Chemotherapy + Stem Cell Transplant for Amyloidosis

Recruiting at 38 trial locations

Overseen By Adam F. Binder

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: SWOG Cancer Research Network

Must be taking: Daratumumab, Cyclophosphamide, Bortezomib, Dexamethasone

Disqualifiers: Hepatitis B, Hepatitis C, Multiple myeloma, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

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

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

Compensation: Varies

Number of Visits: 13

338 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if adding a stem cell transplant after chemotherapy is more effective than chemotherapy alone for treating newly diagnosed amyloid light chain (AL) amyloidosis. AL amyloidosis causes abnormal proteins to accumulate in organs, which can be serious. The trial compares two groups: one receiving a combination of drugs such as daratumumab (an immunotherapy), cyclophosphamide, bortezomib, and dexamethasone, and another adding melphalan and a stem cell transplant to this regimen. It is designed for those diagnosed with AL amyloidosis who have measurable disease, meaning the disease can be tracked by specific tests. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

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

The trial protocol does not specify if you need to stop taking your current medications. However, you may continue taking chronic corticosteroids if they are for conditions other than AL amyloidosis or myeloma. It's best to discuss your specific medications with the study team.

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

Research shows that the treatments in this trial have undergone safety studies. Daratumumab, a monoclonal antibody, has been tested in many patients. About 7% of patients reported reactions at the injection site, and only a few experienced more serious reactions, indicating it is generally well-tolerated.

Melphalan, used in stem cell transplants, has proven safe and effective as a high-dose treatment for patients with AL amyloidosis. Studies with many participants have confirmed its safe use.

Both treatments have been thoroughly tested, indicating safety for many people. However, individual experiences can vary, so discussing any concerns with a healthcare provider is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for amyloidosis because they offer unique approaches compared to current options. Daratumumab, a monoclonal antibody, is used in combination therapies and targets the CD38 protein on plasma cells, which is different from traditional chemotherapy-based treatments. This targeted approach can potentially enhance effectiveness and reduce side effects. Additionally, the trial includes a stem cell transplant arm, which aims to rebuild healthy bone marrow after high-dose chemotherapy, offering a comprehensive treatment strategy for tackling amyloidosis. These innovative methods provide hope for more effective management of this challenging condition.

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

Research has shown that daratumumab, one of the treatments in this trial, is very effective in treating AL amyloidosis when combined with other medications. In one study, 53.3% of patients achieved a complete response, showing no signs of the disease, compared to 18.1% of those who did not receive daratumumab. Another study found that 70% of patients experienced no worsening of their disease after 28 months on a similar treatment plan.

This trial also includes a treatment option involving melphalan combined with a stem cell transplant. For this combination, 43% of patients achieved a complete response, and among these, 78% saw improvement in their affected organs. This combination also produced long-lasting effects, with many patients living for years without the disease returning. ^{1 2 6 7 8}

Who Is on the Research Team?

Patrick A Hagen

Principal Investigator

SWOG Cancer Research Network

Are You a Good Fit for This Trial?

This trial is for adults with newly diagnosed AL amyloidosis, confirmed by specific tests like urine and serum immunofixation electrophoresis, bone marrow analysis, and biopsy. Participants must have a certain level of light chain difference in their blood and can have had up to one cycle of prior therapy. They should be able to perform daily activities on their own or with some effort (ECOG score 0-2) but may be less mobile due to neuropathy.

Inclusion Criteria

My diagnosis of AL amyloidosis is confirmed by biopsy and specific tests.

You have a positive monoclonal serum immunofixation electrophoresis result.

My bone marrow has cancerous cells and my blood test shows a specific protein imbalance.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Induction

Participants receive daratumumab, cyclophosphamide, bortezomib, and dexamethasone for up to 3 cycles

12 weeks

4 visits per cycle (in-person)

Consolidation

Participants receive additional cycles of chemotherapy or undergo stem cell transplant

12 weeks

4 visits per cycle (in-person)

Maintenance

Participants receive maintenance daratumumab and hyaluronidase-fihj for up to 18 cycles

72 weeks

1 visit per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 4 years

Every 3 or 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Daratumumab
• Melphalan

Trial Overview The study compares adding stem cell transplant after Dara-VCD chemotherapy (daratumumab, cyclophosphamide, bortezomib, dexamethasone) versus just the chemotherapy for treating AL amyloidosis. The goal is to see if the transplant helps kill more cancer cells when combined with melphalan chemo.

