Acalabrutinib + CAR T-cell Therapy for B-Cell Lymphoma

Overseen By Ajay K. Gopal

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of Washington

Must not be taking: Proton pump inhibitors

Disqualifiers: Infections, Brain metastases, Seizure disorder, 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: 3

Duration: Up to 3 weeks for acalabrutinib prior to leukapheresis, followed by axicabtagene ciloleucel infusion

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination treatment for B-cell lymphoma, a type of blood cancer. It examines the safety and effectiveness of using two treatments together: acalabrutinib, which aims to stop cancer cell growth, and axicabtagene ciloleucel, an immunotherapy designed to attack cancer cells. The trial targets individuals diagnosed with large B-cell lymphoma, including subtypes like diffuse large B-cell lymphoma and certain follicular lymphomas. Participants must have at least one measurable tumor and meet other health criteria. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop all current medications, but you cannot use strong CYP3A inhibitors or inducers within 7 days of starting the study drugs. If you are on a proton pump inhibitor, you may need to switch to a different type of medication.

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

Research has shown that combining acalabrutinib and axicabtagene ciloleucel is generally safe for patients with B-cell lymphoma. In earlier studies, many patients tolerated this combination well, with 67% showing good tolerance. Most patients experienced high rates of complete response, indicating effective treatment without significant harm.

While side effects can occur, they are usually manageable. This treatment remains under study, and ongoing research will provide more information. Currently, available evidence suggests that this combination offers a promising safety profile for those considering joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about combining acalabrutinib and axicabtagene ciloleucel for B-cell lymphoma because this treatment approach is unique in targeting the disease from two angles. Acalabrutinib is a BTK inhibitor that disrupts the cancer cell's ability to grow and survive, while axicabtagene ciloleucel is a CAR T-cell therapy that uses the patient's own immune cells, reprogrammed to attack lymphoma cells. This dual-action strategy not only enhances the immune response but also directly interferes with cancer cell signaling, potentially offering a more comprehensive approach than standard chemotherapy or monoclonal antibodies alone.

What evidence suggests that acalabrutinib and axicabtagene ciloleucel could be effective for B-cell lymphoma?

Research has shown that combining acalabrutinib with axicabtagene ciloleucel, as studied in this trial, may effectively treat B-cell lymphoma. Acalabrutinib blocks signals that help cancer cells grow, making them more vulnerable. Axicabtagene ciloleucel, a type of immunotherapy, helps the immune system target and attack lymphoma cells. Early results suggest this combination can achieve high rates of complete response, even in patients whose cancer has returned. This treatment option appears promising for those with hard-to-treat B-cell lymphoma. ^{1 2 3 4 6}

Who Is on the Research Team?

Ajay K. Gopal

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Are You a Good Fit for This Trial?

Adults with B-cell lymphoma eligible for axi-cel per FDA, understanding and consenting to the study, ECOG status of 0-1, adequate organ function, no active infections or second cancers needing treatment. Excludes those intolerant to acalabrutinib, with brain metastases or cerebrospinal fluid malignant cells, on strong CYP3A inhibitors/inducers, refractory to BTK inhibition, low blood counts, pregnant/breastfeeding women.

Inclusion Criteria

I have been diagnosed with a specific type of large B-cell lymphoma.

My kidney function is good, with a creatinine clearance over 50 mL/min or serum creatinine <= 2.5.

I breathe well with minimal shortness of breath and my oxygen level is above 92% without assistance.

Exclusion Criteria

I do not have any serious infections that would make treatment risky.

I have not had major surgery in the last 7 days or have fully recovered from it.

I have or had cancer cells in my brain or spinal fluid.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-3 weeks

Treatment

Participants receive acalabrutinib orally every 12 hours and axicabtagene ciloleucel intravenously after lymphodepleting chemotherapy

Up to 3 weeks for acalabrutinib prior to leukapheresis, followed by axicabtagene ciloleucel infusion

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Acalabrutinib
• Axicabtagene Ciloleucel

Trial Overview The trial is testing the combination of acalabrutinib (a drug that blocks tumor growth pathways) and axicabtagene ciloleucel (a CAR T-cell therapy targeting lymphoma cells). It aims to see if acalabrutinib can boost the effectiveness of the immunotherapy in treating B-cell lymphoma.

