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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of three treatments—acalabrutinib, obinutuzumab, and glofitamab—to evaluate their effectiveness for people with mantle cell lymphoma, a cancer affecting white blood cells that has recurred or resisted previous treatments. Acalabrutinib aims to stop cancer cell growth, obinutuzumab helps the immune system attack the cancer, and glofitamab seeks to kill cancer cells by activating immune cells. Individuals with mantle cell lymphoma who have active disease requiring treatment and have tried at least one other treatment may be suitable for this study. As a Phase 2 trial, the research focuses on assessing 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 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.

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

Research has shown that using acalabrutinib, obinutuzumab, and glofitamab together may be safe and effective for patients with relapsed or refractory mantle cell lymphoma. Acalabrutinib, already approved for some blood cancers, is generally well-tolerated. Previous studies with acalabrutinib and other treatments have shown that patients usually do not experience severe side effects.

Obinutuzumab, a type of protein, helps the immune system find and attack cancer cells and is often safely used with other cancer treatments. Glofitamab, a newer medication, connects T cells and cancer cells, aiding the immune system in fighting cancer. Although still under study, early results suggest it can be used safely.

Together, these treatments aim to target cancer more effectively, and studies so far suggest that patients can handle this approach well. However, ongoing research will provide more information on long-term safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of acalabrutinib, obinutuzumab, and glofitamab for treating Mantle Cell Lymphoma because it introduces a novel approach that could enhance treatment efficacy. Unlike standard therapies like chemo-immunotherapy, this combination includes acalabrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, which specifically targets signaling pathways crucial for cancer cell survival. Glofitamab is a bispecific antibody designed to engage the immune system directly to attack the cancer cells, offering a fresh strategy compared to traditional treatments. By integrating these targeted therapies, the combination has the potential to improve outcomes and offer hope for patients with this challenging type of lymphoma.

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

Research has shown that combining acalabrutinib, obinutuzumab, and glofitamab might help treat mantle cell lymphoma that has returned or hasn't responded to treatment. In this trial, participants will receive a combination of these three treatments. Acalabrutinib blocks a protein that aids cancer cell growth. Obinutuzumab is a protein that helps the immune system attack cancer cells. Glofitamab assists immune cells called T cells in connecting to and killing cancer cells. Early results are promising, but further research is needed to confirm their combined effectiveness. ^{1 5 6 7 8}

Who Is on the Research Team?

John Baird, M.D.

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

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 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 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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 (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]

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]

Citations

1. withpower.com withpower.com/trial/phase-2-lymphoma-9-2023-4db67

Acalabrutinib + Obinutuzumab + Glofitamab for Mantle Cell ... Giving acalabrutinib, obinutuzumab, and glofitamab together may be a safe and effective treatment for patients with relapsed or refractory mantle cell lymphoma.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06054776

NCT06054776 | Acalabrutinib, Obinutuzumab, and ... Giving acalabrutinib, obinutuzumab, and glofitamab together may be a safe and effective treatment for patients with relapsed or refractory mantle cell lymphoma.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12248784/

Next-Generation Therapies in Mantle Cell Lymphoma (MCL) Data on the Glofitamab efficacy in R/R MCL are encouraging; however, follow-up is still limited compared to, for example, with CAR-T, and more mature data ...

4. cancer.gov cancer.gov/research/participate/clinical-trials/intervention/acalabrutinib?pn=1

Clinical Trials Using Acalabrutinib - NCI NCI supports clinical trials that test new and more effective ways to treat cancer. Find clinical trials studying acalabrutinib.

5. physicianresources.dana-farber.org physicianresources.dana-farber.org/news/clinical-trials-and-research-for-mantle-cell-lymphoma

Clinical Trials and Research for Mantle Cell Lymphoma Acalabrutinib and venetoclax are oral medicines that target survival pathways of the mantle cell lymphoma cells. Obinutuzumab is administered by ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11665716/

Your chemo is no good here: management of high-risk MCL Acalabrutinib plus bendamustine and rituximab in untreated mantle cell lymphoma: results from the phase 3, double- blind, placebo-controlled ...

7. ascopubs.org ascopubs.org/doi/10.1200/JCO-25-00690

Acalabrutinib Plus Bendamustine-Rituximab in Untreated ... The combination of the Bruton tyrosine kinase inhibitor ibrutinib with bendamustine-rituximab for first-line treatment of mantle cell lymphoma (MCL) prolonged ...

8. haematologica.org haematologica.org/article/view/11822

therapeutic strategies for mantle cell lymphoma relapsed or ... Although these efficacy and safety outcomes are promising, long-term follow-up is needed and will be assessed in the randomized phase III ...