Zanubrutinib + CAR T-Cell Therapy for Richter's Syndrome
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Aseel Alsouqi
Must not be taking: CYP3A inhibitors, Warfarin
Disqualifiers: HIV, Hepatitis B/C, Cardiovascular disease, others
No Placebo Group
Prior Safety Data
Breakthrough Therapy
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.
12345Is 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.
678910What 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.
12111213Eligibility 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.
+8 more
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.
+12 more
Trial 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)
Participant Groups
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.
1Treatment groups
Experimental Treatment
Group I: Treatment (zanubrutinib, liso-cel)Experimental Treatment10 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Ohio State University Comprehensive Cancer CenterColumbus, OH
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Who Is Running the Clinical Trial?
Aseel AlsouqiLead Sponsor
Adam KittaiLead Sponsor
BeiGene USA, Inc.Industry Sponsor
References
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.
Tislelizumab plus zanubrutinib for Richter transformation: the phase 2 RT1 trial. [2023]In patients with chronic lymphocytic leukemia, Richter transformation (RT) reflects the development of an aggressive lymphoma that is associated with poor response to chemotherapy and short survival. We initiated an international, investigator-initiated, prospective, open-label phase 2 study in which patients with RT received a combination of the PD-1 inhibitor tislelizumab plus the BTK inhibitor zanubrutinib for 12 cycles. Patients responding to treatment underwent maintenance treatment with both agents. The primary end point was overall response rate after six cycles. Of 59 enrolled patients, 48 patients received at least two cycles of treatment and comprised the analysis population according to the study protocol. The median observation time was 13.9 months, the median age was 67 (range 45-82) years. Ten patients (20.8%) had received previous RT-directed therapy. In total, 28 out of 48 patients responded to induction therapy with an overall response rate of 58.3% (95% confidence interval (CI) 43.2-72.4), including 9 (18.8%) complete reponse and 19 (39.6%) partial response, meeting the study's primary end point by rejecting the predefined null hypothesis of 40% (P = 0.008). Secondary end points included duration of response, progression-free survival and overall survival. The median duration of response was not reached, the median progression-free survival was 10.0 months (95% CI 3.8-16.3). Median overall survival was not reached with a 12-month overall survival rate of 74.7% (95% CI 58.4-91.0). The most common adverse events were infections (18.0%), gastrointestinal disorders (13.0%) and hematological toxicities (11.4%). These data suggest that combined checkpoint and BTK inhibition by tislelizumab plus zanubrutinib is an effective and well-tolerated treatment strategy for patients with RT. ClinicalTrials.gov Identifier: NCT04271956 .
An update for Richter syndrome - new directions and developments. [2022]High-grade transformation of chronic lymphocytic leukaemia [Richter syndrome (RS)] is rare and represents a unique and uncommon clinical challenge. Clonally related diffuse large B cell type RS is a chemotherapy-resistant and devastating disease. Patients are typically elderly, immunosuppressed and present with a rapidly deteriorating performance status. Historical outcomes suggest a median overall survival of approximately 8 months. RS remains is an area of high unmet clinical need. The molecular profile and treatment needs of patients are likely to change over time with the advent of novel B cell receptor inhibitors, monoclonal antibodies and BH3 mimetics. Herein, we summarise what is known regarding the molecular drivers of RS and the existing clinical trial data, including the recently published CHOP-OR (cyclophosphamide, doxorubicin, vincristine, prednisolone and ofatumumab followed by ofatumumab maintenance in newly diagnosed RS) trial. We discuss novel agents in development with a focus on the second-generation Bruton tyrosine kinase inhibitor acalabrutinib, checkpoint inhibition and the potential role of precision medicine in future trials of RS.
Richter's syndrome: biology and therapy. [2019]Richter's syndrome, that is, transformation of chronic lymphocytic leukemia to a large cell or immunoblastic lymphoma, occurs in up to 10% of patients with chronic lymphocytic leukemia. The onset of Richter's syndrome is characterized by worsening systemic symptoms, rapid tumor growth, and/or extranodal involvement. Median survival with conventional chemotherapy is less than 6 months. Therapy with more recent therapeutic regimens, such as hyperCVXD (fractionated cyclophosphamide, vincristine, liposomal daunorubicin, and dexamethasone), augmented hyperCVXD, and yttrium-90 ibritumomab tiuxetan, has not produced major improvements in response rates or overall survival. Improvement in the outcome of patients with Richter's syndrome may be aided by a more comprehensive understanding of the pathogenesis of Richter's syndrome; therapy could then be targeted against specific abnormalities. Current data indicate that the transformation of chronic lymphocytic leukemia to a large-cell or immunoblastic lymphoma is associated with abnormalities in cell cycle regulation (e.g., loss of the cell cycle inhibitors p16(INK4a) and p27(KIP1) ) and DNA repair (e.g., mutations and/or deletions of the p53, ATM, and p14(ARF) genes and epigenetic silencing of the MLH1 gene). However, the critical event leading to transformation is unclear. Given the poor prognosis of patients with Richter's syndrome, every effort should be made to enroll these patients into clinical trials evaluating novel agents with the appropriate correlative studies.
