Pirtobrutinib + Rituximab for Lymphoma

Overseen By Preetesh Jain, MBBS, MD, DM, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Warfarin, Vitamin K antagonists

Disqualifiers: CNS involvement, High risk MCL, 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

Duration: 24 months

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if a chemo-free combination of pirtobrutinib (a new potential drug) and rituximab can help individuals with low or intermediate risk mantle cell lymphoma (MCL) achieve long-term remission. The trial will include two groups: one will stop pirtobrutinib if no minimal residual disease (MRD, or leftover cancer cells) is detected, while the other will continue treatment if MRD is present. The trial seeks participants who have been newly diagnosed with MCL, have not received prior treatment for it, and are at low to medium risk. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to significant advancements in MCL treatment.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but it does prohibit certain medications like warfarin, vitamin K antagonists, and strong CYP3A4 inhibitors or inducers. It's best to discuss your current medications with the study team to see if any adjustments are needed.

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

Research shows that pirtobrutinib, also known as Jaypirca, has undergone safety testing in patients with certain types of lymphoma. In studies involving patients with mantle cell lymphoma (MCL), some serious infections occurred. About 7% of patients experienced severe reactions, mainly due to infections like COVID-19. However, many patients tolerated the treatment well.

Pirtobrutinib has already received approval for other conditions, indicating a well-understood safety profile. Most patients in these studies had previously undergone multiple treatments.

Rituximab, the other treatment in the trial, is well-known and has been used for years to treat various types of lymphoma. It is generally well-tolerated, though some patients might experience mild to moderate side effects like fevers or chills during infusion.

Overall, both pirtobrutinib and rituximab are generally well-tolerated, though there are some risks of serious side effects, especially infections. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Pirtobrutinib and Rituximab for treating lymphoma because these drugs offer a novel approach compared to standard treatments like chemotherapy and traditional monoclonal antibodies. Pirtobrutinib is a next-generation Bruton’s tyrosine kinase (BTK) inhibitor, which works by specifically targeting and blocking a key enzyme that cancer cells need to grow. This targeted action can potentially lead to fewer side effects and more effective cancer cell death. Additionally, when combined with Rituximab, a monoclonal antibody that targets CD20 on B-cells, the treatment aims to enhance the immune system's ability to fight cancer, offering a powerful one-two punch against lymphoma cells.

What evidence suggests that the combination of pirtobrutinib and rituximab could be effective for lymphoma?

Research has shown that pirtobrutinib holds promise for patients with mantle cell lymphoma (MCL), particularly those who haven't responded to other treatments. One study found it effective for MCL patients who had tried multiple treatments. Another study reported a 52.1% success rate for pirtobrutinib in patients with follicular lymphoma, a similar cancer type. In this trial, participants will receive a combination of pirtobrutinib and Rituximab, a well-known lymphoma treatment that targets and destroys cancer cells. Combining these treatments may enhance their effectiveness, offering new hope for long-term remission in MCL. ^{6 7 8 9 10}

Who Is on the Research Team?

Preetesh Jain, MD, PHD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for people newly diagnosed with a type of cancer called Mantle Cell Lymphoma (MCL), specifically those who are considered low or intermediate risk and have not yet been treated. The specific eligibility criteria to join the study were not provided.

Inclusion Criteria

My lymphoma is confirmed to be mantle cell type and tests positive for CD20.

My cancer is low risk with a small tumor size and no high-risk features.

I am a woman who cannot become pregnant due to surgery, menopause, or a negative pregnancy test.

Exclusion Criteria

I am using steroids for cancer-related pain.

I have not had major surgery in the last 4 weeks.

I have severe ongoing health or mental health issues.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a combination of pirtobrutinib and rituximab for MCL treatment

24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Extension

Participants in Cohort B continue taking pirtobrutinib if MRD positive at 24 months

What Are the Treatments Tested in This Trial?

Interventions

• Pirtobrutinib
• Rituximab

Trial Overview The study is testing a combination of two drugs, Pirtobrutinib and Rituximab, in patients with MCL. It aims to find out if this chemotherapy-free treatment can control the disease effectively.

How Is the Trial Designed?

Group I: Cohort B Experimental Treatment 2 Interventions

If participants test positive for MRD at the 24 month time point, participants will be in Cohort B and the participant will continue taking pirtobrutinib.

Group II: Cohort A Experimental Treatment 2 Interventions

If participants show that they have no MRD, participants will be in Cohort A and will stop taking pirtobrutinib. Participants will continue to be observed and tested for MRD, and participants will be able to continue receiving the drug if you test positive.

