Liso-cel + Nivolumab + Ibrutinib for Richter Syndrome

Recruiting at 1 trial location

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: City of Hope Medical Center

Must not be taking: Strong CYP3A inducers, Warfarin

Disqualifiers: PD1/PD-L1 therapy, Active infection, 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

Duration: Up to 3 cycles

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate the effectiveness of a new combination of treatments for Richter's transformation, a cancer that develops from chronic lymphocytic leukemia or small lymphocytic lymphoma. The treatment includes liso-cel, a CD19-directed chimeric antigen receptor T cell therapy that uses a person's own immune cells to fight cancer, along with nivolumab and ibrutinib, which help the immune system attack cancer cells. Individuals who have tried at least two different treatments for Richter's transformation without success might be suitable candidates for this trial. As a Phase 2 trial, the 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 stopping certain medications before starting. You must stop chemotherapy, radiation therapy, immunotherapy, strong CYP3A inducers, and warfarin within specific timeframes before the trial begins. Check with the study team about your specific medications.

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

Research has shown that lisocabtagene maraleucel (liso-cel) is generally well-tolerated. Studies have found low rates of severe cytokine release syndrome, where the immune system overreacts, and neurological issues. Patients with Richter's transformation who received liso-cel responded well, with many maintaining positive outcomes over time.

Nivolumab, when combined with other treatments, has manageable side effects. Patients might experience some side effects, but they are usually expected and can be effectively handled.

Ibrutinib has been studied for similar conditions. Some patients experienced side effects, but serious ones were uncommon, and most patients handled the treatment well.

Overall, these treatments have demonstrated a promising safety profile. They are generally well-received by patients, with manageable side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of liso-cel, nivolumab, and ibrutinib for treating Richter Syndrome because it targets the disease in innovative ways. Unlike standard treatments that typically involve chemotherapy and immunotherapy separately, this combination uses liso-cel, a CAR T-cell therapy, to directly target and destroy cancer cells. Nivolumab, an immune checkpoint inhibitor, boosts the body’s immune response against cancer, and ibrutinib, a BTK inhibitor, disrupts cancer cell survival pathways. Together, these treatments offer a multi-pronged attack on the disease, potentially improving effectiveness and outcomes for patients who have limited options with existing therapies.

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

This trial will evaluate the combination of lisocabtagene maraleucel (liso-cel), nivolumab, and ibrutinib for treating Richter's transformation. Research has shown that liso-cel is promising, helping 76% to 83.3% of patients by shrinking or eliminating their cancer. Studies suggest that combining nivolumab with ibrutinib results in a response rate of 42%, indicating this combination may work better than using either drug alone. Ibrutinib alone has a response rate of 71%, demonstrating its effectiveness for this condition. These treatments aim to boost the immune system to fight cancer and prevent its spread, offering hope for patients with Richter's transformation. ^{2 4 6 7 8}

Who Is on the Research Team?

Tanya Siddiqi, MD

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

Adults (18+) with Richter's Transformation who've had at least two prior systemic therapies or relapsed within a year of first-line chemoimmunotherapy. They must have adequate organ function, not require oxygen supplementation, and agree to use effective birth control. Excluded are those with HIV, active hepatitis B/C, recent heart issues, autoimmune diseases (except mild conditions like controlled asthma), recent stem cell transplants, or on certain medications.

Inclusion Criteria

Documented informed consent of the participant

Agreement for confirmatory pre-treatment tumor biopsy

I am a woman who can have children and my pregnancy test is negative.

Exclusion Criteria

I had a stem cell transplant 3 months ago and don't have GVHD or need for immunosuppressants.

I have not taken Warfarin in the 5 days before starting the treatment.

I haven't had chemotherapy, radiation, or immunotherapy in the last 14 days.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ibrutinib orally, nivolumab intravenously, fludarabine IV, cyclophosphamide IV, and lisocabtagene maraleucel IV. They also undergo apheresis, PET/CT, biospecimen collection, and bone marrow biopsy.

Up to 3 cycles

Multiple visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of complete response and toxicity.