How Is the Trial Designed?

Group I: Treatment (acalabrutinib, axicabtagene ciloleucel) Experimental Treatment 2 Interventions

Beginning up to 3 weeks and at least 24 hours prior to leukapheresis, patients receive acalabrutinib PO every 12 hours. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients also receive axicabtagene ciloleucel IV at 36-96 hours after completion of lymphodepleting chemotherapy.

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?

University of Washington

Lead Sponsor

Trials

1,858

Recruited

2,023,000+

AstraZeneca

Industry Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Published Research Related to This Trial

Axicabtagene ciloleucel (axi-cel) demonstrated impressive efficacy in treating relapsed/refractory large B-cell lymphoma, with overall and complete response rates of 83% and 58%, respectively, in the pivotal ZUMA-1 trial with a median follow-up of 27.1 months.

While axi-cel shows promise, it is associated with significant toxicities, including cytokine release syndrome (CRS) in 7% to 14% of patients and immune effector cell-associated neurotoxicity syndrome (ICANS) in 31% to 55%, highlighting the need for careful patient management and monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Axicabtagene Ciloleucel: Clinical Data for the Use of CAR T-cell Therapy in Relapsed and Refractory Large B-cell Lymphoma. Halford, Z., Anderson, MK., Bennett, LL.[2021]

Axicabtagene ciloleucel and tisagenlecleucel are FDA-approved CAR T cell therapies specifically designed to target CD19 in patients with relapsed or refractory aggressive B cell non-Hodgkin lymphoma, marking a significant advancement in cellular immunotherapy.

Despite their transformative potential, there are ongoing concerns about the appropriate use and potential short- and long-term toxicities of these therapies, prompting expert consensus to guide clinicians in their application.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of Chimeric Antigen Receptor T Cell Therapy in Clinical Practice for Relapsed/Refractory Aggressive B Cell Non-Hodgkin Lymphoma: An Expert Panel Opinion from the American Society for Transplantation and Cellular Therapy. Jain, T., Bar, M., Kansagra, AJ., et al.[2020]

In a study of 122 patients treated with axicabtagene ciloleucel (axi-cel) for relapsed aggressive B-cell non-Hodgkin lymphoma, the overall response rate was 70% and the complete response rate was 50%, indicating strong efficacy even in a post-commercial setting with relaxed eligibility criteria.

Patients eligible for the original ZUMA-1 trial had significantly better outcomes, including higher complete response rates (63% vs. 42%) and longer duration of response, progression-free survival, and overall survival, while the rates of severe side effects like cytokine release syndrome and neurotoxicity were consistent with those observed in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Axicabtagene Ciloleucel in the Non-Trial Setting: Outcomes and Correlates of Response, Resistance, and Toxicity. Jacobson, CA., Hunter, BD., Redd, R., et al.[2022]

In the ZUMA-12 study involving 40 patients with high-risk large B-cell lymphoma, axicabtagene ciloleucel (axi-cel) demonstrated a high complete response rate of 78% and an overall response rate of 89%, indicating its effectiveness as a first-line treatment.

The safety profile of axi-cel was manageable, with only 8% of patients experiencing severe cytokine release syndrome and 23% experiencing neurological events, and no treatment-related deaths were reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Axicabtagene ciloleucel as first-line therapy in high-risk large B-cell lymphoma: the phase 2 ZUMA-12 trial. Neelapu, SS., Dickinson, M., Munoz, J., et al.[2023]

Axicabtagene ciloleucel (axi-cel) is an effective CAR T-cell therapy targeting CD19, showing high response rates and a manageable safety profile in patients with relapsed or refractory B-cell malignancies, particularly after two or more lines of prior treatment.

Axi-cel is FDA-approved for adult patients with specific types of B-cell lymphomas, including diffuse large B-cell lymphoma, and is currently being studied for its efficacy in other B-cell malignancies in ongoing clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Axicabtagene ciloleucel for the treatment of relapsed/refractory B-cell non-Hodgkin's lymphomas. Sharma, P., King, GT., Shinde, SS., et al.[2018]

In a phase 1 trial involving 12 patients with relapsed/refractory large B-cell lymphoma, the combination of CD19-directed CAR T-cell therapy (axi-cel) and the 4-1BB agonist utomilumab showed a manageable safety profile with no dose-limiting toxicities observed.

