Bendamustine + Venetoclax + Rituximab for Chronic Lymphocytic Leukemia

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

42 Participants Needed

Trial Summary

What is the purpose of this trial?

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 15 months. Bendamustine and rituximab is a commonly used treatment for CLL. Venetoclax is an oral drug that blocks a protein called BCL-2 which is present on CLL cells. It is approved for patients with relapsed (the cancer has come back) or refractory (the cancer did not respond) CLL who harbor a deletion in the short arm of chromosome 17 \[del(17p)\]. When this drug is used by itself, many patients needed to be admitted to the hospital to monitor for a complication known as tumor lysis syndrome. This is an oncologic emergency that is caused by massive destruction of tumor cells with the release of large amounts of electrolytes and other molecules into the blood that can lead to renal failure and potentially death.

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.

What data supports the effectiveness of the drug combination Bendamustine, Venetoclax, and Rituximab for Chronic Lymphocytic Leukemia?

Research shows that the combination of venetoclax and rituximab is more effective than bendamustine and rituximab in prolonging progression-free survival (the time during and after treatment that a patient lives with the disease without it getting worse) in patients with relapsed or refractory chronic lymphocytic leukemia. Venetoclax alone or with rituximab has shown high response rates and durable effects, making it a promising option for treating this condition. ^{1 2 3 4 5}

Is the combination of Bendamustine, Venetoclax, and Rituximab safe for treating Chronic Lymphocytic Leukemia?

The combination of Venetoclax with Bendamustine and Rituximab has been studied for safety in patients with Chronic Lymphocytic Leukemia. While it showed increased toxicity, particularly neutropenia (low white blood cell count) and infections, it generally had a manageable safety profile. No dose-limiting toxicities were observed, but the addition of Bendamustine increased toxicity without clear benefits in effectiveness. ^{2 3 5 6 7}

What makes the drug combination of Bendamustine, Venetoclax, and Rituximab unique for treating chronic lymphocytic leukemia?

This drug combination is unique because Venetoclax is a first-in-class oral drug that targets a specific protein (BCL-2) to help kill cancer cells, and when combined with Rituximab, it has shown to be more effective than Bendamustine plus Rituximab alone in prolonging the time patients live without the disease getting worse. This combination offers a novel approach with a manageable safety profile for patients with relapsed or refractory chronic lymphocytic leukemia. ^{1 2 3 4 5}

Research Team

Nicole Lamanna, MD

Principal Investigator

Columbia University

Eligibility Criteria

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

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

Ability to understand and sign a written informed consent document

Exclusion Criteria

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

I do not have any uncontrolled health conditions.

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

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

References

1. United States 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. [2023]

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

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . [2018]

3. France pubmed.ncbi.nlm.nih.gov

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

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

Venetoclax, bendamustine, and rituximab in patients with relapsed or refractory NHL: a phase Ib dose-finding study. [2021]

5. Austria pubmed.ncbi.nlm.nih.gov

Chronic lymphocytic leukemia at ASH 2017. [2020]

6. New Zealand pubmed.ncbi.nlm.nih.gov

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

7. Italy pubmed.ncbi.nlm.nih.gov

Venetoclax plus bendamustine-rituximab or bendamustine-obinutuzumab in chronic lymphocytic leukemia: final results of a phase 1b study (GO28440). [2021]