Acalabrutinib + Obinutuzumab + Glofitamab for Mantle Cell Lymphoma

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: City of Hope Medical Center

Must not be taking: Bispecific antibodies, BTK inhibitors

Disqualifiers: CNS disease, Cardiovascular disease, 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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 13

Duration: 36 weeks

40 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies the side effects of acalabrutinib, obinutuzumab, and glofitamab and how well they work together for 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). Acalabrutinib is in a class of medications called kinase inhibitors. It blocks a protein called BTK, which is present on B-cell (a type of white blood cells) cancers such as mantel cell lymphoma at abnormal levels. This may help keep cancer cells from growing and spreading. A monoclonal antibody is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens). Immunotherapy with monoclonal antibodies, such as obinutuzumab, may help the body's immune system attack the cancer, and may interfere with the ability of cancer cells to grow and spread. Glofitamab is a class of medications called bispecific antibodies. Bispecific antibodies are designed to simultaneously bind to T cells and cancer cell antigens, leading to T-cell activation, proliferation, and cancer cell death. Giving acalabrutinib, obinutuzumab, and glofitamab together may be a safe and effective treatment for patients with relapsed or refractory mantle cell lymphoma.

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 treatment with certain medications like strong CYP3A4 inhibitors/inducers or systemic immunosuppressive medications within a specific timeframe before starting the trial. It's best to discuss your current medications with the study team to see if they might affect your eligibility.

What data supports the effectiveness of the drug combination Acalabrutinib, Obinutuzumab, and Glofitamab for treating Mantle Cell Lymphoma?

Acalabrutinib has been approved by the FDA for treating mantle cell lymphoma based on a phase II study, showing its effectiveness in this condition. Additionally, Acalabrutinib has shown a favorable safety profile in chronic lymphocytic leukemia, suggesting it may be a well-tolerated option for patients. While specific data on the combination with Obinutuzumab and Glofitamab is not provided, Acalabrutinib's approval and safety profile offer some support for its use in mantle cell lymphoma. ^{1 2 3 4 5}

What makes the drug combination of Acalabrutinib, Glofitamab, and Obinutuzumab unique for treating mantle cell lymphoma?

This drug combination is unique because it includes Acalabrutinib, a highly selective Bruton tyrosine kinase inhibitor, which has shown improved safety and tolerability compared to other similar drugs, and is combined with Glofitamab and Obinutuzumab, which are designed to target and destroy cancer cells more effectively. ^{1 3 4 6 7}

Research Team

John Baird, M.D.

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

This trial is for adults with mantle cell lymphoma that has returned or didn't respond to previous treatments. Participants must be in fairly good health, have a certain level of blood counts and organ function, and agree to use effective birth control. People can't join if they've had certain recent cancer treatments, used T-cell engaging bispecific antibodies before, or been exposed to BTK inhibitors like ibrutinib.

Inclusion Criteria

My white blood cell count is healthy, or I have bone marrow involvement.

I haven't used growth factor treatments in the last 7 days, unless my low blood cell count is due to my disease.

I haven't had a platelet transfusion in the last 7 days unless it was for my disease.

Exclusion Criteria

I have previously been treated with a BTK inhibitor.

I have been treated with a bispecific antibody before.

I haven't had cancer treatment with antibodies, chemo, or radiation in the last 2-4 weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive acalabrutinib orally twice daily, obinutuzumab intravenously on days 1 and 7 of cycle 1, and glofitamab intravenously on days 8 and 15 of cycle 1 and day 1 of subsequent cycles. Treatment repeats every 21 days for up to 12 cycles.

36 weeks

12 cycles, multiple visits per cycle

Follow-up

Participants are monitored for response and survival. Follow-up occurs at 30 days post-treatment, then every 3 months for response and bi-annually for survival.

Up to 4 years

Regular follow-up visits

Extension

Participants with MRD positive complete response, partial response, or stable disease after 12 cycles may continue receiving single agent acalabrutinib per standard of care.

Long-term

Treatment Details

Interventions

• Acalabrutinib
• Glofitamab
• Obinutuzumab

Trial Overview The trial tests the combination of acalabrutinib (a kinase inhibitor), obinutuzumab (a monoclonal antibody), and glofitamab (a bispecific antibody) on patients with relapsed/refractory mantle cell lymphoma. It aims to see how well these drugs work together and what side effects they might cause.

Participant Groups

Group I: Treatment (acalabrutinib, obinutuzumab, glofitamab) Experimental Treatment 9 Interventions

Patients recieve acalabrutinib PO BID of each cycle, obinutuzumab IV on days 1 and 7 of cycle 1 only, and glofitamab IV over 2-4 hours on days 8 and 15 of cycle 1 and day 1 of each subsequent cycle. Treatment repeats every 21 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients with MRD positive CR, PR, or SD after 12 cycles of protocol therapy may continue receiving single agent acalabrutinib per standard of care during the follow-up phase of the study. Patients also undergo a ECHO or MUGA during screening, as well as PET/CT or CT, and blood specimen collection throughout the trial. Patients may also undergo bone marrow biopsies throughout the trial.

