Sonrotoclax + Rituximab + Zanubrutinib for Lymphoma

Overseen By Mazyar Shadman, MD, MPH

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Fred Hutchinson Cancer Center

Must not be taking: Bcl-2 inhibitors, BTK inhibitors

Disqualifiers: Prior malignancy, CNS involvement, 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: 17

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the safety of combining three drugs—sonrotoclax, rituximab, and zanubrutinib—to treat certain blood cancers, specifically chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and mantle cell lymphoma (MCL). Rituximab and zanubrutinib target proteins on cancer cells to halt their growth, while sonrotoclax aids in killing cancer cells by blocking a protein that allows their survival. The trial includes different groups based on patients' responses to previous treatments. This study may suit individuals diagnosed with CLL, SLL, or MCL that has returned after treatment or has not responded to it. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to significant advancements in cancer therapy.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot take certain treatments like Bcl-2 inhibitors, some cancer therapies, or strong CYP3A4 inhibitors close to the start of the trial. It's best to discuss your current medications with the trial team.

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

Research has shown that sonrotoclax, whether used alone or with zanubrutinib, is generally safe at doses up to 640 mg. In some studies, this combination did not cause severe side effects, allowing patients to tolerate the treatment well. It also demonstrated promising results in shrinking tumors, particularly in patients with relapsed or refractory mantle cell lymphoma.

Specific safety information for the combination of rituximab and sonrotoclax is not yet available. However, rituximab is usually well tolerated, and previous studies have shown that sonrotoclax alone is safe up to 640 mg. This suggests it might also be safe when combined with rituximab.

This study is in Phase 2, indicating some evidence of safety for these treatments, but further testing is needed to confirm this and to better understand any side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they offer new approaches for tackling lymphoma. Sonrotoclax, a key component in both treatment combinations, works by targeting proteins that help cancer cells survive, potentially making it more effective in certain resistant cases. Zanubrutinib, used in one arm of the study, is a next-generation BTK inhibitor that has shown promise in providing a more targeted attack on cancer cells with potentially fewer side effects compared to older BTK inhibitors. Meanwhile, the combination with rituximab, a well-established monoclonal antibody, might enhance the overall effectiveness by targeting lymphoma cells from multiple angles. These innovations could offer more effective options for patients who don't respond well to existing therapies.

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

Research has shown that the combination of sonrotoclax and zanubrutinib, one of the treatment arms in this trial, holds promise for treating certain types of lymphoma. In earlier studies, this combination achieved a 100% response rate in some patients, with many reaching undetectable levels of cancer cells in their blood. For patients with relapsed or hard-to-treat mantle cell lymphoma, the treatment showed a 79% response rate, with the cancer disappearing completely in 66% of cases. Another treatment arm in this trial combines rituximab and sonrotoclax. Rituximab is known to extend patient survival and slow disease progression. These findings suggest that both treatment options could be effective for patients facing these challenging conditions. ^{1 3 6 7 8}

Who Is on the Research Team?

Mazyar Shadman, MD, MPH

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Are You a Good Fit for This Trial?

This trial is for adults over 18 with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or mantle cell lymphoma (MCL) that's new, returned, or resistant to treatment. They must meet specific health criteria and agree to use effective contraception. Excluded are those with certain medical conditions, recent major surgery, severe bleeding disorders, active infections needing therapy, known HIV/HBV/HCV infection, inability to swallow capsules or comply with the study.

Inclusion Criteria

Provision of signed and dated written informed consent prior to any study specific procedures, sampling, or analyses

My CLL/SLL or MCL/SLL cancer can be measured.

Specific laboratory values including ANC, platelets, hemoglobin, creatinine clearance, AST, ALT, total bilirubin, serum amylase, and serum lipase

Exclusion Criteria

I have not had cancer in the last 2 years, with some exceptions.

I have no health issues that could affect how a study drug works or is evaluated.

Recent use of certain substances prior to study drug administration

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Debulking and Initial Treatment

Patients undergo debulking and receive either zanubrutinib or rituximab depending on their BTKi refractory status

4 weeks

4 visits (in-person)

Ramp-up Treatment

Patients receive a ramp-up of sonrotoclax until the target dose is reached, continuing with either zanubrutinib or rituximab

12 weeks

12 visits (in-person)

Continued Treatment

Patients continue receiving sonrotoclax with either zanubrutinib or rituximab for up to 15 cycles

up to 15 cycles (28 days each)

Follow-up

Participants are monitored for safety and effectiveness after treatment

up to 5 years

Periodic visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Rituximab
• Sonrotoclax
• Zanubrutinib

Trial Overview The trial tests an escalated dose of Sonrotoclax after initial treatment with Zanubrutinib or Rituximab in patients with CLL/SLL/MCL. It aims to determine if this combination is safe and tolerable when increasing Sonrotoclax dosage quickly. The drugs target proteins essential for tumor cell survival and growth.

