Acalabrutinib + Rituximab and CAR T-Cell Therapy for Mantle Cell Lymphoma

Overseen By Preetesh Jain, MD, PHD

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: HIV, Hepatitis B/C, CNS involvement, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether a combination of treatments—acalabrutinib, rituximab, and CAR T-cell therapy—can help manage mantle cell lymphoma (MCL), a type of blood cancer. It consists of two parts: one involving several cycles of acalabrutinib and rituximab, and another involving a procedure to collect certain immune cells for therapy. Individuals newly diagnosed with high-risk MCL who have not yet started treatment might be eligible. Participants should be prepared to undergo various study procedures and take medications as directed. As an Early Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the chance to be among the first to receive this innovative therapy.

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 use strong CYP3A inhibitors or inducers within a certain period before starting the study drug, and you cannot take warfarin or similar medications. It's best to discuss your current medications with the study team.

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

Previous studies have examined the drugs acalabrutinib and rituximab for treating mantle cell lymphoma. Research shows that patients generally tolerate these treatments well. Common side effects include anemia (low red blood cell count), neutropenia (low white blood cell count), and infections, occurring in more than 30% of patients in some studies.

Brexucabtagene autoleucel, a type of CAR T-cell therapy, is approved for treating mantle cell lymphoma that has recurred or not responded to other treatments. This approval provides some established safety knowledge. However, it can cause serious side effects, such as cytokine release syndrome (a severe immune reaction) and neurological problems. These effects are serious but are known and managed in clinical settings.

These treatments have been tested, offering insights into their safety, though the specific combinations in this trial are still under study. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for Mantle Cell Lymphoma because they offer new ways to target the cancer. Acalabrutinib, part of the first arm, is a next-generation Bruton's tyrosine kinase (BTK) inhibitor that specifically blocks signals needed for the survival of lymphoma cells, potentially leading to fewer side effects compared to traditional chemotherapy. In the second arm, Brexucabtagene Autoleucel is a type of CAR T-cell therapy that involves reprogramming a patient's own T cells to better recognize and fight cancer cells, providing a personalized and potentially more effective approach. Together, these treatments could offer more targeted and individualized options for patients compared to existing therapies.

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

Research has shown that using acalabrutinib and rituximab together is very effective as an initial treatment for mantle cell lymphoma (MCL), particularly in older adults. In this trial, some participants will receive this combination to manage the disease in those who haven't received prior treatment. Conversely, brexucabtagene autoleucel, another treatment option in this trial, proved very effective for patients whose MCL has returned or hasn't responded to other treatments. It has a high success rate, with many patients experiencing a reduction or disappearance of their disease.

Both treatment options in this trial have demonstrated promising results in different scenarios for treating MCL. ^{2 4 5 6 7}

Who Is on the Research Team?

Preetesh Jain, MD, PHD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with newly diagnosed high-risk mantle cell lymphoma who haven't had treatment before. They must have specific genetic markers, be able to swallow pills, and have a good performance status (able to carry out daily activities). Women should not be pregnant and must use birth control. People can't join if they've had other cancers needing active treatment, certain heart or blood conditions, or are HIV positive.

Inclusion Criteria

Bi-dimensional measurable disease using the 2014 Cheson criteria

Specific serum bilirubin and Cr Clearance levels

ANC > 1,000/mm3 and platelet count >100,000/mm3

Exclusion Criteria

I have not received any live vaccines in the last 6 weeks.

Abnormal PT/INR or aPTT levels

I am currently on medication for an infection.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Part 1

Participants receive acalabrutinib and rituximab for up to 12 cycles, each cycle lasting 28 days

48 weeks

Treatment Part 2

Participants undergo leukapheresis to collect T cells, followed by CAR T-cell therapy

4 weeks

Follow-up

Participants are monitored for safety and effectiveness after CAR T-cell therapy

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Acalabrutinib
• Brexucabtagene Autoleucel
• Rituximab

Trial Overview The study tests a combination of acalabrutinib and rituximab followed by brexucabtagene autoleucel therapy in patients with untreated high-risk mantle cell lymphoma. The goal is to see if this regimen controls the disease better than current treatments.

