Rituximab + Venetoclax for Marginal Zone Lymphoma

Overseen By Emma Logan, MSN

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Gottfried von Keudell, MD PhD

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: Prior systemic therapy, Uncontrolled illness, 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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 2

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test whether a combination of two drugs, rituximab (a monoclonal antibody) and venetoclax (a targeted therapy), can effectively treat untreated Marginal Zone Lymphoma (MZL), a type of blood cancer. Participants will receive rituximab weekly for the first four weeks, followed by venetoclax daily for eight weeks, and then enter a maintenance phase with continued doses. The trial seeks individuals with confirmed Marginal Zone Lymphoma who exhibit noticeable symptoms, such as enlarged lymph nodes or spleen. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to medical advancements.

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

The trial protocol does not specify if you need to stop taking your current medications, but you must not have taken moderate or strong CYP3A inhibitors or inducers within 7 days before starting venetoclax.

Is there any evidence suggesting that the combination of rituximab and venetoclax is likely to be safe for humans?

Research has shown that the combination of rituximab and venetoclax was tested for safety in earlier studies, which found the treatment to be generally well-tolerated. Common side effects include a decrease in blood cell levels, closely monitored by doctors.

In other studies with similar conditions, the combination of venetoclax and rituximab has produced positive results in many patients, including those with marginal zone lymphoma, a type of slow-growing blood cancer. Although reports mention side effects like low blood counts, the combination is generally considered safe enough for further testing at this stage.

This trial is in an intermediate phase, indicating that some safety data is available, but researchers continue to collect more information to confirm these findings. Always consult your doctor about possible risks and benefits before joining a clinical trial. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for Marginal Zone Lymphoma?

Researchers are excited about Rituximab and Venetoclax for treating Marginal Zone Lymphoma because these drugs offer a fresh approach compared to traditional treatments like chemotherapy. Rituximab is an antibody that targets CD20 proteins on cancer cells, helping the immune system destroy them. Venetoclax works by inhibiting BCL-2, a protein that helps cancer cells survive, thus promoting cancer cell death. This combination could potentially enhance effectiveness and reduce side effects compared to existing treatments, offering new hope for better patient outcomes.

What evidence suggests that the combination of rituximab and venetoclax could be effective for Marginal Zone Lymphoma?

Research has shown that using venetoclax and rituximab together effectively treats some blood cancers. In studies with patients whose chronic lymphocytic leukemia returned, this combination reduced the risk of disease progression or death by 81%. Additionally, 74% of these patients maintained a strong positive response for five years or more. Although these results pertain to a different condition, the success of this treatment combination offers hope for its potential effectiveness in treating Marginal Zone Lymphoma (MZL). Participants in this trial will receive the combination of venetoclax and rituximab to evaluate its effectiveness specifically for MZL. ^{6 7 8 9 10}

Who Is on the Research Team?

Gottfried von Keudell, MD, PhD

Principal Investigator

Beth Israel Deaconess Medical Center

Are You a Good Fit for This Trial?

This trial is for individuals with untreated Marginal Zone Lymphoma (MZL), a type of lymphoma. Specific eligibility criteria are not provided, but typically participants must meet certain health standards and may be excluded based on factors like other medical conditions or treatments.

Inclusion Criteria

Hemoglobin ≥8.0 g/dL

Platelets ≥50,000 cells/mm3

My liver enzymes are within normal limits, unless due to my cancer.

Exclusion Criteria

I am not eligible for radiation therapy aimed at curing early-stage stomach lymphoma linked to H. pylori.

I have been treated with ibrutinib or another BTK inhibitor.

I haven't taken strong medications like fluconazole within the last week.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Induction

Participants receive Rituximab weekly for 4 weeks and Venetoclax daily for 4 weeks

8 weeks

Weekly visits for Rituximab, daily administration of Venetoclax

Maintenance

Participants receive Venetoclax daily and Rituximab at specified intervals, with regular scans

96 weeks

Regular visits for drug administration and scans

Follow-up

Participants are monitored for safety and effectiveness after treatment

52 weeks

In-clinic visit at 1 year after finishing study drugs

What Are the Treatments Tested in This Trial?

Interventions

• Rituximab
• Venetoclax

Trial Overview The study is testing the effectiveness of combining two drugs, Venetoclax and Rituximab, in treating MZL. Venetoclax is an inhibitor that targets cancer cells, while Rituximab is an antibody that helps the immune system attack cancer.

How Is the Trial Designed?

Group I: Rituximab + Venetoclax Experimental Treatment 2 Interventions

33 participants will be enrolled and will complete study procedures as follows: * Baseline visit with screening assessments, scans, and tumor and bone marrow biopsies. * Induction Period: * CT/MRI scans at week 4. * Weeks 1 - 4: Predetermined dose of Rituximab 1x weekly. * Weeks 5 - 8: Predetermined dose of Venetoclax 1x daily. * Maintenance Period: * CT/MRI scan on weeks 12, 36, 60, 84, and then every 6 months after week 96. * Predetermined dose of Venetoclax 1x daily for up to week 96, then once every 6 months. * Predetermined dose of Rituximab 1x weekly at weeks 12, 24, 36, and 48. * End of Treatment Visit: CT/MRI scan, tumor biopsy, and bone marrow biopsy. * Follow up: In-clinic visit at 1 year after finishing study drugs.

