NKTR-255 + CAR-T Therapy for Large B-cell Lymphoma

Overseen By FHCC Intake

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Fred Hutchinson Cancer Center

Must not be taking: Corticosteroids, Immunosuppressants, IL-2/IL-15 agonists

Disqualifiers: HIV, Hepatitis B/C, Autoimmune disorders, others

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

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

Compensation: Varies

Number of Visits: 30

Duration: 9 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments for large B-cell lymphoma, a cancer that has returned or resisted previous treatments. It combines NKTR-255, which boosts the immune system's natural cancer-fighting ability, with CAR-T cell therapy (specifically Lisocabtagene Maraleucel), a method that modifies a person's own cells to better target cancer. The researchers aim to determine if these treatments work better together than alone. This trial may suit individuals with active large B-cell lymphoma that shows certain markers on imaging tests or pathology. 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.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot use therapeutic doses of corticosteroids or other systemic immunosuppressants shortly before certain procedures. It's best to discuss your specific medications with the trial team.

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

Research has shown that lisocabtagene maraleucel (liso-cel), a type of CAR-T cell therapy, generally has a manageable safety profile. It has been used successfully for patients with B-cell cancers, including large B-cell lymphoma. Common side effects include cytokine release syndrome (CRS), where the immune system becomes overly active, and other immune-related effects. However, proper medical care usually manages these side effects.

Early research suggests that NKTR-255 is generally well-tolerated. Studies indicate it can enhance the effectiveness of CAR-T cell therapies like liso-cel. While researchers are still studying the full safety profile, initial results regarding its tolerability are promising.

In summary, both treatments appear to have manageable safety profiles based on previous studies, but ongoing research will provide more information. Always consult healthcare providers to understand the potential risks and benefits. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for large B-cell lymphoma, which often focus on chemotherapy and traditional CAR-T therapies, NKTR-255 combined with lisocabtagene maraleucel (liso-cel) offers a novel approach. Researchers are excited because NKTR-255 is designed to enhance the persistence and activity of CAR-T cells by targeting the IL-15 receptor pathway, potentially leading to more durable responses. This combination aims to improve patient outcomes by boosting the immune system's ability to fight cancer cells more effectively and for a longer duration. This innovative approach could be a game-changer in the treatment landscape for large B-cell lymphoma.

What evidence suggests that NKTR-255 combined with CAR-T therapy could be effective for large B-cell lymphoma?

Research has shown that lisocabtagene maraleucel (liso-cel), which participants in this trial will receive, effectively treats large B-cell lymphoma that has returned or not responded to other treatments. Studies indicate it works better and lasts longer than standard treatments, with a good safety record. Key findings suggest it might even cure some patients.

In this trial, participants will also receive NKTR-255, a newer treatment aimed at boosting the immune system. Early studies suggest it enhances the effects of CAR-T cell therapy, like liso-cel, by increasing the chances of a complete response (when no signs of cancer are found). In early tests on animals and humans, NKTR-255 showed promise in making CAR-T therapies more effective against B-cell lymphoma. Together, these treatments might offer a stronger way to fight this cancer. ^{3 6 7 8 9}

Who Is on the Research Team?

Alexandre Hirayama

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Are You a Good Fit for This Trial?

Adults with relapsed or refractory large B-cell lymphoma eligible for CAR-T therapy, who have a Karnofsky performance status of at least 60%, proper heart function (LVEF >= 40%), and adequate blood counts. They must not have active central nervous system involvement by malignancy, serious infections, HIV, history of solid organ transplant, recent use of systemic steroids or immunosuppression, prior CD19 CAR-T cell therapy or IL-15 agonist treatment.

Inclusion Criteria

My cancer shows or is likely to show CD19 expression.

My platelet count is at least 50,000 without lymphoma in my bone marrow.

Sa02 >= 92% on room air

Exclusion Criteria

Pregnant or breastfeeding women

I am HIV positive.

History of specific cardiovascular conditions within the past 6 months unless cleared by a cardiologist

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Multiple visits (in-person)

Treatment

Patients receive lymphodepletion therapy followed by liso-cel CAR-T cell infusion and NKTR-255 IV every 3 weeks for up to 3 doses

9 weeks

Weekly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Every 30 days, then every 3 months (in-person)

Extension

Participants may continue to be monitored for long-term outcomes

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• Lisocabtagene Maraleucel
• NKTR-255

Trial Overview This trial is testing NKTR-255 combined with lisocabtagene maraleucel (a type of CAR-T cell therapy) to see if it's more effective in treating large B-cell lymphoma than standard treatments. NKTR-255 aims to enhance the immune response against cancer cells while lisocabtagene maraleucel targets CD19 on cancer cells.

How Is the Trial Designed?

