Zanubrutinib + CAR T-Cell Therapy for Richter's Syndrome

Recruiting at 1 trial location

Overseen By The Ohio State University Comprehensive Cancer Center

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Aseel Alsouqi

Must not be taking: CYP3A inhibitors, Warfarin

Disqualifiers: HIV, Hepatitis B/C, Cardiovascular disease, 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: 10

Duration: 12 weeks

24 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial tests how well zanubrutinib and lisocabtagene maraleucel (liso-cel) work together in treating patients with Richter's syndrome. Richter's syndrome occurs when chronic lymphocytic leukemia and/or small lymphocytic leukemia transforms into an aggressive lymphoma, which is a cancer of the lymph nodes. Zanubrutinib is a class of medication called a kinase inhibitor. These drugs work by preventing the action of abnormal proteins that tell cancer cells to multiply, which helps stop the spread of cancer. Liso-cel is a type of treatment known as chimeric antigen receptor (CAR) T cell therapy. CAR T-cell therapy is a type of treatment in which a patient's T cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T cells are taken from a patient's blood. Then the gene for a special receptor that binds to a certain protein on the patient's cancer cells is added to the T cells in the laboratory. The special receptor is called a chimeric antigen receptor (CAR). Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain cancers. Giving zanubrutinib and liso-cell together may kill more cancer cells in patients with Richter's syndrome.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot take certain medications like moderate or strong CYP3A inhibitors or inducers within 7 days before starting zanubrutinib. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

What data supports the effectiveness of the treatment Zanubrutinib + CAR T-Cell Therapy for Richter's Syndrome?

Research shows that combining checkpoint inhibitors like tislelizumab with BTK inhibitors such as zanubrutinib can be effective for treating Richter's Syndrome, with a study reporting a 58.3% overall response rate. Additionally, chimeric antigen receptor (CAR) T-cell therapy has shown promise in treating similar aggressive lymphomas, suggesting potential effectiveness for Richter's Syndrome. ^{1 2 3 4 5}

Is the combination of Zanubrutinib and CAR T-Cell Therapy safe for humans?

Lisocabtagene maraleucel (a type of CAR T-Cell Therapy) has been studied in patients with certain types of lymphoma, showing a manageable safety profile. Common side effects included low blood cell counts and cytokine release syndrome (a reaction that can cause fever and flu-like symptoms), but severe cases were rare. This suggests that the therapy is generally safe, though individual experiences may vary. ^{6 7 8 9 10}

What makes the treatment Zanubrutinib + CAR T-Cell Therapy unique for Richter's Syndrome?

This treatment combines zanubrutinib, a targeted drug that inhibits a specific protein involved in cancer cell growth, with CAR T-cell therapy, which uses modified immune cells to attack cancer cells. This combination is novel because it targets the cancer from two different angles, potentially improving outcomes for patients with Richter's Syndrome, a condition that typically responds poorly to standard therapies. ^{1 2 11 12 13}

Research Team

Jennifer A Woyach, MD

Principal Investigator

Ohio State University Comprehensive Cancer Center

Eligibility Criteria

Adults with Richter's syndrome, a condition where chronic lymphocytic leukemia transforms into aggressive lymphoma. Participants must have relapsed or refractory disease after at least one treatment cycle, adequate organ function, and meet criteria for CAR T-cell therapy. They should not be pregnant or breastfeeding and must agree to effective contraception.

Inclusion Criteria

I have large B-cell lymphoma with a history of CLL.

My condition has not improved or has worsened despite treatment.

I meet the requirements for CAR T-cell therapy at my treatment center.

Exclusion Criteria

I have another serious illness that may shorten my life to under 5 years.

I have a heart condition.

I have not had certain treatments recently.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive zanubrutinib orally, undergo leukapheresis, and receive fludarabine, cyclophosphamide, and liso-cel intravenously

12 weeks

Weekly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including bone marrow and lymph node biopsies, and imaging studies

24 months

Every 3 months (in-person)

Long-term follow-up

Participants are followed every 6 months until disease progression or death

Until disease progression or death

Every 6 months (in-person)

Treatment Details

Interventions

• Lisocabtagene Maraleucel
• Zanubrutinib

Trial Overview The trial is testing the combination of zanubrutinib (a kinase inhibitor that stops cancer cells from multiplying) and lisocabtagene maraleucel (CAR T-cell therapy that modifies patient's immune cells to attack cancer). The goal is to see if this combo is more effective in treating Richter's syndrome.

Participant Groups

Group I: Treatment (zanubrutinib, liso-cel) Experimental Treatment 10 Interventions

Patients receive zanubrutinib PO, undergo leukaphereis, and receive fludarabine IV, cyclophosphamide IV, and liso-cel IV on study. Patients also undergo BM biopsy and lymph node biopsy at screening and follow up, and undergo collection of blood samples and CT, PET/CT, and/or MRI throughout the trial.

