CAR T-Cell Therapy + Ibrutinib for Chronic Lymphocytic Leukemia
Recruiting in Palo Alto (17 mi)
+59 other locations
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Novartis Pharmaceuticals
No Placebo Group
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?This is a phase I/II study to evaluate the feasibility, safety and preliminary antitumor efficacy of rapcabtagene autoleucel (also known as YTB323). Rapcabtagene autoleucel will be investigated in combination with ibrutinib in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and as single agent in diffuse large B-cell lymphoma (3L+ DLBCL), adult acute lymphoblastic leukemia (ALL) and 1st Line High Risk Large B-Cell Lymphoma (1L HR LBCL).
Will I have to stop taking my current medications?
The trial does not specify if you need to stop all current medications, but you must not take targeted small molecule or kinase inhibitors within 2 weeks before a procedure called leukapheresis.
What data supports the effectiveness of the treatment CAR T-Cell Therapy + Ibrutinib for Chronic Lymphocytic Leukemia?
Research shows that using ibrutinib, a drug that helps improve T-cell function, can enhance the production and effectiveness of CAR T-cells in patients with chronic lymphocytic leukemia (CLL). This combination has shown promise in increasing the viability and function of these cells, potentially leading to better treatment outcomes for CLL patients.
12345Is CAR T-Cell Therapy + Ibrutinib safe for humans?
CAR T-cell therapies, like those from Novartis, have been approved for certain blood cancers and are generally considered safe, but they can cause side effects. Common side effects include cytokine release syndrome (a reaction that can cause fever and flu-like symptoms) and neurological effects, which are manageable with medical care.
678910What makes the CAR T-Cell Therapy + Ibrutinib treatment unique for chronic lymphocytic leukemia?
This treatment combines CAR T-cell therapy, which uses modified immune cells to target cancer, with ibrutinib, a drug that inhibits a protein important for cancer cell survival. The combination may enhance the effectiveness of CAR T-cell therapy and reduce severe side effects, offering a novel approach for patients who have not responded to other treatments.
1112131415Eligibility Criteria
This trial is for adults with certain blood cancers like CLL, SLL, DLBCL, and ALL. Participants must be in stable condition or partial remission after previous treatments (like ibrutinib for CLL/SLL), have not had prior CD19-directed therapy or genetically engineered cellular products, and can't have specific types of lymphoma or active CNS involvement.Inclusion Criteria
My IPI score is between 3 and 5.
My cancer has specific genetic changes in MYC, BCL2, or BCL6.
My leukemia has returned or didn't respond to treatment and tests positive for CD19.
My CLL/SLL is stable or improving after 6+ months on ibrutinib.
I have been diagnosed with CLL or SLL.
I am fully active or can carry out light work.
My leukemia is present in my bone marrow.
I have completed 2 cycles of initial treatment for large B-cell lymphoma.
My DLBCL has not improved after at least 2 treatments, including a stem cell transplant.
My diagnosis is diffuse large B-cell lymphoma.
Exclusion Criteria
I have active lymphoma in my brain or spinal cord.
My condition has progressed from CLL to a more aggressive form.
I have had a stem cell transplant from a donor.
My lymphoma is not one of the specific types listed.
My cancer has spread to my brain or spinal cord.
I have received treatment targeting CD19 before.
I have received a genetically engineered cell therapy before.
Participant Groups
The study tests Rapcabtagene autoleucel alone or with Ibrutinib on different blood cancers. It's to see if it's safe and effective. Phase I checks feasibility; phase II assesses how well the treatment works against these cancers.
4Treatment groups
Experimental Treatment
Group I: CLL/SLLExperimental Treatment2 Interventions
Dose escalation and expansion of rapcabtagene autoleucel in combination with ibrutinib
Group II: Adult ALLExperimental Treatment1 Intervention
Dose escalation and expansion of rapcabtagene autoleucel single agent in adult ALL
Group III: 3L+ DLBCLExperimental Treatment1 Intervention
Dose escalation and expansion of rapcabtagene autoleucel single agent in 3L+ DLBCL
Group IV: 1L HR LBCLExperimental Treatment1 Intervention
Rapcabtagene autoleucel single agent in 1L HR LBCL
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
University of Texas MD Anderson Cancer CenterHouston, TX
University Of California Los Angeles UCLA Hematology OncologyLos Angeles, CA
University of Chicago Medical Center Hematology and OncologyChicago, IL
Mass Gen Hosp Cancer Center .Boston, MA
More Trial Locations
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Who is running the clinical trial?
