Daratumumab Combination Therapy for Amyloidosis

(AQUARIUS Trial)

Not currently recruiting at 64 trial locations

Overseen By Study Contact

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Janssen Research & Development, LLC

Must not be taking: CD38 targeting drugs

Disqualifiers: Multiple myeloma, Stem cell transplant, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 2

Duration: Up to 24 cycles (28-day cycles)

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the safety and effectiveness of a drug combination, including Daratumumab (an immunotherapy), for individuals newly diagnosed with AL amyloidosis, with a particular focus on heart safety. It examines two approaches: one with immediate full treatment and another with delayed treatment. A separate group, focusing on racial and ethnic minorities, will study how these drugs behave in the body. Participants should have AL amyloidosis with heart involvement or belong to a racial or ethnic minority with organ involvement due to the condition. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but if you are taking strong CYP3A4 inducers, you must stop them at least 5 half-lives before starting bortezomib.

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

Research has shown that daratumumab, a main treatment in this trial, is usually well-tolerated when administered as an injection under the skin. In a combined safety study, some serious reactions occurred, but these were rare. The most common side effects were mild to moderate, such as tiredness and nausea.

Bortezomib, another treatment in the study, has helped patients with AL amyloidosis. It is generally safe, though some patients may experience side effects like low blood counts or nerve damage, which can be managed.

Cyclophosphamide is widely used and can cause serious side effects in some patients, such as low white blood cell counts, increasing the risk of infection.

Dexamethasone, the last component, is effective, but high doses can lead to issues like fluid retention and changes in heart rhythm. However, these are usually manageable with careful monitoring.

This trial is in the early stages of testing, focusing on safety, indicating that the treatments have shown some safety in earlier studies but require more detailed testing. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of daratumumab with cyclophosphamide, bortezomib, and dexamethasone (VCd) for treating amyloidosis because it leverages daratumumab's unique ability to target and destroy abnormal plasma cells, which are a root cause of the disease. Unlike standard treatments like VCd alone, adding daratumumab can enhance the immune response against the disease. Additionally, the trial investigates different timing strategies for administering VCd alongside daratumumab, which could optimize effectiveness and reduce side effects, offering a potentially more powerful and tailored treatment option for patients with systemic AL amyloidosis.

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

Research shows that daratumumab, when combined with cyclophosphamide, bortezomib, and dexamethasone (VCd), effectively treats amyloidosis, a condition where abnormal proteins accumulate in organs. In this trial, participants will receive different treatment regimens involving daratumumab and VCd. In Cohort 1 (Arm A), participants will receive daratumumab with immediate VCd, while in Cohort 1 (Arm B), VCd will be deferred. Cohort 2 involves daratumumab with VCd for racial and ethnic minorities. Studies have found that adding daratumumab to this treatment helps newly diagnosed patients achieve better results, such as having fewer cancer cells remaining after treatment. This combination also helps patients live longer without disease progression. Daratumumab, especially in its subcutaneous form, is effective and easier to administer with fewer side effects than the intravenous version. It is also FDA-approved for treating newly diagnosed light chain amyloidosis, demonstrating its proven effectiveness. ^{6 7 8 9 10}

Who Is on the Research Team?

Janssen Research & Development, LLC Clinical Trial

Principal Investigator

Janssen Research & Development, LLC

Are You a Good Fit for This Trial?

This trial is for adults with newly diagnosed AL amyloidosis affecting the heart and possibly other organs. Participants should be able to perform light activities (ECOG score 0-2). Women must test negative for pregnancy and agree to regular tests; men must not donate sperm during and after the study. Racial/ethnic minorities, including Black or African American individuals, are specifically included in one cohort.

Inclusion Criteria

I can take care of myself and am up and about more than half of my waking hours.

One of my organs is affected by AL amyloidosis.

I am a woman who can have children, have tested negative for pregnancy, and agree to ongoing pregnancy tests.

Exclusion Criteria

I haven't used any experimental drugs or devices, or had certain vaccines recently.

I am not planning a stem cell transplant within the first 9 treatment cycles, but collection is okay.

I have had treatment for AL amyloidosis or multiple myeloma, but not more than 160mg dexamethasone.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive daratumumab and VCd treatment regimens. In Arm A, VCd is administered immediately, while in Arm B, VCd is deferred. Cohort 2 focuses on racial and ethnic minorities.

Up to 24 cycles (28-day cycles)

Weekly visits for the first 2 cycles, bi-weekly for cycles 3-6, and monthly for cycles 7-24

Follow-up

Participants are monitored for safety and effectiveness after treatment, including cardiac safety and pharmacokinetics.

Up to 12 months

Long-term Follow-up

Participants are monitored for long-term outcomes such as overall survival and organ response rate.

