Venetoclax + Daratumumab + Dexamethasone for Amyloidosis

Overseen By Kenya Gomez

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Alfred Chung, MD

Must not be taking: BCL-2 inhibitors, CYP3A inducers

Disqualifiers: Multiple myeloma, Non-AL amyloidosis, Cardiovascular conditions, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 32

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the safety and effectiveness of a combination of three drugs—venetoclax, daratumumab, and dexamethasone—in treating systemic light-chain amyloidosis, a condition where abnormal proteins accumulate in organs. Venetoclax, a targeted therapy, aims to kill harmful cells by targeting a specific protein, while daratumumab, an immunotherapy, helps the immune system identify and destroy these cells. Dexamethasone reduces inflammation. Individuals with systemic light-chain amyloidosis who have a specific DNA abnormality called "t(11;14)" and have undergone previous therapy might be suitable for this trial. As a Phase 1, Phase 2 trial, this research focuses on understanding the treatment's effects in people and measuring its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking medical advancements.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you must stop all current medications. However, you must stop any medications or supplements with anti-amyloidogenic effects at least 14 days before starting the trial. Additionally, you cannot take certain medications like strong CYP3A inhibitors or inducers within 7 days before the trial, and you must avoid grapefruit, Seville oranges, and starfruit 3 days before starting the trial. If you are on strong CYP3A4 inducers, you must stop them at least 5 half-lives before the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that the combination of venetoclax, daratumumab, and dexamethasone has been studied for safety and effectiveness in treating amyloidosis. Earlier studies found that venetoclax worked well for many patients, though some experienced blood-related side effects requiring treatments like blood transfusions.

Daratumumab, used for other conditions, is generally well-tolerated and helps the immune system target and destroy cancer cells. Dexamethasone, a steroid commonly used to reduce inflammation, is known to be safe.

This trial is in its early stages, focusing on finding the safest dose and checking for side effects. Early trials involve close monitoring to quickly manage any adverse effects. While these findings are promising, anyone considering joining a trial should talk to their doctor to understand the potential risks and benefits. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of venetoclax, daratumumab, and dexamethasone for treating amyloidosis because it targets the disease in a fresh way. Unlike the standard treatments, which often focus on managing symptoms or slowing the protein deposition, this combination potentially disrupts the formation of amyloid fibrils more effectively. Venetoclax specifically works by inhibiting the BCL-2 protein, which can help induce cancer cell death, offering a promising strategy when combined with the immune system-boosting effects of daratumumab and the anti-inflammatory properties of dexamethasone. This multi-faceted approach could provide a more comprehensive attack on the disease, possibly leading to better outcomes for patients.

What evidence suggests that this trial's treatments could be effective for amyloidosis?

Research has shown that a combination of three drugs—venetoclax, daratumumab, and dexamethasone—may help treat systemic light-chain amyloidosis, especially in patients with a specific DNA change called t(11;14). This trial will evaluate the effectiveness of this combination in participants. Venetoclax targets a protein that helps kill cancer cells. Daratumumab attaches to a part of the cancer cells, making it easier for the immune system to destroy them. Dexamethasone reduces swelling in the body. Although research is ongoing, daratumumab has already demonstrated good results in similar conditions, suggesting that this drug combination could be effective. ^{6 7 8 9 10}

Who Is on the Research Team?

Alfred Chung, MD

Principal Investigator

University of California, San Francisco

Are You a Good Fit for This Trial?

Adults with systemic light-chain amyloidosis and a specific DNA abnormality (t(11;14)) can join this trial. They must have certain levels of blood components, no prior CD38-directed antibody treatment, at least one organ affected by the disease, measurable disease indicators, and be able to use birth control if necessary. People are excluded if they have other medical conditions that could interfere or have had recent vaccinations or surgeries.

Inclusion Criteria

My tests show I have measurable light chain amyloidosis.

One of my organs is affected by AL amyloidosis.

Pretreatment clinical laboratory values meeting specified criteria

Exclusion Criteria

My condition is AL amyloidosis caused by lymphoma.

My condition is a type of amyloidosis that is not AL amyloidosis.

