Venetoclax + Ixazomib + Dexamethasone for AL Amyloidosis

Not currently recruiting at 20 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: CNS involvement, Advanced cardiac amyloidosis, others

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

Compensation: Varies

Number of Visits: 1

Duration: Up to 12 cycles (approximately 12 months)

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of three drugs—venetoclax, ixazomib citrate, and dexamethasone—to treat light chain amyloidosis that has returned or is unresponsive to other treatments. Venetoclax targets cancer cell survival, ixazomib citrate aids in killing cancer cells, and dexamethasone reduces body inflammation. The trial aims to determine the optimal dose and assess side effects. Suitable candidates include those with relapsed or treatment-resistant light chain amyloidosis and a specific genetic change, translocation t(11;14). As a Phase 1 trial, the research focuses on understanding how the treatment works in people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it mentions avoiding certain drugs like strong or moderate CYP3A inhibitors and inducers. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

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

Research has shown that the combination of venetoclax, ixazomib citrate, and dexamethasone is being tested for safety in treating AL amyloidosis. Venetoclax has already shown promise in treating this condition, with studies suggesting it works well and is safe. Together, these drugs aim to stop cancer cell growth and reduce inflammation.

In earlier studies, patients generally handled the combination well. However, like any treatment, reports of side effects have ranged from mild to more serious. This trial is in an early stage, focusing on finding the safest dose and understanding any possible side effects.

Anyone considering joining the trial should discuss the potential risks and benefits with their doctor to make an informed decision. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using venetoclax, ixazomib citrate, and dexamethasone together for treating AL amyloidosis because this combination targets the disease in a novel way. Venetoclax works by inhibiting a protein called BCL-2, which helps cancer cells survive, potentially making it effective against the abnormal cells involved in amyloidosis. Ixazomib citrate adds a unique angle by disrupting the protein breakdown process within cells, helping to clear out the harmful proteins that build up in AL amyloidosis. Unlike standard treatments, which often focus on chemotherapy, this combination offers a targeted approach that could improve treatment outcomes with possibly fewer side effects.

What evidence suggests that this trial's treatments could be effective for relapsed or refractory light chain amyloidosis?

This trial will study a combination of three drugs—venetoclax, ixazomib citrate, and dexamethasone—to treat relapsed or refractory light chain amyloidosis. Research has shown that venetoclax blocks a protein called Bcl-2, which helps cancer cells survive, potentially stopping cancer growth. Ixazomib citrate kills cancer cells by blocking proteasomes, which act as waste disposal units in cells. Dexamethasone, an anti-inflammatory drug, reduces immune responses, aiding in cancer treatment. Early findings suggest this combination could be effective, but further research is needed to confirm its benefits. ^{1 6 7 8 9}

Who Is on the Research Team?

Michael A. Rosenzweig

Principal Investigator

City of Hope Comprehensive Cancer Center LAO

Are You a Good Fit for This Trial?

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.

Inclusion Criteria

My AL amyloidosis shows through specific blood or urine tests.

My white blood cell count is healthy without needing medication for at least 1-2 weeks.

I need treatment after trying at least one other therapy.

Exclusion Criteria

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

I have recovered from side effects of previous cancer treatments, except for hair loss.

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

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive venetoclax, ixazomib citrate, and dexamethasone in 28-day cycles

Up to 12 cycles (approximately 12 months)

Monthly visits for each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

Every 1-3 months until disease progression or death

Regular follow-up visits

What Are the Treatments Tested in This Trial?

Interventions

• Dexamethasone
• Ixazomib Citrate
• Venetoclax

Trial Overview

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.

How Is the Trial Designed?

Group I: Treatment (venetoclax, ixazomib citrate, dexamethasone) Experimental Treatment 11 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 of each cycle. 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 ECHO during screening and 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 and may optionally undergo urine sample collection throughout the study.

Dexamethasone is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Dexamethasone for:

• Inflammation
• Allergic reactions
• Respiratory diseases
• Skin conditions
• Eye diseases
• Immune system disorders

Approved in United States as Dexamethasone for:

• Inflammatory conditions
• Allergic states
• Respiratory diseases
• Blood disorders
• Neoplastic diseases
• Nervous system disorders

Approved in Canada as Dexamethasone for:

• Inflammation
• Allergic reactions
• Respiratory diseases
• Skin conditions
• Eye diseases

Approved in Japan as Dexamethasone for:

• Inflammatory conditions
• Allergic states
• Respiratory diseases
• Blood disorders

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

A milder schedule of high-dose dexamethasone (40 mg for 4 days every 21 days) was tested in 23 AL amyloidosis patients, resulting in a 35% response rate within a median of 4 months, indicating its potential effectiveness.