Novartis PharmaceuticalsLead Sponsor
References
Ibrutinib for improved chimeric antigen receptor T-cell production for chronic lymphocytic leukemia patients. [2021]Chimeric antigen receptor T (CART) cells targeting CD19 have shown promising results in the treatment of chronic lymphocytic leukemia (CLL). However, efficacy seems to be inferior compared to diffuse large B-cell lymphoma or acute lymphoblastic leukemia. Impaired T-cell fitness of CLL patients may be involved in treatment failure. Less-differentiated naïve-like T cells play an important role in CART expansion and long-term persistence in vivo. These cells are sparse in CLL patients. Therefore, optimization of CART cell production protocols enriching less differentiated T cell subsets may overcome treatment resistance. The B-cell receptor inhibitor ibrutinib targeting Bruton's tyrosine kinase (BTK) is approved for the treatment of CLL. Besides BTK, ibrutinib additionally inhibits interleukin-2-inducible T-cell kinase (ITK) which is involved in T-cell differentiation. To evaluate the effect of ibrutinib on CART cell production, peripheral blood mononuclear cells from nine healthy donors and eight CLL patients were used to generate CART cells. T-cell expansion and phenotype, expression of homing and exhaustion makers as well as functionality of CART cells were evaluated. CART cell generation in the presence of ibrutinib resulted in increased cell viability and expansion of CLL patient-derived CART cells. Furthermore, ibrutinib enriched CART cells with less-differentiated naïve-like phenotype and decreased expression of exhaustion markers including PD-1, TIM-3 and LAG-3. In addition, ibrutinib increased the cytokine release capacity of CLL patient-derived CART cells. In summary, BTK/ITK inhibition with ibrutinib during CART cell culture can improve yield and function of CLL patient-derived CART cell products.
Long-Term Outcomes From a Randomized Dose Optimization Study of Chimeric Antigen Receptor Modified T Cells in Relapsed Chronic Lymphocytic Leukemia. [2021]To describe long-term outcomes of anti-CD19 chimeric antigen receptor T (CART) cells in patients with relapsed or refractory chronic lymphocytic leukemia (CLL).
Safety and tolerability of conditioning chemotherapy followed by CD19-targeted CAR T cells for relapsed/refractory CLL. [2021]Subgroups of patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) exhibit suboptimal outcomes after standard therapies, including oral kinase inhibitors. We and others have previously reported on safety and efficacy of autologous CD19-targeted CAR T-cells for these patients; here we report safety and long-term follow-up of CAR T-cell therapy with or without conditioning chemotherapy for patients with R/R CLL and indolent B-cell non-Hodgkin lymphoma (B-NHL).
CAR-modified Cellular Therapies in Chronic Lymphocytic Leukemia: Is the Uphill Road Getting Less Steep? [2023]The clinical development of chimeric antigen receptor (CAR) T-cell therapy has been more challenging for chronic lymphocytic leukemia (CLL) compared to other settings. One of the main reasons is the CLL-associated state of immune dysfunction that specifically involves patient-derived T cells. Here, we provide an overview of the clinical results obtained with CAR T-cell therapy in CLL, describing the identified immunologic reasons for the inferior efficacy. Novel CAR T-cell formulations, such as lisocabtagene maraleucel, administered alone or in combination with the Bruton tyrosine kinase inhibitor ibrutinib, are currently under investigation. These approaches are based on the rationale that improving the quality of the T-cell source and of the CAR T-cell product may deliver a more functional therapeutic weapon. Further strategies to boost the efficacy of CAR T cells should rely not only on the production of CAR T cells with an improved cellular composition but also on additional changes. Such alterations could include (1) the coadministration of immunomodulatory agents capable of counteracting CLL-related immunological alterations, (2) the design of improved CAR constructs (such as third- and fourth-generation CARs), (3) the incorporation into the manufacturing process of immunomodulatory compounds overcoming the T-cell defects, and (4) the use of allogeneic CAR T cells or alternative CAR-modified cellular vectors. These strategies may allow to develop more effective CAR-modified cellular therapies capable of counteracting the more aggressive and still incurable forms of CLL.