The treatment resulted in a high objective response rate of 75%, with 58% of patients achieving a complete response, suggesting that this combination may enhance the efficacy of CAR T-cell therapy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Axicabtagene Ciloleucel in Combination with the 4-1BB Agonist Utomilumab in Patients with Relapsed/Refractory Large B-Cell Lymphoma: Phase 1 Results from ZUMA-11. Jain, MD., Miklos, DB., Jacobson, CA., et al.[2023]

CAR T-cell therapy, particularly with anti-CD19 targeting, has shown significant effectiveness in treating aggressive B-cell non-Hodgkin's lymphoma (NHL), leading to long-term remissions in patients with diffuse large B-cell lymphoma (DLBCL) who have not responded to other treatments.

Two CAR T-cell products, axicabtagene ciloleucel and tisagenlecleucel, have been approved by the FDA for refractory DLBCL, while a third product, liso-cel, is showing promising results in ongoing trials, although potential side effects like cytokine-release syndrome and neurotoxicity are important considerations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T-cell therapy for B-cell lymphomas: clinical trial results of available products. Chavez, JC., Bachmeier, C., Kharfan-Dabaja, MA.[2020]

Axicabtagene ciloleucel (Yescarta) is an approved second-line treatment for patients with large B-cell lymphoma who do not respond to or relapse within 12 months of initial chemoimmunotherapy.

Patient identity confirmation and premedication to reduce hypersensitivity reactions are essential steps in the administration of this autologous infusion therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Second-Line Treatment for B-Cell Lymphoma. Aschenbrenner, DS.[2022]

Yescarta (axicabtagene ciloleucel) is an engineered T-cell therapy that showed a 66% overall response rate and a 47% complete response rate in treating relapsed or refractory diffuse large B-cell lymphoma, based on a phase II study with a median follow-up of 15.1 months.

The therapy was associated with manageable adverse events, including cytokine release syndrome and neurological issues, making it a promising option for patients with limited treatment alternatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

EMA Review of Axicabtagene Ciloleucel (Yescarta) for the Treatment of Diffuse Large B-Cell Lymphoma. Papadouli, I., Mueller-Berghaus, J., Beuneu, C., et al.[2022]

In a phase 2 trial involving 111 patients with refractory large B-cell lymphoma, axicabtagene ciloleucel (axi-cel) demonstrated a high objective response rate of 82%, with 54% achieving a complete response, indicating its efficacy as a treatment option.

The treatment was associated with significant adverse events, including neutropenia in 78% of patients and neurologic events in 28%, highlighting the need for careful monitoring of safety during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. Neelapu, SS., Locke, FL., Bartlett, NL., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04257578

NCT04257578 | Acalabrutinib and Anti-CD19 CAR T-cell ... Acalabrutinib may stop the growth of tumor cells by blocking key pathways needed for cell growth. Immunotherapy with axicabtagene ciloleucel is engineered to ...

2. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/2129/500297/Acalabrutinib-in-Combination-with-Anti-CD19

Acalabrutinib in Combination with Anti-CD19 Chimeric ... We report the initial safety, efficacy and correlative analysis of acalabrutinib in combination with axicabtagene ciloleucel (axi-cel) in R/R B- ...

3. astctjournal.org astctjournal.org/article/S2666-6367(23)01784-0/fulltext

Acalabrutinib in Combination with Anti-CD19 Chimeric ... Acala successfully bridged most patients and when given concurrently with axi-cel, safely maintained high CR rates.

4. onclive.com onclive.com/view/acalabrutinib-axi-cel-generates-preliminary-responses-in-relapsed-refractory-b-cell-lymphoma

Acalabrutinib/Axi-Cel Generates Preliminary Responses in ... Early data seen with acalabrutinib plus axi-cel indicate the combination's feasibility as bridging therapy in relapsed/refractory B-cell ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10981676/

Combination of acalabrutinib with lenalidomide and rituximab ... Combination of acalabrutinib with lenalidomide and rituximab in relapsed/refractory aggressive B-cell non-Hodgkin lymphoma: a single-arm phase II trial

6. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT04257578/

Clinical Trial: NCT04257578 This phase I/II trial studies the safety of acalabrutinib and axicabtagene ciloleucel in treating patients with B-cell lymphoma.