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

24 Participants Needed

Trial Summary

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.

What data supports the effectiveness of this treatment for large B-cell lymphoma?

Research shows that Lisocabtagene Maraleucel, a part of this treatment, has demonstrated strong antitumor activity in patients with relapsed or refractory large B-cell lymphoma, with a 73% response rate and a 53% complete remission rate. Additionally, the treatment has shown a manageable safety profile, making it a promising option for patients who have limited treatment choices. ^{1 2 3 4 5}

Is the NKTR-255 + CAR-T Therapy for Large B-cell Lymphoma safe for humans?

Lisocabtagene maraleucel (liso-cel), a component of the therapy, has been shown to have a manageable safety profile in patients with large B-cell lymphoma. Common side effects include neutropenia (low white blood cell count), leukopenia (low white blood cell count), anemia (low red blood cell count), and thrombocytopenia (low platelet count), with some patients experiencing cytokine release syndrome (a reaction to the treatment) and neurological events, though severe cases were rare. ^{1 2 4 5 6}

What makes the treatment NKTR-255 + CAR-T Therapy for Large B-cell Lymphoma unique?

This treatment is unique because it combines NKTR-255, which may enhance the immune response, with lisocabtagene maraleucel, a CAR-T therapy that uses genetically modified T cells to target and destroy cancer cells. Unlike other CAR-T therapies, lisocabtagene maraleucel is administered as a sequential infusion of separately manufactured CD4 and CD8 T cells, potentially improving its effectiveness and safety profile. ^{2 4 7 8 9}

What is the purpose of this trial?

This phase Ib trial studies the effects of NKTR-255 in combination with chimeric antigen (CAR)-T cell therapy and to see how well they work in treating patients with large B-cell lymphoma that has come back (relapsed) or does not respond to treatment (refractory). NKTR-255 is an investigational IL-15 receptor agonist designed to boost the immune system's natural ability to fight cancer. T cells are infection fighting blood cells that can kill tumor cells. Lisocabtagene maraleucel is a CAR-T cell product that consists of genetically engineered T cells, modified to recognize CD19, a protein on the surface of cancer cells. These CD19-specific T cells may help the body's immune system identify and kill CD19-positive cancer cells. Giving NKTR-255 together with lisocabtagene maraleucel may work better in treating large B-cell lymphoma than either drug alone.

Research Team

Alexandre Hirayama

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Lisocabtagene Maraleucel for the treatment of B-cell lymphoma. [2022]

2. Saudi Arabia pubmed.ncbi.nlm.nih.gov

Lisocabtagene Maraleucel in Relapsed or Refractory Diffuse Large B Cell Lymphoma: What is the Evidence? [2023]

3. England 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. [2022]

4. England 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. [2022]

5. England 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. [2021]

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

Phase 2 results of lisocabtagene maraleucel in Japanese patients with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma. [2023]

7. Spain 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. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Safety evaluation of axicabtagene ciloleucel for relapsed or refractory large B-cell lymphoma. [2023]

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

Translating anti-CD19 CAR T-cell therapy into clinical practice for relapsed/refractory diffuse large B-cell lymphoma. [2022]