Rituximab + Venetoclax for Marginal Zone Lymphoma

Not currently recruiting at 9 trial locations

Overseen By Gilles Salles, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: Prior systemic therapy, Uncontrolled illness, Pregnancy, 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: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines the effectiveness of combining rituximab (an antibody therapy) and venetoclax (a targeted cancer drug) for individuals with untreated Marginal Zone Lymphoma (MZL). The aim is to determine if these drugs can effectively treat lymphoma, a cancer affecting parts of the immune system. Suitable candidates for this trial include those with MZL that can be measured on scans or tests, such as a lymph node larger than 1.5 cm. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, specifically moderate or strong CYP3A inhibitors and inducers, at least 7 days before starting venetoclax. If you're on these medications, you may need to discuss alternatives with your doctor.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that the combination of rituximab and venetoclax has been tested for treating Marginal Zone Lymphoma (MZL). These studies found that most people tolerated the combination well. Experts regularly monitored safety during the studies, closely watching for any issues.

Rituximab is already used for similar conditions, and its safety is well-known. Venetoclax is newer, but earlier research has reviewed its safety. While no treatment is completely risk-free, this combination has demonstrated a manageable safety profile with known side effects. Most patients handled the treatment without serious problems, making it a promising option for those considering joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for lymphoma?

Researchers are excited about combining Rituximab and Venetoclax for Marginal Zone Lymphoma because this treatment targets the cancer cells in a new way. Rituximab is an antibody that targets a specific protein on lymphoma cells, while Venetoclax works by promoting cancer cell death by inhibiting a protein called BCL-2, which helps cancer cells survive. This dual approach can potentially lead to more effective treatment by simultaneously attacking the cancer cells from different angles, offering hope for better outcomes compared to existing therapies that typically focus on just one method of action.

What evidence suggests that the combination of rituximab and venetoclax could be effective for treating marginal zone lymphoma?

This trial will evaluate the combination of rituximab and venetoclax for treating marginal zone lymphoma (MZL). Research suggests that rituximab with venetoclax may help treat certain types of lymphoma, including MZL. Previous studies have shown that venetoclax effectively targets tumors, particularly in patients with other lymphomas like chronic lymphocytic leukemia (CLL). Venetoclax blocks a protein called BCL-2, which helps cancer cells survive. Rituximab, a well-known treatment, aids the immune system in attacking cancer cells by targeting a specific protein on them. Together, these treatments might be effective for MZL, as venetoclax has shown success in similar conditions. Although direct data on this combination for MZL is limited, the mechanisms of these drugs and past results in related cancers suggest potential effectiveness. ^{6 7 8 9 10}

Who Is on the Research Team?

Andrew Zelenetz, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

Adults diagnosed with Marginal Zone Lymphoma (MZL) who haven't been treated before can join this trial. They must have normal organ function, measurable disease, and a life expectancy over two years. Those with certain hepatitis B conditions or controlled HIV are eligible. Pregnant women, those unwilling to use effective contraception post-treatment, or patients previously treated for MZL cannot participate.

Inclusion Criteria

Patients must have normal organ function as defined below: Platelet count ≥ 50,000 cells/mm^3, Hemoglobin ≥ 8.0 g/dL, Absolute neutrophil count ≥ 1000 cells/mcL. If there is documented bone marrow involvement, ANC must be >/= 500 cells/mcL, Total bilirubin < 1.5 x upper normal institutional limits. In patients with Gilbert's disease or documented liver involvement, total bilirubin up to 3x ULN will be allowed, AST(SGOT)/ALT(SGPT) <3 x institutional upper limit of normal unless elevation is caused by liver involvement with MZL, Creatinine clearance >60 mL/min for patients with creatinine levels above institutional normal (by Cockcroft-Gault estimate or 12-24h creatinine clearance measurements)

I have been vaccinated for Hepatitis B or have it under control with negative PCR results.

I can swallow pills.

Exclusion Criteria

I have been treated with ibrutinib or another BTK inhibitor before.

I have Hepatitis B but my viral load is undetectable.

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

Induction

Patients receive rituximab 375 mg/m2 weekly for 4 weeks, followed by restaging imaging and risk stratification for Tumor Lysis Syndrome (TLS)

4 weeks

Ramp-up

Oral venetoclax is administered with a ramp-up dosing schedule for 4 weeks

4 weeks

Maintenance

Patients continue venetoclax for up to 24 months and receive rituximab every 3 months for 12 months

24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

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 in new patients. It aims to understand how well these drugs work together as an initial treatment option for this type of lymphoma.

How Is the Trial Designed?

Group I: Rituximab and Venetoclax Experimental Treatment 2 Interventions

Patients will be treated with an Induction phase of rituximab 375 mg/m2 weekly for 4 weeks. Patients will undergo restaging imaging after the last of 4 weekly rituximab doses and before beginning venetoclax. Based on post-rituximab restaging studies, patients will be risk-stratified for risk of Tumor Lysis Syndrome (TLS) and treated in the appropriate setting with TLS prophylaxis per institutional TLS guide lines starting at week 5. Oral venetoclax will follow a ramp-up dosing schedule and will be taken daily after 4 weeks of rituximab therapy. Following the 4-week ramped-up phase of venetoclax, patients will begin their target dose of venetoclax and continue for a maximum of 24 months. In addition, patients will receive rituximab 375 mg/m2 starting on day 1 of the maintenance phase and repeated once every 3 months for 12 months. Venetoclax may be continued after this period if patient has not achieved a complete remission

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?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

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

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6535706/

Update on the role of venetoclax and rituximab in the ... Initial phase I trials of venetoclax monotherapy confirmed its potent antitumor activity in vivo in patients with relapsed/refractory CLL. Single doses resulted ...

2. 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.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4654800/

ABT-199 (venetoclax) and BCL-2 inhibitors in clinical ... This review focused on the current clinical development of a highly effective class of small molecule BCL-2 inhibitors, including ABT-199/venetoclax.

4. 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 ...

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

A Phase IB/II, Open-Label Study Evaluating the Safety and In an anesthetized dog CV model given intravenous (IV) doses of venetoclax, mild reductions in cardiac output (−11% to −19%) and myocardial contractility (dP/ ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06510309

Rituximab Plus Venetoclax in Front Line Marginal Zone ... The purpose of this study is to see if the combination of rituximab and venetoclax is effective in treating Marginal Zone Lymphoma. The U.S. Food and Drug ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8719063/

Marginal zone lymphoma: present status and future perspectives The addition of rituximab to chlorambucil improved outcomes compared to either agent alone. RCVP followed by rituximab maintenance has been shown to be well ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT04416451?cond=Cancer&aggFilters=funderType%3Aindustry%2CstudyType%3Aint

A Phase II Study Using Rituximab Plus Venetoclax in the ... This study will help researchers understand how effective the combination of venetoclax and rituximab is in treating MZL in people who have not received a ...

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6497517/

Venetoclax plus R- or G-CHOP in non-Hodgkin lymphoma A scientific oversight committee, including 3 experts in NHL, reviewed safety and efficacy data regularly during the conduct of the study, along with the study ...

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

VENCLEXTA efficacy results: 6-year overall survival 1 Learn about VENCLEXTA® 6-year overall survival and treatment efficacy results. See full safety and Prescribing Information for more details.