Immune System Booster for Non-Hodgkin's Lymphoma

No longer recruiting at 27 trial locations

Overseen By Nektar Recruitment

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: Nektar Therapeutics

Must be taking: CAR-T cell therapy

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

Disqualifiers: Hepatitis, HIV, Autoimmune disorders, others

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

Compensation: Varies

Number of Visits: 30

Duration: 5 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests an immune system booster called NKTR-255 to determine its effectiveness in treating large B-cell lymphoma, a type of blood cancer, when administered after CAR-T cell therapy that targets cancer cells. The study aims to assess whether this combination is safer and more effective than either treatment alone. Suitable candidates for this trial have large B-cell lymphoma that has returned or not responded to other treatments and have already undergone CD19 CAR-T therapy. As a Phase 2 trial, this research focuses on evaluating the treatment's effectiveness in an initial, smaller group, offering a chance to benefit from a potentially effective new therapy.

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

The trial protocol does not specify if you need to stop your current medications. However, you cannot use therapeutic doses of corticosteroids or other systemic immunosuppressants within 7 days before leukapheresis or 72 hours before CAR-T cell infusion. Topical and inhaled steroids are allowed. 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 suggests that NKTR-255 might be well-tolerated by patients. Early data show that patients who received NKTR-255 experienced few serious side effects. Some patients had temporary changes in proteins that help cells communicate, but these changes quickly returned to normal. Importantly, no patients stopped the treatment due to side effects, and no serious side effects limited the dose. These findings suggest that NKTR-255 could be a promising option for those who have already tried other treatments for large B-cell lymphoma. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatment?

Researchers are excited about NKTR-255 because it offers a novel approach to treating Non-Hodgkin's Lymphoma. Unlike traditional therapies that might involve chemotherapy or radiation, NKTR-255 works by boosting the body's own immune system. It enhances the activity and longevity of natural killer (NK) cells and memory CD8+ T cells, which are crucial in fighting cancer. This immune-boosting mechanism is different from most current treatments, which directly target cancer cells. This approach could potentially lead to better outcomes by empowering the immune system to more effectively attack and control the disease.

What evidence suggests that this trial's treatments could be effective for large B-cell lymphoma?

Research has shown that NKTR-255, one of the treatments studied in this trial, may benefit patients with difficult-to-treat or recurrent large B-cell lymphoma when combined with CAR T-cell therapy. Participants in this trial will receive varying dosages of NKTR-255 or a placebo. One study found that this combination increased the number of patients whose cancer completely disappeared for at least six months, compared to those who received a placebo. NKTR-255 enhances the immune system's ability to fight cancer cells more effectively and remains active in the body longer. Early studies also showed that patients tolerated it well. These findings suggest that NKTR-255 could strengthen the immune system's capacity to combat this type of cancer. ^{2 3 5 6 7}

Who Is on the Research Team?

Study Director

Principal Investigator

Nektar Therapeutics

Are You a Good Fit for This Trial?

Adults with relapsed/refractory large B-cell lymphoma who've had standard CAR-T cell therapy and specific chemotherapy. They must not have used certain immune therapies recently, have good organ function, and agree to contraception if of reproductive potential. Excluded are those with prior IL-15 agonist treatment, recent steroids or immunosuppression use, other CD19-directed CAR-T treatments, active infections like hepatitis/HIV, CNS lymphoma history, uncontrolled infections requiring IV drugs.

Inclusion Criteria

My lymphoma tests show CD19 presence or it's likely based on my cancer type.

I agree to use birth control if I can become pregnant.

My organs, including my bone marrow, kidneys, liver, lungs, and heart, are working well.

Exclusion Criteria

Presence of any indwelling line or drain

I have had a solid organ transplant.

Use of investigational agents or devices within specified timeframes

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lymphodepletion Chemotherapy

Patients receive lymphodepletion chemotherapy as recommended by the CAR-T cell manufacturer

1 week

CAR-T Cell Infusion

Patients receive a one-time CD19-directed CAR-T cell infusion

1 day

Treatment

Study drug (NKTR-255 or placebo) is administered intravenously every 3 weeks for up to 7 cycles or 5 months

5 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 3 years

Follow-up at 30 days, and then at 9, 12, 18, 24, and 36 months after CAR-T cell infusion

What Are the Treatments Tested in This Trial?

