Isatuximab for Amyloidosis

Not currently recruiting at 5 trial locations

Overseen By Craig C Hofmeister, MD, MPH

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Emory University

Must not be taking: Proteasome inhibitors, CD38 antibodies

Disqualifiers: HIV, Hepatitis B, Hepatitis C, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 6 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests isatuximab, a monoclonal antibody, to evaluate its safety and effectiveness for individuals with high-risk AL amyloidosis. AL amyloidosis causes abnormal proteins to accumulate in organs and tissues, impairing their function. Participants will receive isatuximab alongside other treatments, such as chemotherapy, to determine if it slows disease progression. Individuals diagnosed with AL amyloidosis who experience significant symptoms, like low blood pressure or heart issues, might be suitable for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that patients may continue low-dose corticosteroids for symptom management and comorbid conditions.

Is there any evidence suggesting that isatuximab is likely to be safe for humans?

Research has shown that isatuximab is generally safe for patients with AL amyloidosis who have undergone previous treatments. These patients tolerated the drug well, and it helped manage their disease. Isatuximab targets and disrupts cancer cells, preventing them from growing and spreading. This suggests that isatuximab could be a safe option for those considering joining a trial, although side effects and individual reactions can vary. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for amyloidosis, which often involve chemotherapy and supportive care, Isatuximab offers a unique approach by targeting CD38, a protein commonly found on the surface of plasma cells. This monoclonal antibody helps the immune system recognize and destroy the abnormal cells responsible for amyloidosis. Researchers are excited about Isatuximab because of its potential to enhance the effectiveness of existing therapies and improve patient outcomes by directly targeting the disease process. Additionally, the combination with dexamethasone and other agents like Velcade and cyclophosphamide could provide a more comprehensive attack on the condition, potentially leading to better control and fewer side effects.

What evidence suggests that isatuximab might be an effective treatment for AL amyloidosis?

Research has shown that isatuximab, which participants in this trial will receive, may be a promising treatment for AL amyloidosis. In one study of patients whose AL amyloidosis had returned or didn't respond to previous treatments, 77% experienced improvement in their blood-related symptoms. Another study found that isatuximab led to complete improvement in 3% of patients and significant improvement in 54% of patients. Additionally, after one year, 97% of patients were still alive, and 85% had no worsening of their disease. These results suggest that isatuximab could be an effective treatment option for people with AL amyloidosis. ^{1 2 3 4 6}

Who Is on the Research Team?

Craig C Hofmeister, MD, MPH

Principal Investigator

Emory University

Are You a Good Fit for This Trial?

This trial is for adults with high risk AL amyloidosis, a condition where abnormal proteins build up in organs. Participants must have specific biomarkers indicating severe disease, adequate organ function, and no prior significant treatments for AL amyloidosis. They should not be HIV positive or have hepatitis B/C unless certain conditions are met. Women of childbearing potential must test negative for pregnancy and agree to use contraception.

Inclusion Criteria

My diagnosis of amyloidosis was confirmed through specific tests on my tissue samples.

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, 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

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive isatuximab and dexamethasone with potential escalation to include Velcade and cyclophosphamide based on tolerance

6 months

Weekly visits initially, then bi-weekly

Maintenance

Participants receive maintenance treatment with dexamethasone and isatuximab twice per month

12 months

Bi-weekly visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 months

What Are the Treatments Tested in This Trial?

Interventions

• Isatuximab

Trial Overview The trial tests the safety and effectiveness of isatuximab as an initial treatment option for high risk AL amyloidosis patients. Isatuximab is a monoclonal antibody designed to disrupt tumor cell growth. It's given alongside standard drugs like dexamethasone, bortezomib, and cyclophosphamide to see if it improves outcomes.

How Is the Trial Designed?

Group I: Treatment (isatuximab, chemotherapy) Experimental Treatment 4 Interventions

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.

Isatuximab is already approved in European Union, United States for the following indications:

Approved in European Union as Sarclisa for:

• Multiple myeloma

Approved in United States as Sarclisa for:

• Multiple myeloma in combination with pomalidomide and dexamethasone for adults who have received at least two prior therapies including lenalidomide and a proteasome inhibitor
• Multiple myeloma in combination with carfilzomib and dexamethasone for adults with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy
• Newly diagnosed multiple myeloma in combination with bortezomib, lenalidomide, and dexamethasone for adults who are not eligible for autologous stem cell transplant

Who Is Running the Clinical Trial?