This treatment regimen was associated with minimal toxicity, suggesting it could be a suitable front-line therapy for patients who cannot undergo autologous stem cell transplantation and need a quick response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A modified high-dose dexamethasone regimen for primary systemic (AL) amyloidosis. Palladini, G., Anesi, E., Perfetti, V., et al.[2019]

In a trial involving 81 patients undergoing chemotherapy, the combination of high-dose metoclopramide with dexamethasone and lorazepam significantly reduced vomiting episodes during the first 24 hours, achieving major control in 67% of patients compared to only 25% with the other combination without metoclopramide.

While the metoclopramide combination improved anti-emetic control, it also led to extrapyramidal reactions in 11.5% of patients, highlighting a safety concern associated with its use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of metoclopramide in acute and delayed chemotherapy induced emesis: a randomised double blind trial. O'Brien, ME., Cullen, MH., Woodroffe, C., et al.[2019]

In a meta-analysis of seven trials with 608 patients, dexamethasone was found to be as effective as ondansetron in preventing postoperative nausea and vomiting (PONV) after laparoscopic surgery, with no significant differences in safety.

Dexamethasone was more effective than ondansetron in the late postoperative stage (6-24 hours), while ondansetron was better in the early stage (0-6 hours), suggesting that both medications have specific advantages depending on the timing of administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dexamethasone versus ondansetron in the prevention of postoperative nausea and vomiting in patients undergoing laparoscopic surgery: a meta-analysis of randomized controlled trials. Wang, XX., Zhou, Q., Pan, DB., et al.[2018]

In a study of patients with gynecologic cancer receiving paclitaxel and carboplatin, a history of hyperemesis gravidarum was identified as a significant risk factor for delayed vomiting (grade 1 or greater) despite receiving standard antiemetic treatment with dexamethasone and granisetron.

The study found no significant associations for nausea of grade 2 or greater, indicating that while nausea may be difficult to predict, certain patient histories, like hypertension and hyperemesis gravidarum, can help identify those at higher risk for vomiting during chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of the relation between patient characteristics and the state of chemotherapy-induced nausea and vomiting in patients with gynecologic cancer receiving paclitaxel and carboplatin. Furukawa, N., Akasaka, J., Shigemitsu, A., et al.[2018]

In a study of 90 women undergoing mastectomy, dexamethasone at a dose of 8 mg significantly reduced the incidence of postoperative nausea and vomiting (PONV) to 27%, compared to 67% in the placebo group.

Dexamethasone 8 mg also decreased the need for additional pain relief medication (indomethacin) compared to both placebo and the lower dose of 4 mg, with no serious adverse events reported, indicating its safety and efficacy in this surgical context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduction of postoperative nausea and vomiting and analgesic requirement with dexamethasone in women undergoing general anesthesia for mastectomy. Fujii, Y., Nakayama, M.[2022]

Dexamethasone (Dex) significantly reduces the sensitivity of C6 glioma cells to methotrexate (MTX), allowing more cells to survive even at high concentrations of MTX.

This protective effect of Dex was also observed in human TE671 cells, indicating that the interaction between Dex and MTX is not limited to a specific species.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dexamethasone induced partial resistance to methotrexate in C6-glioma cells. Wolff, JE., Jürgens, H.[2013]

In a study of 81 patients with AL amyloidosis, both CTD and BDex regimens showed high overall hematologic response rates (86% for CTD and 91% for BDex), with BDex achieving a significantly deeper and faster response.

While both treatments had similar overall survival rates, BDex was particularly beneficial for patients with advanced disease, showing improved survival outcomes, although it was associated with higher rates of severe hematologic toxicity and diarrhea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparative study of cyclophosphamide, thalidomide and dexamethasone (CTD) versus bortezomib and dexamethasone (BDex) in light-chain amyloidosis. Liu, B., Wang, Y., Ning, X., et al.[2021]

In a phase 3 study involving 168 patients with relapsed/refractory AL amyloidosis, ixazomib combined with dexamethasone showed a median time to vital organ deterioration or mortality of 34.8 months, significantly longer than the 26.1 months observed with physician's choice treatments, indicating a potential benefit in delaying disease progression.

