CD19 CAR T-Cells + Acalabrutinib for Mantle Cell Lymphoma

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: City of Hope Medical Center

Must be taking: Acalabrutinib

Must not be taking: Systemic steroids, Immunosuppressants

Disqualifiers: Recent HCT, Cardiovascular disability, Auto-immune 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: 3

Duration: 6 months

36 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new approach to combat mantle cell lymphoma, a type of blood cancer that has returned or stopped responding to treatment. It combines a patient's own immune cells, modified to attack cancer cells, with acalabrutinib, a targeted therapy that may help stop cancer growth. The goal is to determine if this combination can kill more cancer cells than either treatment alone. Suitable participants have mantle cell lymphoma that has recurred or is unresponsive to treatment and have been taking acalabrutinib for a few months. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group, providing an opportunity to contribute to significant findings.

Will I have to stop taking my current medications?

The trial requires participants to be on acalabrutinib and may allow switching from other BTK inhibitors to acalabrutinib before starting the study. However, you cannot use other anti-cancer therapies or strong CYP3A4 inhibitors/inducers during the trial. If you are on anticoagulation with warfarin, you must stop it 7 days before leukapheresis and remain off it through the end of the study.

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

Research shows that acalabrutinib is usually well-tolerated by patients with relapsed or hard-to-treat mantle cell lymphoma. Studies indicate that it can be used safely, even by those with high-risk conditions. Common side effects include headaches, diarrhea, and tiredness, but these are often manageable.

Research has found CD19 CAR T cells effective in treating B-cell lymphoma. However, they can sometimes cause side effects like neurologic toxicity, which impacts the nervous system. Despite this, many patients experience long-term benefits with few lasting issues.

Both treatments have shown promise, but understanding the possible side effects is important. Discuss any concerns with the trial team to ensure a good fit. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of CD19 CAR T-cells and acalabrutinib for treating Mantle Cell Lymphoma because it offers a novel approach compared to current therapies. Unlike standard treatments, which often include chemotherapy and BTK inhibitors, this combination harnesses the power of the immune system by using genetically engineered T-cells to specifically target and destroy cancer cells. Acalabrutinib, a BTK inhibitor, enhances this effect by inhibiting pathways that help cancer cells survive, potentially leading to more effective and longer-lasting responses. This dual approach not only targets the cancer more precisely but also has the potential to reduce the side effects associated with traditional chemotherapy.

What evidence suggests that CD19 CAR T cells and acalabrutinib could be effective for mantle cell lymphoma?

Research has shown that CD19 CAR T cells, one of the treatments in this trial, could be promising for treating mantle cell lymphoma. In one study, 82% of patients experienced tumor reduction, and 46% had no detectable cancer. These cells are specially designed to find and attack a protein called CD19 on cancer cells, enhancing the immune system's ability to fight the cancer.

Acalabrutinib, another treatment option in this trial, has also shown success, particularly for mantle cell lymphoma that has recurred or resisted other treatments. A study found that it extended patients' lives by over 16 months without cancer progression compared to standard treatments. In this trial, participants will receive both CD19 CAR T cells and Acalabrutinib, which might further improve cancer cell eradication and patient outcomes. ^{1 3 4 6 7}

Who Is on the Research Team?

Lihua Budde, MD

Principal Investigator

City of Hope Comprehensive Cancer Center

Are You a Good Fit for This Trial?

This trial is for patients with Mantle Cell Lymphoma that has returned or isn't responding to treatment. They must have CD19+ MCL, measurable disease, normal liver and kidney function, and be on acalabrutinib for 3-7 months with at least one failed prior regimen. Participants need a good performance status, no major surgeries recently, not pregnant or breastfeeding, and willing to use birth control.

Inclusion Criteria

Aspartate aminotransferase (AST) < 3 x ULN (performed within 28 days prior to enrollment)

Cardiac function (12 lead-electrocardiogram [ECG]): corrected QT (QTc) must be =< 480 msec

International normalized ratio (INR) OR prothrombin (PT) =< 1.5 x ULN (performed within 28 days prior to enrollment)

Exclusion Criteria

I am experiencing chronic GVHD after a stem cell transplant.

I have an active autoimmune disease needing strong medication.

