Daratumumab + Ixazomib + Dexamethasone for Amyloidosis

Overseen By Hans C. Lee, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Strong CYP3A inducers

Disqualifiers: Non-AL amyloidosis, Myeloma, Cardiac disease, 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: 30

Duration: 48 weeks

21 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot take certain medications like strong CYP3A inducers (e.g., rifampin, carbamazepine) or supplements like St. John's wort within 14 days before starting the trial.

What data supports the effectiveness of the drug Daratumumab in treating amyloidosis?

Research shows that Daratumumab, when combined with other drugs, significantly improves blood and organ responses in patients with amyloidosis, leading to better survival rates. It has been effective in both newly diagnosed and heavily pre-treated patients, showing rapid and deep responses, especially in heart and kidney function. ^{1 2 3 4 5}

How is the drug combination of Daratumumab, Ixazomib, and Dexamethasone unique for treating amyloidosis?

This drug combination is unique because it includes Daratumumab, a monoclonal antibody that targets CD38 on plasma cells, which is not commonly used in standard treatments for amyloidosis. Daratumumab has shown rapid and deep responses in patients, especially when combined with other drugs, and is effective even in patients with severe organ involvement. ^{1 2 3 4 6}

What is the purpose of this trial?

This phase I trial studies the side effects and best dose of daratumumab, ixazomib, and dexamethasone in treating participants with amyloid light chain amyloidosis. Monoclonal antibodies, such as daratumumab, may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as ixazomib and dexamethasone, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving daratumumab, ixazomib, and dexamethasone may be effective in treating participants with light chain amyloidosis.

Research Team

Hans Lee, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults with AL amyloidosis, a condition where abnormal proteins build up in organs. Participants must have an acceptable level of organ function and performance status, not be pregnant or breastfeeding, and agree to use contraception. Those with severe infections, recent major surgeries or treatments, certain other cancers within the last 2 years, or specific heart diseases cannot join.

Inclusion Criteria

I agree to use contraception as required.

I am a woman who is postmenopausal, surgically sterile, or agrees to use contraception.

I have been diagnosed with AL amyloidosis confirmed by specific tests.

Exclusion Criteria

My condition is not light-chain (AL) amyloidosis.

My lung function is severely reduced, with less than half the normal airflow.

Participation in other clinical trials within 30 days of the start of this trial and throughout its duration

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive daratumumab, ixazomib, and dexamethasone in a dose-escalation study. Treatment repeats every 28 days for up to 12 courses.

48 weeks

Multiple visits as per treatment schedule

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-ups at 30 days and then every 90 days for 24 months.

24 months

Follow-up visits at 30 days and every 90 days

Treatment Details

Interventions

• Daratumumab
• Dexamethasone
• Ixazomib

Trial Overview The study tests the combination of daratumumab (a monoclonal antibody), ixazomib (chemotherapy), and dexamethasone (a steroid) to treat AL amyloidosis. It aims to find the safest doses and see how well they work together against this disease by stopping tumor cells from growing.

Participant Groups

Group I: Treatment (daratumumab, ixazomib, dexamethasone) Experimental Treatment 3 Interventions

Participants receive daratumumab IV over 3.5-6.5 hours on days 1, 8, 15, and 22 of courses 1-2, on days 1 and 15 of courses 3-6, and on day 1 of courses 7-12. Participants also receive ixazomib PO on days 1, 8, and 15, and dexamethasone IV over 15 minutes or PO on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unaccepted 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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

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

Takeda

Industry Sponsor

Trials

1,255

Recruited

4,219,000+

Dr. Naoyoshi Hirota

Takeda

Chief Medical Officer since 2020

MD from University of Tokyo

Christophe Weber

Takeda

Chief Executive Officer since 2015

PhD in Molecular Biology from Université de Montpellier

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 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 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]

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]

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. 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

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]

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

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

4. Switzerland pubmed.ncbi.nlm.nih.gov

Daratumumab Monotherapy in Severe Patients with AL Amyloidosis and Biopsy-Proven Renal Involvement: A Real Life Experience. [2020]

5. England pubmed.ncbi.nlm.nih.gov

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

6. England pubmed.ncbi.nlm.nih.gov

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