Although ixazomib-dexamethasone did not significantly outperform physician's choice in hematologic response rates (53% vs 51%), it demonstrated a favorable safety profile with manageable adverse events, making it a promising option for patients with limited treatment alternatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized phase 3 study of ixazomib-dexamethasone versus physician's choice in relapsed or refractory AL amyloidosis. Dispenzieri, A., Kastritis, E., Wechalekar, AD., et al.[2022]

A patient with immunoglobulin light chain amyloidosis (AL) showed a positive response to single-agent venetoclax, tolerating the treatment well for over a year, suggesting its potential efficacy for this condition.

Despite concerns about increased mortality in multiple myeloma patients using venetoclax in combination therapies, this case indicates that venetoclax monotherapy may be a safe and effective option for patients with refractory AL amyloidosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax monotherapy induced rapid and sustained response in a frail patient with refractory AL amyloidosis: Less is more? Yip, PL., Lau, JSM., Lam, CP.[2020]

In a study of 101 patients with AL amyloidosis, bortezomib combined with dexamethasone (VD) showed a hematologic response rate of 68%, while the addition of cyclophosphamide (VCD) resulted in a response rate of 78%, but this difference was not statistically significant (P=0.26).

The median survival rates were similar for both treatment groups (33 months for VD and 36 months for VCD, P=0.45), indicating that higher doses of dexamethasone or the addition of cyclophosphamide do not significantly enhance the efficacy or survival outcomes in patients treated with bortezomib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Addition of cyclophosphamide and higher doses of dexamethasone do not improve outcomes of patients with AL amyloidosis treated with bortezomib. Kastritis, E., Gavriatopoulou, M., Roussou, M., et al.[2018]

Citations

1.

clinicaltrials.gov

clinicaltrials.gov/study/NCT04847453

NCT04847453 | Venetoclax, MLN9708 (Ixazomib Citrate ...

Combination therapy with venetoclax, ixazomib citrate and dexamethasone may be effective in treatment of relapsed or refractory light chain amyloidosis.

2.

trial.medpath.com

trial.medpath.com/clinical-trial/083eaeabc8e69278/nct03000660-venetoclax-dexamethasone-systemic-al-amyloidosis

Trial of Venetoclax (ABT-199) and Dexamethasone for ...

The researchers want to find out if Venetoclax (ABT-199) in addition to dexamethasone will reduce or eliminate AL amyloidosis plasma cells. In this study, ...

3.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC10132994/

Systemic AL amyloidosis: current approach and future ...

In this review, we report the literature on the latest treatment updates of AL amyloidosis and the ongoing clinical trials highlighting the future treatments.

4.

dana-farber.org

dana-farber.org/clinical-trials/22-327

A Phase 1/1a Study of Venetoclax, MLN9708 (ixazomib ...

This phase I/Ia trial finds the best dose and side effects of venetoclax given in combination with ixazomib citrate and dexamethasone in treating patients ...

5.

cancer.gov

cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2021-03038

Venetoclax, MLN9708 (Ixazomib Citrate) and ...

Combination therapy with venetoclax, ixazomib citrate and dexamethasone may be effective in treatment of relapsed or refractory light chain amyloidosis.

6.

uvahealth.com

uvahealth.com/clinical-trials/trial/24142

A Phase 1/1a Study of Venetoclax, MLN9708 (ixazomib ...

The purpose of the study is to evaluate the safety and tolerability of venetoclax, MLN9708 (ixazomib citrate), and dexamethasone when used in combination for ...

7.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11968654/

The potential role of BCL-2 inhibition in amyloidosis and ...

Regimens incorporating venetoclax have also demonstrated promising outcomes in patients with AL amyloidosis, particularly those with ...

8.

oneamyloidosisvoice.com

oneamyloidosisvoice.com/rarehub/venetoclax-dexamethasone-relapsed-andor-refractory-t1114-amyloidosis

Venetoclax-Dexamethasone in Relapsed and/or Refractory t(11

The purpose of this study is assess safety, safest dose, and effectiveness of venetoclax in combination with dexamethasone in participants with t(11;14) ...

9.

withpower.com

withpower.com/trial/phase-1-immunoglobulin-light-chain-amyloidosis-8-2021-5742e

Venetoclax + Ixazomib + Dexamethasone for AL Amyloidosis

Venetoclax alone has shown promise in treating this condition, indicating its potential effectiveness and safety. The drugs work together to kill cancer cells ...