Venetoclax + Dexamethasone for AL Amyloidosis

Recruiting at 3 trial locations

Overseen By Research Nurse Navigator

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Rajshekhar Chakraborty, MD

Must not be taking: BCL-2 inhibitors

Disqualifiers: Other malignancy, Uncontrolled infection, Renal therapy, 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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

53 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the combination of venetoclax (a targeted therapy) and dexamethasone to determine its safety and effectiveness for individuals with a specific form of relapsed or stubborn light chain amyloidosis, where abnormal proteins accumulate in organs. The trial includes different groups to assess various drug doses, aiming to identify the safest and most effective treatment. Individuals who have undergone at least one previous treatment and whose condition exhibits certain genetic traits (t(11;14)) might be suitable candidates. Participants will assist researchers in understanding how these drugs work together to address this challenging condition. As a Phase 1, Phase 2 trial, this research focuses on understanding the treatment's effects in people and measuring its effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial team or your doctor.

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

Previous studies have shown that venetoclax is generally safe for people with certain conditions. When combined with dexamethasone, it can cause some side effects, according to research. These include serious blood-related issues like low white blood cell counts, though these were uncommon. Non-blood-related side effects included swelling.

Venetoclax has been used for other conditions and was found to be well-tolerated. In past studies, most patients did not experience major problems. However, one patient died from an infection, highlighting the importance of careful monitoring.

Overall, initial findings suggest that this combination is fairly well-tolerated, but trial participants will be closely monitored to ensure safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Venetoclax for AL Amyloidosis because it introduces a novel approach by targeting the BCL-2 protein, which is crucial for cancer cell survival. This mechanism is different from many current treatments that focus on other pathways, offering a fresh angle for tackling the disease. Additionally, when combined with Dexamethasone, Venetoclax may enhance treatment effectiveness by leveraging the anti-inflammatory properties of Dexamethasone, potentially improving patient outcomes. This dual-action strategy could offer new hope for patients who have limited options with existing therapies like chemotherapy, monoclonal antibodies, or proteasome inhibitors.

What evidence suggests that this trial's treatments could be effective for AL Amyloidosis?

Research has shown that venetoclax effectively treats AL amyloidosis, particularly in patients whose disease has returned or resisted other treatments. One study reported a high success rate of 88%, with many patients experiencing significant and long-lasting improvements. In this trial, participants may receive venetoclax alone or with dexamethasone. The combination aims to reduce or eliminate the harmful cells causing amyloidosis. Specifically, previous patients in that study demonstrated high rates of complete recovery in their blood counts, meaning their blood returned to normal. These findings suggest that the combination of venetoclax and dexamethasone could be a promising option for those with difficult-to-treat AL amyloidosis. ^{2 5 6 7 8}

Who Is on the Research Team?

Rajshekhar Chakraborty, MD

Principal Investigator

Columbia University

Are You a Good Fit for This Trial?

This trial is for adults over 18 with relapsed or refractory AL amyloidosis, a condition where abnormal proteins build up in organs. Participants must have had prior treatments including an anti-CD38 antibody and be able to follow the study plan. They can't join if they're on dialysis, have certain infections like HIV without effective treatment, severe heart failure, previous use of BCL-2 inhibitors, or other serious health issues.

Inclusion Criteria

I have been treated with an anti-CD38 drug before.

My tests show I have the t(11;14) genetic marker.

Ability to comply with the study protocol, in the investigator's judgment

Exclusion Criteria

I have HIV but am not on HAART, or I have active hepatitis A, B, or C.

My heart condition is at stage IIIB with high NT-Pro BNP levels.

I had cancer before, but it's either been treated successfully or has been in remission for over 2 years.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1: Dose Escalation

Dose escalation to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of venetoclax in combination with dexamethasone

Up to 6 cycles (approximately 6 months)

Phase 2: Randomized Treatment

Randomized open-label study comparing the MTD or RP2D of venetoclax in combination with dexamethasone versus investigator's choice

Up to 1 year

Follow-up

Participants are monitored for safety and effectiveness after treatment

Every 8 weeks for up to 1 year

What Are the Treatments Tested in This Trial?

Interventions

• Venetoclax

Trial Overview

The trial tests the safety and effectiveness of venetoclax combined with dexamethasone in patients whose amyloidosis has returned or didn't respond to treatment. It aims to find the safest dose and see how well it works against this disease that affects organ function by protein accumulation.

