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

Trial Summary

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.

What data supports the effectiveness of the treatment CD19 CAR T-Cells + Acalabrutinib for Mantle Cell Lymphoma?

Acalabrutinib, a drug used in this treatment, has shown effectiveness in treating mantle cell lymphoma, receiving accelerated approval from the FDA based on a phase II study. Additionally, similar treatments using CD19 CAR T-cells have demonstrated high response rates in patients with relapsed or refractory mantle cell lymphoma, suggesting potential effectiveness when combined with acalabrutinib. ^{1 2 3 4 5}

Is the combination of CD19 CAR T-Cells and Acalabrutinib safe for humans?

Acalabrutinib, used for mantle cell lymphoma, has shown a favorable safety profile compared to other therapies, though it may increase the risk of certain blood-related side effects like neutropenia (low white blood cell count). CD19 CAR T-Cells can cause significant side effects like cytokine release syndrome (a severe immune reaction) and neurotoxicity, but these are often manageable and reversible. ^{1 3 4 6 7}

What makes the CD19 CAR T-Cells + Acalabrutinib treatment unique for mantle cell lymphoma?

This treatment combines acalabrutinib, a targeted drug that blocks a protein called Bruton's tyrosine kinase to stop cancer cell growth, with CD19 CAR T-cells, which are modified immune cells designed to attack cancer cells. This combination aims to enhance the effectiveness of treatment by using both a targeted drug and a personalized immune therapy, offering a novel approach for patients who have relapsed or are resistant to other treatments. ^{1 3 4 5 8}

What is the purpose of this trial?

This phase II trial investigates the side effects of CD19 chimeric antigen receptor (CAR) T cells and acalabrutinib, and to see how well they work in treating patients with mantle cell lymphoma that has come back (relapsed) or does not respond to treatment (refractory). T cells are infection fighting blood cells that can kill cancer cells. The T cells given in this study will come from the patient and will have a new gene put in them that makes them able to recognize CD19, a protein on the surface of the cancer cells. These CD19-specific T cells may help the body's immune system identify and kill CD19 positive cancer cells. Acalabrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving CD19 CAR T cells together with acalabrutinib may kill more cancer cells.

Research Team

Lihua Budde, MD

Principal Investigator

City of Hope Comprehensive Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

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]

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]

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]

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]

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 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 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]

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]

References

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

Acalabrutinib: First Global Approval. [2018]

2. United States 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. [2023]

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

CAR T-cells and Time-Limited Ibrutinib as Treatment for Relapsed/Refractory Mantle Cell Lymphoma: Phase II TARMAC Study. [2023]

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

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

5. England pubmed.ncbi.nlm.nih.gov

The role of Bruton's tyrosine kinase inhibitors in the management of mantle cell lymphoma. [2021]

6. 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]

7. 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]

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

Acalabrutinib for mantle cell lymphoma. [2021]