start date: April 28, 2021
estimated completion: September 21, 2026
last updated: May 19, 2023
phase of development:
Phase 1
size / enrollment: 25
study description: PRIMARY OBJECTIVES:
Test the safety and feasibility of isatuximab-based drug treatment.
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.
primary outcomes:
- 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:
- Complete hematologic response proportion
Up to 19 months
inclusion criteria:
• Eligible Ages: 18+
• Eligible Sexes: all
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: 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
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