Group I: Treatment (lymphodepletion, liso-cel, NKTR-255) Experimental Treatment 14 Interventions

Patients receive standard of care lymphodepletion therapy consisting of cyclophosphamide and fludarabine on days -5 to -3 followed by liso-cel CAR-T cell infusion on day 0. Patients then receive NKTR-255 IV over 30 minutes every 3 weeks starting on day 10 or 14 for up to 3 doses in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray and ECHO or MUGA during screening. Patients undergo bone marrow biopsy and aspiration, LP for CSF sample collection during screening, on the study and during follow-up as clinically indicated. Patients also undergo PET/CT throughout the trial. Additionally, patients undergo blood sample collection and may optionally undergo tissue biopsy throughout the trial.

Lisocabtagene Maraleucel is already approved in United States, European Union for the following indications:

Approved in United States as Breyanzi for:

• Large B-cell lymphoma (LBCL)
• Diffuse large B-cell lymphoma (DLBCL)
• High-grade B cell lymphoma
• Primary mediastinal large B-cell lymphoma
• Follicular lymphoma grade 3B
• Chronic lymphocytic leukemia (CLL)
• Small lymphocytic lymphoma (SLL)
• Mantle cell lymphoma (MCL)

Approved in European Union as Breyanzi for:

• Diffuse large B-cell lymphoma
• High-grade B-cell lymphoma
• Primary mediastinal large B-cell lymphoma
• Follicular lymphoma grade 3B

Who Is Running the Clinical Trial?

Fred Hutchinson Cancer Center

Lead Sponsor

Trials

583

Recruited

1,341,000+

Nektar Therapeutics

Industry Sponsor

Trials

59

Recruited

9,900+

Howard W. Robin

Nektar Therapeutics

Chief Executive Officer since 2007

B.S. in Accounting and Finance from Fairleigh Dickinson University

Dr. Dimitry Nuyten

Nektar Therapeutics

Chief Medical Officer since 2022

MD

Published Research Related to This Trial

In a phase 3 study involving 184 patients with primary refractory or early relapsed large B-cell lymphoma (LBCL), lisocabtagene maraleucel (liso-cel) significantly improved median event-free survival to 10.1 months compared to 2.3 months for standard care, indicating its efficacy as a second-line treatment.

The safety profile of liso-cel was manageable, with no new safety concerns identified; serious adverse events were similar between liso-cel and standard care, and there were no treatment-related deaths in the liso-cel group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial. Kamdar, M., Solomon, SR., Arnason, J., et al.[2022]

CD19-directed CAR T-cell therapy, particularly axicabtagene ciloleucel, is highly effective for treating relapsed/refractory large B-cell lymphoma, but it comes with significant risks of treatment-emergent toxicities such as cytokine release syndrome and neurotoxicity.

Understanding the safety profile and potential complications of CAR T-cell therapy is crucial for selecting appropriate patients and implementing preventative measures, which can enhance the overall safety and effectiveness of the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety evaluation of axicabtagene ciloleucel for relapsed or refractory large B-cell lymphoma. Nath, K., Wudhikarn, K., Alarcon Tomas, A., et al.[2023]

In a study involving 14 Japanese patients with relapsed or refractory aggressive large B-cell lymphoma, the CAR T-cell therapy lisocabtagene maraleucel (liso-cel) showed a 70% objective response rate and a 50% complete response rate, indicating significant efficacy.

The treatment had a manageable safety profile, with common side effects including neutropenia (90%) and cytokine release syndrome (50%), but no severe (grade ≥3) cytokine release syndrome events were reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 results of lisocabtagene maraleucel in Japanese patients with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma. Makita, S., Yamamoto, G., Maruyama, D., et al.[2023]

In a phase 2 trial involving 61 patients with relapsed or refractory large B-cell lymphoma, lisocabtagene maraleucel demonstrated a high overall response rate of 80%, indicating its efficacy as a second-line treatment for patients not intended for stem-cell transplantation.

The treatment was generally safe, with no treatment-related deaths reported; however, common serious side effects included neutropenia and cytokine release syndrome, which occurred in 38% of patients, highlighting the need for monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lisocabtagene maraleucel as second-line therapy in adults with relapsed or refractory large B-cell lymphoma who were not intended for haematopoietic stem cell transplantation (PILOT): an open-label, phase 2 study. Sehgal, A., Hoda, D., Riedell, PA., et al.[2022]

Chimeric antigen receptor (CAR) T cell therapies, specifically axicabtagene ciloleucel and tisagenlecleucel, have been approved for treating large B-cell lymphomas after two prior therapies, showing durable remissions in 30% to 40% of patients.

