Pirtobrutinib + Mosunetuzumab for Follicular Lymphoma

Overseen By Mengyang Di, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Washington

Must not be taking: Anticoagulants, Immunosuppressants

Disqualifiers: Autoimmune disease, CNS disease, Cardiovascular, 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: 1

Duration: 52 weeks

22 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot participate if you have used certain cancer treatments or therapies recently, such as monoclonal antibodies or chemotherapeutic agents, within a specified time before starting the trial.

What data supports the effectiveness of the drug mosunetuzumab for follicular lymphoma?

Research shows that mosunetuzumab, a type of drug that helps the immune system fight cancer, has high response rates in patients with follicular lymphoma, especially those who have not responded to other treatments. In a study, 80% of patients responded to the drug, and 60% had a complete response, meaning their cancer was no longer detectable. ^{1 2 3 4 5}

What is known about the safety of molecular target anticancer drugs?

Molecular target anticancer drugs, like those potentially used in your trial, have been shown to increase the risk of serious and fatal adverse events compared to placebo. This means they can cause significant side effects, so careful monitoring is important. ^{6 7 8 9 10}

How is the drug Pirtobrutinib + Mosunetuzumab unique for treating follicular lymphoma?

This drug combination is unique because it includes mosunetuzumab, a bispecific antibody that engages T-cells to target and destroy cancerous B-cells, offering a new approach for patients with relapsed or refractory follicular lymphoma. Mosunetuzumab has shown promising results with manageable side effects, providing an alternative to other treatments like CAR-T cell therapy, which can be more complex to administer. ^{2 4 5 11 12}

What is the purpose of this trial?

This phase II trial tests how well pirtobrutinib and mosunetuzumab work in treating patients with grade 1-3a follicular lymphoma (FL) that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). Pirtobrutinib, a type of tyrosine kinase inhibitor, works by blocking the action of the Bruton tyrosine kinase (BTK) protein. The BTK protein signals cancer cells to multiply, and blocking it may help keep cancer cells from growing. It could also improve T cell fitness and decrease inflammation, therefore, may improve the efficacy and safety of T cell-based therapies, such as mosunetuzumab. Mosunetuzumab is a bispecific antibody that binds both T cells and the lymphoma cancer cells and harnesses T cells to interfere with the ability of cancer cells to grow and spread. Giving pirtobrutinib and mosunetuzumab together may kill more tumor cells in patients with relapsed or refractory grade 1-3a FL and potentially decreases some side effects of mosunetuzumab which are related to T cells being activated (e.g., cytokine release syndrome).

Research Team

Mengyang Di, MD, PhD

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Eligibility Criteria

The PROMOTE-FL trial is for patients with grades 1-3A follicular lymphoma that has either relapsed or hasn't responded to previous treatments. Participants must meet specific health criteria, which are not detailed here.

Inclusion Criteria

Aspartate aminotransferase and alanine aminotransferase ≤ 3 x the upper limit of normal (ULN)

Activated partial thromboplastin time (or partial thromboplastin time) and prothrombin (or international normalized ratio) ≤ 1.5 ULN

Estimated creatinine clearance (CL) ≥ 30 mL/min by Cockcroft-Gault formula: (140 - age) x body weight (kg) x 0.85 (if female) serum creatinine (mg/dl) x 72 or other institutional standard methods (e.g., based on nuclear medicine renal scan)

Exclusion Criteria

Known active cytomegalovirus (CMV) infection. Unknown or negative status are eligible

Patients who have tested positive for human immunodeficiency virus (HIV) are excluded due to risk of opportunistic infections with both HIV and BTK inhibitors. For patients with unknown HIV status, HIV testing will be performed at Screening and result must be negative for enrollment

Pregnant or breast-feeding women

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive pirtobrutinib orally once daily starting 7 days prior to mosunetuzumab and continue for up to 52 weeks. Mosunetuzumab is administered intravenously on days 1, 8, and 15 of cycle 1, then on day 1 of remaining cycles, repeating every 21 days for up to 17 cycles.

