Chemotherapy + Stem Cell Transplant for Amyloidosis

Recruiting at 34 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: SWOG Cancer Research Network

Must be taking: Daratumumab, Cyclophosphamide, Bortezomib, Dexamethasone

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

No Placebo Group

Pivotal Trial (Near Approval)

Prior Safety Data

Breakthrough Therapy

Approved in 2 Jurisdictions

Trial Summary

What is the purpose of this trial?

This phase III trial compares the effect of adding a stem cell transplant with melphalan after completing chemotherapy with daratumumab, cyclophosphamide, bortezomib and dexamethasone (Dara-VCD) versus chemotherapy with Dara-VCD alone for treating patients with newly diagnosed amyloid light chain (AL) amyloidosis. Melphalan is a chemotherapy given prior to a stem cell transplant. Giving chemotherapy before a peripheral blood stem cell transplant helps kill cancer cells in the body and helps make room in the patient's bone marrow for new blood-forming cells (stem cells) to grow. The stem cells are then returned to the patients to replace the blood forming cells that were destroyed by the chemotherapy. Daratumumab is in a class of medications called monoclonal antibodies. It binds to a protein called CD38, which is found on some types of immune cells and cancer cells, including myeloma cells. Daratumumab may block CD38 and help the immune system kill cancer cells. Chemotherapy drugs, such as cyclophosphamide and bortezomib, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Dexamethasone is in a class of medications called corticosteroids. It is used to lower the body's immune response to help stop the growth of cancer cells. Giving a stem cell transplant with melphalan after Dara-VCD may kill more cancer cells in patients with newly diagnosed AL amyloidosis.

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.

What data supports the effectiveness of the drug Daratumumab for treating AL amyloidosis?

Research shows that Daratumumab, when used alone or with other drugs, significantly improves blood and organ responses in patients with AL amyloidosis. It has been effective in both newly diagnosed and previously treated patients, with studies showing high rates of response and good tolerability. ^{1 2 3 4 5}

Is the combination of chemotherapy and stem cell transplant for amyloidosis safe?

Daratumumab, when used in combination with other chemotherapy drugs for treating amyloidosis, has been shown to have a tolerable safety profile with no significant treatment-related adverse events reported in multiple studies. It is generally well tolerated, and no new safety concerns were identified compared to its use in other conditions. ^{1 2 3 6 7}

How is the drug Daratumumab used in treating amyloidosis different from other treatments?

Daratumumab, when combined with other drugs like bortezomib, cyclophosphamide, and dexamethasone, offers a unique treatment for amyloidosis by targeting a specific protein (CD38) on cells, leading to improved blood and organ responses. This combination is particularly effective for patients who are newly diagnosed or have relapsed, providing a promising option with a good safety profile compared to traditional treatments. ^{1 2 3 6 8}

Research Team

Patrick A Hagen

Principal Investigator

SWOG Cancer Research Network

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Daratumumab (Monoclonal Antibodies)
• Melphalan (Alkylating agents)

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.

Participant Groups

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.

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+

Findings from Research

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]

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 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]

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]

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 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]

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]

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]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Progress in research: Daratumumab improves treatment outcomes of patients with AL amyloidosis. [2021]

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

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

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

Efficacy and Safety of Daratumumab-based Regimens in Pretreated Light Chain (AL) Amyloidosis: A Systematic Review. [2022]

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

Daratumumab for the treatment of AL amyloidosis. [2023]

5. 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]

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

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

7. England pubmed.ncbi.nlm.nih.gov

Population Pharmacokinetics and Exposure-Response Modeling of Daratumumab Subcutaneous Administration in Patients With Light-Chain Amyloidosis. [2022]

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

The Role of Autologous Stem Cell Transplantation in Amyloidosis. [2022]