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

Status
Active
Cancer Type
Hematopoietic Malignancies
Plasma cell neoplasm
Unknown Primary
Trial Phase
Phase I
Eligibility
18 Years and older, Male and Female
Study Type
Treatment
NCT ID
NCT04754945
Protocol IDs
Winship5086-20 (primary)
NCI-2020-06548
Study Sponsor
Emory University Hospital/Winship Cancer Institute

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.

Objectives

PRIMARY OBJECTIVES:
I. Test the safety and feasibility of isatuximab-based drug treatment.
II. Evaluate the preliminary efficacy of a slow-go approach in high risk AL amyloid patients.

OUTLINE:
Patients receive dexamethasone intravenously (IV) or orally (PO) and isatuximab IV over 3 hours and 20 minutes for the first dose, over 1 hour and 53 minutes for the second dose, and over 75 minutes for subsequent doses. Treatment repeats weekly for 4 weeks and then every other week thereafter for up to 196 days. Beginning day 15, patients receive bortezomib subcutaneously (SC) weekly for 182 days and beginning day 85, patients receive cyclophosphamide IV or PO weekly for 112 days. Patients then receive dexamethasone and isatuximab as maintenance treatment twice per month for 12 months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 4 weeks. Patient records are reviewed for 2 years from enrollment.

Eligibility

  1. 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)
  2. 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 (equivalent to > 100 ng/L hs-TnI) 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)
  3. Age >= 18 years
  4. Absolute neutrophil count (ANC) >= 1000/uL
  5. Platelet count >= 50,000 and platelet transfusion independent for 1 week prior to screening
  6. Estimated creatinine clearance >= 20 mL/min/1.73 m^2 as defined by Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI)
  7. 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
  8. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x IULN
  9. Left ventricular ejection fraction >= 30%
  10. 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
  11. Ability to understand and the willingness to sign a written informed consent document
  12. 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
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