Pirtobrutinib + CAR T-cell Therapy for Mantle Cell Lymphoma

Recruiting at 2 trial locations

Overseen By Ruthie Chae

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Must not be taking: Steroids, Immunosuppressants

Disqualifiers: Cardiac disease, Active infection, HIV, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two treatments, brexucabtagene autoleucel (a type of CAR T-cell therapy) and pirtobrutinib, for individuals with mantle cell lymphoma that has returned or not responded to previous treatments. Researchers aim to determine if adding pirtobrutinib enhances the effectiveness of the CAR T-cell therapy. Participants will either continue pirtobrutinib alongside the CAR T-cell therapy or stop it before starting the CAR T-cell treatment. Those with mantle cell lymphoma unresponsive to other treatments might be suitable for this trial. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to significant findings.

Will I have to stop taking my current medications?

Yes, you may need to stop taking certain medications before joining the trial. There are specific 'washout' periods (time without taking certain medications) required for different types of treatments, such as 2 weeks for targeted agents or 3 months for bendamustine. Please consult with the trial team for guidance on your specific medications.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that both pirtobrutinib and brexucabtagene autoleucel are safe options for treating relapsed or refractory mantle cell lymphoma (R/R MCL).

Studies have found pirtobrutinib to be safe even for patients who have tried many other treatments. Long-term use does not seem to cause new safety issues, indicating it is well-tolerated over time.

Brexucabtagene autoleucel has also demonstrated a good safety record. Real-world studies confirm that its effectiveness and safety align with earlier trials, and it is considered safe even for patients over 70 years old.

Overall, both treatments are relatively safe, with manageable side effects, making them reasonable options for those considering joining the clinical trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine Pirtobrutinib, a potent BTK inhibitor, with CAR T-cell therapy, offering a novel approach for Mantle Cell Lymphoma (MCL). Unlike traditional chemotherapy or the standard use of BTK inhibitors alone, this combination could provide a more targeted attack on cancer cells. In Arm A of the trial, Pirtobrutinib is used continuously alongside the CAR T-cell therapy, which might enhance the effectiveness and durability of the treatment. On the other hand, Arm B explores the impact of discontinuing Pirtobrutinib before CAR T-cell therapy, which might reduce side effects and improve patient outcomes. This dual approach allows researchers to explore different strategies to potentially improve long-term survival rates for MCL patients.

What evidence suggests that this trial's treatments could be effective for mantle cell lymphoma?

Research has shown that brexucabtagene autoleucel (brexu-cel) effectively treats relapsed or refractory mantle cell lymphoma (R/R MCL). One study found that 93% of patients responded to the treatment, with 67% achieving a complete response, meaning their cancer was undetectable after treatment. This result is impressive for patients with difficult-to-treat lymphoma.

Pirtobrutinib has also shown promise for R/R MCL. Studies have found that it helped more than half of the patients, with a 56.7% overall response rate, indicating a significant reduction in cancer symptoms for many. In this trial, participants in Arm A will receive pirtobrutinib as a bridging therapy and continue with it alongside brexu-cel, while participants in Arm B will receive pirtobrutinib only as a bridging therapy before brexu-cel. Using these treatments together in different ways could potentially improve outcomes for patients with R/R MCL, as each has proven effective on its own. ^{1 2 3 5 6}

Who Is on the Research Team?

Michael Jain, MD, PhD

Principal Investigator

Moffitt Cancer Center

Are You a Good Fit for This Trial?

This trial is for people with a type of lymphoma called relapsed/refractory mantle cell lymphoma (R/R MCL) who qualify for standard CD19 CAR T-cell therapy. Specific eligibility details are not provided, but typically participants need to meet certain health standards and have no conflicting conditions.

Inclusion Criteria

Must have ability to comprehend and the willingness to sign written informed consent for study participation

I have followed the required waiting period before undergoing leukapheresis.

Patients must meet specific laboratory parameters at screening

Exclusion Criteria

I have been treated with pirtobrutinib for more than 2 months before joining this study.

Participants who have not recovered from adverse events (AEs) due to prior anticancer therapy

Pregnant or nursing (breast-feeding) women

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Bridging Therapy

Participants receive pirtobrutinib as bridging therapy from day -27 to day -7

3 weeks

CAR T-cell Therapy

Participants receive CD19 CAR T-cell therapy with brexucabtagene autoleucel

1 day

Post-Therapy Monitoring

Participants are monitored for severe ICANS and CRS in the first 60 days after CAR T infusion

8 weeks

Follow-up

Participants are monitored for progression-free survival and overall survival

12 months

Long-term Follow-up

Participants are monitored for overall response rate and overall survival

48 months

What Are the Treatments Tested in This Trial?

Interventions

• Brexucabtagene Autoleucel
• Pirtobrutinib

Trial Overview The study is testing two treatments: Brexucabtagene Autoleucel, a form of CAR T-cell therapy, and Pirtobrutinib, a medication. It's an open-label trial where patients are randomly assigned to receive one of these interventions.