Up to 3 years

What Are the Treatments Tested in This Trial?

Interventions

• Bortezomib
• Cyclophosphamide
• Daratumumab
• Dexamethasone

Trial Overview

The trial studies Daratumumab-based therapies in two groups: one receives immediate treatment with Daratumumab combined with Cyclophosphamide, Bortezomib, Dexamethasone (D-VCd), while the other has deferred VCd treatment. It aims to assess cardiac safety and understand how different populations process the drug.

How Is the Trial Designed?

Group I: Cohort1 (Arm B): Daratumumab + Deferred VCd Experimental Treatment 4 Interventions

Participants with newly diagnosed systemic AL amyloidosis with Mayo Cardiac Stage II and IIIa cardiac involvement will receive SC daratumumab 1800mg on Day 1 once weekly (q1w) up to Day 22 for cycles 1-2, on Days 1 and 15 for cycles 3-6, and on Day 1 for cycles 7-24 of a 28-day cycle. Participants will also receive VCd (Cyclophosphamide 300 mg/m\^2 either orally or IV, Bortezomib 1.3 mg/m\^2 SC or IV, Dexamethasone 40 mg weekly either orally or IV) starting at Cycle 4 Day 1, weekly (Days 1, 8, 15, 22) in every 28-day cycle for a maximum of 6 cycles (Cycle 9 Day 22).

Group II: Cohort1 (Arm A): Daratumumab + Immediate Cyclophosphamide, Bortezomib and Dexamethasone (VCd) Experimental Treatment 4 Interventions

Participants with newly diagnosed systemic amyloid light chain (AL) amyloidosis with Mayo Cardiac Stage II and IIIa cardiac involvement will receive daratumumab 1800 milligrams (mg) subcutaneously (SC) starting on Day 1 once weekly (q1w) up to Day 22 for cycles 1-2, on Days 1 and 15 for cycles 3-6, and on Day 1 for cycles 7-24 of a 28-day cycle. Participants will also receive VCd (cyclophosphamide 300 milligrams per meter square \[mg/m\^2\] either orally or intravenously \[IV\], bortezomib 1.3 mg/m\^2 SC or IV, dexamethasone 40 mg weekly either orally or IV) weekly starting at Cycle 1 Day 1 up to Day 22 in every 28-day cycle for a maximum of 6 cycles (Cycle 6 Day 22).

Group III: Cohort 2: Daratumumab + VCd Experimental Treatment 4 Interventions

Participants with racial and ethnic minorities, including Black or African American participants, with newly diagnosed AL amyloidosis will receive SC injection of daratumumab 1800 mg SC on Day 1 once weekly (q1w) up to Day 22 for cycles 1-2, on Days 1 and 15 for cycles 3-6, and on Day 1 for cycles 7-24 of a 28-day cycle. Participants will also receive VCd (cyclophosphamide 300 milligrams per meter square \[mg/m\^2\] either orally or intravenously \[IV\], bortezomib 1.3 mg/m\^2 SC or IV, dexamethasone 40 mg weekly either orally or IV) weekly starting at Cycle 1 Day 1 up to Day 22 in every 28-day cycle for a maximum of 6 cycles (Cycle 6 Day 22).

Bortezomib is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Velcade for:

• Multiple myeloma
• Mantle cell lymphoma

Approved in United States as Velcade for:

• Multiple myeloma
• Mantle cell lymphoma

Approved in Canada as Velcade for:

• Multiple myeloma
• Mantle cell lymphoma

Approved in Japan as Velcade for:

• Multiple myeloma
• Mantle cell lymphoma

Who Is Running the Clinical Trial?

Janssen Research & Development, LLC

Lead Sponsor

Trials

1,022

Recruited

6,408,000+

Joaquin Duato

Janssen Research & Development, LLC

Chief Executive Officer since 2022

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

Dr. Jijo James, MD

Janssen Research & Development, LLC

Chief Medical Officer since 2014

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

Published Research Related to This Trial

Docetaxel is highly effective in treating metastatic breast cancer, showing a 59% overall response rate as a first-line therapy in five Phase II trials involving 100 mg/m2 doses every 3 weeks.

While docetaxel can cause significant side effects like neutropenia and fluid retention syndrome, these effects can be managed with premedication and are generally reversible after stopping the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Review of docetaxel (Taxotere), a highly active new agent for the treatment of metastatic breast cancer. Ravdin, PM., Valero, V.[2018]

In a study of 90 cancer patients receiving docetaxel, a single intravenous dose of dexamethasone resulted in hypersensitivity reactions (HSRs) in 7.8% of patients and fluid retention reactions (FRRs) in 12.2%, which is lower than the rates reported with the standard 3-day oral regimen recommended by the manufacturer.