I am scheduled for a stem cell transplant.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase I Treatment

Participants receive venetoclax daily, with dexamethasone and daratumumab depending on dose-level assignment. Cycles repeat every 28 days for up to 2 years.

Up to 2 years

Visits on days 1, 8, 15, and 22 of each cycle

Phase II Treatment

Participants receive venetoclax, dexamethasone, and daratumumab. Cycles repeat every 28 days for up to 2 years.

Up to 2 years

Visits on days 1, 8, 15, and 22 of cycles 1-2, days 1 and 15 of cycles 3-6, then on day 1 of cycles thereafter

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

Every 3 months until the last participant completes 2 years of treatment

Follow-up at 30 days post-treatment, then every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Daratumumab
• Dexamethasone
• Venetoclax

Trial Overview

The trial is testing the combination of Venetoclax, Daratumumab, and Dexamethasone for treating systemic light-chain amyloidosis in patients with t(11;14). It aims to find out the safest doses and observe side effects. Venetoclax targets cancer cells by binding to Bcl-2 protein; Daratumumab attaches to CD38 on cancer cells aiding immune destruction; Dexamethasone helps reduce inflammation.

How Is the Trial Designed?

Group I: Phase II (venetoclax, dexamethasone, daratumumab) Experimental Treatment 4 Interventions

Participants will receive the RP2D of venetoclax QD on days 1-28 of each cycle, dexamethasone on days 1, 8, 15, and 22 of each cycle, and daratumumab on days 1, 8, 15, and 22 of cycles 1-2, days 1 and 15 of cycles 3-6, then on day 1 of cycles thereafter. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity

Group II: Phase I (venetoclax, dexamethasone, daratumumab) Experimental Treatment 4 Interventions

All participants receive 400 mg venetoclax once a day (QD) on days 1-28 of each cycle. Depending on the number of DLTs reported for this dose-level, participants may also receive dexamethasone on days 1, 8, 15, and 22 of each cycle with or without daratumumab on days 1, 8, 15, and 22 of cycles 1-2, days 1 and 15 of cycles 3-6, then on day 1 of cycles thereafter. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

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

Approved in European Union as Darzalex for:

• Relapsed and refractory multiple myeloma
• Newly diagnosed multiple myeloma in combination with bortezomib, melphalan, and prednisone

Approved in United States as Darzalex for:

• Multiple myeloma in patients who have received at least three prior therapies
• Newly diagnosed multiple myeloma in combination with bortezomib, melphalan, and prednisone
• Relapsed or refractory multiple myeloma in combination with lenalidomide and dexamethasone

Who Is Running the Clinical Trial?

Alfred Chung, MD

Lead Sponsor

Trials

2

Recruited

3+

Sandy Wong, MD

Lead Sponsor

Trials

1

AbbVie

Industry Sponsor

Trials

1,079

Recruited

535,000+

Founded

2013

Headquarters

North Chicago, USA

Known For

Immunology treatments

Top Products

Humira (adalimumab), Skyrizi (risankizumab), Rinvoq (upadacitinib)

Dr. Roopal Thakkar

AbbVie

Chief Medical Officer since 2023

MD from Wayne State University School of Medicine

Robert A. Michael

AbbVie

Chief Executive Officer

Bachelor's degree in Finance from the University of Illinois

Janssen Pharmaceuticals

Industry Sponsor

Trials

87

Recruited

208,000+

Joaquin Duato

Janssen Pharmaceuticals

Chief Executive Officer since 2022

MBA from ESADE, Master of International Management from Thunderbird School of Global Management

Dr. Jijo James, MD

Janssen Pharmaceuticals

Chief Medical Officer since 2014

MD from St. Johns Medical College, MPH from Columbia University

Published Research Related to This Trial

The FPD-R regimen, which includes pixantrone instead of mitoxantrone, demonstrated a high overall response rate of 89% in patients with relapsed or refractory indolent non-Hodgkin lymphoma, indicating its efficacy.

