Axicabtagene Ciloleucel for Lymphoma

(ZUMA-23 Trial)

Recruiting at 96 trial locations

Overseen By Medical Information

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Kite, A Gilead Company

Must be taking: R-chemotherapy

Must not be taking: Systemic immunosuppressants

Disqualifiers: CNS disorder, Cardiac disease, Hepatitis, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 6

Duration: 18 weeks

300 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test axicabtagene ciloleucel, a new treatment option for people with high-risk large B-cell lymphoma, against usual care treatments. The researchers seek to determine if this experimental treatment is more effective than standard therapies for this condition. Individuals diagnosed with aggressive large B-cell lymphoma who have already undergone one cycle of chemotherapy might be suitable candidates for this study. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are on medications for HIV, you may continue them if your viral load is undetectable and your CD4 count is above 200 cells/uL. Please consult with the trial coordinators for more details.

Is there any evidence suggesting that axicabtagene ciloleucel is likely to be safe for humans?

Research has shown that axicabtagene ciloleucel, or axi-cel, is generally safe. In earlier studies, most patients tolerated the treatment well, though some experienced significant side effects. Cytokine release syndrome (CRS) is a common side effect, occurring in about 90% of patients. CRS can be serious or even life-threatening, but proper care usually manages it.

Another study found that axi-cel is effective as a second-line treatment, used when the first treatment fails. The safety profile was considered manageable, and older patients often experienced improvements in their quality of life.

While side effects can be serious, most are treatable, and the treatment has shown promising results in fighting lymphoma. Discuss potential risks and benefits with a doctor to determine if this trial is suitable. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for lymphoma?

Axicabtagene ciloleucel is unique because it employs a cutting-edge approach called CAR T-cell therapy. Unlike standard treatments for lymphoma, which often include chemotherapy combinations like R-CHOP or DA-EPOCH-R, this experimental therapy reprograms a patient's own T cells to target and destroy cancer cells. Researchers are excited about axicabtagene ciloleucel because it specifically targets the CD19 protein on B-cell lymphomas, offering a personalized and potentially more effective treatment option. This method could lead to more durable remissions and better outcomes for patients who have limited success with conventional therapies.

What evidence suggests that axicabtagene ciloleucel might be an effective treatment for lymphoma?

Research has shown that axicabtagene ciloleucel, one of the treatments in this trial, holds promise for treating large B-cell lymphoma. In one study, about 82% of patients experienced a reduction or disappearance of their cancer, with 64% showing no detectable cancer. Real-world evidence supports these findings, showing a 79% overall response rate. Participants in this trial may receive axicabtagene ciloleucel, which has been linked to longer survival compared to standard therapies. These results suggest that axicabtagene ciloleucel could be a strong option for people fighting this type of lymphoma. ^{1 4 6 7 8}

Who Is on the Research Team?

Kite Study Director

Principal Investigator

Kite, A Gilead Company

Are You a Good Fit for This Trial?

This trial is for adults with high-risk large B-cell lymphoma, confirmed by local pathology. Participants must have an IPI score of 4 or 5, only one prior cycle of R-chemotherapy, and good organ function. Excluded are those with certain subtypes of LBCL, CNS involvement, severe allergies to study drugs, active hepatitis B/C or HIV not well-controlled on medication.

Inclusion Criteria

I am of childbearing age and have a negative pregnancy test.

My heart, lungs, liver, kidneys, and bone marrow are functioning well.

I have only had one round of treatment with rituximab and chemotherapy.

Exclusion Criteria

My lymphoma is between DLBCL and Hodgkin.

I have had serious heart problems in the last year.

My cancer is primary mediastinal large B-cell lymphoma.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either axicabtagene ciloleucel or standard of care therapy for high-risk large B-cell lymphoma

18 weeks

6 cycles of 21-day treatment

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

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

10 years

What Are the Treatments Tested in This Trial?

Interventions

• Axicabtagene Ciloleucel

Trial Overview The trial compares axicabtagene ciloleucel (a new therapy) against the standard care which includes a combination of chemotherapy drugs like Vincristine and Doxorubicin for first-line treatment in participants with high-risk large B-cell lymphoma.

How Is the Trial Designed?

Group I: Axicabtagene Ciloleucel Experimental Treatment 3 Interventions

Participants will receive cyclophosphamide 500 mg/m\^2/day intravenously (IV) and fludarabine 30 mg/m\^2/day IV lymphodepletion chemotherapy for 3 days followed by axicabtagene ciloleucel administered as a single IV infusion at a target dose of 2 x 10\^6 anti-cluster of differentiation (CD)19 chimeric antigen receptor (CAR) transduced autologous T cells/kg on Day 0.

