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

Recruiting at 2 trial locations

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two treatments, zanubrutinib and liso-cel, for Richter's syndrome, a condition where a type of leukemia transforms into a more aggressive lymphoma. Zanubrutinib blocks proteins that promote cancer cell growth, while liso-cel (lisocabtagene maraleucel) is a CAR T-cell therapy that modifies a patient's immune cells to attack cancer. The researchers aim to determine if these treatments together can more effectively combat the cancer. Individuals with chronic lymphocytic leukemia or small lymphocytic leukemia that has progressed to aggressive lymphoma, and who have experienced treatment setbacks, might be suitable candidates for this trial. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

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.

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

Research has shown that both zanubrutinib and lisocabtagene maraleucel (liso-cel) have been tested for safety in treating conditions like Richter's syndrome.

For zanubrutinib, studies found that common side effects include a drop in neutrophil count, affecting more than half of the patients. Neutrophils, a type of white blood cell, help fight infections. Other frequent side effects include low platelet counts and upper respiratory infections. Despite these side effects, the treatment is generally considered manageable.

Regarding lisocabtagene maraleucel, research indicates it is generally safe, with a low chance of severe side effects like cytokine release syndrome (CRS) and neurotoxicity. CRS can cause fever and tiredness, while neurotoxicity can lead to confusion or trouble speaking. These side effects are usually mild and manageable with medical care.

Both treatments have shown promise in studies, suggesting they might be well-tolerated for patients with Richter's syndrome. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for Richter's Syndrome, which typically involve chemotherapy and immunotherapy, zanubrutinib combined with CAR T-cell therapy offers a novel approach. Zanubrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor, which helps to block signals that encourage cancer cells to grow. This is paired with lisocabtagene maraleucel, a form of CAR T-cell therapy, that uses genetically modified T-cells to directly target and kill cancerous cells. This combination is exciting because it not only offers a targeted approach but also has the potential to be more effective against cancer cells while reducing harm to normal cells.

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

Research has shown promising results for the treatment combination in this trial. Zanubrutinib, when paired with another drug, achieved a 58.3% success rate in treating Richter's transformation. Many patients also maintained or improved their condition using zanubrutinib alone. Lisocabtagene maraleucel (liso-cel) has proven effective as well, with a 76% success rate in real-world settings. In some studies, the success rate reached 83.3%. These findings suggest that combining zanubrutinib and lisocabtagene maraleucel could effectively manage Richter's syndrome. ^{2 3 4 6 7}

Who Is on the Research Team?

Jennifer A Woyach, MD

Principal Investigator

Ohio State University Comprehensive Cancer Center

Are You a Good Fit for This Trial?

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 still have side effects from my previous cancer treatment.

Timeline for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

BeOne Medicines

Industry Sponsor

Published Research Related to This Trial

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 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]

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]

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]

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 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 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 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]

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]

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]

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]

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]

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]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.7010

Real-world outcomes of lisocabtagene maraleucel (liso-cel ... Median time from leukapheresis to liso-cel infusion was 35 d (range, 28–63). At median follow-up of 12.3 mo, ORR was 76% among evaluable pts (n ...

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2152265024012680

CLL-189 Real-World Outcomes of Lisocabtagene ... Median time to first response was 1.1 months (range, 0-3.1). Median DOR was not reached (NR); 12-month DOR was 77% (95% CI, 49.5-91). Median PFS (n=29) and ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40066130

Lisocabtagene Maraleucel for Richter's Transformation-A ... Results: The best overall response was 83.3%. The four patients who received ibrutinib concurrent with liso-cel therapy continue to show MRD- ...

4. onclive.com onclive.com/view/dr-winter-on-real-world-outcomes-with-liso-cel-in-richter-transformation

Dr Winter on Real-World Outcomes With Liso-Cel in ... At a median follow-up of 12.3 months (95% CI, 6.1-12.5), liso-cel elicited an overall response rate of 76% (n = 22; 95% CI, 56.5%-89.7%), ...

5. bloodcancerstoday.com bloodcancerstoday.com/post/liso-cel-safe-effective-in-patients-with-richter-transformation

Liso-Cel Safe, Effective in Patients With Richter ... Regarding survival outcomes, the median PFS and OS were not reached. The 12-month PFS was 54% (95% CI, 33–72), and the 12-month OS was 67% (95% ...

6. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2666636725003574

Effectiveness and Safety Outcomes of Standard of Care ... Safety remained predictable with low gr ≥ 3 CRS and ICANS rates, consistent with clinical study and real-world reports. These results continue to support the ...

7. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK602637/

Clinical Review - Lisocabtagene Maraleucel (Breyanzi) - NCBI Outcomes are worse in patients with chemotherapy-refractory disease, with only 7% achieving a complete response (CR) to standard treatment and overall survival ...