Daratumumab Combination Therapy for Amyloidosis

(AQUARIUS Trial)

Recruiting at50 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Janssen Research & Development, LLC

Must not be taking: CD38 targeting drugs

Disqualifiers: Multiple myeloma, Stem cell transplant, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial tests a combination of four drugs on patients with a specific heart-related disease. The drugs work together to attack abnormal cells and reduce inflammation. The study aims to ensure the treatment is safe for the heart and understand how it behaves in different racial and ethnic groups.

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.

What data supports the effectiveness of the drugs used in the Daratumumab Combination Therapy for Amyloidosis?

Research shows that bortezomib, one of the drugs in the combination, is effective when used with other cancer treatments, suggesting it may enhance the effectiveness of the combination therapy. Additionally, dexamethasone is used to prevent side effects in other treatments, indicating its supportive role in combination therapies. ^{1 2 3 4 5}

Is daratumumab combination therapy safe for humans?

Daratumumab combination therapy, when used with bortezomib, cyclophosphamide, and dexamethasone, has been shown to have an acceptable safety profile in clinical trials for amyloidosis, with no new safety concerns compared to its use in other conditions like multiple myeloma. The treatment was generally well tolerated, with some patients experiencing mild infusion-related reactions. ^{6 7 8 9 10}

What makes the daratumumab combination therapy unique for treating amyloidosis?

The daratumumab combination therapy is unique because it adds daratumumab, a CD38-targeting antibody, to the standard treatment of bortezomib, cyclophosphamide, and dexamethasone, significantly improving complete response rates and organ responses in patients with systemic AL amyloidosis, as shown in the ANDROMEDA trial. ^{6 9 11 12 13}

Research Team

Janssen Research & Development, LLC Clinical Trial

Principal Investigator

Janssen Research & Development, LLC

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Bortezomib (Proteasome Inhibitor)
• Cyclophosphamide (Alkylating agents)
• Daratumumab (Monoclonal Antibodies)
• Dexamethasone (Corticosteroid)

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.

Participant Groups

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 Canada, Japan for the following indications:

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+

Giacomo Salvadore

Janssen Research & Development, LLC

Chief Medical Officer since 2023

MD from the University of Rome, Tor Vergata

Ricardo Attar

Janssen Research & Development, LLC

Chief Executive Officer since 2008

PhD in Molecular Biology from the University of Buenos Aires

Findings from Research

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 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 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 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]

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 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 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]

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 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 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]

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]

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]

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]

References

1. United States 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. [2020]

2. England 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. [2022]

3. United States 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. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Single premedication dose of dexamethasone 20 mg IV before docetaxel administration. [2018]

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

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

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

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

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

Daratumumab plus CyBorD for patients with newly diagnosed AL amyloidosis: safety run-in results of ANDROMEDA. [2021]

8. 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]

9. 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]

10. Germany pubmed.ncbi.nlm.nih.gov

Daratumumab plus bortezomib, cyclophosphamide, and dexamethasone in Asian patients with newly diagnosed AL amyloidosis: subgroup analysis of ANDROMEDA. [2023]

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

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

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

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

13. England pubmed.ncbi.nlm.nih.gov

Daratumumab plus CyBorD for patients with newly diagnosed light chain (AL) amyloidosis. [2021]