Lactating women

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive acalabrutinib orally twice daily and CD19 CAR T cells intravenously, with treatment cycles repeating every 28 days for up to 6 cycles

6 months

Monthly visits for each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment, with follow-up at 3, 6, and 12 months, then yearly for up to 15 years

15 years

3 visits in the first year, then annual visits

What Are the Treatments Tested in This Trial?

Interventions

• Acalabrutinib
• CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytes

Trial Overview The trial tests modified immune cells (CD19 CAR T Cells) combined with Acalabrutinib in treating relapsed/refractory Mantle Cell Lymphoma. The patient's own T cells are engineered to target the CD19 protein on cancer cells while Acalabrutinib aims to block enzymes needed for cancer cell growth.

How Is the Trial Designed?

Group I: Treatment (CD19 CAR T cells, acalabrutinib) Experimental Treatment 2 Interventions

Patients receive acalabrutinib PO BID on days -5 to 28 of cycle 1 and on days 1-28 of subsequent cycles. Patients also receive CD19 CAR T cells IV on day 0. Treatment with acalabrutinib repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients who have not attained CR after the first disease assessment and tolerated the initial CAR T cell infusion may receive a second CAR T cell infusion in cycle 2.

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

In a phase 2 study involving 20 patients with relapsed/refractory mantle cell lymphoma, the combination of ibrutinib and CD19-directed CAR-T therapy resulted in an impressive 80% complete response rate four months post-infusion, indicating strong efficacy.

While 75% of patients experienced cytokine release syndrome, most cases were mild to moderate, suggesting that the combination therapy is relatively safe and warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T-cells and Time-Limited Ibrutinib as Treatment for Relapsed/Refractory Mantle Cell Lymphoma: Phase II TARMAC Study. Minson, A., Hamad, N., Cheah, CY., et al.[2023]

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]

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, 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 patients with relapsed/refractory mantle cell lymphoma (MCL) who previously failed a Bruton tyrosine kinase inhibitor, brexucabtagene autoleucel (brexu-cel) showed significantly improved overall survival compared to standard of care treatments, with hazard ratios indicating a strong survival benefit.

The analysis used multiple methods to adjust for differences in patient characteristics, consistently showing that brexu-cel led to better outcomes, highlighting its potential as an effective therapy for this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Indirect treatment comparison of brexucabtagene autoleucel (ZUMA-2) versus standard of care (SCHOLAR-2) in relapsed/refractory mantle cell lymphoma. Hess, G., Dreyling, M., Oberic, L., et al.[2023]

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]

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, 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]

Citations

1. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/7744/528340/Real-World-Effectiveness-and-Safety-Outcomes-of

Real-World Effectiveness and Safety Outcomes of ... Results: Among 181 pts with MCL treated with acala, 127 were treated in the R/R setting (study cohort) (acala monotherapy: 94 pts; combination ...

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

Final results and overall survival data from a phase II study ... The final results of this study demonstrated that efficacy and safety of acalabrutinib were maintained compared with data from a previous analysis (median ...

3. astrazeneca-us.com astrazeneca-us.com/media/press-releases/2025/calquence-acalabrutinib-plus-chemoimmunotherapy-approved-in-the-us-for-patients-with-previously-untreated-mantle-cell-lymphoma.html

CALQUENCE® (acalabrutinib) plus chemoimmunotherapy ... Based on ECHO Phase III trial results which showed more than 16 months of progression-free survival improvement vs. chemoimmunotherapy alone.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6777435/

Evaluating Acalabrutinib In The Treatment Of Mantle Cell ... The median duration of response was 17.5 months with PFS and OS rates of 31% and 47%, respectively, at 2 years and are the highest reported for a single agent ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT02213926

NCT02213926 | An Open-label, Phase 2 Study of ACP-196 ... The purpose of this study is to characterize the safety and efficacy profile of ACP-196 (acalabrutinib) in subjects with relapsed or refractory Mantle Cell ...

6. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497124105708

Real-World Effectiveness and Safety Outcomes of ... This RW study demonstrated that, among pts with MCL who received acala in the R/R setting, effectiveness was similar to a recently presented RW evidence study ...

7. 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) ...