Emory University

Lead Sponsor

Trials

1,735

Recruited

2,605,000+

Sanofi

Industry Sponsor

Trials

2,246

Recruited

4,085,000+

Paul Hudson

Sanofi

Chief Executive Officer since 2019

Degree in Economics from Manchester Metropolitan University

Christopher Corsico

Sanofi

Chief Medical Officer

MD from Cornell University, MPH in Chronic Disease Epidemiology from Yale University

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a study of 49 patients with relapsed/refractory AL amyloidosis treated with daratumumab, the overall hematologic response rate was 81%, with 64% achieving a very good partial response or better, indicating strong efficacy in this challenging patient population.

Daratumumab was found to be safe and well tolerated, with no patients discontinuing treatment due to toxicity, and it demonstrated significant cardiac and renal responses (74% and 73%, respectively), supporting its use in real-world settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab for relapsed AL amyloidosis-When cumulative real-world data precedes clinical trials: A multisite study and systematic literature review. Shragai, T., Gatt, M., Lavie, N., et al.[2021]

Daratumumab, an anti-CD38 immunotherapy, has shown significant efficacy in treating newly diagnosed systemic light-chain (AL) amyloidosis by improving hematologic and organ response rates, suggesting it may become a new standard of care.

In relapsed or refractory cases, daratumumab alone or in combination therapies has also demonstrated promising results, highlighting the potential of targeting CD38 on plasma cells for effective treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab in the Treatment of Light-Chain (AL) Amyloidosis. Palladini, G., Milani, P., Malavasi, F., et al.[2021]

In a case study of a 95-year-old patient with systemic immunoglobulin light-chain (AL) amyloidosis, traditional chemotherapy treatments showed poor effectiveness, highlighting the challenges of treating this condition in very elderly patients.

The anti-CD38 antibody daratumumab demonstrated the best hematologic response with minimal side effects, suggesting it could be a safer and more effective treatment option for AL amyloidosis in older patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Interest of daratumumab in refractory AL amyloidosis in a 96-year-old patient]. Vial, G., Lafargue, A., Mercié, P., et al.[2022]

In a real-life study involving 33 patients with AL amyloidosis, daratumumab demonstrated good efficacy, achieving a 60% rate of favorable hematological responses and a 50% rate of organ responses.

The treatment was well-tolerated, indicating an acceptable toxicity profile, making daratumumab a promising option for patients with relapsed or refractory AL amyloidosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab in AL Amyloidosis: A Real-Life Experience of the "RTM" (Regional Tuscan Myeloma Network). Sammartano, V., Antonioli, E., Buda, G., et al.[2022]

Citations

1. ashpublications.org ashpublications.org/blood/article/doi/10.1182/blood.2024027962/547199/Isatuximab-for-Relapsed-and-or-Refractory-AL

Isatuximab for Relapsed and/or Refractory AL Amyloidosis Isatuximab in relapsed and/or refractory AL amyloidosis resulted in an overall hematologic response rate of 77%. The high rates of hematologic ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S0006497118699215

A Phase II Study of Isatuximab (SAR650984) (NSC-795145 ... Conclusions: Isatuximab demonstrates encouraging efficacy in previously treated patients with AL amyloidosis. The administration of isatuximab ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT01084252

Study Details | NCT01084252 | Phase 1/2 Dose Escalation ... Data for this outcome measure was planned to be collected and analyzed separately for dose 0.3 mg/kg, 1 mg/kg and not for 0.0001, 0.001, 0.01, 0.03 and 0.1 dose ...

4. jons-online.com jons-online.com/multiple-myeloma/isatuximab-for-patients-with-previously-treated-al-amyloidosis-a-phase-2-study

Isatuximab for Patients with Previously Treated AL ... Of the patients receiving ≥1 doses of isatuximab, hematologic complete response, very good partial response, and partial response were observed in 3%, 54%, and ...

5. conference-correspondent.com conference-correspondent.com/highlights/ash/ash-2020-mm/503:a-phase-2-study-of-isatuximab-for-patients-with-previously-treated-al-amyloidosis

A Phase 2 Study of Isatuximab for Patients with Previously ... One-year estimated OS is 97%, and 1-year estimated PFS is 85%. The results of the preliminary analysis of this study showed encouraging efficacy for isatuximab ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40257476/

Efficacy and safety of isatuximab monotherapy to treat ... Isatuximab demonstrated rapid and sustained efficacy when used as monotherapy, with a median time to response of 1.0 month and a median duration ...