Bendamustine + Venetoclax + Rituximab for Chronic Lymphocytic Leukemia

Not currently recruiting at 1 trial location

Overseen By Research Nurse Navigator

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Nicole Lamanna

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: HIV, Active infections, Heart failure, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 3

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of three drugs—bendamustine, rituximab, and venetoclax—to evaluate their effectiveness in treating chronic lymphocytic leukemia (CLL), a type of blood cancer. Bendamustine and rituximab are common treatments, while venetoclax is a newer pill that blocks cancer cell growth. The trial aims to determine if this combination can effectively manage CLL, particularly in patients who have not been treated before and possess a certain genetic feature. Those diagnosed with CLL but not yet treated might be suitable for this study. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop all current medications, but you cannot take certain medications like moderate or strong CYP3A inhibitors or inducers within 7 days before starting the study drug. You also need to avoid grapefruit, Seville oranges, and star fruit within 3 days before the first dose.

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

Research has shown that the combination of bendamustine and rituximab often treats chronic lymphocytic leukemia (CLL), with many patients tolerating it well. These drugs have proven effective in cases where CLL has returned or is difficult to treat, and they are generally considered safe, with manageable side effects.

Venetoclax, another drug in this treatment, blocks a protein that helps CLL cells survive. It is approved for certain types of CLL but can cause a serious side effect called tumor lysis syndrome. This occurs when many cancer cells are destroyed quickly, releasing substances into the blood that can harm the kidneys.

Overall, studies suggest that while this combination of drugs shows promise for treating CLL, risks are involved. Patients should be closely monitored for any side effects, especially when starting venetoclax. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Bendamustine, Venetoclax, and Rituximab for treating Chronic Lymphocytic Leukemia (CLL) because it offers a novel approach that differs from traditional therapies. Most current treatments focus on chemotherapy or targeted therapy alone. However, this regimen combines Bendamustine, a chemotherapy agent, with Venetoclax, which targets the BCL-2 protein to promote cancer cell death, and Rituximab, an antibody that marks cancer cells for the immune system to attack. This combination aims to enhance the effectiveness of treatment by attacking the cancer from multiple angles, potentially leading to better outcomes and fewer relapses.

What evidence suggests that this trial's treatments could be effective for chronic lymphocytic leukemia?

Research has shown that combining bendamustine, rituximab, and venetoclax may effectively treat chronic lymphocytic leukemia (CLL). In this trial, participants will first receive bendamustine and rituximab (BR), a combination that previous studies have found effective for CLL. Venetoclax will then be added, as it targets a protein called BCL-2, which helps cancer cells survive. This combination is particularly beneficial for patients whose CLL has returned or did not respond to other treatments. Venetoclax, specifically, has proven very effective in killing CLL cells when used with rituximab. Although venetoclax can cause a serious side effect called tumor lysis syndrome, which occurs when cancer cells are destroyed too quickly, its ability to target CLL cells makes it a strong component of this treatment plan. ^{1 2 3 4 6}

Who Is on the Research Team?

Nicole Lamanna, MD

Principal Investigator

Columbia University

Are You a Good Fit for This Trial?

Adults diagnosed with Chronic Lymphocytic Leukemia (CLL) who have not had prior treatment for their condition, except corticosteroids for symptom relief. Participants must be over 18, able to use contraception, and have adequate organ function. Excluded are those with allergies to trial drugs, active non-CLL cancers within the last 2 years (with some exceptions), significant health issues as assessed by the investigator, or current severe infections.

Inclusion Criteria

My liver is working well.

Adequate blood counts (absolute neutrophil count > 1.0 10^9/L, hemoglobin > 8 g/dL, platelet count > 50 x 10^9/L)

Activated partial thromboplastin time (aPTT) and prothrombin time (PT) not to exceed 1.5x the upper limit of reference ranges

Exclusion Criteria

I do not have any uncontrolled health conditions.

Significant history of various medical conditions that may adversely affect study participation

I have been treated for CLL or SLL, but only with corticosteroids for symptoms.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Treatment

Participants receive bendamustine and rituximab for three cycles, each cycle being 28 days

12 weeks

3 visits (in-person)

Consolidation Treatment

Participants receive venetoclax with a five-week dose escalation to 400 mg daily, followed by six cycles of rituximab

12 months

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

What Are the Treatments Tested in This Trial?

Interventions

• Bendamustine
• Rituximab
• Venetoclax

Trial Overview

The study is testing a combination of treatments: initially Bendamustine and Rituximab (BR) followed by Venetoclax plus Rituximab for CLL. The total therapy duration is 15 months. Venetoclax targets a protein on CLL cells but requires hospital monitoring due to risk of tumor lysis syndrome—a potentially fatal complication from rapid cancer cell breakdown.

How Is the Trial Designed?

Group I: BR followed by venetoclax and rituximab Experimental Treatment 3 Interventions

Subjects will be on Bendamustine 50-90 mg/m2 on days 1-2 for three cycles with each cycle being 28 days, and Rituximab 375 mg/m2 on day 1 or days 1-2 for three cycles with each cycle being 28 days. Venetoclax will then be started in a step-wise fashion per the package insert.