Pirtobrutinib is already approved in United States for the following indications:

Approved in United States as Jaypirca for:

• Mantle Cell Lymphoma
• Chronic Lymphocytic Leukemia
• Small Lymphocytic Lymphoma

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Published Research Related to This Trial

The study indicates that adding acalabrutinib to R-CHOP therapy poses a low risk of drug-drug interactions (DDIs) with vincristine, suggesting it may not significantly increase the risk of peripheral neuropathy associated with vincristine treatment.

In contrast, the BTK inhibitor ibrutinib was found to increase vincristine exposure in muscle tissue, indicating a higher potential for toxicity when used with vincristine compared to acalabrutinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mechanistic physiology-based pharmacokinetic modeling to elucidate vincristine-induced peripheral neuropathy following treatment with novel kinase inhibitors. Pilla Reddy, V., Fretland, AJ., Zhou, D., et al.[2022]

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]

In a phase 2 study involving 80 adults with untreated follicular lymphoma, the combination of ibrutinib and rituximab showed a high overall response rate of 85% in the first treatment arm and 75% in the second arm, indicating strong efficacy.

The treatment was generally well-tolerated, with common side effects including fatigue, diarrhea, and nausea, while serious adverse events were rare, suggesting a favorable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The combination of ibrutinib and rituximab demonstrates activity in first-line follicular lymphoma. Fowler, NH., Nastoupil, L., De Vos, S., et al.[2021]

In a study of 60 patients with symptomatic or bulky follicular lymphoma, a combination of short-course chemoimmunotherapy (CHOP-R) followed by radioimmunotherapy (RIT) led to a significant increase in complete response (CR) rates, from 40% after CHOP-R to 82% after RIT, as assessed by imaging.

The study found that patients who did not achieve a complete metabolic response on PET imaging after CHOP-R had a higher risk of relapse, highlighting the importance of early PET assessment in predicting treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of short-course CHOP-R followed by 90Y-ibritumomab tiuxetan and extended rituximab in previously untreated follicular lymphoma. Jacobs, SA., Swerdlow, SH., Kant, J., et al.[2016]

Rituximab is highly effective for treating low-grade CD20+ lymphoma, especially when combined with chemotherapy, which is the standard treatment for follicular lymphoma (FL).

The efficacy of rituximab can be enhanced by combining it with biological agents like interferon-alpha-2a, bortezomib, or lenalidomide, but more research is needed to determine the best combinations and timing of these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biological therapy doublets: pairing rituximab with interferon, lenalidomide, and other biological agents in patients with follicular lymphoma. Kimby, E.[2021]

The combination of rituximab and ibrutinib in a 57-year-old patient with mantle cell lymphoma led to a severe disseminated enterovirus infection, highlighting the significant risk of immunodeficiency and severe immune-related side effects from this treatment regimen.

High-dose intravenous immunoglobulins were effective in clearing the virus and restoring organ function, suggesting that this treatment should be considered for patients experiencing severe enterovirus infections while on rituximab and ibrutinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Life-threatening disseminated enterovirus infection during combined rituximab and ibrutinib maintenance treatment for mantle cell lymphoma: a case report. Higer, M., Cana, D., Podlech, J., et al.[2021]

Pirtobrutinib, a selective BTK inhibitor, received accelerated approval in January 2023 for treating adult patients with relapsed or refractory mantle cell lymphoma (MCL) after at least two prior therapies, including a BTK inhibitor.

The approval was based on the drug's response rate, but continued approval will depend on further confirmation of its clinical benefits in ongoing trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pirtobrutinib: First Approval. Keam, SJ.[2023]

Rituximab, when added to standard chemotherapy, significantly improved survival rates in patients with non-Hodgkin's lymphoma.

In patients with chronic B-cell lymphocytic leukemia, the addition of rituximab to fludarabine-based regimens enhanced both response rates and overall survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Review of the safety and feasibility of rapid infusion of rituximab. Atmar, J.[2022]

PI3K inhibitors, including idelalisib, copanlisib, and duvelisib, are FDA-approved for treating relapsed and refractory indolent non-Hodgkin lymphoma, demonstrating their efficacy in managing this type of cancer.

