What side effects are associated with this type of intervention?

Common treatments for AL Amyloidosis, such as Venetoclax, Ixazomib Citrate, and Dexamethasone, as well as other regimens like bortezomib, cyclophosphamide, and lenalidomide, are associated with several side effects. Venetoclax can cause neutropenia, infections, and gastrointestinal issues. Ixazomib Citrate may lead to gastrointestinal disturbances, peripheral neuropathy, and thrombocytopenia. Dexamethasone, an anti-inflammatory, can result in hyperglycemia, increased risk of infections, and mood changes. Bortezomib is known for causing peripheral neuropathy and gastrointestinal symptoms. Cyclophosphamide can lead to myelosuppression and hemorrhagic cystitis, while lenalidomide is associated with hematologic toxicities and thromboembolic events.

What prior FDA approvals exist?

The FDA has approved several drugs for the treatment of AL Amyloidosis, particularly those involving proteasome inhibitors and anti-inflammatory agents. Bortezomib, a proteasome inhibitor, is commonly used in combination with cyclophosphamide and dexamethasone (CyBorD regimen) and has shown efficacy in treating AL Amyloidosis. Daratumumab, an anti-CD38 monoclonal antibody, has also been approved and is often used in combination with bortezomib, cyclophosphamide, and dexamethasone. These combinations are similar to the trial studying venetoclax, ixazomib citrate, and dexamethasone, as they involve proteasome inhibitors and anti-inflammatory drugs.

What other types of research exist?

Promising novel alternatives for AL Amyloidosis treatment in 2024 include: 1) Daratumumab, an anti-CD38 monoclonal antibody, which has shown efficacy in multiple myeloma and amyloidosis. 2) CAEL-101, a monoclonal antibody targeting amyloid fibrils, currently in phase 3 trials. 3) Birtamimab, another monoclonal antibody targeting amyloid deposits, also in advanced clinical trials. These therapies offer targeted approaches and have demonstrated potential in clinical studies.

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Corticosteroid

Venetoclax + Ixazomib + Dexamethasone for AL Amyloidosis

Q: What is the mechanism of action of this treatment?

The most common treatments for AL Amyloidosis include BCL-2 inhibitors like venetoclax, proteasome inhibitors such as ixazomib citrate, and anti-inflammatory drugs like dexamethasone. BCL-2 inhibitors work by blocking the Bcl-2 protein, which is essential for cancer cell survival, thereby promoting cancer cell death. Proteasome inhibitors disrupt the degradation of proteins within cancer cells, leading to cell death and reduced amyloid production. Anti-inflammatory drugs like dexamethasone reduce inflammation and modulate the immune response, which can help manage symptoms and improve the efficacy of other treatments. These mechanisms are crucial for AL Amyloidosis patients as they target the underlying pathology of the disease, aiming to reduce amyloid deposits and improve organ function.

Phase 1

Recruiting

Led By Michael A Rosenzweig

Research Sponsored by National Cancer Institute (NCI)

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Age >= 18 years

Measurable disease of AL amyloidosis as defined by at least one of the following: 1) serum or urine monoclonal protein >= 500 mg/dL by protein electrophoresis, or 2) serum free light chain >= 20 mg/L with an abnormal kappa:lambda ratio or the difference between involved and uninvolved free light chains (dFLC) >= 20 mg/L

Must not have

Patients with New York Heart Association classification III/IV. Patients with advanced cardiac amyloidosis, Mayo stage IIIB based on European Modification of the 2004 Standard Mayo Clinic Staging in patients with advanced cardiac involvement with NT-Pro BNP > 8500 pg/mL (Wechalekar et al., 2013)

Known gastrointestinal disease or gastrointestinal procedure that could interfere with the oral absorption or tolerance of MLN9708 (ixazomib citrate), including difficulty swallowing

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 2.5 years

Awards & highlights

No Placebo-Only Group

Summary

This trial tests a combination of venetoclax, ixazomib citrate, and dexamethasone in patients with difficult-to-treat light chain amyloidosis. Venetoclax alone has shown promise in treating this condition, indicating its potential effectiveness and safety. The drugs work together to kill cancer cells and reduce inflammation.

Who is the study for?

Adults with relapsed or refractory light chain amyloidosis, specifically those who have a genetic change known as translocation t(11;14). They should be in relatively good health (ECOG <=2), not HIV positive unless undetectable viral load on therapy, and without major organ damage from multiple myeloma. Prior cancer treatments must be completed at certain intervals before joining.

What is being tested?

The trial is testing the combination of venetoclax, ixazomib citrate, and dexamethasone to find the safest dose with the fewest side effects for treating light chain amyloidosis that has returned or isn't responding to treatment. Venetoclax blocks proteins cancer cells need to survive, while ixazomib helps kill them and dexamethasone reduces inflammation.

What are the potential side effects?