Group II: Standard of Care Therapy Active Control 6 Interventions

Participants will receive the investigator's choice of one of the following therapies/dosing schedules: * Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for a total of 6 cycles (21-day cycle) * Rituximab 375 mg/m\^2 on Day 1 * Cyclophosphamide 750 mg/m\^2 on Day 1 * Doxorubicin 50 mg/m\^2 on Day 1 * Vincristine 1.4 mg/m\^2 (maximum 2 mg) on Day 1 * Prednisone 40 mg/m\^2 on Day 1 through Day 5 * Dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) for a total of 6 cycles (21-day cycle) * Rituximab 375 mg/m\^2 on Day 1 * Etoposide 50 mg/m\^2 on Days 1 to 4 * Doxorubicin 10 mg/m\^2 on Days 1 to 4 * Vincristine 0.4 mg/m\^2 on Days 1 to 4 * Cyclophosphamide 750 mg/m\^2 on Day 5 * Prednisone 60 mg/m\^2 twice daily on Days 1 to 5

Axicabtagene Ciloleucel is already approved in United States, European Union for the following indications:

Approved in United States as Yescarta for:

• Large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy
• Relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy
• Relapsed or refractory follicular lymphoma after two or more lines of systemic therapy

Approved in European Union as Yescarta for:

• Diffuse large B-cell lymphoma (DLBCL) and high-grade B-cell lymphoma (HGBL) that relapses within 12 months from completion of, or is refractory to, first-line chemoimmunotherapy
• Relapsed or refractory DLBCL and primary mediastinal large B-cell lymphoma, after two or more lines of systemic therapy
• Relapsed or refractory follicular lymphoma after three or more lines of systemic therapy

Who Is Running the Clinical Trial?

Kite, A Gilead Company

Lead Sponsor

Trials

45

Recruited

4,300+

Published Research Related to This Trial

In a phase 2 clinical trial involving 51 patients with relapsed aggressive lymphomas, ixabepilone demonstrated a modest overall response rate of 27%, with complete responses observed in 12% of patients, all of whom had chemosensitive disease.

Ixabepilone was well-tolerated, with common side effects including neutropenia and peripheral sensory neuropathy, indicating it may be a viable treatment option for patients who have previously responded to chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 2 study of epothilone B analog BMS-247550 (NSC 710428) in patients with relapsed aggressive non-Hodgkin lymphomas. Churpek, JE., Pro, B., van Besien, K., et al.[2021]

Ixabepilone is a promising treatment for taxane-resistant tumors, showing significant cytotoxicity in preclinical studies and activity in clinical trials for breast and gynecologic cancers.

The toxicity profile of ixabepilone is comparable to that of taxanes, suggesting it can be managed effectively with supportive care, making it a viable option for heavily pretreated patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of ixabepilone monotherapy in the treatment of breast and gynecologic malignancies. Gupta, D., Mani, S.[2019]

In a retrospective study of 275 patients with relapsed/refractory large B-cell lymphoma (LBCL) receiving axicabtagene ciloleucel (axi-cel), the overall response rate was 82% and the complete response rate was 64%, demonstrating strong efficacy similar to the original ZUMA-1 trial.

Safety profiles showed that 7% of patients experienced severe cytokine release syndrome and 31% had neurotoxicity, with a nonrelapse mortality rate of 4.4%, indicating manageable risks associated with the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Standard-of-Care Axicabtagene Ciloleucel for Relapsed or Refractory Large B-Cell Lymphoma: Results From the US Lymphoma CAR T Consortium. Nastoupil, LJ., Jain, MD., Feng, L., et al.[2022]

In a phase I trial involving 30 patients with advanced taxane-pretreated ovarian and breast cancer, the combination of ixabepilone and pegylated liposomal doxorubicin (PLD) was found to be safe, with a recommended dose of 16 mg/m² of ixabepilone and 30 mg/m² of PLD.

The treatment showed objective responses in 23% of breast cancer patients and 29% of ovarian cancer patients, indicating potential efficacy and warranting further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of ixabepilone plus pegylated liposomal doxorubicin in patients with adenocarcinoma of breast or ovary. Chuang, E., Wiener, N., Christos, P., et al.[2021]

Taxotere, a semisynthetic analogue of Taxol, has shown significant efficacy in treating various cancers, including ovarian and breast carcinoma, with a recommended dose of 100 mg/m2 every 3 weeks based on a study of 65 patients.