How Is the Trial Designed?

Group I: Maintenance (daratumumab and hyaluronidase-fihj) Experimental Treatment 6 Interventions

Patients receive maintenance daratumumab and hyaluronidase-fihj SC over 3-5 minutes on day 1 of each cycle. Cycles repeat every 28 days for up 18 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography at screening, 12 months post consolidation treatment and at progression. Patients undergo bone marrow aspiration and biopsy 12 months post consolidation treatment and at progression. Patients undergo blood and urine sample collection at screening, during treatment, 12 months post consolidation treatment and during follow up or at progression.

Group II: Induction (Chemotherapy) Experimental Treatment 13 Interventions

Patients receive daratumumab and hyaluronidase-fihj SC over 3-5 minutes on days 1, 8, 15 and 22 for 2 cycles and then days 1 and 15 for cycle 3. Patients receive bortezomib SC over 3-5 minutes, cyclophosphamide PO or IV, and dexamethasone PO or IV on days 1, 8, 15 and 22 of each cycle. Cycles repeat every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT, MRI or PET-CT and fat pad aspiration at screening. Patients undergo echocardiography at screening, the completion of induction, and at progression. Patients undergo bone marrow aspiration and biopsy at screening, post induction treatment and at progression. Patients undergo blood and urine sample collection at screening, at the start of each cycle, and the end of treatment and during follow up or at progression.

Group III: Consolidation Arm II (Chemotherapy, ASCT) Experimental Treatment 8 Interventions

Patients undergo collection of peripheral blood stem cells. Patients receive melphalan IV for 1 cycle and then 2 days later receive the stem cell transplant IV in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography at screening and at progression. Patients undergo bone marrow aspiration and biopsy within 60-90 days post initiation of stem cell transplant. Patients undergo blood and urine sample collection at screening, during treatment, and the end of treatment and during follow up or at progression.

Group IV: Consolidation Arm I (Chemotherapy) Active Control 9 Interventions

Patients receive daratumumab and hyaluronidase-fihj SC over 3-5 minutes on days 1 and 15 as well as bortezomib SC over 3-5 minutes, cyclophosphamide PO or IV, and dexamethasone PO or IV on days 1, 8, 15 and 22 of each cycle. Cycles repeat every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography at screening and at progression. Patients undergo bone marrow aspiration and biopsy within14-28 days post consolidation treatment and at progression. Patients undergo blood and urine sample collection at screening, at the start of each cycle, and the end of treatment and during follow up or at progression.

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?

SWOG Cancer Research Network

Lead Sponsor

Trials

403

Recruited

267,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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]

Daratumumab, a monoclonal antibody targeting CD38, shows promising results in treating AL amyloidosis, with early phase I and II studies indicating it is well-tolerated and induces rapid, deep responses in patients.

As autologous stem cell transplantation is not an option for most patients at diagnosis, daratumumab may become a crucial part of AL amyloidosis treatment, especially as phase III trials are underway.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab for the treatment of AL amyloidosis. Sidiqi, MH., Gertz, MA.[2023]

The population pharmacokinetics (popPK) analysis of subcutaneous daratumumab in combination with bortezomib, cyclophosphamide, and dexamethasone showed that the 1800-mg flat dose is effective for treating newly diagnosed systemic amyloid light-chain amyloidosis, based on data from 183 patients in the ANDROMEDA study.

There was no significant relationship found between daratumumab systemic exposure and safety or efficacy outcomes, indicating that the selected dose does not require adjustments based on patient characteristics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population Pharmacokinetics and Exposure-Response Modeling of Daratumumab Subcutaneous Administration in Patients With Light-Chain Amyloidosis. Luo, MM., Zhu, PP., Nnane, I., et al.[2022]

Daratumumab (Dara) has shown remarkable efficacy and a tolerable safety profile in treating newly diagnosed and relapsed refractory AL amyloidosis, making it a promising treatment option for patients who are often ineligible for intensive therapies.