[Richter Syndrome: Diagnostic and Therapeutic Management]. [2021]Richter syndrome (RS) is defined as the occurrence of an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL) and rarely Hodgkin lymphoma (HL), in a patient with prior or concomitant chronic lymphocytic leukemia (CLL). RS is estimated to occur in 0.5-1 % per year and is associated with adverse outcome. In the vast majority of patients (80 %), RS is clonally related to the prior CLL. Those with unrelated RS appear to have better outcome. The therapeutic approach is based on those of de novo DLBCL or HL. However, even with modern immunochemotherapy regimens, response rate remains low. In eligible patients with related RS, a consolidation by autologous or allogeneic stem-cell transplantation must be proposed. Combinations including therapies targeting BCR or BCL2 and effective in CLL are currently being evaluated in RS. Novels immunotherapies could be promising approaches based on preliminary results.
Phase 2 results of lisocabtagene maraleucel in Japanese patients with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma. [2023]The autologous anti-CD19 chimeric antigen receptor (CAR) T-cell product, lisocabtagene maraleucel (liso-cel), is administered at equal target doses of CD8+ and CD4+ CAR+ T cells. This analysis assessed safety and efficacy of liso-cel in Japanese patients with relapsed or refractory (R/R) aggressive large B-cell lymphoma (LBCL) in Cohort 3 of TRANSCEND WORLD (NCT03484702). Liso-cel (100 × 106 total CAR+ T cells) was administered 2-7 days after lymphodepletion. The primary efficacy endpoint was objective response rate (ORR; Lugano 2014 criteria) assessed by an independent review committee. Fourteen patients were enrolled; 10 received liso-cel infusion (median time to liso-cel availability, 23 days) and were evaluable at data cutoff (median follow-up, 12.5 months). Grade ≥ 3 treatment-emergent adverse events were neutropenia (90%), leukopenia (80%), anemia (70%), and thrombocytopenia (70%). All-grade cytokine release syndrome (CRS) was observed in 50% of patients, though no grade ≥3 CRS events were reported. Grade 1 neurological events occurred in 1 patient but were resolved without any intervention. Prolonged cytopenia (grade ≥ 3 at day 29) was reported for 60% of patients. The ORR was 70%, and complete response rate was 50%. The median duration of response was 9.1 months (95% confidence interval [CI], 2.1-not reached), and overall survival was 14.7 months (95% CI, 1.7-not reached). One patient diagnosed with central nervous system involvement after screening but before liso-cel infusion, responded to liso-cel. Liso-cel demonstrated meaningful efficacy and a manageable safety profile in Japanese patients with R/R LBCL.
Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. [2021]Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, chimeric antigen receptor (CAR) T-cell product. We aimed to assess the activity and safety of liso-cel in patients with relapsed or refractory large B-cell lymphomas.
Lisocabtagene Maraleucel in Relapsed or Refractory Diffuse Large B Cell Lymphoma: What is the Evidence? [2023]Lisocabtagene maraleucel (liso-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T cell product, with a CD3ζ activatory domain connected to 4-1BB costimulatory domain. Liso-cel, unlike the other two approved products-axicabtagene ciloleucel and tisagenlecleucel-is manufactured separately from CD4 and CD8 T cells and then administered as a sequential infusion of the two components at equal target doses. The approval of liso-cel was based on the results of Transcend NHL 001, a single-arm, open-label, multicenter, seamless design trial that enrolled 344 patients, of whom 269 received conforming liso-cel. The most common histology was diffuse large B cell lymphoma, not otherwise specified (DLBCL NOS; n = 137, 51%) followed by DLBCL transformed from indolent lymphomas (n = 78, 29%). Encouraging results were reported, yielding an objective response rate across all dose levels of 73% [complete remission (CR) = 53%], with an estimated duration of response at 1 year of 55% for all patients and 65% for those achieving a CR. The estimated 12-month overall survival was 58% for all patients and 86% for those achieving a CR. Cytokine release syndrome and neurological adverse events were reported in 42% and 30%, respectively. This review summarizes the evidence on the safety and effectiveness of liso-cel, resulting in its addition to the current treatment armamentarium of relapsed or refractory large B cell lymphoma.