Up to 2 years

Regular follow-up visits for monitoring

Open-label extension (optional)

Participants may opt into continuation of treatment long-term

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• Ibrutinib
• Lisocabtagene Maraleucel
• Nivolumab

Trial Overview The trial is testing the combination of lisocabtagene maraleucel (liso-cel), nivolumab, and ibrutinib for treating Richter's transformation. Liso-cel uses the patient's own immune cells to fight cancer; nivolumab helps slow cancer growth by aiding the immune system; and ibrutinib blocks proteins that tell cancer cells to multiply.

How Is the Trial Designed?

Group I: Treatment (nivolumab, ibrutinib, chemotherapy, liso-cel) Experimental Treatment 11 Interventions

Patients receive ibrutinib PO, nivolumab IV, fludarabine IV, cyclophosphamide IV, and liso-cel IV on study. Patients also undergo apheresis, PET/CT, biospecimen collection, and bone marrow biopsy on study. Patients may receive low-moderate intensity chemotherapy in combination with the study induction therapy per treating physician discretion with approval of study principal investigator.

Ibrutinib is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Imbruvica for:

• Chronic lymphocytic leukemia
• Mantle cell lymphoma
• Waldenström's macroglobulinemia
• Marginal zone lymphoma
• Graft-versus-host disease

Approved in United States as Imbruvica for:

• Chronic lymphocytic leukemia/small lymphocytic lymphoma
• Mantle cell lymphoma
• Waldenström's macroglobulinemia
• Marginal zone lymphoma
• Graft-versus-host disease

Approved in Canada as Imbruvica for:

• Chronic lymphocytic leukemia
• Mantle cell lymphoma
• Waldenström's macroglobulinemia
• Marginal zone lymphoma

Approved in Japan as Imbruvica for:

• Chronic lymphocytic leukemia
• Mantle cell lymphoma
• Waldenström's macroglobulinemia

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Ibrutinib, a Bruton tyrosine kinase inhibitor, was effective in treating chronic lymphocytic leukemia (CLL) in a patient who had previously experienced Richter syndrome (RS), leading to significant improvements in blood cell counts and reduction of lymphadenopathy and splenomegaly after 12 months of treatment.

The therapy was well-tolerated with no recurrence of RS, suggesting that ibrutinib may provide a beneficial treatment option for CLL patients at risk of RS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib treatment of a patient with relapsing chronic lymphocytic leukemia and sustained remission of Richter syndrome. Albi, E., Baldoni, S., Aureli, P., et al.[2021]

In a phase 2 study involving 25 patients with relapsed chronic lymphocytic leukemia (CLL) and Richter transformation (RT), pembrolizumab showed a 44% objective response rate in RT patients who had previously progressed on ibrutinib, indicating its potential efficacy in this difficult-to-treat population.

Despite manageable treatment-related adverse events in 60% of patients, the study found that pembrolizumab may improve overall survival in RT patients, with a median survival of 10.7 months, suggesting a promising new therapeutic option for those with RT following ibrutinib treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL. Ding, W., LaPlant, BR., Call, TG., et al.[2022]

Ibrutinib is a first-in-class oral Bruton's tyrosine kinase inhibitor that effectively blocks B-cell signaling, leading to reduced proliferation and increased cell death in B cell malignancies, including chronic lymphocytic leukaemia (CLL) and mantle cell lymphoma (MCL).

It has received FDA approval for treating MCL in previously treated patients based on phase Ib/II study results and is currently undergoing further phase III trials for CLL, diffuse large B cell lymphoma (DLBCL), and other B cell cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib: first global approval. Cameron, F., Sanford, M.[2022]

The study shows that combining CAR T-cell therapy (specifically lisocabtagene maraleucel) with ibrutinib or acalabrutinib enhances the effectiveness of the CAR T-cells in treating CD19 B-cell malignancies, as evidenced by improved tumor clearance and prolonged survival in tumor-bearing mice.

Ibrutinib, in particular, was found to induce beneficial gene expression changes in CAR T-cells, promoting a memory-like T-cell phenotype, which may contribute to more durable responses against tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor Potency of an Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy, Lisocabtagene Maraleucel in Combination With Ibrutinib or Acalabrutinib. Qin, JS., Johnstone, TG., Baturevych, A., et al.[2022]

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]

A 53-year-old man with Richter syndrome, who was heavily pretreated and resistant to previous therapies, showed a significant response to a combination of rituximab and ibrutinib after just one month of treatment.