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

Approved in United States as Rituxan for:

• Non-Hodgkin's lymphoma
• Chronic lymphocytic leukemia
• Rheumatoid arthritis
• Granulomatosis with polyangiitis
• Microscopic polyangiitis

Approved in European Union as MabThera for:

• Non-Hodgkin's lymphoma
• Chronic lymphocytic leukemia
• Rheumatoid arthritis
• Granulomatosis with polyangiitis
• Microscopic polyangiitis

Approved in Canada as Rituxan for:

• Non-Hodgkin's lymphoma
• Chronic lymphocytic leukemia
• Rheumatoid arthritis
• Granulomatosis with polyangiitis
• Microscopic polyangiitis

Who Is Running the Clinical Trial?

Gottfried von Keudell, MD PhD

Lead Sponsor

Trials

2

Recruited

50+

AbbVie

Industry Sponsor

Trials

1,079

Recruited

535,000+

Founded

2013

Headquarters

North Chicago, USA

Known For

Immunology treatments

Top Products

Humira (adalimumab), Skyrizi (risankizumab), Rinvoq (upadacitinib)

Dr. Roopal Thakkar

AbbVie

Chief Medical Officer since 2023

MD from Wayne State University School of Medicine

Robert A. Michael

AbbVie

Chief Executive Officer

Bachelor's degree in Finance from the University of Illinois

Published Research Related to This Trial

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]

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 323 patients with relapsed or refractory chronic lymphocytic leukemia (CLL), a daily dose of 400 mg of venetoclax resulted in a median progression-free survival (PFS) of 1.8 years.

The addition of 6 cycles of rituximab to venetoclax treatment significantly increased the median PFS to 3.9 years, demonstrating a synergistic effect that enhances treatment efficacy beyond increasing the venetoclax dose alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relationship between venetoclax exposure, rituximab coadministration, and progression-free survival in patients with relapsed or refractory chronic lymphocytic leukemia: demonstration of synergy. Freise, KJ., Jones, AK., Menon, RM., et al.[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]

In a study involving 10 patients with relapsed/refractory chronic lymphocytic leukemia (CLL), the addition of rituximab to venetoclax therapy resulted in a 50% response rate, with three patients achieving complete responses and two achieving partial responses.

The combination treatment was well tolerated, suggesting that adding rituximab after progression on venetoclax may provide a beneficial option for some patients with R/R CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Addition of rituximab in relapsed/refractory chronic lymphocytic leukemia after progression on venetoclax monotherapy. Handunnetti, S., Anderson, MA., Roberts, AW., et al.[2022]

Citations

1. 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.

2. gene.com gene.com/media/press-releases/14889/2020-12-05/genentech-announces-new-data-reinforcing

Genentech: Press Releases | Saturday, Dec 5, 2020 Venclexta plus Rituxan reduced the risk of disease progression or death by 81% (HR=0.19; 95% CI: 0.15, 0.26; p<0.0001) compared to bendamustine ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9710452/

Efficacy of venetoclax plus rituximab for relapsed CLL In relapsed CLL, 74% of deep responses to VenR are maintained for 5 years or more with either continuous or limited-duration venetoclax.

4. venclextahcp.com venclextahcp.com/cll/efficacy/ven-g/data.html

VENCLEXTA efficacy results: 6-year overall survival 1 In patients with CLL, Grade 3 or 4 neutropenia developed in 63% to 64% of patients and Grade 4 neutropenia developed in 31% to 33% of patients when treated with ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT04840602?term=SWOG%20S2005&rank=1

Testing the Combination of Venetoclax and Rituximab, in ... This phase II trial studies the effects of venetoclax and rituximab in comparison to ibrutinib and rituximab in treating patients with previously untreated ...

6. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/20/NCT02055820/Prot_002.pdf

A Phase IB/II, Open-Label Study Evaluating the Safety and Additional hematological effects included reductions in red cell mass (hemoglobin, hematocrit) that were adverse at 600 mg/kg/day in mice and at 150 mg/kg/day ...

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

Venetoclax, bendamustine, and rituximab in patients with ... An ORR of up to 90%, CRs of 41%–60%, and median progression-free survival (PFS) of 23–24 months have been observed in the indolent subtypes [MCL, FL, small ...

8. ashpublications.org ashpublications.org/blood/article/126/23/254/112989/A-Phase-1-Study-of-Venetoclax-ABT-199-GDC-0199

A Phase 1 Study of Venetoclax (ABT-199 / GDC-0199 ... We present updated data on the safety profile and efficacy as of June 10, 2015. ... Rescue Therapy of Refractory Diffuse Large B-Cell Lymphomas ...

9. sciencedirect.com sciencedirect.com/science/article/pii/S0006497118472345

A Dose-Escalation Study of Venetoclax (ABT-199/GDC ... Twenty-seven patients (57%) had been diagnosed with follicular lymphoma, 15 (32%) with DLBCL, and 5 (11%) with marginal zone lymphoma.

10. conference-correspondent.com conference-correspondent.com/highlights/ash/1101:venetoclax-abt-199-gdc-0199-plus-bendamustine-rituximab-in-relapsed-refractory-nhl-results-of-a-dose-escalation-study

Venetoclax (ABT-199/GDC-0199) plus Bendamustine ... Of these, objective responses were achieved by 38% of patients with DLBCL, 78% of those with FL, and 80% of MZL. Based on these preliminary results, venetoclax ...