52 weeks

Multiple visits (in-person) for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up at 30 days and then at standard of care intervals for up to 4 years.

4 years

Regular visits (in-person) at standard of care intervals

Treatment Details

Interventions

• Mosunetuzumab
• Pirtobrutinib

Trial Overview This phase II trial tests the combination of pirtobrutinib and mosunetuzumab in treating relapsed/refractory follicular lymphoma. Pirtobrutinib blocks a protein that signals cancer cells to grow, while mosunetuzumab recruits T cells to attack the cancer.

Participant Groups

Group I: Treatment (pirtobrutinib, mosunetuzumab) Experimental Treatment 9 Interventions

Patients receive pirtobrutinib PO QD on 7 days prior to the start of mosunetuzumab (day -7) and continue it until up to 52 weeks. Patients receive mosunetuzumab intravenously (IV) on days 1, 8, and 15 of cycle 1 then on day 1 of remaining cycles. Cycles of mosunetuzumab repeat every 21 days for up to 17 cycles in the absence of disease progression or unacceptable toxicity. Patients with a CR after cycle 8 discontinue mosunetuzumab. Patients also undergo blood sample and oral swab and/or rectal swab collection, tissue biopsy, CT, and PET/CT throughout the study. Additionally, patients may undergo bone marrow aspiration and biopsy at screening and after cycle 8.

Who Is Running the Clinical Trial?

University of Washington

Lead Sponsor

Trials

1,858

Recruited

2,023,000+

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

Findings from Research

In a study comparing 90 patients from a mosunetuzumab clinical trial to 158 patients from real-world data, mosunetuzumab showed higher overall response (80% vs. 75%) and complete response rates (60% vs. 33%) in treating relapsed/refractory follicular lymphoma.

The results indicate that mosunetuzumab provides a clinically meaningful benefit as a chemotherapy-free treatment option, with better progression-free survival and overall survival outcomes compared to the real-world cohort.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative effectiveness between mosunetuzumab monotherapy clinical trial and real-world data in relapsed/refractory follicular lymphoma in third or subsequent lines of systemic therapy. McGough, SF., Shamas, N., Wang, J., et al.[2023]

Mosunetuzumab, a bispecific antibody targeting CD20 and CD3, has received conditional approval in the EU for treating adults with relapsed or refractory follicular lymphoma after at least two prior therapies.

This approval marks a significant milestone in the development of mosunetuzumab, highlighting its potential as a new treatment option for patients with difficult-to-treat lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mosunetuzumab: First Approval. Kang, C.[2022]

A meta-analysis of 53 Phase II/III/IV trials involving nearly 20,000 patients revealed that molecular target anticancer drugs significantly increase the risk of serious adverse events (SAEs) by 57% and fatal adverse events (FAEs) by 51% compared to placebo.

The overall incidence rates for SAEs and FAEs were found to be 26.9% and 2.3%, respectively, highlighting the need for careful monitoring and preventive measures for patients receiving these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk of serious adverse event and fatal adverse event with molecular target anticancer drugs in cancer patients: A meta-analysis. Wang, Z., Yang, X., Wang, J., et al.[2020]

In a study of 64 HER2-positive metastatic breast cancer patients treated with pyrotinib, the objective response rate was 73.4%, indicating that pyrotinib is highly effective even for patients previously treated with lapatinib.

The most common grade 3 adverse events were manageable, with diarrhea occurring in 28.1% of patients, suggesting that pyrotinib has an acceptable safety profile for treating this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Analysis of the Efficacy and Safety of a Novel Irreversible HER2 Tyrosine Kinase Inhibitor Pyrotinib in Patients with HER2-Positive Metastatic Breast Cancer. Sun, Y., Chen, B., Li, J., et al.[2022]

HER2-positive metastatic breast cancer is more aggressive and often develops resistance to treatments compared to HER2-negative tumors, making effective management crucial.