Interventions

• NKTR-255

Trial Overview The trial tests NKTR-255's effectiveness in enhancing the body's immune response after CD19-directed CAR-T cell therapy in patients with stubborn large B-cell lymphoma. It compares different doses of NKTR-255 against a placebo to see if it improves cancer-fighting outcomes.

How Is the Trial Designed?

Group I: Stage 1 NKTR-255 at 3.0/6.0 μg/kg Experimental Treatment 1 Intervention

In this arm of Stage 1 (Phase 2 of the study), patients will be dosed with 3.0 μg/kg NKTR-255 in Cycle 1 (C1) and continue in Cycle 2 and subsequent cycles (C+) with 6.0 μg/kg NKTR-255 (hereinafter referred to as 3.0/6.0 µg/kg NKTR-255). NKTR-255 will be administered intravenously approximately 14 days after CD19-directed CAR-T cell infusion. Patients will be dosed every 3 weeks for up to 7 cycles or 5 months, whichever is earlier, in the absence of disease progression or unacceptable toxicity. The dose regimen for Stage 2 (Phase 3 of the study) will be selected based on the results of Stage 1 as reviewed by the Data Monitoring Committee (DMC) and the study team.

Group II: Stage 1 NKTR-255 at 3.0 μg/kg Experimental Treatment 1 Intervention

In this arm of Stage 1 (Phase 2 of the study), NKTR-255 will be dosed at 3.0 μg/kg. NKTR-255 will be administered intravenously approximately 14 days after CD19-directed CAR-T cell infusion. Patients will be dosed every 3 weeks for up to 7 cycles or 5 months, whichever is earlier, in the absence of disease progression or unacceptable toxicity. The dose regimen for Stage 2 (Phase 3 of the study) will be selected based on the results of Stage 1 as reviewed by the Data Monitoring Committee (DMC) and the study team.

Group III: Stage 1 NKTR-255 at 1.5 µg/kg Experimental Treatment 1 Intervention

In this arm of Stage 1 (Phase 2 of the study), NKTR-255 will be dosed at 1.5 µg/kg. NKTR-255 will be administered intravenously approximately 14 days after CD19-directed CAR-T cell infusion. Patients will be dosed every 3 weeks for up to 7 cycles or 5 months, whichever is earlier, in the absence of disease progression or unacceptable toxicity. The dose regimen for Stage 2 (Phase 3 of the study) will be selected based on the results of Stage 1 as reviewed by the Data Monitoring Committee (DMC) and the study team.

Group IV: Placebo Placebo Group 1 Intervention

Placebo is commercially available 0.9% Sodium Chloride Solution for Injection (USP). Placebo will be administered intravenously approximately 14 days after CD19-directed CAR-T cell infusion. Placebo will be infused every 3 weeks for up to 7 cycles or 5 months, whichever is earlier.

Who Is Running the Clinical Trial?

Nektar Therapeutics

Lead 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

Extranodal NK/T-cell lymphoma (ENKTCL) is a highly aggressive form of non-Hodgkin's lymphoma with poor prognosis and limited efficacy from traditional chemoradiotherapy.

Recent advancements in immunotherapy have shown promising results in treating ENKTCL, suggesting a potential shift in treatment strategies for this aggressive cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Advances in immunotherapy of extranodal NK/T cell lymphoma]. Hao, DQ., Li, LQ., Li, MC., et al.[2020]

Natural killer (NK)/T-cell lymphomas are aggressive cancers commonly found in Asian and South American populations, with Epstein-Barr virus (EBV) infection present in all cases, making EBV DNA levels a useful marker for assessing lymphoma load and treatment response.

Standard treatment for early-stage nasal NK/T-cell lymphoma involves non-anthracycline asparaginase-based regimens combined with radiotherapy, while advanced cases require asparaginase-containing regimens and may benefit from allogeneic stem cell transplantation, highlighting the need for tailored therapeutic approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

How we treat NK/T-cell lymphomas. Tse, E., Zhao, WL., Xiong, J., et al.[2023]

In a phase 1 trial involving three children with relapsed or resistant neuroblastoma, engineered NKT cells showed promising safety, with no dose-limiting toxicities observed after infusion, despite some hematologic adverse events linked to pre-treatment conditioning.