The main side effect observed was dose-dependent neutropenia, which was reversible, along with delayed skin reactions and alopecia at higher doses, indicating a manageable safety profile for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I and pharmacokinetic study of Taxotere (RP 56976; NSC 628503) given as a short intravenous infusion. Extra, JM., Rousseau, F., Bruno, R., et al.[2018]

In a Phase 2 study involving 17 Japanese patients with relapsed/refractory large B-cell lymphoma, axicabtagene ciloleucel (axi-cel) demonstrated a high objective response rate of 86.7%, indicating its efficacy as a treatment option.

While no dose-limiting toxicities were observed, all patients experienced grade ≥3 treatment-emergent adverse events, with the most common being neutropenia and cytokine release syndrome, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 study of axicabtagene ciloleucel in Japanese patients with relapsed or refractory large B-cell lymphoma. Kato, K., Makita, S., Goto, H., et al.[2022]

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 (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]

Ixabepilone, approved by the US FDA in 2007, has shown effectiveness in treating metastatic breast cancer that is resistant to standard treatments like taxanes and anthracyclines, with over 2000 patients participating in clinical trials.

Combination therapy of ixabepilone with capecitabine has demonstrated a progression-free survival advantage compared to capecitabine alone, particularly benefiting certain hard-to-treat patient subgroups while maintaining a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances in breast cancer treatment: the emerging role of ixabepilone. Frye, DK.[2012]

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]

The interim analysis of the phase 2 ZUMA-5 study showed that axicabtagene ciloleucel (axicel; Yescarta) provided significant and durable clinical benefits for patients with relapsed or refractory indolent non-Hodgkin lymphoma, indicating its efficacy in this patient population.

The treatment demonstrated a high overall response rate (ORR) and complete response (CR) rate, while maintaining a manageable safety profile, suggesting it is a viable option for patients with this type of lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interim Phase 2 ZUMA-5 Results Show Promise for Axi-Cel in R/R iNHL. Slater, H.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8555382/

Outcomes of patients with large B-cell lymphoma ... We previously reported on 275 axi-cel patients treated with standard-of-care axi-cel, finding a best ORR and CR rate of 82% and 64%, respectively. Median PFS ...

2. yescartahcp.com yescartahcp.com/large-b-cell-lymphoma/real-world-evidence

Real World Evidence | YESCARTA® (axicabtagene ciloleucel) Real world data showing the benefits of YESCARTA® and how patients received the therapy. See Prescribing Information, BOXED WARNING, and Medication Guide.

3. gilead.com gilead.com/news/news-details/2024/kite-presents-new-data-underscoring-curative-potential-of-yescarta-in-relapsedrefractory-large-b-cell-lymphoma-at-ash

Kite Presents New Data Underscoring Curative Potential of ... Largest real-world evidence (RWE) analysis of Yescarta in second-line shows 71% overall survival rate, consistent with pivotal ZUMA-7 study, in broader patient ...

4. nejm.org nejm.org/doi/full/10.1056/NEJMoa2301665

Survival with Axicabtagene Ciloleucel in Large B-Cell ... Axi-cel as second-line treatment for patients with early relapsed or refractory large B-cell lymphoma resulted in significantly longer overall survival than ...

5. onclive.com onclive.com/view/real-world-data-confirm-efficacy-of-axi-cel-across-patient-related-factors-in-r-r-lbcl

Real-World Data Confirm Efficacy of Axi-Cel Across Patient ... Among 454 evaluable patients in the real-world study, the overall response (ORR) was 79%, including a complete response (CR) rate of 64% and ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6990602/

Safety and efficacy of axicabtagene ciloleucel in refractory ... We provide an overview of axi-cel therapy, including efficacy and safety data, along with a practical discussion of current treatment considerations.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT02348216

NCT02348216 | Study Evaluating the Safety and Efficacy of ... A Comparison of Two-Year Outcomes in ZUMA-1 (Axicabtagene Ciloleucel) and SCHOLAR-1 in Patients With Refractory Large B Cell Lymphoma. Blood (ASH Annual Meeting ...

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36999993/

Safety and Efficacy of Axicabtagene Ciloleucel versus ... Conclusions: Axi-cel is an effective second-line curative-intent therapy with a manageable safety profile and improved PROs for patients ≥65 ...