The treatment was well-tolerated, with no cases of congestive heart failure or severe cardiac events, and most adverse effects were hematologic, suggesting a favorable safety profile for pixantrone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pixantrone dimaleate in combination with fludarabine, dexamethasone, and rituximab in patients with relapsed or refractory indolent non-Hodgkin lymphoma: phase 1 study with a dose-expansion cohort. Srokowski, TP., Liebmann, JE., Modiano, MR., et al.[2015]

The combination of venetoclax, a BCL-2 inhibitor, and daratumumab, an anti-CD38 antibody, shows enhanced effectiveness against multiple myeloma (MM) cell lines, particularly in those with the t(11;14) translocation and high BCL-2 expression.

This study suggests that this combination therapy could be a promising treatment option for MM patients who are resistant to existing therapies, as it enhances natural killer (NK) cell-mediated cytotoxicity against MM cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synergistic Effects of Venetoclax and Daratumumab on Antibody-Dependent Cell-Mediated Natural Killer Cytotoxicity in Multiple Myeloma. Nakamura, A., Suzuki, S., Kanasugi, J., et al.[2021]

In a phase 2 study involving 49 adults with relapsed/refractory multiple myeloma, the combination of venetoclax, carfilzomib, and dexamethasone (VenKd) demonstrated an overall response rate of 80%, with even higher rates (92%) in patients with the t(11;14) genetic alteration.

The treatment was generally well tolerated, with a median progression-free survival of 22.8 months, although some patients experienced significant side effects, including diarrhea and fatigue.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 study of venetoclax plus carfilzomib and dexamethasone in patients with relapsed/refractory multiple myeloma. Costa, LJ., Davies, FE., Monohan, GP., et al.[2022]

In a study of 21 patients with light chain amyloidosis treated with daratumumab, bortezomib, and limited-duration dexamethasone (Dara-Vd), 90% achieved a hematologic response, indicating the regimen's high efficacy, especially in patients with significant organ dysfunction.

Dara-Vd was well-tolerated and resulted in rapid responses, with a median time to response of just 11 days, and a 1-year overall survival rate of 76%, demonstrating its potential as a frontline treatment option for patients who may not tolerate more intensive therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab Plus Bortezomib and Dexamethasone in Newly Diagnosed Systemic Light Chain Amyloidosis. Kennedy, VE., Natsuhara, K., Maringanti, SA., et al.[2023]

In the phase 3 ANDROMEDA trial, patients treated with the combination of daratumumab, bortezomib, cyclophosphamide, and dexamethasone (D-VCd) showed significantly higher rates of organ and hematologic response compared to those receiving VCd alone, indicating enhanced efficacy of the D-VCd regimen.

Patient-reported outcomes (PROs) indicated that the D-VCd group experienced more meaningful improvements in health-related quality of life (HRQoL) without compromising their well-being, with benefits continuing even after transitioning to daratumumab monotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health-related quality of life in patients with light chain amyloidosis treated with bortezomib, cyclophosphamide, and dexamethasone ± daratumumab: Results from the ANDROMEDA study. Sanchorawala, V., Palladini, G., Minnema, MC., et al.[2022]

In the phase III ANDROMEDA trial, subcutaneous daratumumab combined with bortezomib, cyclophosphamide, and dexamethasone significantly improved the rate of complete hematological response in patients with newly diagnosed systemic AL amyloidosis compared to the standard treatment alone.

This combination therapy not only produced rapid and deep responses but also resulted in better progression-free survival and higher rates of cardiac and renal responses at 6 and 12 months, while maintaining an acceptable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab: A Review in Newly Diagnosed Systemic Light Chain Amyloidosis. Blair, HA.[2022]

In a study of 119 patients with newly diagnosed stage IIIb AL amyloidosis, the addition of daratumumab to first-line therapy resulted in significantly improved overall survival compared to standard bortezomib-based treatments, with median survival not reached in the daratumumab group after 14.5 months of follow-up.

The daratumumab group also showed better hematologic response rates at 2 and 6 months, and a notable cardiac response rate of 46% at 6 months, indicating that daratumumab may offer a more effective treatment option for this challenging stage of amyloidosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab in first-line treatment of patients with light chain amyloidosis and Mayo stage IIIb improves treatment response and overall survival. Oubari, S., Hegenbart, U., Schoder, R., et al.[2023]

In a study of 22 relapsed/refractory multiple myeloma patients, low-dose venetoclax (≤250 mg/day) combined with bortezomib, daratumumab, and dexamethasone showed an impressive overall response rate of 80% in patients with the t(11;14) chromosomal marker, indicating its efficacy as a salvage therapy.