This case highlights the potential effectiveness of rituximab and ibrutinib as a therapeutic option for patients with Richter syndrome, suggesting further investigation into their use in this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib and rituximab induced rapid response in refractory Richter syndrome. Lamar, Z., Kennedy, L., Kennedy, B., et al.[2020]

In a phase 2 clinical trial involving 24 patients with Richter transformation (RT) of chronic lymphocytic leukemia (CLL), the combination of nivolumab and ibrutinib showed an overall response rate of 42%, with a median duration of response of 15 months, indicating promising efficacy for this difficult-to-treat condition.

The treatment was associated with manageable safety, as only 17% of patients experienced immunological toxicities related to checkpoint inhibition, suggesting that this combination therapy could be a viable option for patients with limited treatment alternatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 2 study of nivolumab combined with ibrutinib in patients with diffuse large B-cell Richter transformation of CLL. Jain, N., Senapati, J., Thakral, B., et al.[2023]

Ibrutinib is a powerful oral medication that effectively treats relapsed/refractory mantle cell lymphoma (MCL) and chronic lymphocytic leukaemia (CLL), showing high response rates and significantly improving survival outcomes, especially in patients with poor prognostic factors like chromosome 17 deletion (del 17p).

The drug has a good safety profile, with less than 10% of patients discontinuing treatment due to side effects, making it a promising option for patients with these types of blood cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib: a review of its use in patients with mantle cell lymphoma or chronic lymphocytic leukaemia. Kim, ES., Dhillon, S.[2022]

Ibrutinib is an effective oral treatment for patients with relapsed/refractory mantle cell lymphoma (MCL) and chronic lymphocytic leukaemia (CLL), showing a 68% overall response rate in MCL and significant improvements in progression-free survival and overall survival in CLL patients, including those with specific genetic mutations.

The drug has a good safety profile, with less than 10% of patients discontinuing treatment due to adverse effects, making it a promising option for patients with various B-cell malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Ibrutinib: A new drug of B-cell malignancies]. Thieblemont, C.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4351511/

The efficacy of ibrutinib in the treatment of Richter syndrome In a pivotal phase 1B/2 study of ibrutinib in 85 pretreated CLL patients, the overall response rate (ORR) was 71%. Despite this remarkable activity, 7 patients ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5498945/

Successful Treatment of Richter Transformation with ... Approximately 2–9% of patients with CLL progress to RT [1, 5, 6, 7, 8]. The transformation rate is 0.5–1% per year [9]. The median time from the diagnosis to RT ...

3. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/4640/503449/A-Prospective-Phase-II-Study-to-Evaluate-the

A Prospective, Phase-II Study to Evaluate the Efficacy and ... In patients with RS triplet treatment with ibrutinib, venetoclax, and obinutuzmab was well tolerated, achieved high rates of early metabolic response (ORR-70% ...

4. nature.com nature.com/articles/s41375-025-02666-8

Richter transformation in diffuse large B-cell lymphoma in ... In a large series of patients with CLL receiving ibrutinib, mainly after prior chemoimmunotherapy, we found a seven-year cumulative incidence of ...

5. ascopubs.org ascopubs.org/doi/10.1200/EDBK_390804

Practical Management of Richter Transformation in 2023 ... The prognosis for RT remains dismal, with retrospective studies consistently reporting a median overall survival (OS) of only 6-12 months.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11720094/

Updates in the Management of Richter Transformation - PMC The median PFS was 10 months, with median OS not reached and a 12-month OS rate of 74.7% (95% CI 58.4–91.0) [48]. Zanubrutinib plus tislelizumab ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11971162/

Final results on effectiveness and safety of Ibrutinib in patients ... A total of 14.6% of the retrospective patients and 22.4% of the prospective patients had an adverse event leading to death. Our findings on ...

8. conference-correspondent.com conference-correspondent.com/highlights/asco/clinical-outcomes-of-patients-with-dlbcl-fl-and-richter-transformation-treated-with-ibrutinib-a-real-world-experience-of-off-label-ibrutinib-use

Clinical Outcomes of Patients with DLBCL, FL, and Richter ... Overall, results in this real-world study were similar to prior clinical trial data. In FL, responses appear to be durable, with median PFS exceeding 10 months.