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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04754945
Recruitment Status : Recruiting
First Posted : February 15, 2021
Last Update Posted : May 4, 2022
Sponsor:
Collaborators:
Sanofi
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Craig Hofmeister, Emory University

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.

Condition or disease Intervention/treatment Phase
AL Amyloidosis Drug: Bortezomib Drug: Cyclophosphamide Drug: Dexamethasone Biological: Isatuximab Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

  1. Test the safety and feasibility of isatuximab-based drug treatment.
  2. Evaluate the preliminary efficacy of a slow-go approach in high risk AL amyloid patients.

STUDY TREATMENT

Each patient starts by receiving increasing intensity of treatment for AL Amyloidosis up to maximum tolerance, and then maintenance Isatuximab thereafter for a specified period.

All patients will receive Isatuximab (weekly x 4 then every other week) plus dexamethasone 4 mg PO/IV days weekly. If tolerating Isatuximab/Dex4 (earliest time to escalate C1D15), add Velcade to 1 mg/m2 SQ weekly. If tolerating Isa/Vel1.0/Dex4 (earliest time to escalate C2D1), increase dexamethasone to 12 mg weekly. If tolerating Isa/Velcade1.0/Dex12 (earliest time to escalate C3D1), increase Velcade to 1.3 mg/m2 SQ. If tolerating Isa/Velcade1.3/Dex12 (earliest time to escalate C4D1), add cyclophosphamide 300 mg IV weekly. If tolerating Isa/Velcade1.3/Cy300/Dex12 (earliest time to escalate C5D1), increase cyclophosphamide to 400 mg IV weekly. If tolerating Isa/Velcade1.3/Cy400/Dex12 (earliest time to escalate C6D1), increase cyclophosphamide to 500 mg IV weekly.

Tolerance determined by the patient not reaching an escalation limiting toxicity AND patient approval to dose escalate.

Patients then receive dexamethasone and isatuximab as maintenance treatment twice per month for 12 months in the absence of disease progression or unacceptable toxicity.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 25 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Slow-Go Strategy for High Risk AL Amyloidosis: Isatuximab for Upfront Therapy
Actual Study Start Date : April 28, 2021
Estimated Primary Completion Date : September 21, 2024
Estimated Study Completion Date : September 21, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Amyloidosis
Drug Information available for: Isatuximab

Arm Intervention/treatment
Experimental: Treatment (isatuximab, chemotherapy)

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
Given SC
Other Names:
  • [(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic Acid
  • LDP 341
  • MLN341
  • PS-341
  • PS341
  • Velcade

Drug: Cyclophosphamide
Given IV or PO
Other Names:
  • (-)-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

Drug: Dexamethasone
Given IV or PO
Other Names:
  • 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

Biological: Isatuximab
Given IV
Other Names:
  • Hu 38SB19
  • Isatuximab-irfc
  • SAR 650984
  • SAR650984
  • Sarclisa




Primary Outcome Measures :
  1. Event-free proportion [ Time Frame: At 3 months ]
    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.


Secondary Outcome Measures :
  1. Complete hematologic response proportion [ Time Frame: Up to 19 months ]
    Will be calculated with an exact 95% confidence interval.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • > 1 prior line of therapy
  • Refractory to any proteasome inhibitor
  • Prior CD38 antibody exposure
  • Cardiac exclusions:

    • 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
  • Known or suspected of not being able to comply with the study protocol (e.g. alcoholism, drug dependency, or psychological disorder) or the subject has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (e.g., compromise their well-being) or that could prevent, limit, or confound the protocol-specified assessments
  • Pregnant women are excluded from this study because protocol therapy has the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to protocol treatment of the mother, breastfeeding should be discontinued. Women planning to become pregnant 1 year after discontinuation of cyclophosphamide or 3 months following discontinuation of isatuximab

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04754945


Contacts
Layout table for location contacts
Contact: Craig C Hofmeister, MD, MPH 404-778-1900 craig.hofmeister@emory.edu

Locations
Layout table for location information
United States, California
University of California Not yet recruiting
Orange, California, United States, 92868
Principal Investigator: Sandy Wong, MD         
United States, Georgia
Emory University Hospital/Winship Cancer Institute Recruiting
Atlanta, Georgia, United States, 30322
Contact: Shondolyn C. Richburg    404-778-3612    shondolyn.k.richburg@emory.edu   
Principal Investigator: Craig C. Hofmeister         
Emory University Hospital Midtown Not yet recruiting
Atlanta, Georgia, United States, 39322
Contact: Shondolyn Richburg    404-778-3612    shondolyn.richburg@emory.edu   
United States, Michigan
Karmanos Cancer Institute Not yet recruiting
Detroit, Michigan, United States, 48201
Principal Investigator: Jeffrey Zonder, MD         
United States, New York
Columbia University Not yet recruiting
New York, New York, United States, 10032
Principal Investigator: Suzanne Lentzsch, MD, PhD         
United States, Texas
UT Southwestern Not yet recruiting
Dallas, Texas, United States, 75390
Principal Investigator: Ankit Kasangra, MD         
Sponsors and Collaborators
Emory University
Sanofi
National Cancer Institute (NCI)
Investigators
Layout table for investigator information
Principal Investigator: Craig C Hofmeister, MD, MPH Emory University
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Responsible Party: Craig Hofmeister, Principal Investigator, Emory University
ClinicalTrials.gov Identifier: NCT04754945    
Other Study ID Numbers: STUDY00001440
NCI-2020-06548 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
Winship5086-20 ( Other Identifier: Emory University Hospital/Winship Cancer Institute )
P30CA138292 ( U.S. NIH Grant/Contract )
First Posted: February 15, 2021    Key Record Dates
Last Update Posted: May 4, 2022
Last Verified: May 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
Layout table for MeSH terms
Immunoglobulin Light-chain Amyloidosis
Amyloidosis
Proteostasis Deficiencies
Metabolic Diseases
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Paraproteinemias
Dexamethasone
Dexamethasone acetate
Cyclophosphamide
Bortezomib
Ichthammol
Antibodies, Monoclonal
BB 1101
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents