Pirtobrutinib + Rituximab for Marginal Zone Lymphoma

Recruiting at 2 trial locations

Overseen By Rachel Kingsford

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Narendranath Epperla

Must not be taking: Anticoagulants, Live-virus vaccines

Disqualifiers: HIV, Active hepatitis B, 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: 4

Duration: 7 months

23 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if combining two drugs, Pirtobrutinib (a new potential drug) and Rituximab, can effectively treat marginal zone lymphoma, a cancer affecting the lymphatic system. The research targets patients recently diagnosed and beginning their first systemic treatment, which affects the whole body. Suitable candidates are those with marginal zone lymphoma who require treatment and have not undergone extensive prior cancer therapy. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you require certain blood thinners like warfarin or have had live-virus vaccines recently. It's best to discuss your specific medications with the trial team.

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

Research shows that patients generally tolerate the combination of Pirtobrutinib and Rituximab well. Previous studies found that Pirtobrutinib, used for certain blood cancers, is safe for most people and usually doesn't cause serious side effects. Studies on combining Pirtobrutinib with Rituximab suggest it is a safe treatment for newly diagnosed marginal zone lymphoma. While any treatment can have side effects, the results so far are encouraging for this combination therapy. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of pirtobrutinib and rituximab for treating marginal zone lymphoma because it offers a novel approach compared to the standard therapies like chemotherapy or monoclonal antibodies alone. Pirtobrutinib is a next-generation Bruton's tyrosine kinase (BTK) inhibitor, which means it specifically targets and disrupts signals that help cancer cells grow, while rituximab is a well-known monoclonal antibody that targets CD20 on B cells. This combination has the potential to enhance effectiveness by attacking the cancer through different mechanisms, possibly leading to better outcomes for patients.

What evidence suggests that Pirtobrutinib and Rituximab could be effective for marginal zone lymphoma?

Research has shown that combining Pirtobrutinib and Rituximab may be promising for treating marginal zone lymphoma. In this trial, all participants will receive this combination of study drugs. Pirtobrutinib has effectively treated various blood cancers, such as mantle cell lymphoma and chronic lymphocytic leukemia. Rituximab is already known to work well against certain lymphomas. Together, these drugs aim to provide a stronger treatment by attacking cancer cells in different ways. Early results suggest that using Pirtobrutinib with Rituximab might improve outcomes for patients with marginal zone lymphoma. ^{1 3 4 5 6}

Who Is on the Research Team?

Narendranath Epperla, M.D.

Principal Investigator

Ohio State University Comprehensive Cancer Center

Are You a Good Fit for This Trial?

This trial is for patients newly diagnosed with marginal zone lymphoma, a type of cancer affecting white blood cells. Participants should be suitable for both biopsy and imaging tests like CT and PET scans to monitor the disease.

Inclusion Criteria

Adequate coagulation as defined

I can swallow pills.

Life expectancy of > 3 months

Exclusion Criteria

I do not have any uncontrolled health conditions.

I have a condition that affects how my body absorbs nutrients.

I have not had a stroke or brain bleed in the last 6 months.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Pirtobrutinib and Rituximab for the treatment of newly diagnosed marginal zone lymphoma

7 months

Cycle-based visits, likely every 4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

7 years

What Are the Treatments Tested in This Trial?

Interventions

• Pirtobrutinib
• Rituximab

Trial Overview

The study is testing pirtobrutinib combined with rituximab as a treatment. Pirtobrutinib blocks proteins that help tumor cells grow, while rituximab targets certain immune cells potentially aiding in killing cancer cells.

How Is the Trial Designed?

Group I: Rituximab+Pirtobrutinib, Pirtobrutinib Alone Experimental Treatment 2 Interventions

This arm included participants who had a complete response to Rituximab and Pirtobrutinib in Stage 1. In Stage 1, all participants will receive Rituximab and Pirtobrutinib for 6 Cycles (42 days). In Stage 2, subjects who experience a complete response will discontinue rituximab and continue treatment with pirtobrutinib only for 6 additional cycles. Participants in this arm will not have Stage 3 treatment. After completing Stage II treatment, subjects will discontinue treatment and proceed to End of Treatment (EOT) and Long-Term Follow-Up (LTFU) visits.

Group II: Rituximab+Pirtobrutinib, Continuded Rituximab+Pirtobrutinib, Pirtobrutinib Alone (6 Cycles) Experimental Treatment 2 Interventions

This arm included participants who had a Partial Response or Stable Disease response to Rituximab and Pirtobrutinib in Stage 1 and a Complete Response to continued Rituximab and Pirtobrutinib in Stage 2. In Stage 1, all participants will receive Rituximab and Pirtobrutinib for 6 Cycles (42 days). In Stage II, subjects who experienced a Partial Response or Stable Disease will continue Rituximab and Pirtobrutinib treatment for 6 additional cycles. In Stage III, subjects who experienced a Complete Response will discontinue rituximab and continue treatment with Pirtobrutinib only for 6 additional cycles. After completing Stage III treatment, subjects will discontinue treatment and proceed to End of Treatment (EOT) and Long-Term Follow-Up (LTFU) visits.

Group III: Rituximab+Pirtobrutinib, Continuded Rituximab+Pirtobrutinib, Pirtobrutinib Alone (24 Cycles) Experimental Treatment 2 Interventions

This arm included participants who had a Partial Response or Stable Disease response to Rituximab and Pirtobrutinib in Stage 1 and a Progressive Disease after continued Rituximab and Pirtobrutinib in Stage 2. In Stage I, all participants will receive Rituximab and Pirtobrutinib for 6 Cycles (42 days). In Stage II, subjects who experience a Partial Response or Stable Disease will continue Rituximab and Pirtobrutinib treatment for 6 additional cycles. In Stage III, subjects who experience Progressive Disease will discontinue treatment and proceed to End of Treatment (EOT) and Long-Term Follow-Up (LTFU) visits.