Acalabrutinib is already approved in United States, European Union for the following indications:

Approved in United States as Calquence for:

• Mantle cell lymphoma
• Chronic lymphocytic leukemia
• Small lymphocytic lymphoma

Approved in European Union as Calquence for:

• Chronic lymphocytic leukemia
• Small lymphocytic lymphoma
• Mantle cell lymphoma

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

Acalabrutinib (Calquence®) has received accelerated approval from the US FDA for treating mantle cell lymphoma, based on promising results from a phase II study.

Phase III trials are currently ongoing for acalabrutinib in mantle cell lymphoma and chronic lymphocytic leukaemia, indicating its potential for broader application in treating hematological cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib: First Global Approval. Markham, A., Dhillon, S.[2018]

Acalabrutinib demonstrated significantly higher overall response rates (ORR) and complete response (CR) rates compared to other targeted therapies for relapsed/refractory mantle cell lymphoma (MCL), indicating its efficacy in treating this condition.

The safety profile of acalabrutinib was comparable or better than that of other monotherapies, although it did show increased risks of infection and anemia compared to certain combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Matching-adjusted Indirect Comparisons of the Efficacy and Safety of Acalabrutinib Versus Other Targeted Therapies in Relapsed/Refractory Mantle Cell Lymphoma. Telford, C., Kabadi, SM., Abhyankar, S., et al.[2021]

Acalabrutinib, a selective BTK inhibitor, is effective for treating mantle cell lymphoma (MCL) in patients who have already undergone at least one therapy, with serious side effects being rare.

While common side effects like headaches are generally mild and resolve quickly, patients should be cautious about drug interactions and consult their physician before taking additional medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of acalabrutinib in patients with mantle cell lymphoma. Awan, FT., Jurczak, W.[2021]

Acalabrutinib, a selective Bruton tyrosine kinase inhibitor, showed improved safety outcomes compared to other targeted therapies for treatment-naïve chronic lymphocytic leukemia (CLL) patients, although it was associated with a higher risk of neutropenia and leukopenia in some cases.

The analysis indicated that acalabrutinib (with or without obinutuzumab) had similar efficacy in terms of progression-free survival compared to other treatments, suggesting it is a safe and effective option for CLL patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Matching-adjusted indirect comparisons of safety and efficacy of acalabrutinib versus other targeted therapies in patients with treatment-naïve chronic lymphocytic leukemia. Davids, MS., Telford, C., Abhyankar, S., et al.[2021]

Ofatumumab, an anti-CD20 monoclonal antibody, showed greater effectiveness than rituximab in preclinical models of mantle cell lymphoma (MCL), particularly in cases resistant to rituximab.

In murine models, ofatumumab not only enhanced tumor cell destruction but also delayed tumor progression and extended survival, suggesting its potential as a promising treatment option for MCL when combined with standard chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ofatumumab Exhibits Enhanced In Vitro and In Vivo Activity Compared to Rituximab in Preclinical Models of Mantle Cell Lymphoma. Barth, MJ., Mavis, C., Czuczman, MS., et al.[2019]

In a pivotal phase 3 study with 310 patients, acalabrutinib significantly improved progression-free survival (PFS) compared to standard treatments (Idelalisib plus rituximab or bendamustine plus rituximab), with a median PFS not reached for acalabrutinib versus 16.8 months for IdR/BR.

After approximately 4 years of follow-up, acalabrutinib demonstrated a favorable safety profile, with lower rates of treatment discontinuation due to adverse events compared to IdR/BR, while maintaining similar rates of serious infections and other significant side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib Versus Investigator's Choice in Relapsed/Refractory Chronic Lymphocytic Leukemia: Final ASCEND Trial Results. Ghia, P., Pluta, A., Wach, M., et al.[2022]

In a phase 2 trial involving 124 patients with relapsed or refractory mantle cell lymphoma, acalabrutinib was associated with common treatment-related adverse events (AEs) like headache and diarrhea, but these did not lead to any treatment discontinuations.

Effective management strategies, including patient education and the use of over-the-counter medications for mild AEs, helped maintain treatment adherence and allowed for better tracking and management of nonadherence issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib: Managing Adverse Events and Improving Adherence in Patients With Mantle Cell Lymphoma. Badillo, M., Nava, D., Rosa, M., et al.[2022]

References

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

Acalabrutinib: First Global Approval. [2018]

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

Matching-adjusted Indirect Comparisons of the Efficacy and Safety of Acalabrutinib Versus Other Targeted Therapies in Relapsed/Refractory Mantle Cell Lymphoma. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Use of acalabrutinib in patients with mantle cell lymphoma. [2021]

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

Matching-adjusted indirect comparisons of safety and efficacy of acalabrutinib versus other targeted therapies in patients with treatment-naïve chronic lymphocytic leukemia. [2021]

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

Ofatumumab Exhibits Enhanced In Vitro and In Vivo Activity Compared to Rituximab in Preclinical Models of Mantle Cell Lymphoma. [2019]

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

Acalabrutinib Versus Investigator's Choice in Relapsed/Refractory Chronic Lymphocytic Leukemia: Final ASCEND Trial Results. [2022]

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

Acalabrutinib: Managing Adverse Events and Improving Adherence in Patients With Mantle Cell Lymphoma. [2022]