Liso-cel + Nivolumab + Ibrutinib for Richter Syndrome

Recruiting at 1 trial location

Overseen by Tanya Siddiqi, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

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

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial tests a combination of three treatments for patients with a type of cancer called Richter's transformation. The treatments include a personalized cell therapy, an immune-boosting drug, and a drug that stops cancer cells from growing. The goal is to see if this combination can better fight the cancer. Richter transformation is a condition where chronic lymphocytic leukemia (CLL) transforms into a more aggressive form of lymphoma.

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.

What data supports the effectiveness of the treatment Liso-cel + Nivolumab + Ibrutinib for Richter Syndrome?

Ibrutinib has shown effectiveness in treating Richter Syndrome, with cases reporting significant responses. Additionally, combining nivolumab with ibrutinib has demonstrated a 42% response rate in patients with diffuse large B-cell lymphoma Richter transformation, suggesting potential benefits of this combination in treating Richter Syndrome. ^{1 2 3 4 5}

Is the combination of Liso-cel, Nivolumab, and Ibrutinib safe for humans?

Ibrutinib has been shown to have an acceptable safety profile in patients with certain blood cancers, with less than 10% of patients stopping treatment due to side effects. Lisocabtagene maraleucel (Liso-cel) is being tested in combination with Ibrutinib for blood cancers, and this combination has shown promising results in improving treatment effectiveness, although specific safety data for this combination is not detailed in the available research. ^{5 6 7 8 9}

What makes the treatment with Liso-cel, Nivolumab, and Ibrutinib unique for Richter Syndrome?

This treatment combines a chimeric antigen receptor (CAR) T-cell therapy (Liso-cel) with a PD-1 blocking antibody (Nivolumab) and a Bruton tyrosine kinase inhibitor (Ibrutinib), offering a novel approach by targeting cancer cells through multiple mechanisms, which may enhance effectiveness compared to traditional therapies. ^{1 2 3 4 5}

Research Team

Tanya Siddiqi, MD

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

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

I am 18 years old or older.

Documented informed consent of the participant

Agreement for confirmatory pre-treatment tumor biopsy

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.

Trial Timeline

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

Treatment Details

Interventions

• Ibrutinib (Kinase Inhibitor)
• Lisocabtagene Maraleucel (CAR T-cell Therapy)
• Nivolumab (Monoclonal Antibodies)

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.

Participant Groups

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 Canada, Japan for the following indications:

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+

Findings from Research

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]

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 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, 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]

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]

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]

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]

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]

References

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

Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL. [2022]

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

Treatment of Richter's syndrome. [2023]

3. United States 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. [2023]

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

Ibrutinib treatment of a patient with relapsing chronic lymphocytic leukemia and sustained remission of Richter syndrome. [2021]

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

Ibrutinib and rituximab induced rapid response in refractory Richter syndrome. [2020]

6. New Zealand pubmed.ncbi.nlm.nih.gov

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

7. France pubmed.ncbi.nlm.nih.gov

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

8. United States 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. [2022]

9. New Zealand pubmed.ncbi.nlm.nih.gov

Ibrutinib: first global approval. [2022]