How Is the Trial Designed?

Group I: Treatment (zanubrutinib + sonrotoclax) Experimental Treatment 6 Interventions

Patients not refractory to a BTKi undergo debulking and receive zanubrutinib PO QD on day 1 of cycles 1-15. Beginning on day 1 of cycle 4, patients receive a ramp up of sonrotoclax PO QD until target dose is reached. Patients who tolerate receiving sonrotoclax continue to receive sonrotoclax together with zanubrutinib PO QD for all subsequent cycles. Cycles repeat every 28 days for up to 15 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT during screening and on study and blood sample collection throughout the study. Additionally, patients may undergo bone marrow biopsy and endoscopy on study.

Group II: Treatment (rituximub + sonrotoclax) Experimental Treatment 6 Interventions

Patients who are refractory to a BTKi undergo debulking and receive rituximab PO QD on days 1, 8, 15, and 22 of 1 cycle. Beginning on day 1 of cycle 2, patients receive a ramp up of sonrotoclax PO QD until target dose is reached. Patients will continue sonrotoclax PO QD through cycle 13. Patients also continue to receive ritiximab PO QD on day 1 of cycles 3-6. Cycles repeat every 28 in the absence of disease progression or unacceptable toxicity. Patients also undergo CT during screening and on study and blood sample collection throughout the study. Additionally, patients may undergo bone marrow biopsy and endoscopy on study.

Who Is Running the Clinical Trial?

Fred Hutchinson Cancer Center

Lead Sponsor

Trials

583

Recruited

1,341,000+

BeiGene

Industry Sponsor

Trials

216

Recruited

32,500+

BeOne Medicines

Industry Sponsor

Published Research Related to This Trial

Rituximab, a chimeric anti-CD20 monoclonal antibody, is a standard treatment for non-Hodgkin's lymphoma (NHL) and has been used in over 300,000 patients worldwide, demonstrating its widespread acceptance and efficacy.

The combination of rituximab with standard CHOP chemotherapy is approved for treating diffuse large B-cell lymphoma, and while it is generally well tolerated, common side effects include infusion-related reactions like chills and fever.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An overview of the current clinical use of the anti-CD20 monoclonal antibody rituximab. Boye, J., Elter, T., Engert, A.[2020]

Rituximab, a chimeric monoclonal anti-CD20 antibody, shows enhanced effectiveness when combined with interferon alpha, leading to higher complete response rates and longer response durations in treatment.

While other immunomodulatory agents like interleukin-2 and Epratuzumab show potential for synergy with Rituximab, further randomized trials are needed to confirm their efficacy compared to Rituximab alone, particularly in indolent lymphomas where chemotherapy might be unnecessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Role of anti-CD20 monoclonal antibody in association with immunomodulatory agents]. Bosly, A.[2017]

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]

In a study of 265 patients with non-Hodgkin lymphoma receiving rituximab, 177 infections were reported, with febrile neutropenia and mucosal barrier injury-related infections being the most common, highlighting the need for careful monitoring during treatment.

The study found that age over 60, failure to achieve a complete response, and the occurrence of infections significantly increased the risk of death, emphasizing the importance of screening for infections like tuberculosis before starting rituximab therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

INFECTIOUS COMPLICATIONS AS A PREDICTOR OF MORTALITY IN PATIENTS WITH NON-HODGKIN LYMPHOMA RECEIVING RITUXIMAB-CONTAINING CHEMOTHERAPY. Meza-Meneses, P., Cornejo-Juárez, P., Vilar-Compte, D., et al.[2022]

A phase 3 study involving 407 treatment-naïve patients with diffuse large B-cell lymphoma demonstrated that HLX01, a biosimilar to rituximab, has comparable efficacy to the reference drug, with overall response rates of 94.1% for HLX01 and 92.8% for rituximab, falling within the pre-defined equivalence margin.