How Is the Trial Designed?

Group I: Arm B Experimental Treatment 2 Interventions

Participants will recieve pirtobrutinib as bridging therapy from day -27 to day -7. Participants on Arm B (n=30) will discontinue pirtobrutinib after day -7 and will not receive concurrent pirtobrutinib ("con-none") between day -6 and 1-year post-CD19 CAR T-cell therapy.

Group II: Arm A Experimental Treatment 2 Interventions

Participants will recieve pirtobrutinib as bridging therapy from day -27 to day -7. Participants randomized to Arm A (n=30) will continue to receive concurrent pirtobrutinib ("con-pirto"), starting at day -6 and continued until 1-year post-CD19 CAR T-cell therapy with brexucel.

Brexucabtagene Autoleucel is already approved in European Union, United States for the following indications:

Approved in European Union as Tecartus for:

• Mantle cell lymphoma (MCL)
• Acute lymphoblastic leukemia (ALL)

Approved in United States as Tecartus for:

• Mantle cell lymphoma (MCL)
• Acute lymphoblastic leukemia (ALL)

Who Is Running the Clinical Trial?

H. Lee Moffitt Cancer Center and Research Institute

Lead Sponsor

Trials

576

Recruited

145,000+

Eli Lilly and Company

Industry Sponsor

Trials

2,708

Recruited

3,720,000+

Dr. Daniel Skovronsky

Eli Lilly and Company

Chief Medical Officer since 2018

MD from Harvard Medical School

David A. Ricks

Eli Lilly and Company

Chief Executive Officer since 2017

BSc from Purdue University, MBA from Indiana University

Bankhead-Coley Florida Biomedical Research Program

Collaborator

Trials

3

Recruited

280+

Published Research Related to This Trial

A large multicenter retrospective analysis of patients with mantle cell lymphoma who had previously failed Bruton tyrosine kinase inhibitors (BTKis) provides important outcome data that can serve as a benchmark for future studies.

The study highlights the significant challenges in managing patients with relapsed or refractory mantle cell lymphoma, indicating a need for improved treatment strategies, especially before the introduction of new therapies like brexucabtagene autoleucel (Tecartus).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Post-BTK inhibitor mantle cell lymphoma: When is CAR-T not the answer? McCulloch, R.[2023]

Pirtobrutinib, a new non-covalent Bruton's tyrosine kinase inhibitor, has shown a 52% overall response rate in patients with relapsed/refractory mantle cell lymphoma, demonstrating its efficacy in a heavily pre-treated population.

The drug was well-tolerated with no maximum tolerated dose identified in the initial trials, although neutropenia was the most common serious side effect, indicating a favorable safety profile for patients resistant to other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pirtobrutinib: A novel non-covalent BTK inhibitor for the treatment of adults with relapsed/refractory mantle cell lymphoma. Davis, DD., Ohana, Z., Pham, HM.[2023]

Pirtobrutinib received accelerated FDA approval for treating adult patients with relapsed or refractory mantle cell lymphoma (MCL) after at least two prior therapies, showing a 50% overall response rate in a study of 120 patients.

While effective, pirtobrutinib has potential side effects including fatigue, diarrhea, and increased risk of infections and bleeding, necessitating postmarketing studies to further assess its long-term safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pirtobrutinib for Relapsed or Refractory Mantle Cell Lymphoma. Telaraja, D., Kasamon, YL., Collazo, JS., et al.[2023]

Pirtobrutinib, a noncovalent Bruton tyrosine kinase inhibitor, has shown high response rates in patients with chronic lymphocytic leukemia and mantle cell lymphoma who are resistant to conventional covalent BTK inhibitors, addressing a significant unmet need in this population.

The early studies indicate that pirtobrutinib has a favorable toxicity profile, suggesting it may be suitable for use in combination therapies, and it has recently received accelerated FDA approval for use in mantle cell lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pirtobrutinib: a new hope for patients with BTK inhibitor-refractory lymphoproliferative disorders. Thompson, PA., Tam, CS.[2023]

Pirtobrutinib is a noncovalent Bruton tyrosine kinase inhibitor that effectively targets both normal and mutant forms of BTK, showing promise in treating relapsed mantle cell lymphoma, especially in patients who have not previously received BTK inhibitors.

This ongoing phase III study aims to determine if pirtobrutinib is more effective than existing covalent BTK inhibitors in patients with previously treated mantle cell lymphoma, highlighting its potential as a new treatment option for those with poor prognosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BRUIN MCL-321: phase III study of pirtobrutinib versus investigator choice of BTK inhibitor in BTK inhibitor naive mantle cell lymphoma. Eyre, TA., Shah, NN., Dreyling, M., et al.[2023]

Pirtobrutinib, approved by the FDA in January 2023, is specifically designed to treat relapsed or refractory mantle cell lymphoma, especially in patients who have developed resistance to other BTK inhibitors like ibrutinib.

