CAR T-Cell Therapy + Ibrutinib for Chronic Lymphocytic Leukemia

Recruiting at 59 trial locations

Overseen By Novartis Pharmaceuticals

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Novartis Pharmaceuticals

Must be taking: Ibrutinib

Must not be taking: CD19-directed therapy

Disqualifiers: Richter's transformation, Active CNS lymphoma, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

225 Participants Needed

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. ^{1 2 3 4 5}

Is 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. ^{6 7 8 9 10}

What 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. ^{11 12 13 14 15}

Research Team

Novartis Pharmaceuticals

Principal Investigator

Novartis Pharmaceuticals

Eligibility 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 PET scan shows cancer activity but not worsening after initial treatment.

My cancer has specific genetic changes in MYC, BCL2, or BCL6.

Exclusion Criteria

I have active lymphoma in my brain or spinal cord.

My condition has progressed from CLL to a more aggressive form.

There may be other specific requirements or restrictions that apply to this study.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase I Treatment

Dose escalation and expansion of rapcabtagene autoleucel in combination with ibrutinib for CLL/SLL and as a single agent for DLBCL and ALL

24 months

Multiple visits for dose escalation and monitoring

Phase II Treatment

Continuation of rapcabtagene autoleucel treatment at recommended dose for DLBCL and LBCL

24 months

Regular visits for treatment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Regular follow-up visits

Long-term Follow-up

Post-study long-term follow-up for lentiviral vector safety

Up to 15 years

Treatment Details

Interventions

• Ibrutinib
• YTB323

Trial Overview 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.

Participant Groups

Group I: CLL/SLL Experimental Treatment 2 Interventions

Dose escalation and expansion of rapcabtagene autoleucel in combination with ibrutinib

Group II: Adult ALL Experimental Treatment 1 Intervention

Dose escalation and expansion of rapcabtagene autoleucel single agent in adult ALL

Group III: 3L+ DLBCL Experimental Treatment 1 Intervention

Dose escalation and expansion of rapcabtagene autoleucel single agent in 3L+ DLBCL

Group IV: 1L HR LBCL Experimental Treatment 1 Intervention

Rapcabtagene autoleucel single agent in 1L HR LBCL

Who Is Running the Clinical Trial?

Novartis Pharmaceuticals

Lead Sponsor

Trials

2,963

Recruited

4,275,000+

Founded

1996

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Gleevec, Cosentyx, Entresto, Kisqali

Dr. Vas Narasimhan

Novartis Pharmaceuticals

Chief Executive Officer since 2018

MD from Harvard Medical School

Dr. Shreeram Aradhye

Novartis Pharmaceuticals

Chief Medical Officer since 2021

MD

Findings from Research

Chimeric antigen receptor T (CART) cells targeting CD19 show promise in treating chronic lymphocytic leukemia (CLL), but their effectiveness is lower compared to other blood cancers, possibly due to impaired T-cell fitness in CLL patients.

The use of ibrutinib during CART cell production enhances the viability and expansion of CART cells from CLL patients, enriches them with less-differentiated T cell subsets, and improves their functionality by reducing exhaustion markers, suggesting a potential strategy to overcome treatment resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib for improved chimeric antigen receptor T-cell production for chronic lymphocytic leukemia patients. Fan, F., Yoo, HJ., Stock, S., et al.[2021]

In a study of 42 patients with relapsed or refractory chronic lymphocytic leukemia (CLL), those treated with anti-CD19 CAR T cells showed a complete response (CR) rate of 28% and an overall response rate of 44% after 4 weeks, with a median overall survival of 64 months.

Achieving a complete response was linked to significantly longer overall survival and progression-free survival, indicating that the effectiveness of CAR T cell therapy is enhanced in patients who reach CR, regardless of whether they received a low or high dose.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Outcomes From a Randomized Dose Optimization Study of Chimeric Antigen Receptor Modified T Cells in Relapsed Chronic Lymphocytic Leukemia. Frey, NV., Gill, S., Hexner, EO., et al.[2021]

In a phase 1 clinical trial involving 20 patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and indolent B-cell non-Hodgkin lymphoma (B-NHL), CAR T-cell therapy combined with conditioning chemotherapy was found to be well-tolerated, with serious side effects like cytokine release syndrome occurring in only 10% of patients.

