Brexucabtagene Autoleucel for Leukemia and Lymphoma

(ZUMA-4 Trial)

Recruiting at 32 trial locations

Overseen By Medical Information

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Kite, A Gilead Company

Must be taking: Anti-CD20 antibody

Must not be taking: Aminoglycosides, Alemtuzumab

Disqualifiers: CNS disorders, Cardiac disease, Infections, others

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

Compensation: Varies

Number of Visits: 1

Duration: 4 weeks

95 Participants Needed

Trial Summary

What is the purpose of this trial?

The primary objectives of this study are to evaluate the safety and efficacy of brexucabtagene autoleucel (KTE-X19) in pediatric and adolescent participants with relapsed/refractory (r/r) B-precursor acute lymphoblastic leukemia (ALL) or relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (NHL). As of October 2022, no further patients with acute B-cell Acute Lymphoblastic Leukemia (ALL) will be asked to join the study. The study remains open for recruitment for patients that have B-cell Non Hodgkin Lymphoma (NHL).

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but certain prior treatments like alemtuzumab, clofarabine, or cladribine must not have been taken within specific time frames before joining. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the treatment Brexucabtagene Autoleucel (KTE-X19) for leukemia and lymphoma?

Brexucabtagene autoleucel (KTE-X19) has shown effectiveness in treating relapsed or refractory B-cell acute lymphoblastic leukemia and mantle cell lymphoma, as demonstrated in the ZUMA-3 and ZUMA-2 studies, respectively. These studies reported positive outcomes, leading to its approval for these conditions. ^{1 2 3 4 5}

Is Brexucabtagene Autoleucel safe for humans?

Brexucabtagene autoleucel has been shown to have significant side effects, including cytokine release syndrome (a severe immune reaction) and neurologic toxicities (problems with the nervous system), which can be severe and require special management. Serious adverse reactions occurred in 79% of patients, and fatal reactions occurred in 5% of cases, including cerebral edema (swelling in the brain) and infections. ^{2 3 4 5 6}

How is the treatment Brexucabtagene Autoleucel different from other treatments for leukemia and lymphoma?

Brexucabtagene Autoleucel is a unique treatment because it is a CAR T-cell therapy, which means it uses a patient's own modified immune cells to target and destroy cancer cells. This approach is different from traditional chemotherapy or radiation, as it specifically targets the CD19 protein on cancer cells, offering a personalized and potentially more effective treatment for relapsed or refractory B-cell acute lymphoblastic leukemia and mantle cell lymphoma. ^{1 2 4 5 7}

Research Team

Kite Study Director

Principal Investigator

Kite, A Gilead Company

Eligibility Criteria

This trial is for children and adolescents up to 21 years old with relapsed/refractory B-precursor acute lymphoblastic leukemia or B-cell non-Hodgkin lymphoma. They must have a certain level of disease in the bone marrow, be intolerant or unresponsive to specific therapies, weigh at least 6 kg, and have good performance status and organ function. Those with CNS involvement, other cancers within 3 years (except some skin cancers), severe allergies, or recent heart issues cannot join.

Inclusion Criteria

I am 21 or younger, weigh at least 6 kg, and can do most activities.

Adequate renal, hepatic, pulmonary and cardiac function defined as: Creatinine clearance (as estimated by Cockcroft Gault or Schwartz) ≥ 60 mL/min, Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤ 5 x upper limit of normal (ULN), Total bilirubin ≤ 1.5 x ULN, except in individuals with Gilbert's syndrome, Left ventricular shortening fraction (LVSF) ≥ 30% or left ventricular ejection fraction (LVEF) ≥ 50%, as determined by an echocardiogram or multi-gated acquisition scan (MUGA), no evidence of pericardial effusion (except trace or physiological) as determined by an echocardiogram (ECHO) and no clinically significant arrhythmias, No clinically significant pleural effusion, Baseline oxygen saturation > 92% on room air

My B-precursor ALL has come back or didn't respond to treatment.