The safety profiles of HLX01 and rituximab were similar, with nearly identical rates of treatment-emergent adverse events (99.5% vs. 99.0%) and serious adverse events (34.0% vs. 32.5%), confirming that HLX01 is a safe alternative to rituximab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 3 study of rituximab biosimilar HLX01 in patients with diffuse large B-cell lymphoma. Shi, Y., Song, Y., Qin, Y., et al.[2021]

Rituximab has been shown to significantly improve progression-free and overall survival in patients with various types of non-Hodgkin lymphoma and chronic lymphocytic leukaemia (CLL), based on a systematic review of 56 randomized controlled trials.

The consensus guidelines recommend rituximab for use in combination with chemotherapy for initial treatment of aggressive B-cell lymphomas, maintenance therapy for indolent B-cell lymphomas, and as part of treatment regimens for CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab in Lymphoma and Chronic Lymphocytic Leukaemia: A Practice Guideline. Prica, A., Baldassarre, F., Hicks, LK., et al.[2018]

The addition of rituximab, a monoclonal antibody, to conventional chemotherapy (R-CHOP regimen) significantly enhances treatment outcomes for patients with diffuse large B-cell lymphoma (DLBCL), improving response rates, progression-free survival (PFS), and overall survival (OS).

Rituximab also boosts response rates and PFS in mantle cell lymphoma (MCL) and improves outcomes in follicular lymphoma (FL), highlighting its critical role in enhancing the efficacy of chemotherapy across various types of non-Hodgkin's lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemotherapy combinations with monoclonal antibodies in non-Hodgkin's lymphoma. Kahl, B.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06839053

Study Details | NCT06839053 | Sonrotoclax, Rituximab ... This phase II trial studies the side effects of an escalated ramp-up of sonrotoclax following initial debulking with zanubrutinib or rituximab in treating ...

2. trialx.com trialx.com/clinical-trials/listings/296961/sonrotoclax-rituximab-and-zanubrutinib-in-treating-participants-with-chronic-lymphocytic-leukemia-small-lymphocytic-lymphoma-and-mantle-cell-lymphoma/

Sonrotoclax, Rituximab, and Zanubrutinib in Treating ... This phase II trial studies the side effects of an escalated ramp-up of sonrotoclax following initial debulking with zanubrutinib or rituximab ...

3. conference-correspondent.com conference-correspondent.com/highlights/ash/ash-2023-cll/phase-1-2-study-data-of-combination-sonrotoclax-bgb-11417-plus-zanubrutinib-in-treatment-naive-cll-sll

Phase 1/2 Study Data of Combination Sonrotoclax (BGB- ... Any grade adverse events occurred in 89.7% of all patients; 92.2% with sonrotoclax 160 mg and 87.5% with sonrotoclax 320 mg. The most common treatment-emergent ...

4. withpower.com withpower.com/trial/sonrotoclax-rituximab-zanubrutinib-for-lymphoma-3cfbd

Sonrotoclax + Rituximab + Zanubrutinib for Lymphoma Rituximab has been shown to improve response rates, progression-free survival (the time during which the disease does not get worse), and overall survival in ...

5. ir.beonemedicines.com ir.beonemedicines.com/news/beigene-advances-leadership-in-cll-at-ash-2024-with-new-data-from-its-hematology-franchise/87890a63-8c41-48a8-b427-48eda46e4b7e

BeiGene Advances Leadership in CLL at ASH 2024 with ... 5-year follow-up from SEQUOIA study demonstrated treatment with BRUKINSA reduced the risk of progression or death by 71% compared to bendamustine-rituximab.

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.TPS7090

BGB-11417-203: An ongoing, phase 2 study of sonrotoclax ... In a phase 1 trial, sonrotoclax monotherapy was well tolerated at all dose levels tested up to 640 mg and showed promising evidence of antitumor ...

7. cancer.gov cancer.gov/research/participate/clinical-trials/intervention/sonrotoclax?pn=1

Clinical Trials Using Sonrotoclax - NCI A Study to Investigate the Safety of Novel Dose Ramp-up Schedule(s) When Initiating Sonrotoclax in Participants Treated for Blood Cancers. Status: Active.

8. clinicaltrials.gov clinicaltrials.gov/study/NCT06943872

NCT06943872 | A Study to Investigate Progression-Free ... The goal of this study is to compare how well sonrotoclax plus obinutuzumab works versus venetoclax plus rituximab in treating adults with relapsed and/or ...