Among the CLL patients who received conditioning chemotherapy, 25% achieved complete remission, and all patients who reached this remission remained progression-free for a median follow-up of 53 months, indicating the potential for long-lasting treatment effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of conditioning chemotherapy followed by CD19-targeted CAR T cells for relapsed/refractory CLL. Geyer, MB., Rivière, I., Sénéchal, B., et al.[2021]

CAR T-cell therapy has faced challenges in treating chronic lymphocytic leukemia (CLL) due to the immune dysfunction of patient-derived T cells, leading to inferior efficacy compared to other cancers.

New strategies, including novel CAR T-cell formulations like lisocabtagene maraleucel combined with ibrutinib, aim to enhance T-cell quality and functionality, potentially improving treatment outcomes for CLL patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-modified Cellular Therapies in Chronic Lymphocytic Leukemia: Is the Uphill Road Getting Less Steep? Vitale, C., Griggio, V., Perutelli, F., et al.[2023]

Bruton kinase inhibitors (BTK inhibitors) like ibrutinib, acalabrutinib, and zanubrutinib have transformed the treatment of high-risk chronic lymphocytic leukemia (CLL), proving effective across all therapy lines and reducing the reliance on traditional chemotherapy and stem cell transplants.

Chimeric antigen receptor (CAR) T-cell therapy shows promise for long-term remission in CLL with a favorable safety profile, although it is still considered investigational and not yet standard treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T-cell therapy for CLL: a new addition to our treatment toolbox? Iovino, L., Shadman, M.[2023]

In the updated ZUMA-3 study with a median follow-up of 26.8 months, brexucabtagene autoleucel (KTE-X19) achieved a 71% complete remission rate in adults with relapsed or refractory B-precursor acute lymphoblastic leukemia, indicating its efficacy as a treatment option.

Patients treated with KTE-X19 had a median overall survival of 25.4 months, significantly longer than the 5.5 months observed in matched historical controls, demonstrating a meaningful survival benefit with manageable safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Shah, BD., Ghobadi, A., Oluwole, OO., et al.[2023]

Two CAR T cell therapies, Tisagenlecleucel and Axicabtagene ciloleucel, have been approved for treating specific types of blood cancers, including B-cell acute lymphoblastic leukemia and large B-cell lymphoma, in patients who have not responded to other treatments.

This review emphasizes the importance of recognizing and managing the toxicities associated with CAR T cell therapies, while also suggesting future strategies to reduce these side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T Cell Toxicity: Current Management and Future Directions. Yáñez, L., Sánchez-Escamilla, M., Perales, MA.[2020]

Tisagenlecleucel (Kymriah) is an effective treatment for B-cell precursor acute lymphoblastic leukemia (ALL) in patients up to 25 years old, achieving a complete remission rate of 63% in a study of 63 participants, with all remissions showing minimal residual disease (MRD) below 0.01%.

While the treatment shows promise, it is associated with serious side effects, including cytokine release syndrome (79%) and neurologic events (65%), but the overall benefit-risk profile is considered acceptable for patients with resistant forms of ALL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Tisagenlecleucel for Treatment of Patients with Relapsed or Refractory B-cell Precursor Acute Lymphoblastic Leukemia. O'Leary, MC., Lu, X., Huang, Y., et al.[2020]

In a phase 2 trial involving 61 patients with relapsed or refractory large B-cell lymphoma, lisocabtagene maraleucel demonstrated a high overall response rate of 80%, indicating its efficacy as a second-line treatment for patients not intended for stem-cell transplantation.

The treatment was generally safe, with no treatment-related deaths reported; however, common serious side effects included neutropenia and cytokine release syndrome, which occurred in 38% of patients, highlighting the need for monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Sehgal, A., Hoda, D., Riedell, PA., et al.[2022]

Brexucabtagene autoleucel is the first FDA-approved CAR T-cell therapy targeting CD19 for adults with relapsed and refractory B-cell acute lymphoblastic leukemia, marking a significant advancement in treatment options.

The approval was based on the outcomes of the Zuma-3 trial, which demonstrated the efficacy of this therapy in improving patient outcomes in a challenging-to-treat population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Approval of brexucabtagene autoleucel for adults with relapsed and refractory acute lymphocytic leukemia. Frey, NV.[2022]

Ibrutinib, a targeted therapy, showed longer progression-free survival (PFS) compared to chemoimmunotherapy (CIT) in patients with chronic lymphocytic leukemia (CLL), particularly in high-risk subgroups, based on a cross-trial comparison of data from the RESONATE-2 study and various CIT studies.