One patient experienced a significant anti-tumor response, with regression of bone metastatic lesions, indicating that CAR-NKT cells can effectively target tumors and expand in the body after treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-GD2 CAR-NKT cells in patients with relapsed or refractory neuroblastoma: an interim analysis. Heczey, A., Courtney, AN., Montalbano, A., et al.[2023]

The phase I study involving 12 subjects with acute myeloid leukemia or relapsed/refractory multiple myeloma demonstrated that NKG2D-CAR T cells were safe, with no dose-limiting toxicities or significant adverse events observed, indicating a favorable safety profile for this treatment approach.

While no objective tumor responses were achieved, there were transient improvements in hematologic parameters in one AML patient, suggesting potential for disease stability, but further modifications to enhance CAR T-cell expansion and effectiveness may be necessary for better clinical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Trial of Autologous CAR T Cells Targeting NKG2D Ligands in Patients with AML/MDS and Multiple Myeloma. Baumeister, SH., Murad, J., Werner, L., et al.[2021]

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) can lead to long-term survival in about 48.6% of patients with relapsed/refractory natural killer/T-cell lymphomas (NKTCL), based on a study of 135 patients over a median follow-up of 4.8 years.

The timing of the transplant and the patient's condition at the time of transplantation significantly affect progression-free survival, with shorter intervals between diagnosis and transplant and not being in complete or partial remission associated with poorer outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allogeneic hematopoietic stem cell transplantation for NK/T-cell lymphoma: an international collaborative analysis. Berning, P., Schmitz, N., Ngoya, M., et al.[2023]

A therapeutic vaccine using α-galactosylceramide (α-GalCer) loaded onto irradiated tumor cells significantly inhibited tumor growth and prolonged survival in a mouse model of B-cell lymphoma, highlighting its potential efficacy in boosting antitumor immunity.

The vaccine's effectiveness relied on the activation of NKT cells, NK cells, and CD8 T cells, with a notable increase in IFN-γ production, suggesting that targeting NKT cell ligands could be a promising strategy for immunotherapy in hematologic cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NKT cell adjuvant-based tumor vaccine for treatment of myc oncogene-driven mouse B-cell lymphoma. Mattarollo, SR., West, AC., Steegh, K., et al.[2021]

Combining α-galactosylceramide (α-GalCer)-loaded tumor cell vaccination with an anti-4-1BB antibody significantly improved survival rates in mice with B cell lymphoma, with over 50% of treated mice completely eradicating their tumors.

The enhanced immune response was linked to the expansion of CD8+ T cells and the development of immunological memory, as 'cured' mice remained resistant to lymphoma re-challenge 80 days later, suggesting a durable anticancer immunity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NKT cell-targeted vaccination plus anti-4-1BB antibody generates persistent CD8 T cell immunity against B cell lymphoma. Kobayashi, T., Doff, BL., Rearden, RC., et al.[2021]

Natural killer/T cell lymphoma (NKTCL) is a rare and aggressive form of lymphoma associated with Epstein-Barr virus, primarily affecting patients in East Asia and Latin America, and current treatments have limited effectiveness for advanced cases.

Immunotherapy, including strategies targeting PD-1/PD-L1 and CTLA-4, as well as CAR T cell therapy, shows promise in improving outcomes for NKTCL patients, highlighting the need for novel treatment approaches in this challenging disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances and challenges of immunotherapies in NK/T cell lymphomas. He, L., Chen, N., Dai, L., et al.[2023]

The study found that overexpression of the IL-2 receptor α (IL-2Rα) in NKTCL cells leads to increased cell proliferation and resistance to chemotherapy drugs like gemcitabine and doxorubicin, indicating a mechanism of chemoresistance in this aggressive lymphoma.