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

Approved in United States as Treanda for:

• Chronic lymphocytic leukemia
• Non-Hodgkin lymphoma

Approved in European Union as Ribomustin for:

• Chronic lymphocytic leukemia
• Non-Hodgkin lymphoma
• Multiple myeloma

Approved in Canada as Levact for:

• Chronic lymphocytic leukemia
• Non-Hodgkin lymphoma

Approved in Japan as Bendamustine hydrochloride for:

• Chronic lymphocytic leukemia
• Non-Hodgkin lymphoma

Who Is Running the Clinical Trial?

Nicole Lamanna

Lead Sponsor

Trials

1

Recruited

40+

Published Research Related to This Trial

In a study of 389 patients with relapsed or refractory chronic lymphocytic leukemia (CLL), fixed-duration venetoclax plus rituximab (VenR) showed significantly better long-term outcomes compared to bendamustine plus rituximab (BR), with 4-year progression-free survival (PFS) rates of 57.3% versus 4.6%.

Achieving undetectable minimal residual disease (uMRD) at the end of treatment was linked to superior PFS, and patients who received ibrutinib after VenR had a remarkable 100% response rate, highlighting the effectiveness of VenR and its potential for durable responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax Plus Rituximab in Relapsed Chronic Lymphocytic Leukemia: 4-Year Results and Evaluation of Impact of Genomic Complexity and Gene Mutations From the MURANO Phase III Study. Kater, AP., Wu, JQ., Kipps, T., 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]

The combination of venetoclax with rituximab showed remarkable efficacy and a manageable safety profile in treating chronic lymphocytic leukemia (CLL), both in relapsed/refractory cases and as a first-line therapy for high-risk patients.

Similarly, the combination of ibrutinib with venetoclax also demonstrated striking efficacy, suggesting that these combinations could become new standard treatment options for CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic lymphocytic leukemia at ASH 2017. Wanner, D., Steurer, M.[2020]

In the phase III CLL14 trial, a 12-month treatment with venetoclax combined with obinutuzumab significantly improved progression-free survival and rates of undetectable minimal residual disease compared to traditional chemoimmunotherapy with chlorambucil and obinutuzumab in patients with untreated chronic lymphocytic leukaemia.

Venetoclax + obinutuzumab is a well-tolerated, chemotherapy-free treatment option for CLL, with manageable side effects like neutropenia, making it suitable for patients who cannot undergo intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Previously Untreated Chronic Lymphocytic Leukaemia. Blair, HA.[2021]

The combination of venetoclax with bendamustine-rituximab (BR) was found to be safe and tolerable in a study of 60 patients with relapsed/refractory non-Hodgkin's lymphoma, with the recommended phase II dose established at 800 mg daily.

The overall response rate to the treatment was 65%, with a median duration of response of 38.3 months, indicating preliminary efficacy for this combination therapy in managing B-cell NHL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax, bendamustine, and rituximab in patients with relapsed or refractory NHL: a phase Ib dose-finding study. de Vos, S., Swinnen, LJ., Wang, D., et al.[2021]

Venetoclax is an effective oral treatment for relapsed or refractory chronic lymphocytic leukemia (CLL), showing durable responses and a manageable safety profile in clinical trials, including patients with poor prognostic factors.

In combination with rituximab, venetoclax significantly improved progression-free survival and achieved undetectable minimal residual disease compared to bendamustine plus rituximab, with benefits lasting for at least 36 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Relapsed/Refractory Chronic Lymphocytic Leukemia. Scott, LJ.[2020]

Citations

1.

clinicaltrials.gov

clinicaltrials.gov/study/NCT03609593

Study Details | NCT03609593 | Bendamustine/rituximab ...

The purpose of this study is to determine the efficacy of bendamustine and rituximab (BR) followed by venetoclax for 12 months. The total time on therapy is ...

2.

clinicaltrials.gov

clinicaltrials.gov/study/NCT01671904

A Study of Venetoclax in Combination With Bendamustine ...

Participants with 1L CLL received 6 months of single-agent venetoclax for a total of 1-year treatment duration. Single-agent venetoclax could be extended if ...

3.

nejm.org

nejm.org/doi/full/10.1056/NEJMoa1713976

Venetoclax–Rituximab in Relapsed or Refractory Chronic ...

We evaluated the efficacy of venetoclax in combination with rituximab in patients with relapsed or refractory chronic lymphocytic leukemia.

4.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC8561296/

Venetoclax plus bendamustine-rituximab or ... - PubMed Central

Venetoclax (Ven), an orally administered, potent BCL-2 inhibitor, has demonstrated efficacy in chronic lymphocytic leukemia (CLL) in combination with rituximab ...

5.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC6158762/

Venetoclax, bendamustine, and rituximab in patients with ...

Preclinical data demonstrated that venetoclax monotherapy has broad cell-killing activity against a panel of NHL cell lines including follicular lymphoma (FL), ...

6.

sciencedirect.com

sciencedirect.com/science/article/pii/S0006497118478081

642. CLL: Therapy, excluding Transplantation

Bendamustine (B) and rituximab (R) combination has demonstrated efficacy in relapsed/refractory (R/R) and previously untreated (frontline, 1L) ...