Glofitamab + Pirtobrutinib for Mantle Cell Lymphoma

Overseen By UCSF Hematopoietic Malignancies Clinical Trial Recruitment

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: C. Babis Andreadis

Must be taking: Antivirals

Must not be taking: Anticoagulants, CYP3A modulators

Disqualifiers: Pregnancy, CNS disease, Autoimmune, 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: 36 weeks

30 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial tests the safety and effectiveness of glofitamab given in combination with pirtobrutinib in treating patients with mantle cell lymphoma that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). Glofitamab and obinutuzumab are monoclonal antibodies that may interfere with the ability of cancer cells to grow and spread. Obinutuzumab may also reduce the risk of immune-related conditions from treatment. Pirtobrutinib is in a class of medications called kinase inhibitors. It works by blocking the action of the protein that signals cancer cells to multiply. Giving glofitamab in combination with pirtobrutinib may be safe, tolerable and/or effective in treating patients with relapsed or refractory mantle cell lymphoma.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, if you are on strong CYP3A inhibitors or inducers, you will need to stop them and have a washout period (time without taking certain medications) of at least 5 half-lives before starting the study treatment.

Is the combination of Glofitamab and Pirtobrutinib safe for humans?

Pirtobrutinib has been approved for use in mantle cell lymphoma and has shown some common side effects like fatigue, muscle pain, diarrhea, and bruising. Serious warnings include risks of infection, bleeding, and heart rhythm problems. Glofitamab's safety profile is not detailed in the provided research, but it is important to consult with healthcare providers for comprehensive safety information. ^{1 2 3 4 5}

What makes the drug combination of Glofitamab and Pirtobrutinib unique for treating Mantle Cell Lymphoma?

Glofitamab is a novel drug that works by engaging T-cells to attack cancer cells, using a unique structure that targets specific proteins on both T-cells and cancer cells, which may offer a new option for patients with limited treatment choices. Pirtobrutinib is a targeted therapy that inhibits a protein involved in cancer cell growth, and together, these drugs may provide a more effective treatment for Mantle Cell Lymphoma compared to traditional therapies. ^{6 7 8 9 10}

Research Team

C. Babis Andreadis, MD

Principal Investigator

University of California, San Francisco

Eligibility Criteria

This trial is for individuals with mantle cell lymphoma that has returned or hasn't responded to treatment. Participants should have tried at least one prior therapy and be suitable for bone marrow biopsy, tumor imaging, and biospecimen collection.

Inclusion Criteria

Negative serum pregnancy test for women of childbearing potential

Hemoglobin ≥ 9 g/dL

Creatinine clearance >= 50 mL/min

Exclusion Criteria

Pregnant or intention of becoming pregnant within specified timeframes

Prolongation of QTc for heart rate using Fridericia's Formula > 470 msec

Known hypersensitivity to any of the excipients of pirtobrutinib or intended study medications

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive obinutuzumab, glofitamab, and pirtobrutinib in cycles of 21 days for up to 12 cycles

36 weeks

Multiple visits per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

Up to 2 years

Every 3 months

Treatment Details

Interventions

• Glofitamab
• Obinutuzumab
• Pirtobrutinib

Trial Overview The trial tests the combination of glofitamab (a monoclonal antibody) with pirtobrutinib (a kinase inhibitor) against mantle cell lymphoma. It also uses obinutuzumab potentially to reduce immune-related side effects.

Participant Groups

Group I: Treatment (obinutuzumab, glofitamab, pirtobrutinib) Experimental Treatment 7 Interventions

Participants receive obinutuzumab IV on days 1 and 2 of cycle 1 for a total of 2 doses. Participants receive glofitamab IV on days 8 and 15 of cycle 1 and day 1 of remaining cycles. Cycles repeat every 21 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Participants receive pirtobrutinib PO once a day (QD) on days 1-21. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity. Participants also undergo FDG-PET/CT at screening, after every 4 cycles through cycle 13 and then after every 6 cycles. Participants will undergo a bone marrow biopsy and aspiration at cycle 13 and blood sample collection throughout study and a tissue biopsy at relapse or progression.

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

Approved in United States as COLUMVI for:

• Relapsed or refractory diffuse large B-cell lymphoma not otherwise specified (DLBCL), or large B-cell lymphoma (LBCL) arising from follicular lymphoma, after two or more lines of systemic therapy

Who Is Running the Clinical Trial?

C. Babis Andreadis

Lead Sponsor

Trials

5

Recruited

130+

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

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

Adaptive Biotechnologies

Industry Sponsor

Trials

14

Recruited

3,700+

Findings from Research

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]

Acalabrutinib, a Bruton's tyrosine kinase inhibitor, has been shown to be effective and safe for treating chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), with significant improvements in efficacy observed in both monotherapy and combination treatments.

In clinical studies, acalabrutinib demonstrated a high rate of molecular remission when combined with venetoclax, while maintaining an acceptable safety profile, although some adverse events occurred in over 20% of patients, including myelosuppression and gastrointestinal issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib and its use in the treatment of chronic lymphocytic leukemia. Egyed, M., Lueff, S., Borbely, J., et al.[2022]

Ibrutinib and acalabrutinib are effective BTK inhibitors that have been approved for treating relapsed or refractory mantle cell lymphoma (MCL), showing significant therapeutic benefits in clinical trials.