Lisocabtagene Maraleucel for the treatment of B-cell lymphoma. [2022]Introduction: Lisocabtagene Maraleucel (Liso-cel) is a second-generation Chimeric Antigen Receptor T-cell (CAR-T) therapy product targeting CD19. It is currently being evaluated for B-cell lymphomas with pivotal trials conducted in Aggressive B-cell LymphomasAreas covered: To prepare this article reviewing preclinical and clinical data studying Liso-cel, we performed a Pubmed search using the terms 'JCAR017' and 'Lisocabtagene maraleucel'. Pre-clinical work done with Liso-cel demonstrate the synergistic activity of CD4 + T-cells and CD8+ central memory T-cells (TCM) at a predefined ratio of 1:1. The trial, TRANSCEND NHL001 in aggressive B-cell lymphoma, confirms robust antitumor activity while demonstrating manageable toxicity profile.Expert Opinion: There are inherent differences amongst the three CD19 directed CAR-T products. This could explain the differences in efficacy and safety profiles of the products. In the absence of randomized data, it would be scientifically unsound to prioritize one product over another. Nevertheless, when aiming to balance efficacy and safety, current prospective data indicate that Liso-cel is well positioned with impressive response rates.
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]Patients with relapsed or refractory large B-cell lymphoma after first-line treatment who are not intended for haematopoietic stem-cell transplantation (HSCT) have poor outcomes and limited treatment options. We assessed the antitumour activity and safety of lisocabtagene maraleucel, an autologous, CD19-directed chimeric antigen receptor (CAR) T-cell product, as second-line treatment in adults with relapsed or refractory large B-cell lymphoma not intended for HSCT.
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]Therapy for patients with Richter syndrome (RS) or fludarabine-refractory chronic lymphocytic leukemia (CLL) is unsatisfactory. A Phase II study was conducted to evaluate an alternating combination cytotoxic regimen given with rituximab and granulocyte-macrophage-colony stimulating factor (GM-CSF) in these patients.
Zanubrutinib for the treatment of lymphoid malignancies: Current status and future directions. [2023]Zanubrutinib (BGB-3111, Brukinsa®, BeiGene) is a next-generation irreversible inhibitor of Bruton's tyrosine kinase (BTK), developed by BeiGene in 2012 for the treatment of B-cell malignancies. It was designed to minimize off-target inhibition of TEC- and EGFR-family kinases. Zanubrutinib is more selective than ibrutinib for BTK versus EGFR, FGR, FRK, HER2, HER4, ITK, JAK3, LCK, BLK and TEC. In addition, compared to ibrutinib, zanubrutinib has improved oral absorption and better target occupancy. Zanubrutinib demonstrated a lower incidence of off-target toxicities and reduced severity than ibrutinib. Moreover, zanubrutinib is similar to acalabrutinib, with less activity against TEC and ITK. The preliminary phase 1 results suggest that zanubrutinib has clinical activity and the drug is well tolerated in patients with B-cell lymphoid malignancies. Recent clinical trials have found it to demonstrate excellent efficacy and good tolerability in patients with chronic lymphocytic leukemia (CLL), Waldenstrom macroglobulinemia (WM) and mantle cell lymphoma (MCL). In recent phase 3 studies, zanubrutinib was compared with ibrutinib in patients with relapsed/refractory (R/R) MW and RR CLL. In both trials, zanubrutinib was found to demonstrate clinically meaningful advantages in safety and tolerability over ibrutinib; in particular, it was associated with a lower risk of atrial fibrillation/flutter and major bleeding events. In the recent SEQUOIA study, comparing zanubrutinib with bendamustine and rituximab (BR) in patients with previously untreated CLL, zanubrutinib significantly improved progression-free survival versus BR, with an acceptable safety profile consistent with previous studies. Zanubrutinib also demonstrated good activity and tolerability in patients with R/R MCL, marginal zone lymphoma and follicular lymphoma. Trials examining the efficacy and safety of the combination of zanubrutinib with obinutuzumab venetoclax and other drugs are ongoing. This review summarizes the clinical efficacy and safety of zanubrutinib in lymphoid malignancies.
Emerging Therapies for the Management of Richter Transformation. [2023]Richter transformation (RT) refers to the development of an aggressive lymphoma in patients with underlying chronic lymphocytic leukemia/small lymphocytic lymphoma. Aside from a small subgroup of patients with clonally unrelated and previously untreated chronic lymphocytic leukemia, the disease responds poorly to standard therapies and prognosis is dismal. Recent developments in the understanding of the biology of RT and the advent of several targeted agents may result in improved outcomes for these patients. The purpose of this review is to analyze recent data on the pathogenesis and treatment of RT. We reviewed studies addressing the pathophysiology of RT and analyzed the data for frontline chemoimmunotherapy and emerging targeted therapies likely to play a significant role in the future management of RT. Several biologic and clinical factors may help identify those who are unlikely to respond to conventional chemoimmunotherapy; where possible, these patients should be managed with a novel approach. Emerging therapies for the management of RT include chimeric antigen receptor T-cell therapy, noncovalent Bruton tyrosine kinase inhibitors, and T-cell-engaging bispecific antibodies. The use of less toxic and more effective targeted therapies may result in improved outcomes. Larger, prospective clinical trials are required to confirm efficacy and safety of novel agents for the management of RT, particularly when used in combination with other targeted therapies and in addition to chemoimmunotherapy regimens.