Lisocabtagene Maraleucel is already approved in United States, European Union for the following indications:

Approved in United States as Breyanzi for:

• Large B-cell lymphoma (LBCL)
• Diffuse large B-cell lymphoma (DLBCL)
• High-grade B cell lymphoma
• Primary mediastinal large B-cell lymphoma
• Follicular lymphoma grade 3B
• Chronic lymphocytic leukemia (CLL)
• Small lymphocytic lymphoma (SLL)
• Mantle cell lymphoma (MCL)

Approved in European Union as Breyanzi for:

• Diffuse large B-cell lymphoma
• High-grade B-cell lymphoma
• Primary mediastinal large B-cell lymphoma
• Follicular lymphoma grade 3B

Who Is Running the Clinical Trial?

Aseel Alsouqi

Lead Sponsor

Trials

1

Recruited

20+

Adam Kittai

Lead Sponsor

Trials

1

Recruited

20+

BeiGene USA, Inc.

Industry Sponsor

Trials

5

Recruited

490+

Findings from Research

Richter's syndrome (RS), a severe transformation of chronic lymphocytic leukemia (CLL) into diffuse large B-cell lymphoma (DLBCL), has poor outcomes with only about 20% achieving complete remission with standard chemoimmunotherapy, highlighting the need for new treatment strategies.

Promising new treatments for RS include PD-1 inhibitors, which show effectiveness especially when combined with ibrutinib, and the BCL2 inhibitor venetoclax, which achieved a 50% complete remission rate in combination with R-EPOCH therapy, indicating potential for improved outcomes in this challenging condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of Richter's syndrome. Thompson, PA., Siddiqi, T.[2023]

In a phase 2 study involving 59 patients with Richter transformation of chronic lymphocytic leukemia, the combination of the PD-1 inhibitor tislelizumab and the BTK inhibitor zanubrutinib resulted in a significant overall response rate of 58.3%, surpassing the predefined threshold of 40%.

The treatment was well-tolerated, with a 12-month overall survival rate of 74.7%, indicating that this combination therapy is both effective and safe for patients with this aggressive form of lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tislelizumab plus zanubrutinib for Richter transformation: the phase 2 RT1 trial. Al-Sawaf, O., Ligtvoet, R., Robrecht, S., et al.[2023]

Richter syndrome (RS), a high-grade transformation of chronic lymphocytic leukaemia, is a chemotherapy-resistant condition with a poor prognosis, showing a median overall survival of only about 8 months, particularly affecting elderly and immunosuppressed patients.

Emerging treatments, including second-generation Bruton tyrosine kinase inhibitors like acalabrutinib and novel monoclonal antibodies, may offer new hope for improving outcomes in RS, highlighting the need for ongoing clinical trials and precision medicine approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An update for Richter syndrome - new directions and developments. Eyre, TA., Schuh, A.[2022]

Richter's syndrome, which occurs in up to 10% of chronic lymphocytic leukemia patients, leads to a rapid decline in health and has a median survival of less than 6 months with conventional chemotherapy.

Current therapies like hyperCVXD and yttrium-90 ibritumomab tiuxetan have not significantly improved survival rates, highlighting the need for targeted treatments based on the specific genetic and epigenetic abnormalities associated with the transformation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Richter's syndrome: biology and therapy. Yee, KW., O'Brien, SM., Giles, FJ.[2019]

Richter syndrome (RS) occurs in 0.5-1% of chronic lymphocytic leukemia (CLL) patients per year and is often linked to a poor prognosis, with 80% of cases being clonally related to the prior CLL.

Current treatments for RS, including modern immunochemotherapy, show low response rates, but promising strategies such as stem-cell transplantation and novel immunotherapies are being explored to improve outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Richter Syndrome: Diagnostic and Therapeutic Management]. Croizier, C., Guièze, R.[2021]

In a study involving 14 Japanese patients with relapsed or refractory aggressive large B-cell lymphoma, the CAR T-cell therapy lisocabtagene maraleucel (liso-cel) showed a 70% objective response rate and a 50% complete response rate, indicating significant efficacy.

The treatment had a manageable safety profile, with common side effects including neutropenia (90%) and cytokine release syndrome (50%), but no severe (grade ≥3) cytokine release syndrome events were reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 results of lisocabtagene maraleucel in Japanese patients with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma. Makita, S., Yamamoto, G., Maruyama, D., et al.[2023]

In a study involving 344 patients with relapsed or refractory large B-cell lymphomas, lisocabtagene maraleucel (liso-cel) demonstrated a high objective response rate of 73%, with 53% achieving a complete response, indicating its efficacy as a treatment option.

The safety profile of liso-cel was acceptable, with a low incidence of severe cytokine release syndrome (2%) and neurological events (10%), suggesting it can be safely administered to patients with various high-risk features.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Abramson, JS., Palomba, ML., Gordon, LI., et al.[2021]

Lisocabtagene maraleucel (liso-cel) is an effective CAR T cell therapy for relapsed or refractory large B cell lymphoma, showing a 73% objective response rate and a 53% complete remission rate in a study of 344 patients.