Acalabrutinib has a greater selectivity for BTK compared to ibrutinib, which reduces the risk of certain side effects like atrial fibrillation, although both drugs can still cause headaches and other toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bruton tyrosine kinase inhibitors for the treatment of mantle cell lymphoma: review of current evidence and future directions. Bond, DA., Alinari, L., Maddocks, K.[2021]

Zanubrutinib, a next-generation Bruton tyrosine kinase inhibitor, shows promise as a targeted therapy for mantle cell lymphoma, particularly for patients who are elderly or have comorbidities and cannot undergo standard treatments.

An ongoing Phase III study is evaluating the safety and efficacy of zanubrutinib combined with rituximab compared to bendamustine with rituximab in patients with untreated mantle cell lymphoma who are not eligible for stem cell transplant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase III study of zanubrutinib plus rituximab versus bendamustine plus rituximab in transplant-ineligible, untreated mantle cell lymphoma. Dreyling, M., Tam, CS., Wang, M., et al.[2021]

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]

Glofitamab, a bispecific monoclonal antibody targeting CD20 and CD3, was conditionally approved in Canada on March 25, 2023, for adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who have undergone multiple prior therapies and are ineligible for CAR T-cell therapy.

The drug is currently under regulatory review in the EU and USA, with ongoing clinical development as both a standalone treatment and in combination with other therapies for non-Hodgkin lymphomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glofitamab: First Approval. Shirley, M.[2023]

Glofitamab is a promising new treatment for B cell lymphomas that do not respond to standard R-CHOP chemotherapy, which fails in over one-third of cases.

As a bispecific antibody targeting CD20 and CD3, glofitamab works by engaging T cells to attack tumor cells, offering a novel approach for patients with relapsed or refractory lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glofitamab therapy for diffuse large B cell lymphoma: latest updates from the 2022 ASH Annual Meeting. Wang, C., Liu, Y.[2023]

Glofitamab is a novel bispecific T-cell recruiting antibody that targets both CD20 on B-cells and CD3 on T-cells, showing over 50% complete response rates in heavily treated patients with aggressive and indolent B-cell lymphoma during Phase 1 trials.

The unique 2:1 configuration of glofitamab allows for an extended half-life and superior binding to CD20, making it a promising option for patients with limited treatment choices, with ongoing trials evaluating its efficacy in combination therapies and earlier treatment lines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glofitamab CD20-TCB bispecific antibody. Minson, A., Dickinson, M.[2022]

Glofitamab, a bispecific antibody, demonstrated a 53.8% overall response rate in patients with relapsed or refractory B-cell non-Hodgkin lymphoma, with a complete response rate of 36.8%, indicating its efficacy in a heavily pretreated population.

The treatment had a manageable safety profile, with cytokine release syndrome occurring in 50.3% of patients but mostly at lower grades, and only 2.9% of patients withdrew due to adverse events, suggesting that glofitamab can be safely administered with prior obinutuzumab pretreatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glofitamab, a Novel, Bivalent CD20-Targeting T-Cell-Engaging Bispecific Antibody, Induces Durable Complete Remissions in Relapsed or Refractory B-Cell Lymphoma: A Phase I Trial. Hutchings, M., Morschhauser, F., Iacoboni, G., et al.[2023]

In a study of 57 patients with untreated mantle-cell lymphoma, a treatment regimen of four cycles of R-CHOP followed by yttrium-90 (90Y)-ibritumomab tiuxetan resulted in an overall response rate of 82%, indicating strong efficacy.

The median time to treatment failure was 34.2 months, and the estimated 5-year overall survival rate was 73%, demonstrating that this combination therapy is well-tolerated and offers promising outcomes compared to historical data with six cycles of R-CHOP.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone immunochemotherapy followed by yttrium-90-ibritumomab tiuxetan in untreated mantle-cell lymphoma: Eastern Cooperative Oncology Group Study E1499. Smith, MR., Li, H., Gordon, L., et al.[2021]

References

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

FDA Approval Summary: Pirtobrutinib for Relapsed or Refractory Mantle Cell Lymphoma. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Acalabrutinib and its use in the treatment of chronic lymphocytic leukemia. [2022]

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

Bruton tyrosine kinase inhibitors for the treatment of mantle cell lymphoma: review of current evidence and future directions. [2021]

4. England pubmed.ncbi.nlm.nih.gov

A Phase III study of zanubrutinib plus rituximab versus bendamustine plus rituximab in transplant-ineligible, untreated mantle cell lymphoma. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Pirtobrutinib: A novel non-covalent BTK inhibitor for the treatment of adults with relapsed/refractory mantle cell lymphoma. [2023]

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

Glofitamab: First Approval. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Glofitamab therapy for diffuse large B cell lymphoma: latest updates from the 2022 ASH Annual Meeting. [2023]

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

Glofitamab CD20-TCB bispecific antibody. [2022]

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

Glofitamab, a Novel, Bivalent CD20-Targeting T-Cell-Engaging Bispecific Antibody, Induces Durable Complete Remissions in Relapsed or Refractory B-Cell Lymphoma: A Phase I Trial. [2023]

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

Phase II study of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone immunochemotherapy followed by yttrium-90-ibritumomab tiuxetan in untreated mantle-cell lymphoma: Eastern Cooperative Oncology Group Study E1499. [2021]