Glofitamab + Pirtobrutinib for Mantle Cell Lymphoma

Recruiting at 1 trial location

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the safety and effectiveness of two drugs, glofitamab and pirtobrutinib, for individuals with mantle cell lymphoma that has returned after treatment or did not respond to it. Glofitamab (also known as COLUMVI) and obinutuzumab aim to stop cancer cells from growing, while pirtobrutinib (also known as Jaypirca) blocks signals that help these cells multiply. This study may suit individuals who have tried other treatments for mantle cell lymphoma but still experience symptoms. As a Phase 2 trial, the research focuses on measuring how well the treatment works in an initial, smaller group of people.

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

Research shows that combining glofitamab and pirtobrutinib holds promise for safely treating relapsed or refractory mantle cell lymphoma. Studies have found this combination effective with manageable side effects. For instance, previous trials indicated that patients handled glofitamab's side effects well when used with appropriate support. Additionally, pirtobrutinib has demonstrated good response rates in patients who have undergone several prior treatments, though real-world data remains limited. Overall, the combination appears well-tolerated, with side effects that patients can manage. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of glofitamab and pirtobrutinib for treating mantle cell lymphoma because these treatments work together to target the disease in a novel way. Glofitamab is a bispecific antibody, which means it can simultaneously bind to both the cancer cells and the immune cells, helping the immune system directly attack the lymphoma cells. Pirtobrutinib, on the other hand, is a next-generation BTK inhibitor that blocks signals cancer cells use to survive and grow, and it has shown effectiveness even in cases where other BTK inhibitors might fail. This dual approach not only provides a new mechanism of action but also has the potential to improve outcomes for patients who might not respond to existing therapies like chemotherapy or other BTK inhibitors.

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

Research has shown that combining glofitamab and pirtobrutinib may help treat mantle cell lymphoma that has returned or resisted other treatments. In this trial, participants will receive a combination of glofitamab, pirtobrutinib, and obinutuzumab. Studies have found that glofitamab, an antibody, can help the immune system target and attack cancer cells. Pirtobrutinib, a drug, blocks signals that promote cancer cell growth. Early results suggest this combination works well and is generally safe for patients. This approach could offer new hope for those with challenging cases of mantle cell lymphoma. ^{1 2 3 5 6}

Who Is on the Research Team?

Madhav Seshadri, MD

Principal Investigator

University of California, San Francisco

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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 up to Cycle 30, Day 22. 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+

University of California, San Francisco

Lead Sponsor

Trials

2,636

Recruited

19,080,000+

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+

Published Research Related to This Trial

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]

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]

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]

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, 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]

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 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 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06252675

NCT06252675 | Glofitamab With Pirtobrutinib for Relapsed ... This phase II trial tests the safety and effectiveness of glofitamab given in combination with pirtobrutinib in treating patients with mantle cell lymphoma ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.23.02470

Glofitamab in Relapsed/Refractory Mantle Cell Lymphoma This phase I/II NP30179 study investigated the efficacy and safety of glofitamab, a T-cell–engaging CD20 × CD3 bispecific antibody, for the ...

3. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/3042.3/529187/Combination-of-Glofitamab-with-Pirtobrutinib-in

Combination of Glofitamab with Pirtobrutinib in BTK Inhibitor ... The combination of pirtobrutinib with glofitamab will be highly effective with tolerable toxicity in BTKi-naive or BTKi-intolerant patients with R/R MCL.

4. 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.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT05833763?term=AREA%5BConditionSearch%5D(%22Mantle%20Cell%20Lymphoma%22)%20AND%20AREA%5BInterventionSearch%5D(%22Enzyme%20Inhibitors%22)&rank=4

A Phase 2 Trial of GlOfitamab anD pIrtobrutinib in Mantle ... The goal of this clinical trial is to evaluate the safety and response of combining Pirtobrutinib and Glofitimab in patients with relapsed MCL.

6. onclive.com onclive.com/view/glofitamab-plus-pirtobrutinib-yields-high-activity-tolerability-in-covalent-btk-inhibitor-exposed-mcl

Glofitamab Plus Pirtobrutinib Yields High Activity ... - OncLive Results from the GoldiLox trial showed high complete and MRD-negative responses with glofitamab plus pirtobrutinib in covalent BTK inhibitor–exposed MCL.