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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of three drugs—daratumumab (an immunotherapy), ixazomib (a proteasome inhibitor), and dexamethasone (a corticosteroid)—to determine the optimal dose and identify side effects in treating amyloid light chain amyloidosis. Amyloidosis occurs when abnormal proteins accumulate in organs and tissues. These drugs may help by preventing the growth or spread of these harmful proteins. Individuals diagnosed with amyloid light chain amyloidosis who have not responded well to previous treatments might be suitable candidates for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this potentially groundbreaking therapy.

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.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that daratumumab is already approved for treating light chain amyloidosis when combined with other drugs, indicating its general safety for humans. Studies have found that the newer, under-the-skin form of daratumumab causes fewer administration-related side effects.

Research on similar drug combinations with daratumumab has shown they are well-tolerated by most patients, with serious side effects being rare. However, some individuals might experience mild to moderate side effects, such as injection site reactions or mild flu-like symptoms.

This trial is in its early stages (Phase 1), focusing on the safety and optimal dose of the treatment. While daratumumab has been safe in other uses, the specific combination with ixazomib and dexamethasone for amyloidosis is still under investigation. It is important to discuss any concerns with the trial team. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of daratumumab, ixazomib, and dexamethasone for treating amyloidosis because it offers a new approach compared to existing therapies like chemotherapy and autologous stem cell transplant. Daratumumab is an antibody that targets a specific protein on amyloidosis cells, marking them for destruction by the immune system. Ixazomib, an oral proteasome inhibitor, disrupts protein recycling in these cells, leading to their death. Together, these drugs could potentially enhance treatment effectiveness and are easier to administer, offering a promising alternative to current standards.

What evidence suggests that this treatment might be an effective treatment for amyloidosis?

Research has shown that the combination of daratumumab, ixazomib, and dexamethasone, which participants in this trial will receive, may help treat light chain amyloidosis. Daratumumab, approved for use with other medicines for this condition, has shown promise in slowing the disease by targeting and interfering with the growth of harmful cells. Studies have found that patients receiving daratumumab experienced better outcomes, including more control over the disease. Ixazomib and dexamethasone enhance this effect by further preventing cancer cells from growing and spreading. Together, these drugs aim to provide a strong defense against the disease. ^{1 3 5 6 7}

Who Is on the Research Team?

Hans Lee, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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, Master of International Management from Thunderbird School of Global Management

Dr. Jijo James, MD

Janssen Pharmaceuticals

Chief Medical Officer since 2014

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

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

Published Research Related to This Trial

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]

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 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 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

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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 ...

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Adverse Event - DARZALEX FASPRO® ANDROMEDA is a phase 3 study evaluating the efficacy and safety of DARZALEX FASPRO for subcutaneous (SC) use in combination with bortezomib, ...

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DARZALEX FASPRO® (daratumumab and hyaluronidase- ... APOLLO is a phase 3 study evaluating the safety and efficacy of DARZALEX FASPRO for subcutaneous (SC) use + pomalidomide + dexamethasone (D-Pd) ...

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DARZALEX® (daratumumab) SC-based regimens improve ... New analysis from Phase 3 CEPHEUS study demonstrates 85 percent of patients who achieved MRD negativity (10-6) with daratumumab SC were ...