Liso-cel + Nivolumab + Ibrutinib for Richter Syndrome
Recruiting in Palo Alto (17 mi)
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.
12345Is 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.
56789What 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.
12345Eligibility 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
+21 more
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.
+20 more
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
Participant Groups
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.
1Treatment groups
Experimental Treatment
Group I: Treatment (nivolumab, ibrutinib, chemotherapy, liso-cel)Experimental Treatment11 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
City of Hope Medical CenterDuarte, CA
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Who Is Running the Clinical Trial?
City of Hope Medical CenterLead Sponsor
National Cancer Institute (NCI)Collaborator
References
Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL. [2022]Chronic lymphocytic leukemia (CLL) patients progressed early on ibrutinib often develop Richter transformation (RT) with a short survival of about 4 months. Preclinical studies suggest that programmed death 1 (PD-1) pathway is critical to inhibit immune surveillance in CLL. This phase 2 study was designed to test the efficacy and safety of pembrolizumab, a humanized PD-1-blocking antibody, at a dose of 200 mg every 3 weeks in relapsed and transformed CLL. Twenty-five patients including 16 relapsed CLL and 9 RT (all proven diffuse large cell lymphoma) patients were enrolled, and 60% received prior ibrutinib. Objective responses were observed in 4 out of 9 RT patients (44%) and in 0 out of 16 CLL patients (0%). All responses were observed in RT patients who had progression after prior therapy with ibrutinib. After a median follow-up time of 11 months, the median overall survival in the RT cohort was 10.7 months, but was not reached in RT patients who progressed after prior ibrutinib. Treatment-related grade 3 or above adverse events were reported in 15 (60%) patients and were manageable. Analyses of pretreatment tumor specimens from available patients revealed increased expression of PD-ligand 1 (PD-L1) and a trend of increased expression in PD-1 in the tumor microenvironment in patients who had confirmed responses. Overall, pembrolizumab exhibited selective efficacy in CLL patients with RT. The results of this study are the first to demonstrate the benefit of PD-1 blockade in CLL patients with RT, and could change the landscape of therapy for RT patients if further validated. This trial was registered at www.clinicaltrials.gov as #NCT02332980.
Treatment of Richter's syndrome. [2023]Richter's syndrome (RS) is an aggressive histologic transformation of chronic lymphocytic leukemia (CLL), most commonly to diffuse large B-cell lymphoma (DLBCL). Outcomes are generally poor, with complete remission (CR) rates of only about 20% and less than 20% long-term survival with chemoimmunotherapy (CIT). RS is biologically heterogeneous, and in 80% of patients with CLL who develop DLBCL, the disease is clonally related to the CLL. Clonally unrelated cases are genetically and immunologically distinct from clonally related DLBCL-RS, have more favorable responses to CIT, and are best treated as de novo DLBCL. Relatively favorable outcomes with CIT are also seen in patients who have never previously received treatment for CLL and who lack TP53 mutation or deletion. For the remaining patients, treatment on a clinical trial is optimal. Fortunately, numerous agents are now in clinical development that show encouraging results. Here we review clinical data for some of the most promising approaches. DLBCL-RS tumor cells frequently express programmed cell death 1 protein (PD-1), and several studies have demonstrated activity for PD-1 inhibitors, especially in combination with ibrutinib. The BCL2 inhibitor venetoclax in combination with R-EPOCH CIT achieved CR in 50% of patients, and a study of venetoclax-R-CHOP is ongoing. The noncovalent Bruton's tyrosine kinase inhibitor pirtobrutinib has achieved responses in approximately two-thirds of heavily pretreated patients and, given its favorable toxicity profile, appears ideally suited to combining with other active agents. Finally, we review available data for bispecific antibodies, antibody-drug conjugates, and chimeric antigen receptor T-cell therapy, which, after revolutionizing the treatment of DLBCL, are now being evaluated in RS.