Exclusion Criteria

Presence or suspicion of fungal, bacterial, viral, or other infection that is uncontrolled or requiring IV antimicrobials for management., Prior medication: Prior CD19 directed therapy (other than blinatumomab), including CAR+ T cell, bispecific T cell engager (BiTE), and antibody drug conjugate (ADC), with the exception of individuals who received brexucabtagene autoleucel (KTE-X19) in this study and are eligible for re-treatment, Treatment with alemtuzumab within 6 months prior to leukapheresis, or treatment with clofarabine or cladribine within 3 months prior to leukapheresis, Donor lymphocyte infusion (DLI) within 28 days prior to enrollment, Any drug used for graft-versus-host disease (GVHD) within 4 weeks prior to enrollment, Acute GVHD grade II-IV by Glucksberg criteria or severity B-D by IBMTR index; acute or chronic GVHD requiring systemic treatment within 4 weeks prior to enrollment, Live vaccine ≤ 6 weeks prior to enrollment, Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant. Females who have undergone surgical sterilization are not considered to be of childbearing potential, Individuals of both genders of child-bearing potential who are not willing to use a birth control method considered to be highly effective per protocol from the time of consent through 6 months after conditioning chemotherapy or brexucabtagene autoleucel (KTE-X19) infusion, whichever is longer.

You have any tumors or abnormalities in your brain or spine, high levels of white blood cells in your cerebrospinal fluid with lymphoblasts, or any neurological symptoms. You also have a history or current presence of a brain disorder, stroke, or autoimmune disease affecting the brain. Additionally, if you have had a stroke or seizure within the past year or require medication for seizures, you cannot participate in the study.

You have been diagnosed with a specific type of leukemia or lymphoma, or have had any type of cancer (except non-melanoma skin cancer or in situ carcinoma) within the last 3 years. Additionally, you have experienced a severe allergic reaction to certain types of medication.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning Chemotherapy

Participants receive a conditioning chemotherapy regimen of fludarabine and cyclophosphamide

1 week

Treatment

Participants receive a single infusion of chimeric antigen receptor (CAR) transduced autologous T cells

4 weeks

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Long-term Follow-up

Participants transition to a separate long-term follow-up study to complete the remainder of the 15-year follow-up assessments

Up to 15 years

Treatment Details

Interventions

• Brexucabtagene Autoleucel (KTE-X19)
• Cyclophosphamide
• Fludarabine

Trial Overview The study tests the safety and effectiveness of brexucabtagene autoleucel (KTE-X19) combined with fludarabine and cyclophosphamide chemotherapy in young patients who haven't responded well to previous treatments. The focus is now on those with B-cell non-Hodgkin lymphoma as recruitment for acute B-cell ALL has ended.

Participant Groups

Group I: Single Arm Experimental Treatment 3 Interventions

A conditioning chemotherapy regimen of fludarabine and cyclophosphamide will be administered followed by a single infusion of chimeric antigen receptor (CAR) transduced autologous T cells administered intravenously at a target dose of 2 x 10\^6 anti-CD19 CAR+ T cells/kg or 1 x 10\^6 anti-CD19 CAR+ T cells/kg

Who Is Running the Clinical Trial?

Kite, A Gilead Company

Lead Sponsor

Trials

45

Recruited

4,300+

Findings from Research

In the pivotal ZUMA-2 trial, brexucabtagene autoleucel (brexu-cel) showed high efficacy in treating relapsed or refractory mantle cell lymphoma, with an objective response rate of 85% and a complete response rate of 59%, even among high-risk patients.

While brexu-cel has a similar toxicity profile to other CAR T-cell therapies, it is associated with significant treatment-related adverse effects, including severe cytopenias (94%) and neurotoxicity (31%), highlighting the need for careful management by a specialized medical team.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brexucabtagene Autoleucel: A Novel Chimeric Antigen Receptor T-cell Therapy for the Treatment of Mantle Cell Lymphoma. Anderson, MK., Torosyan, A., Halford, Z.[2022]

Axicabtagene ciloleucel and brexucabtagene autoleucel are effective anti-CD19 T-cell therapies that have shown high response rates in patients with relapsed and refractory B-cell malignancies, leading to FDA approvals for specific types of lymphoma.

Despite their effectiveness, these therapies can cause significant toxicities, such as cytokine release syndrome and neurologic issues, which necessitate careful management and monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Axicabtagene ciloleucel and brexucabtagene autoleucel in relapsed and refractory diffuse large B-cell and mantle cell lymphomas. Reagan, PM., Friedberg, JW.[2021]

Brexucabtagene autoleucel is the first FDA-approved CAR T-cell therapy targeting CD19 for adults with relapsed and refractory B-cell acute lymphoblastic leukemia, marking a significant advancement in treatment options.