CAR T-cell therapy for CLL: a new addition to our treatment toolbox? [2023]Treatment of high-risk chronic lymphocytic leukemia (CLL) has undergone a revolution in recent years with the introduction of novel agents. Bruton kinase inhibitors (BTK) inhibitors, such as ibrutinib, acalabrutinib, and zanubrutinib, are effective at controlling CLL in all lines of therapy, including in patients with high-risk features. BTK inhibitors can be used in sequence or in combination with the BCL2 inhibitor venetoclax. As a result, standard chemotherapy and allogeneic stem cell transplant (allo-SCT)-once major treatment approaches in high-risk patients-are used much less commonly in the current era. Despite the outstanding efficacy of these novel agents, a proportion of patients still experience disease progression. Chimeric antigen receptor (CAR) T-cell therapy has received regulatory approval for several B-cell malignancies in which it has shown efficacy, but it remains investigational for CLL. Several studies have shown the potential for long-term remission in CLL with CAR T-cell therapy, with a favorable safety profile compared with conventional approaches. This review focuses on selected literature on CAR T-cell therapy for CLL, including the interim results of key ongoing studies, with an emphasis on recent research.
Two-year follow-up of KTE-X19 in patients with relapsed or refractory adult B-cell acute lymphoblastic leukemia in ZUMA-3 and its contextualization with SCHOLAR-3, an external historical control study. [2023]Brexucabtagene autoleucel (KTE-X19) is an autologous anti-CD19 CAR T-cell therapy approved in the USA to treat adult patients with relapsed or refractory B-precursor acute lymphoblastic leukemia (R/R B-ALL) based on ZUMA-3 study results. We report updated ZUMA-3 outcomes with longer follow-up and an extended data set along with contextualization of outcomes to historical standard of care.
CAR T Cell Toxicity: Current Management and Future Directions. [2020]By late 2018, 2 chimeric antigen receptor T (CAR T) cell products have been approved by US and European regulatory authorities. Tisagenlecleucel (Kymriah, Novartis) is indicated in the treatment of patients up to 25 years of age with B-cell acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse, or adult patients with large B-cell lymphoma relapsed or refractory (r/r) after 2 or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma. Axicabtagene ciloleucel (Yescarta, Kite) is indicated for the treatment of adult patients with large B-cell lymphoma relapsed or refractory after 2 or more lines of systemic therapy, including DLBCL not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma (ZUMA-1 trial). This review will offer a practical guide for the recognition and management of the most important toxicities related to the use of the current commercial CAR T cells, and also highlight strategies to diminish these side effects in the future.
FDA Approval Summary: Tisagenlecleucel for Treatment of Patients with Relapsed or Refractory B-cell Precursor Acute Lymphoblastic Leukemia. [2020]Tisagenlecleucel (Kymriah; Novartis Pharmaceuticals) is a CD19-directed genetically modified autologous T-cell immunotherapy. On August 30, 2017, the FDA approved tisagenlecleucel for treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory in second or later relapse. Approval was based on the complete remission (CR) rate, durability of CR, and minimal residual disease (MRD)
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.
Approval of brexucabtagene autoleucel for adults with relapsed and refractory acute lymphocytic leukemia. [2022]In October 2021, brexucabtagene autoleucel became the first anti-CD19 chimeric antigen receptor T-cell product to receive approval from the Food and Drug Administration to treat adults with relapsed and refractory B-cell acute lymphoblastic leukemia. The approval is based on results from the Zuma-3 trial and significantly widens treatment options for this patient population. In this article, we review outcomes from this study and its implications.
