older who have cardiac involvement only and subjects of African descent, mass spectrometry typing of AL amyloid in a tissue biopsy is recommended to rule out other types of amyloidosis such as age-related amyloidosis or hereditary amyloidosis (ATTR mutation)
• Must have evidence of high risk AL amyloidosis defined as one of the following any time within the 6 months prior to consent:
• Biomarker-based indicators of severe disease: NT-proBNP \> 8500 ng/L OR hs-cTnT \>= 50 ng/L
• BUMC 2019 stage 3b requiring both TnI \> 0.1 ng/mL and BNP \> 700 pg/mL
• Mayo 2012 stage 4 that includes each of the following a) cTnT \>= 0.025 ng/mL or hs-cTnT \>= 40 ng/mL; b) NT-proBNP \>= 1800 pg/mL; and c) dFLC \>= 180 mg/L
• Significant AL amyloid related hypotension (systolic blood pressure \[SBP\] \< 100 mm Hg or symptomatic orthostatic hypotension defined as a decrease in systolic blood pressure upon standing of \> 20 mm Hg despite medical management \[fludrocortisone, midodrine, etc\] in the absence of volume depletion)
• Absolute neutrophil count (ANC) \>= 1000/uL
• Platelet count \>= 50,000 and platelet transfusion independent for 1 week prior to screening
• Estimated creatinine clearance \>= 20 mL/min/1.73 m\^2 as defined by Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI)
• Total bilirubin \< 1.5 x institutional upper limit of normal (IULN) except for patients with Gilbert syndrome in which case total bilirubin =\< 2 x IULN
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \< 3 x IULN
• Left ventricular ejection fraction \>= 30%
• Females of childbearing potential (FCBP) must 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. The effects of protocol therapy on the developing human fetus are unknown. For this reason, FCBP and men 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 completion of protocol therapy. Men must refrain from donating sperm during the same period that they must agree to use contraception. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. A female of childbearing potential (FCBP) is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months
• Ability to understand and the willingness to sign a written informed consent document
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial

You may not qualify if:

• \> 1 prior line of therapy
• Refractory to any proteasome inhibitor
• Prior CD38 antibody exposure
• Subjects with a history of sustained ventricular tachycardia EXCEPT in patients with a pacemaker/implantable cardioverter defibrillator (ICD)
• Baseline QT interval as corrected by institutional rate correction algorithm (e.g. corrected QT interval by Bazett formula \[QTc\]B or corrected QT interval by Fridericia formula \[QTcF\]) \> 500 msec EXCEPT in patients with a pacemaker
• Grade 2 or greater peripheral sensory neuropathy
• Received any investigational drug within 14 days or 5 half-lives of the investigational drug, whichever is longer
• 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 H2 blockers or would prohibit further treatment with these agents
• Human immunodeficiency virus (HIV) positive EXCEPT if the patient meets all the following: CD4 \> 350 cells/mm3, undetectable viral load, maintained on modern therapeutic regimen utilizing non CYP interacting agents (e.g. excluding ritonavir), and no untreated acquired immune deficiency syndrome defining opportunistic infections
• Seropositive for hepatitis B surface antigen \[HBsAg\]) EXCEPT subjects with resolved infection (i.e., subjects 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) deoxyribonucleic acid (DNA) levels. Those who are PCR positive will be excluded. Subjects 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
• Seropositive for hepatitis C EXCEPT in the setting of a sustained virologic response \[SVR\], defined as without viremia for at least 12 weeks after completion of antiviral therapy
• Polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes (POEMS) syndrome, wild type or mutated (ATTR) amyloidosis, and Waldenstrom macroglobulinemia
• Known allergies, hypersensitivity, or intolerance to monoclonal antibodies, hyaluronidase, human proteins, or their excipients (refer to investigational brochure \[IB\]), or known sensitivity to mammalian-derived products
• Patients who have had any plasma cell directed treatment, radiotherapy, plasmapheresis, or major surgery (as defined by the investigator) within 1 week prior to cycle 1 day 1 of the study. Patients may be receiving concomitant therapy with low dose corticosteroids (e.g., prednisone up to but no more than 10 mg by mouth daily or its equivalent) for symptom management and comorbid conditions
• Concurrent medical condition or disease (e.g., active infection requiring treatment with a parenteral antibiotic, active tuberculosis, etc) that would expose excessive risk to the patient or may interfere with compliance or interpretation of the study results

Sponsors & Collaborators

• Emory University: lead
• Sanofi: collaborator
• National Cancer Institute (NCI): collaborator

Study Sites (6)

University of California

Orange, California, 92868, United States

Location

Emory University Hospital/Winship Cancer Institute

Atlanta, Georgia, 30322, United States

Location

Emory University Hospital Midtown

Atlanta, Georgia, 39322, United States

Location

Karmanos Cancer Institute

Detroit, Michigan, 48201, United States

Location

Columbia University

New York, New York, 10032, United States

Location

UT Southwestern

Dallas, Texas, 75390, United States

Location

MeSH Terms

Conditions

Immunoglobulin Light-chain Amyloidosis

Interventions

Bortezomib; Cyclophosphamide; Dexamethasone; Calcium Dobesilate; auricularum; dexamethasone acetate; dexamethasone 21-phosphate; isatuximab

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Amyloidosis; Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Paraproteinemias

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; Benzenesulfonates; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Arylsulfonates; Arylsulfonic Acids; Sulfonic Acids; Sulfur Acids; Sulfur Compounds

Study Officials

• Craig C Hofmeister, MD, MPH

  Emory University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: February 9, 2021
• First Posted: February 15, 2021
• Study Start: April 28, 2021
• Primary Completion (Estimated): May 6, 2027
• Study Completion (Estimated): July 24, 2028
• Last Updated: July 14, 2026

Record last verified: 2026-07

Locations

US (6)