While these agents are effective, their use can lead to significant adverse events, especially when combined with other therapies, highlighting the need for careful monitoring and management in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PI3K Inhibitors and Their Role as Novel Agents for Targeted Therapy in Lymphoma. Sapon-Cousineau, V., Sapon-Cousineau, S., Assouline, S.[2021]

Rituximab, a chimeric anti-CD20 monoclonal antibody, has shown to induce responses in nearly 50% of patients with relapsed follicular/low-grade non-Hodgkin's lymphoma, with complete remissions occurring in 6% of cases, highlighting its efficacy in treating this type of cancer.

The drug is generally well tolerated, with common side effects being mild to moderate fevers and chills, and it is also effective against various other B-cell malignancies, suggesting its potential for broader applications in both cancer treatment and autoimmune disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab: clinical development and future directions. Cheson, BD.[2019]

Rituximab is a highly effective monoclonal antibody for treating various B-cell lymphomas, including follicular lymphoma and diffuse large B-cell lymphoma, demonstrating a strong activity with low toxicity.

The combination of rituximab with chemotherapy (R-CHOP) has shown the highest efficacy reported for any chemotherapy regimen in treating diffuse large B-cell lymphoma and follicular lymphoma, although some patients may still be resistant to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab therapy in malignant lymphoma. Coiffier, B.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11106640/

Outcomes of pirtobrutinib for relapsed/refractory mantle cell ... Pirtobrutinib shows promising response rates in heavily pretreated MCL patients according to the approval study, but the real‐world data are scarce.

2. ashpublications.org ashpublications.org/bloodadvances/article/doi/10.1182/bloodadvances.2024014975/546861/Pirtobrutinib-a-Highly-Selective-Non-covalent

Pirtobrutinib, a Highly Selective, Non-covalent (Reversible ... Pirtobrutinib demonstrates efficacy in relapsed/refractory follicular lymphoma with an ORR of 52.1% and median DOR of 10.2 months.

3. appliedclinicaltrialsonline.com appliedclinicaltrialsonline.com/view/jaypirca-strong-efficacy-treating-chronic-lymphocytic-leukemia-small-lymphocytic-lymphoma

Jaypirca Demonstrates Strong Efficacy Treating Chronic ... Results from the Phase III BRUIN CLL-314 trial (NCT05254743) showed that Jaypirca (pirtobrutinib) achieved superiority in overall response rates ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO-25-00166

Phase III Trial of Pirtobrutinib Versus Idelalisib/Rituximab or ... At the prespecified final OS analysis, 18-month OS was 73.4% (95% CI, 63.9 to 80.7) in the pirtobrutinib group and 70.8% (95% CI, 60.9 to 78.7) ...

5. investor.lilly.com investor.lilly.com/news-releases/news-release-details/phase-3-results-lillys-jaypircar-pirtobrutinib-covalent-btk

Phase 3 results for Lilly's Jaypirca® (pirtobrutinib) in ... Results from BRUIN CLL-321 show Lilly's pirtobrutinib reduced the risk of disease progression or death by 46% compared to idelalisib plus rituximab or ...

6. jaypirca.lilly.com jaypirca.lilly.com/hcp/mcl/safety

Safety & Adverse Events in MCL | Jaypirca® (pirtobrutinib) Fatal ARs within 28 days of the last Jaypirca dose occurred in 7% of patients with MCL, most commonly due to infections (4.7%), including COVID-19 (3.1% of all ...

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2023/216059s001lbl.pdf

JAYPIRCA® (pirtobrutinib) tablets - accessdata.fda.gov Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. BRUIN. The safety of JAYPIRCA was evaluated in the BRUIN trial in 110 patients with CLL/SLL, with 98 ...

8. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/6778/528384/The-Real-World-Safety-and-Tolerability-of

The Real-World Safety and Tolerability of Pirtobrutinib Among ... The real-world safety and tolerability of pirtobrutinib among patients with B cell lymphomas; a single center experience.

9. prnewswire.com prnewswire.com/news-releases/lillys-jaypirca-pirtobrutinib-the-first-and-only-approved-non-covalent-reversible-btk-inhibitor-met-its-primary-endpoint-in-a-head-to-head-phase-3-trial-versus-imbruvica-ibrutinib-in-cllsll-302515393.html

Lilly's Jaypirca (pirtobrutinib), the first and only approved ... IMPORTANT SAFETY INFORMATION FOR JAYPIRCA (pirtobrutinib). Infections: Fatal and serious infections (including bacterial, viral, fungal) and ...

10. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38043933/

Pirtobrutinib: A novel non-covalent BTK inhibitor for the ... Pirtobrutinib has demonstrated safety and efficacy in heavily pre-treated adult patients with r/r MCL. Advantages of this drug include its ...