Single-agent ibrutinib versus chemoimmunotherapy regimens for treatment-naïve patients with chronic lymphocytic leukemia: A cross-trial comparison of phase 3 studies. [2021]Chemoimmunotherapy (CIT) and targeted therapy with single-agent ibrutinib are both recommended first-line treatments for chronic lymphocytic leukemia (CLL), although their outcomes have not been directly compared. Using ibrutinib data from the RESONATE-2 (PCYC-1115/1116) study conducted in patients ≥65 years without del(17p), we performed a cross-trial comparison with CIT data from published phase 3 studies in first-line treatment of CLL. Progression-free survival (PFS), overall survival (OS), and safety data for ibrutinib (median follow-up 35.7 months) were evaluated alongside available CIT data. CIT regimens included: fludarabine + cyclophosphamide + rituximab (CLL8, CLL10), bendamustine + rituximab (CLL10), obinutuzumab + chlorambucil and rituximab + chlorambucil (CLL11), and ofatumumab + chlorambucil (COMPLEMENT-1). Median age across studies was 61-74 years, with older populations receiving ibrutinib, obinutuzumab + chlorambucil, or rituximab + chlorambucil. Median follow-up varied across studies/regimens (range 14.5-37.4 months). Among all patients, PFS appeared longer with ibrutinib relative to CIT and OS appeared comparable. Relative to CIT studies that similarly excluded patients with del(17p) (CLL10) or enrolled older/less-fit patients (CLL11), PFS appeared favorable for ibrutinib in high-risk subgroups, including advanced disease, bulky lymph nodes, unmutated IGHV status, and presence of del(11q). Grade ≥ 3 infections ranged from 9% (ofatumumab + chlorambucil) to 40% (fludarabine + cyclophosphamide + rituximab), and was 25% with ibrutinib. Grade ≥ 3 neutropenia was 12% for ibrutinib and 26%-84% for CIT. Although definitive conclusions cannot be made due to inherent limitations of cross-trial comparisons, this report suggests that ibrutinib has a favorable benefit/risk profile and may potentially eliminate the need for chemotherapy in some patients. Randomized, comparative studies are needed to support these findings.
Ibrutinib as a Bruton Kinase Inhibitor in the Management of Chronic Lymphocytic Leukemia: A New Agent With Great Promise. [2021]The recent discovery of the role of the B-cell antigen receptor (BCR) signaling pathway in the propagation and maintenance of both normal B-cell function and in B-cell malignancies has highlighted the importance of many protein kinases involved in BCR signal propagation. Considerable research attention has focused on the Bruton tyrosine kinase (BTK) as a potential therapeutic target in B-cell malignancies. Treatment paradigms including ibrutinib, a potent inhibitor of the BTK recently approved by the US Food and Drug Administration, have significantly improved disease outcome among high-risk and relapsed/refractory cases of chronic lymphocytic leukemia. This has provided additional treatment options, especially among the elderly, where improved disease response has been accompanied by more manageable treatment-associated toxicity than commonly found with chemoimmunotherapy. In this review, we provide a synopsis of the current data on the efficacy and clinical utilization of ibrutinib and management of its resistance in the treatment of chronic lymphocytic leukemia.
Keeping a balance in chronic lymphocytic leukemia (CLL) patients taking ibrutinib: ibrutinib-associated adverse events and their management based on drug interactions. [2021]Ibrutinib is a highly effective drug for patients with chronic lymphocytic leukemia (CLL), and is well tolerated even by older patients and those unfit to receive conventional immuno-chemotherapy.
Ibrutinib May Boost Efficacy of CAR T Cells. [2019]Preliminary results from two studies indicate that concurrent treatment with ibrutinib may boost CAR T-cell therapy response rates among patients with relapsed/refractory CLL, while also minimizing the risk of severe cytokine release syndrome.
Ibrutinib: a novel Bruton's tyrosine kinase inhibitor with outstanding responses in patients with chronic lymphocytic leukemia. [2021]New treatment options are urgently needed for patients with relapsed chronic lymphocytic leukemia (CLL) who fail to respond to currently available therapies or cannot achieve a sustained response. Moreover, targeted agents with less myelotoxicity are necessary to treat patients with multiple comorbidities who would otherwise be unable to tolerate standard regimens. Ibrutinib, a Bruton's tyrosine kinase inhibitor, has shown highly encouraging results in phase I/II trials in patients with treatment-naive, relapsed and refractory CLL even in the presence of high risk disease or poor prognostic markers. In phase I/II trials, ibrutinib 420 mg or 840 mg - given continuously as single agent or at a dose of 420 mg daily in combination with a monoclonal antibody or chemoimmunotherapy - has been associated with high response rates and durable clinical remissions. Phase II and III trials are currently under way for treatment-naive patients, relapsed/refractory patients, and for those patients harboring a 17p deletion.