While these therapies are effective, they can cause serious side effects like cytokine release syndrome and neurotoxicity, necessitating treatment in specialized medical centers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Translating anti-CD19 CAR T-cell therapy into clinical practice for relapsed/refractory diffuse large B-cell lymphoma. Chow, VA., Shadman, M., Gopal, AK.[2022]

CAR-T therapy has transformed the treatment of diffuse large B-cell lymphoma (DLBCL) in patients who do not respond to or relapse after standard immunochemotherapy, by using genetically modified T cells to target tumor antigens.

In Spain, two anti-CD19 CAR-T therapies are approved for use after two or more treatment lines, with ongoing clinical trials aimed at exploring their effectiveness in earlier treatment stages, highlighting the evolving understanding of their efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric antigen receptor T-cell (CAR-T) therapy in patients with aggressive B-cell lymphomas. Current outlook after a decade of treatment. Catalá, E., Iacoboni, G., Barba, P.[2022]

Lisocabtagene Maraleucel (Liso-cel) is a promising CAR-T therapy targeting CD19, showing strong antitumor activity in aggressive B-cell lymphomas with manageable toxicity, as confirmed in the TRANSCEND NHL001 trial.

Preclinical studies indicate that a specific ratio of CD4+ and CD8+ T-cells enhances the effectiveness of Liso-cel, suggesting a well-balanced approach to maximizing both efficacy and safety in treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lisocabtagene Maraleucel for the treatment of B-cell lymphoma. Iragavarapu, C., Hildebrandt, G.[2022]

In a study involving 344 patients with relapsed or refractory large B-cell lymphomas, lisocabtagene maraleucel (liso-cel) demonstrated a high objective response rate of 73%, with 53% achieving a complete response, indicating its efficacy as a treatment option.

The safety profile of liso-cel was acceptable, with a low incidence of severe cytokine release syndrome (2%) and neurological events (10%), suggesting it can be safely administered to patients with various high-risk features.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Abramson, JS., Palomba, ML., Gordon, LI., et al.[2021]

Lisocabtagene maraleucel (liso-cel) is an effective CAR T cell therapy for relapsed or refractory large B cell lymphoma, showing a 73% objective response rate and a 53% complete remission rate in a study of 344 patients.

The treatment demonstrated a 12-month overall survival rate of 58% for all patients and 86% for those who achieved complete remission, although it was associated with adverse events such as cytokine release syndrome (42%) and neurological issues (30%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lisocabtagene Maraleucel in Relapsed or Refractory Diffuse Large B Cell Lymphoma: What is the Evidence? Kharfan-Dabaja, MA., Yassine, F., Moustafa, MA., et al.[2023]

Citations

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Lisocabtagene Maraleucel Versus Standard of Care for ... These data support liso-cel as an effective second-line treatment with curative potential for relapsed/refractory LBCL. Trial registration: ...

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Lisocabtagene maraleucel for relapsed/refractory large B-cell ... Real-world use of liso-cel in patients with advanced age and comorbidities yielded similar results compared with pivotal trials.

3. ascopubs.org ascopubs.org/doi/10.1200/JCO-25-00399

Lisocabtagene Maraleucel Versus Standard of Care for ... At 3-year follow-up, liso-cel confirmed superior, more durable efficacy versus SOC with a favorable safety profile and no new safety signals.

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39657136/

Lisocabtagene maraleucel for relapsed/refractory large B-cell ... These analyses confirm similar efficacy and safety of commercial liso-cel compared with pivotal trial results. Notably, these outcomes were ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S2473952923006894

Cost-effectiveness of second-line lisocabtagene ... This aligns with observed long-term outcomes in patients with DLBCL treated with immunochemotherapy, based on 60-month median follow-up data.

6. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/472/531301/Real-World-RW-Outcomes-of-Lisocabtagene-Maraleucel

Real-World (RW) Outcomes of Lisocabtagene Maraleucel (liso ... Safety outcomes included cytokine release syndrome (CRS), immune effector cell ... Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: ...

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2666636725003574

Effectiveness and Safety Outcomes of Standard of Care ... Liso-cel, an autologous, CD19-directed, CAR T cell product, has shown favorable efficacy with manageable safety across B-cell malignancies.

8. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/470/531306/Real-World-RW-Outcomes-of-Lisocabtagene-Maraleucel

Real-World (RW) Outcomes of Lisocabtagene Maraleucel (liso ... Here, we report on the effectiveness and safety of liso-cel as SOC based ... Most pts (80%) had DLBCL (germinal center B cell type, 50 pts; activated B ...

9. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40305658/

Lisocabtagene maraleucel for R/R LBCL in patients not ... We report final analysis results from the PILOT study of lisocabtagene maraleucel (liso-cel) for patients with relapsed/refractory (R/R) large B-cell lymphoma ...