Potential side effects include nausea, diarrhea, fatigue, risk of infection due to low blood counts, liver issues reflected by changes in blood tests results. There may also be risks related to heart function given the nature of amyloidosis affecting different organs.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I am 18 years old or older.

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My AL amyloidosis shows through specific blood or urine tests.

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My bone marrow biopsy shows I have the t(11;14) genetic marker.

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I can take care of myself but might not be able to do heavy physical work.

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My AL amyloidosis is at a cardiac risk stage of I, II, or IIIa.

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My condition is confirmed AL amyloidosis needing treatment.

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I had hepatitis C but have been treated and cured.

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My kidneys work well enough, with a clearance rate of at least 15 mL/min.

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My hepatitis B virus load is undetectable with treatment.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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My heart condition is severe, classified as NYHA III/IV or I have advanced cardiac amyloidosis.

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I have no stomach or intestine problems that affect how I absorb pills.

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I am not taking any strong or moderate drugs that affect enzyme activity.

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My cancer has spread to my brain or spinal cord.

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I have severe diarrhea.

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I am not pregnant or breastfeeding while considering treatment with MLN9708.

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I am allergic to venetoclax, ixazomib, or dexamethasone.

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I do not have any serious ongoing illnesses or recent heart issues.

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I have severe nerve pain or numbness.

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I have been treated with MLN9708 or venetoclax before.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 2.5 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 2.5 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 2.5 years for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Incidence of adverse events

Maximum tolerated dose

Recommended phase 2 dose (RP2D)

Secondary study objectives

Overall response rate (complete hematologic response)

Other study objectives

Expression of BCL-2, BCL-XL, BAX, BAK, BIM, NOXA, and MCL-1

Hematologic response rates

Immune profile in the peripheral blood

+1 more

Side effects data

From 2022 Phase 3 trial • 389 Patients • NCT02005471

33%

Neutropenia

11%

SARS-CoV-2 test positive

11%

Sepsis

11%

Abdominal pain

11%

Pneumonia

11%

Rhinovirus infection

11%

COVID-19

11%

Gastroenteritis

11%

Pneumonia pseudomonal

11%

Electrocardiogram QT prolonged

11%

Anaemia

11%

Neutrophil count decreased

11%

Hypokalaemia

11%

Febrile neutropenia

11%

Supraventricular tachycardia

11%

Blood creatinine increased

11%

White blood cell count decreased

11%

Dermatitis

100%

80%

60%

40%

20%

Study treatment Arm

Bendamustine + Rituximab Crossover Substudy

Venetoclax + Rituximab Re-Treatment Substudy

Venetoclax + Rituximab Main Study

Bendamustine + Rituximab Main Study

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

1Treatment groups

Experimental Treatment

Group I: Treatment (venetoclax, ixazomib citrate, dexamethasone)Experimental Treatment10 Interventions

Patients receive venetoclax PO QD on days 1-28, ixazomib citrate PO on days 1, 8 and 15, and dexamethasone PO on days 1, 8, 15 and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients may undergo x-ray imaging and abdominal ultrasound during screening. Patients undergo bone marrow biopsy and/or aspiration as well as blood sample collection throughout the study. Patients may undergo CT scans, and/or MRI, and/or PET scans throughout the study.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Dexamethasone

2007

Completed Phase 4

~2650

Biospecimen Collection

2004

Completed Phase 3

~2030

Bone Marrow Aspiration and Biopsy

2016

Completed Phase 1

~40

Computed Tomography

2017

Completed Phase 2

~2790

Ixazomib Citrate

2012

Completed Phase 3

~970

Magnetic Resonance Imaging

2017

Completed Phase 3

~1180

Positron Emission Tomography

2011

Completed Phase 2

~2200

Transabdominal Ultrasound

2020

N/A

~50

Venetoclax

2019

Completed Phase 3

~2240

0 / 19Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

The most common treatments for AL Amyloidosis include BCL-2 inhibitors like venetoclax, proteasome inhibitors such as ixazomib citrate, and anti-inflammatory drugs like dexamethasone. BCL-2 inhibitors work by blocking the Bcl-2 protein, which is essential for cancer cell survival, thereby promoting cancer cell death. Proteasome inhibitors disrupt the degradation of proteins within cancer cells, leading to cell death and reduced amyloid production. Anti-inflammatory drugs like dexamethasone reduce inflammation and modulate the immune response, which can help manage symptoms and improve the efficacy of other treatments. These mechanisms are crucial for AL Amyloidosis patients as they target the underlying pathology of the disease, aiming to reduce amyloid deposits and improve organ function.

Daratumumab: A Review in Newly Diagnosed Systemic Light Chain Amyloidosis.Multiple myeloma with onset of pancreas involvement: A case report.Lenalidomide and dexamethasone for systemic AL amyloidosis following prior treatment with thalidomide or bortezomib regimens.