How Is the Trial Designed?

Group I: Phase 2: Venetoclax MTD with Dexamethasone Experimental Treatment 1 Intervention

Venetoclax MTD (200 mg or 400 mg) with Dexamethasone (10 mg or 20 mg) as determined by the phase I results

Group II: Phase 1: Venetoclax 400mg + Dexamethasone 20 mg Experimental Treatment 3 Interventions

Cohort 4: Venetoclax 400 mg tablet, once daily and Dexamethasone 20 mg tablet once weekly, for up to 2 cycles after achieving best response, for a maximum of 6 cycles (1 cycle = 28 days)

Group III: Phase 1: Venetoclax 400mg + Dexamethasone 10 mg Experimental Treatment 3 Interventions

Cohort 3: Venetoclax 400 mg tablet, once daily and Dexamethasone 10 mg tablet once weekly, for up to 2 cycles after achieving best response, for a maximum of 6 cycles (1 cycle = 28 days)

Group IV: Phase 1: Venetoclax 400mg Experimental Treatment 2 Interventions

Cohort 2: Venetoclax 400 mg tablet, once daily for up to 2 cycles after achieving best response, for a maximum of 6 cycles (1 cycle = 28 days)

Group V: Phase 1: Venetoclax 200 mg Experimental Treatment 2 Interventions

Cohort 1: Venetoclax 200 mg tablet, once daily for up to 2 cycles after achieving best response, for a maximum of 6 cycles (1 cycle = 28 days)

Group VI: Phase 2: Control Arm (Investigator's Choice) Active Control 5 Interventions

Participants will receive one of the following as determined by the investigator: Daratumumab, Pomalidomide, Bendamustine, or Ixazomib (+/- dexamethasone)

Venetoclax is already approved in United States, European Union for the following indications:

Approved in United States as Venclexta for:

• Chronic lymphocytic leukemia (CLL)
• Small lymphocytic lymphoma (SLL)
• Acute myeloid leukemia (AML)

Approved in European Union as Venclyxto for:

• Chronic lymphocytic leukemia (CLL)
• Small lymphocytic lymphoma (SLL)
• Acute myeloid leukemia (AML)

Who Is Running the Clinical Trial?

Rajshekhar Chakraborty, MD

Lead Sponsor

Trials

2

Recruited

140+

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Published Research Related to This Trial

In a study of 120 female patients at high risk for postoperative nausea and vomiting (PONV) following lumbar spinal surgery, the combination of ramosetron and dexamethasone was found to be as effective as ondansetron and dexamethasone in preventing PONV, with similar rates of nausea and vomiting between the two groups.

Despite the use of both antiemetic regimens, the overall incidence of PONV remained high, indicating that while both combinations are effective, there is still a significant risk of PONV in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy comparison of ramosetron with ondansetron on preventing nausea and vomiting in high-risk patients following spine surgery with a single bolus of dexamethasone as an adjunct. Choi, YS., Shim, JK., Ahn, SH., et al.[2021]

In a study of 22 relapsed/refractory multiple myeloma patients, low-dose venetoclax (≤250 mg/day) combined with bortezomib, daratumumab, and dexamethasone showed an impressive overall response rate of 80% in patients with the t(11;14) chromosomal marker, indicating its efficacy as a salvage therapy.

The low-dose regimen significantly reduced the incidence of serious adverse events, particularly infections, which are commonly associated with higher doses of venetoclax, suggesting a safer treatment option for this specific patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low dose venetoclax in combination with bortezomib, daratumumab, and dexamethasone for the treatment of relapsed/refractory multiple myeloma patients-a single-center retrospective study. Regidor, B., Goldwater, MS., Wang, J., et al.[2021]

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]

A heart-transplanted patient with immunoglobulin light-chain amyloidosis (AL), who was resistant to multiple treatments, achieved a rapid complete response using the Bcl-2 inhibitor venetoclax as a single-agent therapy.

This case suggests that venetoclax may be a promising treatment option for AL, particularly in patients with the t(11;14) cytogenetic aberration, who typically have limited therapeutic options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapid Complete Response to Single-Agent Bcl-2 Inhibitor Venetoclax in a Heart-Transplanted Patient with Triple Refractory Immunoglobulin Light-Chain Amyloidosis. Gran, C., Borg Bruchfeld, J., Ellin, F., et al.[2020]

In a study of 26 patients with relapsed refractory light-chain amyloidosis, venetoclax demonstrated a high overall hematologic response rate of 88%, with 35% achieving complete response (CR) and another 35% achieving very good partial response (VGPR).