LMP1 was shown to activate the MAPK/NF-κB pathway, which in turn up-regulates IL-2Rα levels, suggesting that targeting IL-2Rα could be a promising therapeutic strategy for improving treatment outcomes in patients with NKTCL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

IL-2Rα up-regulation is mediated by latent membrane protein 1 and promotes lymphomagenesis and chemotherapy resistance in natural killer/T-cell lymphoma. Wang, L., Bi, XW., Zhu, YJ., et al.[2020]

The study developed a therapeutic vaccine using A20 lysate and an NKT cell agonist, α-galactosylceramide, which provided long-term immune protection against aggressive B cell lymphoma in a murine model, primarily through CD8 T cell responses.

Key immune biomarkers, such as the strength of the germinal center reaction and the Th1 type humoral response, were identified as predictors of long-term survival, highlighting the potential for this vaccine to be a simple and effective treatment option for B lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A simple, clinically relevant therapeutic vaccine shows long-term protection in an aggressive, delayed-treatment B lymphoma model. Pradhan, P., Leleux, J., Liu, J., et al.[2019]

An autologous lymphoma vaccine that activates NKT cells was shown to generate effective tumor-specific immunity in mice, leading to significant tumor regression and resistance to tumor rechallenge.

The study identified that conventional CD4(+) T cells, rather than CD8(+) T cells, were crucial for mediating this antitumor immunity, suggesting a targeted approach for developing immunotherapies against human lymphomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An NKT-mediated autologous vaccine generates CD4 T-cell dependent potent antilymphoma immunity. Chung, Y., Qin, H., Kang, CY., et al.[2022]

In patients receiving anti-CD20 antibodies and cytotoxic chemotherapy for lymphomas, a third dose of the BNT162b2 vaccine improved CD4+Th1+T cell responses, indicating a potential benefit for enhancing immune response in severely immunosuppressed individuals.

However, the effect on CD8+ T cell responses was only marginal, suggesting that while the booster dose can help some aspects of the immune response, it may not be as effective for all T cell types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-SARS-CoV-2 cellular response after 2 and 3 doses of BNT162b2 mRNA vaccine in lymphoma patients receiving anti-CD20 antibodies. Gressens, SB., Wiedemann, A., Déchenaud, M., et al.[2023]

Citations

1. ir.nektar.com ir.nektar.com/news-releases/news-release-details/nektar-therapeutics-presents-clinical-data-nktr-255-patients

Nektar Therapeutics Presents Clinical Data for NKTR-255 ... NKTR-255 was well tolerated and early evidence of clinical activity was observed in this heavily pre-treated and highly refractory patient ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04136756

Study Details | NCT04136756 | NKTR-255 in Relapsed/ ... This is a Phase 1 study to evaluate safety and tolerability of NKTR-255 alone and in combination with daratumumab or rituximab.

3. onclive.com onclive.com/view/nktr-255-plus-anti-cd19-car-t-cell-therapy-demonstrates-safety-and-preliminary-efficacy-in-r-r-lbcl

NKTR-255 Plus Anti-CD19 CAR T-Cell Therapy ... NKTR-255 combined with CAR T-cell therapy improved 6-month CR rates in relapsed/refractory LBCL patients compared to placebo, showing potential ...

4. ashpublications.org ashpublications.org/blood/article/140/Supplement%201/10357/489531/Safety-Tolerability-PK-PD-and-Preliminary-Efficacy

Safety, Tolerability, PK/PD and Preliminary Efficacy of NKTR ... The average t1/2 of NKTR-255 was ~34-87 hours over the dose range of 3-12 µg/kg. No/minimal accumulation was observed with q3w dosing. There was ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8130760/

NKTR-255, a novel polymer-conjugated rhIL-15 with potent ... In vivo, NKTR-255 exhibited a PK profile with reduced clearance and a longer half-life relative to rhIL-15 and demonstrated prolonged IL-15R ...

6. onclive.com onclive.com/view/dr-ahmed-on-the-safety-profile-of-nktr-255-in-relapsed-refractory-lbcl

Dr Ahmed on the Safety Profile of NKTR-255 in Relapsed ... Overall, these early data suggest that NKTR-255 may be a well-tolerated and efficacious approach to improving outcomes following CAR T-cell ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S0006497121050680

Safety, Tolerability, PK/PD and Preliminary Efficacy of ... NKTR-255 was well tolerated with minimal treatment-related toxicities and transient upregulation and rapid decline of cytokines to baseline levels.