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

Trial Summary

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.

What data supports the effectiveness of the drug Rituximab in treating 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 patients with various types of non-Hodgkin's lymphoma, including diffuse large B-cell lymphoma and follicular lymphoma, when combined with chemotherapy. ^{1 2 3 4 5}

Is the combination of Sonrotoclax, Rituximab, and Zanubrutinib safe for humans?

Rituximab has been used safely in many patients with different types of lymphoma, with most side effects being mild and related to the infusion, like chills and fever. There is no specific safety data available for Sonrotoclax and Zanubrutinib in this combination, but Rituximab is generally well tolerated. ^{1 5 6 7 8}

What makes the combination of Sonrotoclax, Rituximab, and Zanubrutinib unique for treating lymphoma?

This treatment is unique because it combines Sonrotoclax, a novel drug, with Rituximab and Zanubrutinib, which are known to target specific proteins on cancer cells, potentially offering a new approach for patients with lymphoma. The combination aims to enhance the effectiveness of treatment by using different mechanisms to attack the cancer cells. ^{3 5 9 10 11}

What is the purpose of this trial?

This phase II trial studies the side effects of an escalated ramp-up of sonrotoclax following initial debulking with zanubrutinib or rituximab in treating patients with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and mantle cell lymphoma (MCL) that is newly diagnosed, has come back after a period of improvement (relapsed) or does not respond to treatment (refractory). Rituximab is a monoclonal antibody that binds to a protein called CD20, which is found on B-cells, and may kill tumor cells. Zanubrutinib may stop the growth of tumor cells by blocking a protein called Bruton's tyrosine kinase (BTK), which is needed for tumor cell growth. Sonrotoclax works by blocking a protein called B-cell lymphoma-2 (BCL-2). This protein helps certain types of blood tumor cells to survive and grow. When sonrotoclax blocks Bcl-2 it slows down or stops the growth of tumor cells and helps them die. Giving an increased dose of sonrotoclax over a shorter period of time in combination with zanubrutinib or rituximab may be safe and tolerable in treating patients with newly diagnosed, relapsed or refractory CLL, SLL, and MCL.

Research Team

Mazyar Shadman, MD, MPH

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Eligibility Criteria

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

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

References

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

Rituximab in B-Cell Hematologic Malignancies: A Review of 20 Years of Clinical Experience. [2023]

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

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

3. England pubmed.ncbi.nlm.nih.gov

The therapeutic use of rituximab in non-Hodgkin's lymphoma. [2015]

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

Rituximab in Lymphoma and Chronic Lymphocytic Leukaemia: A Practice Guideline. [2018]

5. England pubmed.ncbi.nlm.nih.gov

An overview of the current clinical use of the anti-CD20 monoclonal antibody rituximab. [2020]

6. England pubmed.ncbi.nlm.nih.gov

A phase 3 study of rituximab biosimilar HLX01 in patients with diffuse large B-cell lymphoma. [2021]

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

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

Exposure-response analysis of venetoclax in combination with rituximab in patients with relapsed or refractory chronic lymphocytic leukemia: pooled results from a phase 1b study and the phase 3 MURANO study. [2022]

9. England 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. [2018]

10. Mexico pubmed.ncbi.nlm.nih.gov

INFECTIOUS COMPLICATIONS AS A PREDICTOR OF MORTALITY IN PATIENTS WITH NON-HODGKIN LYMPHOMA RECEIVING RITUXIMAB-CONTAINING CHEMOTHERAPY. [2022]

11. France pubmed.ncbi.nlm.nih.gov

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