A phase 2 study of nivolumab combined with ibrutinib in patients with diffuse large B-cell Richter transformation of CLL. [2023]Richter transformation (RT) is a rare complication of chronic lymphocytic leukemia (CLL) that has dismal outcomes. Upregulation of PD-1/PD-L1 drives immunological evasion in patients with RT. We hypothesized that combining nivolumab, a PD-1 blocking antibody, with the BTK inhibitor (BTKi) ibrutinib could potentiate tumor-cell killing. We conducted an investigator-initiated phase 2 clinical trial to assess the efficacy of combined nivolumab and ibrutinib in patients with diffuse large B-cell lymphoma (DLBCL) RT and CLL. Patients included were ≥18 years of age with adequate hepatic and renal function. Patients received nivolumab every 2 weeks of a 4-week cycle for a maximum of 24 cycles. A standard dose ibrutinib was initiated from cycle 2 onward and continued daily until progression. For patients who were already on ibrutinib at the time of study entry, the same was continued while nivolumab was initiated. A total of 24 patients with RT with a median age of 64.5 years (range, 47-88) were enrolled. Ten patients (42%) had received prior treatment for RT and 13 patients (54%) had received a prior BTKi. A total of 10 patients (42%) responded with a median duration of response of 15 months. The median overall survival was 13 months. Four of 24 (17%) patients had checkpoint inhibition-related immunological toxicities. In the CLL cohort, 10 patients were enrolled, of whom 3 patients converted from partial to complete remission; 1 patient had a grade 2 immunological toxicity. Combined nivolumab and ibrutinib is an active regimen for patients with DLBCL RT with an overall response rate of 42%. Given the limited treatment options for patients with RT, checkpoint inhibition provides a potential therapeutic option. This trial is registered at www.clinicaltrials.gov as #NCT02420912.
Ibrutinib treatment of a patient with relapsing chronic lymphocytic leukemia and sustained remission of Richter syndrome. [2021]Richter syndrome (RS) is a rare event in chronic lymphocytic leukemia (CLL) that is influenced by biological factors and prior CLL treatments. Ibrutinib is a Bruton tyrosine kinase inhibitor that has shown remarkable efficacy in CLL; however, little is known about its relationship to RS. We report a case of ibrutinib efficacy against CLL in a patient with prolonged remission of RS.
Ibrutinib and rituximab induced rapid response in refractory Richter syndrome. [2020]We report a 53-year-old man diagnosed with Richter syndrome. He was heavily pretreated and was refractory to prior therapy. He received rituximab and ibrutinib, and achieved a significant response after 1 month of therapy. Our case illustrates the importance of investigation of rituximab and ibrutinib in Richter's syndrome.
Ibrutinib: a review of its use in patients with mantle cell lymphoma or chronic lymphocytic leukaemia. [2022]Ibrutinib (Imbruvica®) is a first-in-class, potent, orally administered, covalent inhibitor of Bruton's tyrosine kinase (BTK) that inhibits B-cell antigen receptor signalling downstream of BTK. Oral ibrutinib is indicated for the treatment of patients with relapsed/refractory mantle cell lymphoma (MCL) or chronic lymphocytic leukaemia (CLL) and for the treatment of patients with CLL and a chromosome 17 deletion (del 17p) or TP53 mutation. This article summarizes pharmacological, efficacy and tolerability data relevant to the use of ibrutinib in these indications. In clinical studies, ibrutinib induced a high overall response rate in patients with relapsed/refractory MCL (phase II study). In addition, ibrutinib significantly prolonged progression-free survival and significantly improved the partial response rate and overall survival in patients with relapsed/refractory CLL (RESONATE study), including in those with del 17p, a subgroup with a poor prognosis. Ibrutinib had an acceptable tolerability profile in these studies with
[Ibrutinib: A new drug of B-cell malignancies]. [2021]Ibrutinib (Imbruvica®) is a first-in-class, orally administered once-daily, that inhibits B-cell antigen receptor signaling downstream of Bruton's tyrosine kinase (BTK). Ibrutinib has been approved in USA in February 2014 and in France in October 2014 for the treatment of patients with relapsed/refractory mantle cell lymphoma (MCL) or chronic lymphocytic leukaemia (CLL) and for the treatment of patients with CLL and a chromosome 17 deletion (del 17p) or TP53 mutation. In clinical studies, ibrutinib induced an impressive overall response rate (68%) in patients with relapsed/refractory MCL (phase II study). In CLL, ibrutinib has shown to significantly improve progression-free survival, response rate and overall survival in patients with relapsed/refractory CLL, including in those with del 17p. Ibrutinib had an acceptable tolerability profile. Less than 10% of patients discontinued their treatment because of adverse events. Results are pending in other B-cell lymphomas subtypes such as in diffuse large B-cell lymphoma and in follicular lymphoma. An approval extension has already been enregistered for Waldenström disease in USA in January 2015. Given its efficacy and tolerability, ibrutinib is an emerging treatment option for patients with B-cell malignancies.