The approval was based on the outcomes of the Zuma-3 trial, which demonstrated the efficacy of this therapy in improving patient outcomes in a challenging-to-treat population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Approval of brexucabtagene autoleucel for adults with relapsed and refractory acute lymphocytic leukemia. Frey, NV.[2022]

In the updated ZUMA-3 study with a median follow-up of 26.8 months, brexucabtagene autoleucel (KTE-X19) achieved a 71% complete remission rate in adults with relapsed or refractory B-precursor acute lymphoblastic leukemia, indicating its efficacy as a treatment option.

Patients treated with KTE-X19 had a median overall survival of 25.4 months, significantly longer than the 5.5 months observed in matched historical controls, demonstrating a meaningful survival benefit with manageable safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two-year follow-up of KTE-X19 in patients with relapsed or refractory adult B-cell acute lymphoblastic leukemia in ZUMA-3 and its contextualization with SCHOLAR-3, an external historical control study. Shah, BD., Ghobadi, A., Oluwole, OO., et al.[2023]

Brexucabtagene autoleucel (KTE-X19) CAR T-cell therapy showed a remarkable 91% objective response rate and 68% complete response rate in 68 patients with relapsed/refractory mantle cell lymphoma after a median follow-up of 35.6 months, indicating its efficacy in this challenging patient population.

The therapy demonstrated durable long-term responses with manageable safety, as late-onset toxicities were infrequent, occurring in only 3% of patients, suggesting that KTE-X19 is a safe and effective treatment option even for those with high-risk characteristics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Three-Year Follow-Up of KTE-X19 in Patients With Relapsed/Refractory Mantle Cell Lymphoma, Including High-Risk Subgroups, in the ZUMA-2 Study. Wang, M., Munoz, J., Goy, A., et al.[2023]

Brexucabtagene autoleucel (brexu-cel) is an FDA-approved CAR T-cell therapy for adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (B-ALL), showing a complete remission (CR) rate of 52% within 3 months after treatment in a study of 54 patients.

While brexu-cel demonstrates significant efficacy, it is associated with serious adverse reactions in 79% of patients, including severe cytokine release syndrome (92%) and neurological toxicities (87%), necessitating a risk evaluation and mitigation strategy (REMS) for patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Brexucabtagene Autoleucel for Treatment of Adults With Relapsed or Refractory B-Cell Precursor Acute Lymphoblastic Leukemia. Bouchkouj, N., Lin, X., Wang, X., et al.[2022]

Brexucabtagene autoleucel (brexu-cel) demonstrated a high overall complete remission rate of 73% and a median overall survival of 25.4 months in adults with relapsed or refractory B-cell acute lymphoblastic leukemia, based on a study of 78 patients with a median follow-up of 29.7 months.

The therapy was effective across various prior treatment subgroups, with high remission rates regardless of previous therapies, indicating its potential as a robust treatment option for patients with R/R B-ALL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of prior therapies and subsequent transplantation on outcomes in adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia treated with brexucabtagene autoleucel in ZUMA-3. Shah, BD., Cassaday, RD., Park, JH., et al.[2023]

References

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

Brexucabtagene Autoleucel: A Novel Chimeric Antigen Receptor T-cell Therapy for the Treatment of Mantle Cell Lymphoma. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Axicabtagene ciloleucel and brexucabtagene autoleucel in relapsed and refractory diffuse large B-cell and mantle cell lymphomas. [2021]

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

Approval of brexucabtagene autoleucel for adults with relapsed and refractory acute lymphocytic leukemia. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Two-year follow-up of KTE-X19 in patients with relapsed or refractory adult B-cell acute lymphoblastic leukemia in ZUMA-3 and its contextualization with SCHOLAR-3, an external historical control study. [2023]

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

Three-Year Follow-Up of KTE-X19 in Patients With Relapsed/Refractory Mantle Cell Lymphoma, Including High-Risk Subgroups, in the ZUMA-2 Study. [2023]

6. England pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Brexucabtagene Autoleucel for Treatment of Adults With Relapsed or Refractory B-Cell Precursor Acute Lymphoblastic Leukemia. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Impact of prior therapies and subsequent transplantation on outcomes in adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia treated with brexucabtagene autoleucel in ZUMA-3. [2023]