Group IV: Rituximab+Pirtobrutinib, Continuded Rituximab+Pirtobrutinib Experimental Treatment 2 Interventions

This arm included participants who had a Partial Response or Stable Disease response to Rituximab and Pirtobrutinib in Stage 1 and a Partial Response or Stable Disease to continued Rituximab and Pirtobrutinib in Stage 2. In Stage I, all participants will receive Rituximab and Pirtobrutinib for 6 Cycles (42 days). In Stage II, subjects who experience a Partial Response or Stable Disease will continue Rituximab and Pirtobrutinib treatment for 6 additional cycles. In Stage III, subjects who experience a Partial Response or Stable Disease will discontinue rituximab and continue treatment with Pirtobrutinib only until progression or other treatment discontinuation criteria are met. After progression or other treatment discontinuation criteria are met, subjects will discontinue treatment and proceed to End of Treatment (EOT) and Long-Term Follow-Up (LTFU) visits.

Group V: Rituximab+Pirtobrutinib Only Experimental Treatment 2 Interventions

This arm included participants who had Progressive Disease after Rituximab and Pirtobrutinib treatment in Stage 1. In Stage 1, all participants will receive Rituximab and Pirtobrutinib for 6 Cycles (42 days). If participants had Progressive Disease after Stage I, they will not have Stage II or Stage III of treatment. After completing Stage I treatment, subjects will discontinue treatment and proceed to End of Treatment (EOT) and Long-Term Follow-Up (LTFU) visits.

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?

Narendranath Epperla

Lead Sponsor

Trials

3

Recruited

50+

University of Utah

Lead Sponsor

Trials

1,169

Recruited

1,623,000+

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

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]

The phase III CHRONOS-3 trial demonstrated that adding copanlisib, a pan-PI3K inhibitor, to standard rituximab significantly benefits patients with relapsed indolent non-Hodgkin lymphoma.

This combination therapy was found to be safe and reduced the risk of disease progression or death by nearly 50% compared to the placebo plus rituximab group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NHL Progression Risk Cut with Copanlisib-Rituximab Combo. [2021]

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 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]

In a study of 70 patients with splenic marginal zone lymphoma (SMZL), treatment with rituximab alone showed an impressive overall response rate of 88% and a 3-year survival rate of 95%, indicating its efficacy as a primary treatment option.

Rituximab-based therapies, whether alone or combined with chemotherapy, resulted in significantly better survival and failure-free survival rates compared to chemotherapy alone, suggesting that rituximab should be the preferred treatment for older patients with SMZL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes in patients with splenic marginal zone lymphoma and marginal zone lymphoma treated with rituximab with or without chemotherapy or chemotherapy alone. Tsimberidou, AM., Catovsky, D., Schlette, E., et al.[2023]

Novel agents like lenalidomide, bortezomib, and 90yttrium-ibrutumomab tiuxetan have shown efficacy in treating marginal zone lymphoma, based on trials specifically designed for this patient group.

Targeted therapies such as obinutuzumab, ibrutinib, and idelalisib, along with newer drugs like venetoclax and copanlisib, are being explored for their safety and effectiveness, indicating a promising direction for treatment in indolent non-Hodgkin's lymphomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Possible novel agents in marginal zone lymphoma. Zinzani, PL., Broccoli, A.[2021]

In a Phase III study involving 21 patients with relapsed indolent B-cell lymphoma, copanlisib was safely combined with immunochemotherapy regimens (R-B and R-CHOP) without any dose-limiting toxicities, establishing a recommended Phase III dose of 60 mg.

The combination therapy showed high efficacy, with objective response rates of 90% for copanlisib plus R-B and 100% for copanlisib plus R-CHOP, indicating that copanlisib can be effectively integrated into treatment plans for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Feasibility of Combining the Phosphatidylinositol 3-Kinase Inhibitor Copanlisib With Rituximab-Based Immunochemotherapy in Patients With Relapsed Indolent B-cell Lymphoma. Matasar, MJ., Dreyling, M., Leppä, S., et al.[2022]

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 phase II study involving 68 patients with relapsed/refractory marginal zone lymphoma, zanubrutinib showed a high overall response rate (ORR) of 68.2% and a complete response (CR) rate of 25.8% after a median follow-up of 15.7 months.

The treatment was well tolerated, with most adverse events being mild (grade 1 or 2), and serious side effects were rare, indicating a favorable safety profile for zanubrutinib in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The MAGNOLIA Trial: Zanubrutinib, a Next-Generation Bruton Tyrosine Kinase Inhibitor, Demonstrates Safety and Efficacy in Relapsed/Refractory Marginal Zone Lymphoma. Opat, S., Tedeschi, A., Linton, K., et al.[2023]

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]

In the phase IIb UNITY-NHL trial, the PI3Kδ inhibitor umbralisib demonstrated a promising response rate of 55% in patients with relapsed or refractory marginal zone lymphoma.

Patients treated with umbralisib experienced a 1-year progression-free survival rate of 71%, and the side effects were manageable, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Umbralisib: Treatment for a Rare Lymphoma? [2020]

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Pirtobrutinib + Rituximab for Marginal Zone Lymphoma

The purpose of this clinical trial is to learn if the drugs Pirtobrutinib and Rituximab are effective for the treatment of newly diagnosed marginal zone ...

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This phase II trial studies how well pirtobrutinib in combination with rituximab works in treating patients with newly diagnosed marginal zone lymphoma.

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Marginal zone lymphoma (MZL) is the second most common subtype of inert B-cell non-Hodgkin's lymphoma, accounting for 5–15% of non-Hodgkin's lymphoma cases.