The treatment demonstrated a 12-month overall survival rate of 58% for all patients and 86% for those who achieved complete remission, although it was associated with adverse events such as cytokine release syndrome (42%) and neurological issues (30%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lisocabtagene Maraleucel in Relapsed or Refractory Diffuse Large B Cell Lymphoma: What is the Evidence? Kharfan-Dabaja, MA., Yassine, F., Moustafa, MA., et al.[2023]

Lisocabtagene Maraleucel (Liso-cel) is a promising CAR-T therapy targeting CD19, showing strong antitumor activity in aggressive B-cell lymphomas with manageable toxicity, as confirmed in the TRANSCEND NHL001 trial.

Preclinical studies indicate that a specific ratio of CD4+ and CD8+ T-cells enhances the effectiveness of Liso-cel, suggesting a well-balanced approach to maximizing both efficacy and safety in treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lisocabtagene Maraleucel for the treatment of B-cell lymphoma. Iragavarapu, C., Hildebrandt, G.[2022]

In a phase 2 trial involving 61 patients with relapsed or refractory large B-cell lymphoma, lisocabtagene maraleucel demonstrated a high overall response rate of 80%, indicating its efficacy as a second-line treatment for patients not intended for stem-cell transplantation.

The treatment was generally safe, with no treatment-related deaths reported; however, common serious side effects included neutropenia and cytokine release syndrome, which occurred in 38% of patients, highlighting the need for monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lisocabtagene maraleucel as second-line therapy in adults with relapsed or refractory large B-cell lymphoma who were not intended for haematopoietic stem cell transplantation (PILOT): an open-label, phase 2 study. Sehgal, A., Hoda, D., Riedell, PA., et al.[2022]

In a Phase II study involving 49 patients with Richter syndrome or fludarabine-refractory chronic lymphocytic leukemia, the combination therapy showed an overall response rate of 41%, with 18% achieving complete remission and 22% achieving partial remission.

Despite the treatment's activity, it did not demonstrate significant improvements in overall survival or failure-free survival compared to the previous hyper-CVXD regimen alone, indicating that while the new regimen has some efficacy, it also carries significant toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fractionated cyclophosphamide, vincristine, liposomal daunorubicin, and dexamethasone plus rituximab and granulocyte-macrophage-colony stimulating factor (GM-CSF) alternating with methotrexate and cytarabine plus rituximab and GM-CSF in patients with Richter syndrome or fludarabine-refractory chronic lymphocytic leukemia. Tsimberidou, AM., Kantarjian, HM., Cortes, J., et al.[2015]

Zanubrutinib is a next-generation BTK inhibitor that shows improved selectivity and reduced off-target toxicities compared to ibrutinib, making it a safer option for treating B-cell malignancies.

In recent clinical trials, zanubrutinib demonstrated significant efficacy in improving progression-free survival in patients with chronic lymphocytic leukemia (CLL) and showed better safety profiles, including a lower risk of serious side effects like atrial fibrillation and major bleeding compared to ibrutinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zanubrutinib for the treatment of lymphoid malignancies: Current status and future directions. Wolska-Washer, A., Robak, T.[2023]

Richter transformation (RT) is a severe form of lymphoma that arises in patients with chronic lymphocytic leukemia, and it generally has a poor response to standard treatments, highlighting the need for new therapeutic strategies.

Recent advancements in targeted therapies, such as CAR T-cell therapy and Bruton tyrosine kinase inhibitors, show promise for improving outcomes in RT patients, but further large-scale clinical trials are necessary to establish their safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emerging Therapies for the Management of Richter Transformation. Smyth, E., Eyre, TA., Cheah, CY.[2023]

References

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

Treatment of Richter's syndrome. [2023]

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

Tislelizumab plus zanubrutinib for Richter transformation: the phase 2 RT1 trial. [2023]

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

An update for Richter syndrome - new directions and developments. [2022]

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

Richter's syndrome: biology and therapy. [2019]

5. France pubmed.ncbi.nlm.nih.gov

[Richter Syndrome: Diagnostic and Therapeutic Management]. [2021]

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

Phase 2 results of lisocabtagene maraleucel in Japanese patients with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. [2021]

8. Saudi Arabia pubmed.ncbi.nlm.nih.gov

Lisocabtagene Maraleucel in Relapsed or Refractory Diffuse Large B Cell Lymphoma: What is the Evidence? [2023]

9. England pubmed.ncbi.nlm.nih.gov

Lisocabtagene Maraleucel for the treatment of B-cell lymphoma. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Lisocabtagene maraleucel as second-line therapy in adults with relapsed or refractory large B-cell lymphoma who were not intended for haematopoietic stem cell transplantation (PILOT): an open-label, phase 2 study. [2022]

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

Fractionated cyclophosphamide, vincristine, liposomal daunorubicin, and dexamethasone plus rituximab and granulocyte-macrophage-colony stimulating factor (GM-CSF) alternating with methotrexate and cytarabine plus rituximab and GM-CSF in patients with Richter syndrome or fludarabine-refractory chronic lymphocytic leukemia. [2015]

12. Switzerland pubmed.ncbi.nlm.nih.gov

Zanubrutinib for the treatment of lymphoid malignancies: Current status and future directions. [2023]

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

Emerging Therapies for the Management of Richter Transformation. [2023]