The review highlights the importance of timely diagnosis and the use of novel therapies like Dara, which have contributed to improved outcomes for patients with systemic light-chain amyloidosis over the past two decades.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Progress in research: Daratumumab improves treatment outcomes of patients with AL amyloidosis. Hassan, H., Anwer, F., Javaid, A., et al.[2021]

Autologous stem cell transplantation (ASCT) can lead to long overall survival in patients with light chain (AL) amyloidosis who achieve a complete hematologic response, but it is only suitable for about 20% of patients due to high transplant-related mortality (24%).

The introduction of newer treatments like bortezomib and daratumumab, which have favorable safety profiles and lead to significant responses, suggests that the role and timing of ASCT in treating AL amyloidosis may need to be reevaluated in light of these advancements.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Role of Autologous Stem Cell Transplantation in Amyloidosis. Vaxman, I., Dispenzieri, A.[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]

Daratumumab shows promising efficacy in treating AL amyloidosis, with hematologic responses observed in 50%-90% of patients and organ responses (cardiac/renal) in 50%-80% based on a review of 16 studies.

The treatment is well tolerated, with no significant treatment-related adverse events reported, making it a safe option for both newly diagnosed and relapsed refractory AL amyloidosis patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Daratumumab-based Regimens in Pretreated Light Chain (AL) Amyloidosis: A Systematic Review. Ehsan, H., Rafae, A., Masood, A., 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10758190/

Safety and Efficacy of Subcutaneous Daratumumab in ... At median follow-up of 7.5 months, progression of disease had been observed in 51% of patients in each arm. Median progression-free survival was ...

2. jnj.com jnj.com/media-center/press-releases/darzalex-faspro-daratumumab-and-hyaluronidase-fihj-based-regimens-demonstrate-improved-rates-of-minimal-residual-disease-mrd-negativity-and-progression-free-survival-in-patients-with-newly-diagnosed-multiple-myeloma

DARZALEX FASPRO® (daratumumab and hyaluronidase ... New analysis from Phase 3 CEPHEUS study demonstrates 85 percent of patients who achieved MRD negativity (10-6) with DARZALEX FASPRO® were ...

3. jnj.com jnj.com/media-center/press-releases/updated-data-demonstrate-significant-improvement-in-hematologic-complete-response-with-darzalex-faspro-daratumumab-and-hyaluronidase-fihj-in-patients-with-newly-diagnosed-light-chain-al-amyloidosis

Updated Data Demonstrate Significant Improvement in ... “These updated efficacy and safety results show the potential impact DARZALEX FASPRO can have in treating AL amyloidosis,” said Jessica ...

4. jnjmedicalconnect.com jnjmedicalconnect.com/products/darzalex-faspro/medical-content/darzalex-faspro-amy3001-andromeda-study

DARZALEX FASPRO - AMY3001 (ANDROMEDA) Study The primary endpoint of hematologic complete response (CR) was achieved in 53.3% of the D-VCd arm vs 18.1% of the VCd arm, respectively ( ...

5. ema.europa.eu ema.europa.eu/en/medicines/human/EPAR/darzalex

Darzalex | European Medicines Agency (EMA) After about 28 months, 70% (246 out of 350) of patients treated with Darzalex in combination with the other three medicines had no worsening of their disease ...

6. darzalexhcp.com darzalexhcp.com/

DARZALEX® (daratumumab) & DARZALEX FASPRO ... Response data presented are cumulative deepest response rates achieved by 6, 9, and 18 months for patients who continued all trial treatment for at least 18 ...

7. aetna.com aetna.com/cpb/medical/data/900_999/0904.html?ref=counterforcehealth.org

Daratumumab (Darzalex) and Daratumumab and ... In the cohort that received 16 mg/kg, the median progression-free survival (PFS) was 5.6 months (95 % CI: 4.2 to 8.1), and 65 % (95 % CI: 28 to 86) of the ...

8. jnj.com jnj.com/media-center/press-releases/darzalex-faspro-daratumumab-and-hyaluronidase-fihj-based-regimen-shows-95-percent-progression-free-survival-at-four-years-in-transplant-eligible-newly-diagnosed-patients-with-multiple-myeloma-who-achieved-sustained-mrd-negativity

DARZALEX FASPRO® (daratumumab and hyaluronidase ... In this pooled safety population, injection-site reactions occurred in 7 percent of patients, including Grade 2 reactions in 0.8 percent. The ...