The low-dose regimen significantly reduced the incidence of serious adverse events, particularly infections, which are commonly associated with higher doses of venetoclax, suggesting a safer treatment option for this specific patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low dose venetoclax in combination with bortezomib, daratumumab, and dexamethasone for the treatment of relapsed/refractory multiple myeloma patients-a single-center retrospective study. Regidor, B., Goldwater, MS., Wang, J., et al.[2021]

In a study of 18 children with steroid-dependent idiopathic nephrotic syndrome (SDNS) treated with rituximab (RTX) over an average of 3.2 years, 22% maintained sustained remission without relapse, and all patients experienced increased duration of remission.

Rituximab was found to be safe, with no serious adverse events reported, and the best results were achieved with repeated infusions timed to CD19-cell recovery, leading to 44.5% of patients being free from oral drug therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term outcome of children treated with rituximab for idiopathic nephrotic syndrome. Tellier, S., Brochard, K., Garnier, A., et al.[2022]

Two women with dermatomyositis (DM) showed improvement in their skin symptoms while taking antiestrogen medications, suggesting a potential new treatment avenue for this autoimmune disorder.

The improvement may be linked to the anti-TNF-alpha properties of tamoxifen and anastrozole, indicating that antiestrogen therapy could inhibit TNF-alpha production and benefit DM patients, warranting further research into its long-term effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improvement in dermatomyositis rash associated with the use of antiestrogen medication. Sereda, D., Werth, VP.[2018]

Rituximab (RTX) treatment in four patients with refractory rapidly progressive interstitial lung disease (RP-ILD) due to anti-MDA5 Ab-positive amyopathic dermatomyositis led to significant improvements in respiratory symptoms and lung function, with all patients showing better results after treatment.

While RTX was effective in improving symptoms and reducing the need for steroids, there is a notable risk of infections, as two patients developed chest infections and one had a wound infection following treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab for refractory rapidly progressive interstitial lung disease related to anti-MDA5 antibody-positive amyopathic dermatomyositis. So, H., Wong, VTL., Lao, VWN., et al.[2021]

In a nationwide survey of 64 patients with type I cryoglobulinemia vasculitis (CryoVas), the prognosis appears better than previously thought, with 10-year survival rates at 87%.

Treatment regimens including alkylating agents, rituximab, thalidomide, lenalidomide, and bortezomib showed similar efficacy in managing symptoms, with clinical response rates between 80% and 86%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The spectrum of type I cryoglobulinemia vasculitis: new insights based on 64 cases. Terrier, B., Karras, A., Kahn, JE., et al.[2022]

In a study of 72 previously treated patients with multiple myeloma and AL amyloidosis, daratumumab showed a high efficacy, with 82% of patients achieving a hematologic response after eight infusions, including 16% complete responses and 42% very good partial responses.

Daratumumab also demonstrated notable renal responses in 60% of patients and cardiac responses in 29%, indicating its potential as an effective treatment option for patients with relapsed/refractory AL amyloidosis, especially those with high plasma cell burden.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High rate of profound clonal and renal responses with daratumumab treatment in heavily pre-treated patients with light chain (AL) amyloidosis and high bone marrow plasma cell infiltrate. Milani, P., Fazio, F., Basset, M., et al.[2020]

Daratumumab (DARA IV) shows significant efficacy in treating AL amyloidosis, with a 66% response rate and a 30% complete response rate based on a systematic review of 30 studies involving 997 patients.

The treatment is generally safe, with only 2.5% of patients experiencing severe adverse events, primarily lymphocytopenia, indicating that DARA IV can be a viable option for patients with AL amyloidosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of intravenous daratumumab-based treatments for AL amyloidosis: a systematic review and meta-analysis. Sun, C., Wang, X., Zhang, R., et al.[2023]

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