How Is the Trial Designed?

Group I: Brexucabtagene Autoleucel (Part 2) Experimental Treatment 3 Interventions

Participants will have a procedure called leukapheresis to collect enough T cells.

Group II: Acalabrutinib and Rituximab (Part 1) Experimental Treatment 4 Interventions

Participants may receive acalabrutinib and rituximab for up to 12 cycles. Each cycle is 28 days.

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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Acerta Pharma, LLC

Collaborator

Trials

8

Recruited

390+

Kite, A Gilead Company

Industry Sponsor

Trials

45

Recruited

4,300+

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]

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]

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]

Bruton's tyrosine kinase inhibitors, such as ibrutinib, acalabrutinib, and zanubrutinib, are effective and well-tolerated treatment options for patients with mantle cell lymphoma who have already undergone one line of therapy.

These inhibitors offer a promising alternative for patients who experience relapse or drug resistance after initial chemo-immunotherapy, highlighting the need for novel treatment strategies in this aggressive lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of Bruton's tyrosine kinase inhibitors in the management of mantle cell lymphoma. Hanna, KS., Campbell, M., Husak, A., et al.[2021]

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 Bruton tyrosine kinase inhibitor, showed a 53% overall response rate in patients with relapsed/refractory marginal zone lymphoma, indicating its efficacy in this patient population.

The treatment was generally well tolerated, with a median progression-free survival of 27.4 months and a low incidence of severe adverse events, suggesting improved safety compared to other treatments like ibrutinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 2, multicentre, open-label trial (ACE-LY-003) of acalabrutinib in patients with relapsed or refractory marginal zone lymphoma. Strati, P., Coleman, M., Champion, R., et al.[2022]

Acalabrutinib, an oral Bruton tyrosine kinase inhibitor, has shown an impressive overall response rate of 81% in patients with relapsed mantle cell lymphoma (MCL), indicating its efficacy as a treatment option.

This novel therapy is not only approved for relapsed MCL but is also being tested as a first-line treatment, highlighting its potential to improve outcomes for patients with this challenging type of lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib for mantle cell lymphoma. Witzig, TE., Inwards, D.[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]

Citations

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Acalabrutinib and Rituximab in Elderly Patients with Newly ... Acalabrutinib with Rituximab Is Highly Effective First Line Treatment for Older Patients with Mantle Cell Lymphoma. Preetesh Jain, Chi Young ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04765111

Acalabrutinib and Rituximab for the Treatment of ... This phase II trial studies the side effects of acalabrutinib and rituximab and its effect in treating patients with previously untreated mantle cell lymphoma.

3. 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 ...

4. bostongene.com bostongene.com/news-and-publications/publications/acalabrutinib-with-rituximab-is-highly-effective-as-a-first-line-treatment-for-older-patients-with-mantle-cell-lymphoma?qr=event

Acalabrutinib with rituximab is highly effective as a first-line ... Acalabrutinib with rituximab is highly effective as a first-line treatment for older patients with mantle cell lymphoma. 3 min to read. Authors. Preetesh Jain¹, ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10772531/

Final results and overall survival data from a phase II study ... Acalabrutinib monotherapy in patients with relapsed/refractory mantle cell lymphoma: longterm efficacy and safety results from a phase 2 study. Blood. 2020 ...

6. haematologica.org haematologica.org/article/view/haematol.2023.284896

Safety and efficacy of acalabrutinib plus bendamustine and ... Results indicate that ABR was safe and efficacious, supporting further study in patients with TN MCL. Introduction. Mantle cell lymphoma (MCL) ...

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2024/216387s004lbl.pdf

Clinical Trials - accessdata.fda.gov In this pooled safety population, adverse reactions in ≥ 30% of 1029 patients were anemia, neutropenia, upper respiratory tract infection, thrombocytopenia, ...