The findings suggest that using a single dose of dexamethasone may be a safer and more convenient alternative for preventing HSRs and FRRs in patients undergoing docetaxel treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single premedication dose of dexamethasone 20 mg IV before docetaxel administration. Chouhan, JD., Herrington, JD.[2018]

In a subgroup analysis of 60 Asian patients from the ANDROMEDA study, the combination of daratumumab with bortezomib/cyclophosphamide/dexamethasone (D-VCd) showed a significantly higher overall hematologic complete response rate compared to VCd alone (58.6% vs. 9.7%).

D-VCd also improved major organ deterioration progression-free survival (MOD-PFS) and event-free survival (MOD-EFS), indicating better long-term outcomes for patients with newly diagnosed AL amyloidosis, while maintaining a safety profile consistent with the global population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab plus bortezomib, cyclophosphamide, and dexamethasone in Asian patients with newly diagnosed AL amyloidosis: subgroup analysis of ANDROMEDA. Suzuki, K., Wechalekar, AD., Kim, K., et al.[2023]

Combining bortezomib with trastuzumab significantly enhances the effectiveness of trastuzumab in HER-2-positive breast cancer cells, demonstrating a synergistic effect that leads to increased apoptosis at low drug concentrations.

The mechanism behind this enhanced efficacy involves the targeting of NF-kappaB activation and the localization of the cyclin-dependent kinase inhibitor p27, suggesting a promising avenue for improving treatment outcomes in patients with metastatic breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bortezomib (PS-341, Velcade) increases the efficacy of trastuzumab (Herceptin) in HER-2-positive breast cancer cells in a synergistic manner. Cardoso, F., Durbecq, V., Laes, JF., et al.[2020]

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 phase II study involving 69 patients with metastatic HER2-positive breast cancer, the combination of weekly paclitaxel, trastuzumab, and pertuzumab achieved an impressive 6-month progression-free survival (PFS) rate of 86%, indicating strong efficacy.

The treatment was well tolerated, with no cases of febrile neutropenia or symptomatic left ventricular dysfunction reported, suggesting it may be a safer alternative to traditional docetaxel-based therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of paclitaxel given once per week along with trastuzumab and pertuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. Dang, C., Iyengar, N., Datko, F., et al.[2022]

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]

Intravenous daratumumab, when combined with bortezomib, melphalan, and prednisone, significantly improves progression-free survival in patients with newly diagnosed multiple myeloma who cannot undergo autologous stem cell transplantation, as shown in the phase 3 ALCYONE trial.

The addition of daratumumab does not increase overall toxicity compared to the standard treatment, although it may lead to more infusion-related reactions and infections, making it a promising and relatively safe treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab: A Review in Combination Therapy for Transplant-Ineligible Newly Diagnosed Multiple Myeloma. Syed, YY.[2021]

In a study of 493 patients with HER2-amplified early stage breast cancer, a regimen of docetaxel and cyclophosphamide combined with trastuzumab resulted in a high 2-year disease-free survival (DFS) rate of 97.8% for TOP2A-amplified patients and 97.9% for TOP2A-non-amplified patients, indicating its efficacy regardless of TOP2A status.

The treatment was generally well-tolerated, with common side effects including fatigue and neutropenia; however, 6% of patients experienced cardiac dysfunction, highlighting the need for monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant docetaxel and cyclophosphamide plus trastuzumab in patients with HER2-amplified early stage breast cancer: a single-group, open-label, phase 2 study. Jones, SE., Collea, R., Paul, D., 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]

The addition of daratumumab, an anti-CD38 monoclonal antibody, to the standard treatment regimen of cyclophosphamide-bortezomib-dexamethasone (CyBorD) significantly improves hematologic complete response rates and organ responses in previously untreated patients with primary systemic AL amyloidosis, as shown in the large phase-III ANDROMEDA study.

Daratumumab has a favorable toxicity profile and demonstrates rapid and deep responses in patients with relapsed or refractory AL amyloidosis, making it a promising treatment option and leading to its approval as the first therapy for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab plus CyBorD for patients with newly diagnosed light chain (AL) amyloidosis. Theodorakakou, F., Dimopoulos, MA., Kastritis, E.[2021]

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 safety run-in of the ANDROMEDA study involving 28 patients with newly diagnosed AL amyloidosis, the combination of daratumumab and CyBorD showed a high overall hematologic response rate of 96%, with 54% achieving a complete response.

The treatment was well tolerated, with minimal adverse events and no new safety concerns compared to the intravenous formulation, indicating its potential as a safe and effective option for patients with AL amyloidosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab plus CyBorD for patients with newly diagnosed AL amyloidosis: safety run-in results of ANDROMEDA. Palladini, G., Kastritis, E., Maurer, MS., et al.[2021]

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