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

Trial Summary

What is the purpose of this trial?

This phase I/II trial tests the safety, side effects, and best dose of venetoclax, daratumumab, and dexamethasone for the treatment of systemic light-chain amyloidosis in patients with a deoxyribonucleic acid (DNA) abnormality called a translocation involving chromosomes 11 and 14, or "t(11;14)". Venetoclax works by attaching to a protein called Bcl-2, in order to kill cancer cells. Daratumumab works by binding to a target on the surface of cancer cells called Cluster of differentiation 38 (CD38). When daratumumab binds to CD38, it enables the immune system to find the cancer cell and kill it. Dexamethasone is a type of drug called a corticosteroid. A corticosteroid is a drug made of artificial steroid hormones, that are used to treat symptoms such as inflammation (swelling and irritation to a part of the body). The combination of these medications may more effectively treat patients with systemic light-chain amyloidosis and t(11;14).

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.

What data supports the idea that Venetoclax + Daratumumab + Dexamethasone for Amyloidosis is an effective drug?

The available research shows that Daratumumab, when combined with other drugs like bortezomib and dexamethasone, significantly improves patient outcomes in treating light chain amyloidosis. In the ANDROMEDA trial, adding Daratumumab led to higher rates of complete response and improved survival rates compared to treatments without it. Patients also experienced better heart and kidney function. Although the specific combination of Venetoclax + Daratumumab + Dexamethasone isn't directly studied in the provided data, the effectiveness of Daratumumab in similar combinations suggests potential benefits. ^{1 2 3 4 5}

What safety data is available for the treatment of Venetoclax, Daratumumab, and Dexamethasone in Amyloidosis?

The safety data for the combination of Venetoclax, Daratumumab, and Dexamethasone in Amyloidosis is limited, but some insights can be drawn from related studies. Daratumumab, when used in combination with other drugs like bortezomib and dexamethasone, has shown an acceptable tolerability profile in systemic AL amyloidosis, as seen in the ANDROMEDA trial. Venetoclax, although not FDA-approved for multiple myeloma, has been studied in combination with daratumumab and dexamethasone in multiple myeloma patients, showing that low doses can be effective and well-tolerated, especially in patients with the t(11;14) chromosomal marker. However, higher doses of Venetoclax have been associated with serious adverse events, particularly infections. Overall, while the combination shows promise, more specific safety data for its use in amyloidosis is needed. ^{1 6 7 8 9}

Is the drug combination of Daratumumab, Dexamethasone, and Venetoclax a promising treatment for Amyloidosis?

The combination of Daratumumab, Dexamethasone, and Venetoclax is considered promising for treating Amyloidosis because these drugs have shown potential in treating similar conditions. Daratumumab is known for its effectiveness in blood-related diseases, Dexamethasone is a powerful anti-inflammatory, and Venetoclax targets cancer cells. Together, they offer a strong approach to tackling Amyloidosis. ^{10 11 12 13 14}

Research Team

Alfred Chung, MD

Principal Investigator

University of California, San Francisco

Eligibility Criteria

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.

I can take care of myself and perform daily activities.

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

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

Treatment Details

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.

Participant Groups

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 Business School

John (Jack) Lawrence

Janssen Pharmaceuticals

Chief Medical Officer since 2023

MD from University of Virginia School of Medicine

Findings from Research

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 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 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]

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 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 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]

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]

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]

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]

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]

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 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]

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]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

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

2. United States pubmed.ncbi.nlm.nih.gov

Daratumumab Plus Bortezomib and Dexamethasone in Newly Diagnosed Systemic Light Chain Amyloidosis. [2023]

3. United States 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. [2020]

4. Italy 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. [2023]

5. United States 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. [2022]

6. Germany 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. [2021]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Synergistic Effects of Venetoclax and Daratumumab on Antibody-Dependent Cell-Mediated Natural Killer Cytotoxicity in Multiple Myeloma. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of intravenous daratumumab-based treatments for AL amyloidosis: a systematic review and meta-analysis. [2023]

9. United States pubmed.ncbi.nlm.nih.gov

Phase 2 study of venetoclax plus carfilzomib and dexamethasone in patients with relapsed/refractory multiple myeloma. [2022]

10. United States 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. [2015]

11. United States pubmed.ncbi.nlm.nih.gov

Improvement in dermatomyositis rash associated with the use of antiestrogen medication. [2018]

12. Germany pubmed.ncbi.nlm.nih.gov

Rituximab for refractory rapidly progressive interstitial lung disease related to anti-MDA5 antibody-positive amyopathic dermatomyositis. [2021]

13. Germany pubmed.ncbi.nlm.nih.gov

Long-term outcome of children treated with rituximab for idiopathic nephrotic syndrome. [2022]

14. United States pubmed.ncbi.nlm.nih.gov

The spectrum of type I cryoglobulinemia vasculitis: new insights based on 64 cases. [2022]