Trastuzumab is the standard treatment for HER2-positive cases, but lapatinib has been developed as a targeted therapy that works inside the cell to disrupt harmful signaling pathways, offering a potential solution to overcome resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overcoming treatment challenges in advanced breast cancer. Harkins, B., Geyer, CE.[2018]

A total of 3120 adverse event cases related to avapritinib were reported to the FDA, with 44% occurring within the first 30 days of treatment, highlighting the importance of monitoring patients closely during this period.

The study found that elderly male patients are at a higher risk for serious adverse events, indicating that clinicians should exercise caution when prescribing avapritinib to this demographic.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A post-marketing pharmacovigilance study of avapritinib: Adverse event data mining and analysis based on the United States Food and Drug Administration Adverse Event Reporting System database. Rong, L., Xie, M., Jiang, M., et al.[2023]

In a study of 470 Japanese patients with imatinib-resistant or intolerant gastrointestinal stromal tumors, sunitinib demonstrated good efficacy with a 20% objective response rate and a median progression-free survival of 22.4 weeks.

The treatment was generally well-tolerated, with 70% of patients experiencing grade ≥ 3 adverse events, but specific early adverse events like hand-foot syndrome and leukopenia were linked to improved progression-free survival, indicating they may serve as positive prognostic markers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, efficacy and prognostic analyses of sunitinib in the post-marketing surveillance study of Japanese patients with gastrointestinal stromal tumor. Komatsu, Y., Ohki, E., Ueno, N., et al.[2022]

In a first-in-human trial involving 230 patients with relapsed or refractory B-cell non-Hodgkin lymphomas, mosunetuzumab demonstrated a manageable safety profile with common side effects like neutropenia and cytokine release syndrome, mostly low-grade and occurring primarily in the first treatment cycle.

The treatment showed promising efficacy, with overall response rates of 34.9% for aggressive and 66.2% for indolent B-NHL, and complete response rates of 19.4% and 48.5%, respectively, indicating that mosunetuzumab can induce durable responses in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-Agent Mosunetuzumab Shows Durable Complete Responses in Patients With Relapsed or Refractory B-Cell Lymphomas: Phase I Dose-Escalation Study. Budde, LE., Assouline, S., Sehn, LH., et al.[2023]

References

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

Comparative effectiveness between mosunetuzumab monotherapy clinical trial and real-world data in relapsed/refractory follicular lymphoma in third or subsequent lines of systemic therapy. [2023]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Mosunetuzumab: First Approval. [2022]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Cost effectiveness of rituximab maintenance therapy in follicular lymphoma: long-term economic evaluation. [2022]

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

Bispecific Antibody Takes Down FL. [2022]

5. New Zealand pubmed.ncbi.nlm.nih.gov

Targeted Treatment of Relapsed or Refractory Follicular Lymphoma: Focus on the Therapeutic Potential of Mosunetuzumab. [2023]

6. India pubmed.ncbi.nlm.nih.gov

Risk of serious adverse event and fatal adverse event with molecular target anticancer drugs in cancer patients: A meta-analysis. [2020]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Real-World Analysis of the Efficacy and Safety of a Novel Irreversible HER2 Tyrosine Kinase Inhibitor Pyrotinib in Patients with HER2-Positive Metastatic Breast Cancer. [2022]

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

Overcoming treatment challenges in advanced breast cancer. [2018]

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

A post-marketing pharmacovigilance study of avapritinib: Adverse event data mining and analysis based on the United States Food and Drug Administration Adverse Event Reporting System database. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Safety, efficacy and prognostic analyses of sunitinib in the post-marketing surveillance study of Japanese patients with gastrointestinal stromal tumor. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Follicular lymphoma: Update on management and emerging therapies at the dawn of the new decade. [2020]

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

Single-Agent Mosunetuzumab Shows Durable Complete Responses in Patients With Relapsed or Refractory B-Cell Lymphomas: Phase I Dose-Escalation Study. [2023]