Antitumor Potency of an Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy, Lisocabtagene Maraleucel in Combination With Ibrutinib or Acalabrutinib. [2022]Chimeric antigen receptor (CAR) T-cell therapy is a promising treatment for patients with CD19 B-cell malignancies. Combination strategies that improve CAR T-cell potency, limit tumor environment-mediated immune dysfunction, and directly reduce tumor burden may increase the potential for durable clinical benefit of CAR T-cell therapy. Lisocabtagene maraleucel (liso-cel) is a product therapy candidate being tested in patients with relapsed/refractory non-Hodgkin lymphoma or chronic lymphocytic leukemia. This study assessed the in vitro and in vivo functionality of CAR T cells transduced to express the anti-CD19 CAR of liso-cel in combination with ibrutinib or acalabrutinib. In prolonged stimulation assays, the presence of ibrutinib or acalabrutinib improved the CAR T-cell effector function. RNA-Seq analysis and surface marker profiling of these CAR T cells treated with ibrutinib but not acalabrutinib revealed gene expression changes consistent with skewing toward a memory-like, type 1 T-helper, Bruton tyrosine kinase phenotype. Ibrutinib or acalabrutinib improved CD19 tumor clearance and prolonged survival of tumor-bearing mice when used in combination with CAR T cells. A combination of the defined cell product therapy candidate, liso-cel, with ibrutinib or acalabrutinib is an attractive approach that may potentiate the promising clinical responses already achieved in CD19 B-cell malignancies with each of these single agents.
Ibrutinib: first global approval. [2022]Ibrutinib (Imbruvica™) is a small molecule, first-in-class, once-daily, orally available, Bruton's tyrosine kinase inhibitor that is under development for the treatment of B cell malignancies, including chronic lymphocytic leukaemia (CLL), mantle cell lymphoma (MCL) and diffuse large B cell lymphoma (DLBCL), as well as multiple myeloma (MM), follicular lymphoma (FL) and Waldenstrom's macroglobulinemia (WM). It has been developed by Pharmacyclics, Inc. and Janssen Biotech, Inc. Ibrutinib acts by blocking B-cell antigen receptor signalling, thereby reducing malignant proliferation of B cells and inducing cell death. Based chiefly on findings from a phase Ib/II study, ibrutinib has been approved in the USA for the treatment of MCL in previously treated patients and is one of the first approvals through the US FDA's Breakthrough Therapy Designation Pathway. An application has been filed in the EU seeking regulatory approval in this indication. In both the USA and EU, further applications have been filed with regulatory bodies seeking approval for the use of ibrutinib in patients with previously treated CLL/small lymphocytic lymphoma (SLL). Phase III trials are underway worldwide to evaluate ibrutinib in the treatment of patients with CLL/SLL, DLBCL and MCL, and the agent is in phase II development for use in WM, FL and MM. This article summarizes the milestones in the development of ibrutinib leading to its first approval in MCL.