Venetoclax + Ixazomib + Dexamethasone for AL Amyloidosis

Recruiting at 15 trial locations

Overseen by Michael A. Rosenzweig

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: CNS involvement, Advanced cardiac amyloidosis, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

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.

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.

What data supports the effectiveness of the drug combination Venetoclax, Ixazomib, and Dexamethasone for AL Amyloidosis?

Research shows that Ixazomib combined with Dexamethasone improved the time before organ deterioration or death in AL amyloidosis patients compared to other treatments. Additionally, Venetoclax has shown promise in treating AL amyloidosis, especially in patients with a specific genetic feature, and was well-tolerated in a reported case. ^{1 2 3 4 5}

What makes the drug combination of Venetoclax, Ixazomib, and Dexamethasone unique for treating AL Amyloidosis?

This drug combination is unique because it combines Venetoclax, which targets specific proteins in cancer cells to induce cell death, with Ixazomib, a proteasome inhibitor that disrupts protein breakdown in cells, and Dexamethasone, a steroid that reduces inflammation and can enhance the effects of other cancer treatments. This multi-faceted approach may offer a novel way to treat AL Amyloidosis, a condition with limited standard treatment options. ^{6 7 8 9 10}

Research Team

Michael A. Rosenzweig

Principal Investigator

City of Hope Comprehensive Cancer Center LAO

Eligibility Criteria

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

I am 18 years old or older.

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.

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.

Trial Timeline

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

Treatment Details

Interventions

• Dexamethasone (Corticosteroid)
• Ixazomib Citrate (Proteasome Inhibitor)
• Venetoclax (BCL-2 Inhibitor)

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.

Participant Groups

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 Canada, Japan for the following indications:

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+

Dr. Douglas R. Lowy

National Cancer Institute (NCI)

Chief Executive Officer since 2023

MD from New York University School of Medicine

Dr. Monica Bertagnolli

National Cancer Institute (NCI)

Chief Medical Officer since 2022

MD from Harvard Medical School

Findings from Research

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 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]

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 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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

A randomized phase 3 study of ixazomib-dexamethasone versus physician's choice in relapsed or refractory AL amyloidosis. [2022]

2. Japan pubmed.ncbi.nlm.nih.gov

Venetoclax monotherapy induced rapid and sustained response in a frail patient with refractory AL amyloidosis: Less is more? [2020]

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

A comparative study of cyclophosphamide, thalidomide and dexamethasone (CTD) versus bortezomib and dexamethasone (BDex) in light-chain amyloidosis. [2021]

4. England pubmed.ncbi.nlm.nih.gov

A modified high-dose dexamethasone regimen for primary systemic (AL) amyloidosis. [2019]

5. United States 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. [2018]

6. Germany 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. [2018]

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

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

8. England pubmed.ncbi.nlm.nih.gov

The role of metoclopramide in acute and delayed chemotherapy induced emesis: a randomised double blind trial. [2019]

9. England 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. [2018]

10. Greece pubmed.ncbi.nlm.nih.gov

Dexamethasone induced partial resistance to methotrexate in C6-glioma cells. [2013]