The safety profile of ibrutinib was favorable, with lower rates of grade ≥3 neutropenia (12%) compared to CIT regimens (26%-84%), and a moderate rate of grade ≥3 infections (25%), suggesting it may reduce the need for chemotherapy in some patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-agent ibrutinib versus chemoimmunotherapy regimens for treatment-naïve patients with chronic lymphocytic leukemia: A cross-trial comparison of phase 3 studies. Robak, T., Burger, JA., Tedeschi, A., et al.[2021]

Ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor, has been shown to significantly improve disease outcomes in high-risk and relapsed/refractory chronic lymphocytic leukemia (CLL) patients, providing a new treatment option especially for the elderly.

The use of ibrutinib is associated with more manageable side effects compared to traditional chemoimmunotherapy, making it a safer alternative for patients undergoing treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib as a Bruton Kinase Inhibitor in the Management of Chronic Lymphocytic Leukemia: A New Agent With Great Promise. Foluso, O., Glick, A., Stender, M., et al.[2021]

Ibrutinib is an effective treatment for chronic lymphocytic leukemia (CLL) and is generally well tolerated, even in older patients or those unable to undergo traditional chemotherapy.

However, adverse events, such as lymphocytosis and potential drug interactions, can lead to treatment interruptions and complications like major hemorrhage and atrial fibrillation, highlighting the need for careful monitoring and possible dose adjustments when used with certain medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Keeping a balance in chronic lymphocytic leukemia (CLL) patients taking ibrutinib: ibrutinib-associated adverse events and their management based on drug interactions. Cho, HJ., Baek, DW., Kim, J., et al.[2021]

Concurrent treatment with ibrutinib may enhance the effectiveness of CAR T-cell therapy in patients with relapsed or refractory chronic lymphocytic leukemia (CLL), based on preliminary results from two studies.

Ibrutinib treatment appears to reduce the risk of severe cytokine release syndrome, a common side effect associated with CAR T-cell therapy, suggesting a safer treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib May Boost Efficacy of CAR T Cells. [2019]

Ibrutinib, a Bruton's tyrosine kinase inhibitor, has shown promising efficacy in treating relapsed chronic lymphocytic leukemia (CLL), demonstrating high response rates and durable remissions in phase I/II trials involving patients with high-risk disease.

This treatment option is particularly beneficial for patients who cannot tolerate standard therapies due to comorbidities, as it has less myelotoxicity and is being further evaluated in ongoing phase II and III trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib: a novel Bruton's tyrosine kinase inhibitor with outstanding responses in patients with chronic lymphocytic leukemia. Barrientos, J., Rai, K.[2021]

References

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

Ibrutinib for improved chimeric antigen receptor T-cell production for chronic lymphocytic leukemia patients. [2021]

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

Long-Term Outcomes From a Randomized Dose Optimization Study of Chimeric Antigen Receptor Modified T Cells in Relapsed Chronic Lymphocytic Leukemia. [2021]

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

Safety and tolerability of conditioning chemotherapy followed by CD19-targeted CAR T cells for relapsed/refractory CLL. [2021]

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

CAR-modified Cellular Therapies in Chronic Lymphocytic Leukemia: Is the Uphill Road Getting Less Steep? [2023]

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

CAR T-cell therapy for CLL: a new addition to our treatment toolbox? [2023]

6. England pubmed.ncbi.nlm.nih.gov

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]

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

CAR T Cell Toxicity: Current Management and Future Directions. [2020]

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

FDA Approval Summary: Tisagenlecleucel for Treatment of Patients with Relapsed or Refractory B-cell Precursor Acute Lymphoblastic Leukemia. [2020]

9. England pubmed.ncbi.nlm.nih.gov

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]

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

Approval of brexucabtagene autoleucel for adults with relapsed and refractory acute lymphocytic leukemia. [2022]

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

Single-agent ibrutinib versus chemoimmunotherapy regimens for treatment-naïve patients with chronic lymphocytic leukemia: A cross-trial comparison of phase 3 studies. [2021]

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

Ibrutinib as a Bruton Kinase Inhibitor in the Management of Chronic Lymphocytic Leukemia: A New Agent With Great Promise. [2021]

13. England pubmed.ncbi.nlm.nih.gov

Keeping a balance in chronic lymphocytic leukemia (CLL) patients taking ibrutinib: ibrutinib-associated adverse events and their management based on drug interactions. [2021]

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

Ibrutinib May Boost Efficacy of CAR T Cells. [2019]

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

Ibrutinib: a novel Bruton's tyrosine kinase inhibitor with outstanding responses in patients with chronic lymphocytic leukemia. [2021]