The treatment was relatively safe, with a median overall survival of 33 months and no cases of tumor lysis syndrome reported, although there were some infections, highlighting the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax in Relapse/Refractory AL Amyloidosis-A Multicenter International Retrospective Real-World Study. Lebel, E., Kastritis, E., Palladini, G., et al.[2023]

Venetoclax is a highly effective treatment for relapsed or refractory chronic lymphocytic leukemia (CLL), achieving response rates of about 80% in clinical trials involving 240 patients from 2011 to 2016.

While venetoclax has an acceptable safety profile, common side effects include neutropenia and diarrhea, and there is a risk of tumor lysis syndrome (TLS), which can be managed through careful dose ramp-up and patient education, leading to no reported TLS events in ongoing trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . Brumbaugh Paradis, H., Alter, D., Llerandi, D.[2018]

In a study of 70 patients undergoing minimally invasive thoracic surgery, dexamethasone did not significantly reduce morphine consumption or postoperative pain scores compared to those who did not receive it.

However, patients who did not receive dexamethasone required more rescue pain therapy, suggesting that dexamethasone may help in managing pain as part of a multimodal approach, while also being safe with no increase in surgical wound infections or significant differences in postoperative nausea and vomiting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dexamethasone and postoperative analgesia in minimally invasive thoracic surgery: a retrospective cohort study. Umari, M., Paluzzano, G., Stella, M., et al.[2023]

In a study of 242 patients experiencing postoperative nausea and vomiting (PONV), adding dexamethasone to anti-emetic treatments significantly reduced the recurrence of PONV from 51% to 33%.

The combination of dexamethasone with either dolasetron or haloperidol was found to be more effective than using dolasetron or haloperidol alone, indicating that dexamethasone enhances the efficacy of these anti-emetics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The addition of dexamethasone to dolasetron or haloperidol for treatment of established postoperative nausea and vomiting. Rüsch, D., Arndt, C., Martin, H., et al.[2013]

In a phase I study involving 48 patients with relapsed or refractory multiple myeloma (RRMM), the combination of venetoclax with daratumumab and dexamethasone (VenDd) showed a remarkable overall response rate of 96%, indicating its strong efficacy, especially in patients with the t(11;14) translocation.

The combination of venetoclax with bortezomib, daratumumab, and dexamethasone (VenDVd) also demonstrated significant efficacy, with a 92% overall response rate, and an 18-month progression-free survival rate of 66.7%, suggesting that these combinations could provide durable responses in RRMM treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Study of Venetoclax Plus Daratumumab and Dexamethasone, With or Without Bortezomib, in Patients With Relapsed or Refractory Multiple Myeloma With and Without t(11;14). Bahlis, NJ., Baz, R., Harrison, SJ., et al.[2022]

In a study of 93 women undergoing laparoscopic gynecologic surgery, intravenous dexamethasone (both 4mg and 8mg) was more effective than ondansetron (4mg) in preventing postoperative nausea and vomiting (PONV), with the ondansetron group experiencing a 61% incidence of PONV compared to lower rates in the dexamethasone groups.

Dexamethasone not only reduced the incidence of PONV but also resulted in fewer requests for rescue antiemetics, particularly in the 4mg group, indicating it is a safe and cost-effective option for PONV prophylaxis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative study of dexamethasone and ondansetron for prophylaxis of postoperative nausea and vomiting in laparoscopic gynecologic surgery. D'souza, N., Swami, M., Bhagwat, S.[2022]

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Venetoclax in Relapse/Refractory AL Amyloidosis—A ...

We found a very high response rate (88%), and most responses were deep and prolonged. Treatment was effective even when doses were reduced.

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According to GlobalData, Phase II drugs for Amyloidosis have a 72% phase transition success rate (PTSR) indication benchmark for progressing into Phase III.

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Venetoclax induces deep hematologic remissions in t(11

Venetoclax is efficacious in relapsed/refractory t(11;14) multiple myeloma, thus warranting investigation in light-chain amyloidosis (AL).

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Venetoclax for the treatment of translocation (11;14) AL ...

Venetoclax could induce a complete response (CR) in a patient with AL amyloidosis whose disease markers plateaued on bortezomib, ...