Unlike traditional covalent BTK inhibitors, pirtobrutinib offers a new treatment option with potentially fewer off-target side effects, making it a promising alternative for patients facing limitations with existing therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pirtobrutinib: First Non-covalent Tyrosine Kinase Inhibitor for Treating Relapsed or Refractory Mantle Cell Lymphoma in Adults. De, SK.[2023]

In patients with relapsed/refractory mantle cell lymphoma (MCL) who previously failed a Bruton tyrosine kinase inhibitor, brexucabtagene autoleucel (brexu-cel) showed significantly improved overall survival compared to standard of care treatments, with hazard ratios indicating a strong survival benefit.

The analysis used multiple methods to adjust for differences in patient characteristics, consistently showing that brexu-cel led to better outcomes, highlighting its potential as an effective therapy for this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Indirect treatment comparison of brexucabtagene autoleucel (ZUMA-2) versus standard of care (SCHOLAR-2) in relapsed/refractory mantle cell lymphoma. Hess, G., Dreyling, M., Oberic, L., et al.[2023]

The Mantle Cell Lymphoma International Prognostic Index-Combined, which includes the Ki67 index and clinical factors, is crucial for risk stratification at diagnosis, helping to predict patient outcomes more accurately.

New targeted therapies, such as Bruton tyrosine kinase inhibitors and CAR T-cell therapies, show promising efficacy in treating mantle cell lymphoma, especially in high-risk patients, and may lead to improved survival rates after traditional treatments fail.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Directions for Mantle Cell Lymphoma in 2022. Kumar, A., Eyre, TA., Lewis, KL., et al.[2022]

Idelalisib, a PI3Kδ inhibitor, has shown effectiveness in patients with mantle cell lymphoma who have undergone extensive prior treatments.

This suggests that idelalisib could be a promising therapeutic option for patients with difficult-to-treat mantle cell lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Idelalisib has activity in mantle cell lymphoma. [2019]

In the pivotal ZUMA-2 trial, brexucabtagene autoleucel (brexu-cel) showed high efficacy in treating relapsed or refractory mantle cell lymphoma, with an objective response rate of 85% and a complete response rate of 59%, even among high-risk patients.

While brexu-cel has a similar toxicity profile to other CAR T-cell therapies, it is associated with significant treatment-related adverse effects, including severe cytopenias (94%) and neurotoxicity (31%), highlighting the need for careful management by a specialized medical team.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brexucabtagene Autoleucel: A Novel Chimeric Antigen Receptor T-cell Therapy for the Treatment of Mantle Cell Lymphoma. Anderson, MK., Torosyan, A., Halford, Z.[2022]

Pirtobrutinib, a novel noncovalent Bruton tyrosine kinase inhibitor, showed a 57.8% overall response rate in patients with relapsed/refractory mantle-cell lymphoma who had previously been treated with covalent BTK inhibitors, indicating its efficacy in a challenging patient population.

The treatment was well tolerated, with only 3% of patients discontinuing due to adverse events, and the most common side effects included fatigue and diarrhea, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pirtobrutinib in Covalent Bruton Tyrosine Kinase Inhibitor Pretreated Mantle-Cell Lymphoma. Wang, ML., Jurczak, W., Zinzani, PL., et al.[2023]

Citations

1. ashpublications.org ashpublications.org/bloodadvances/article/9/20/5382/546349/Real-world-outcomes-of-brexucabtagene-autoleucel

Real-world outcomes of brexucabtagene autoleucel for ... Here, we report real-world effectiveness and safety outcomes of brexu-cel in a prospective study of patients with R/R MCL, including subgroups based on prior ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40706035/

Real-world outcomes of brexucabtagene autoleucel for ... Here, we report real-world effectiveness and safety outcomes of brexu-cel in a prospective study of patients with r/r MCL, including subgroups ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT02601313

NCT02601313 | Study of Brexucabtagene Autoleucel (KTE ... The goal of this clinical study is to test how well the study drug, brexucabtagene autoleucel (KTE-X19), works in participants with relapsed/refractory (r/r) ...

4. onclive.com onclive.com/view/brexu-cel-demonstrates-efficacy-safety-in-older-patients-with-r-r-mantle-cell-lymphoma

Brexu-Cel Demonstrates Efficacy, Safety in Older Patients ... Brexu-cel demonstrated clinical activity and safety in patients over 70 years of age with relapsed/refractory mantle cell lymphoma.

5. asco.org asco.org/abstracts-presentations/ABSTRACT361758

Three-year follow-up of outcomes with KTE-X19 in patients ... In ZUMA-2, a 93% objective response rate (ORR; 67% complete response [CR] rate) was reported with KTE-X19 in pts with R/R MCL (median follow-up: 12.3 mo; 60 ...

6. ash.confex.com ash.confex.com/ash/2024/webprogram/Paper198018.html

4388 Five-Year Outcomes of Patients (Pts) with Relapsed/ ... After ~4 years (y) of median follow-up, Brexu-cel demonstrated a median overall survival (OS) of 46.4 months (mo) in 68 pts with R/R MCL in ...