N-803 + PD-L1 t-haNK + Bevacizumab for Glioblastoma

Recruiting at 2 trial locations

Overseen By Mark Nelson

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: ImmunityBio, Inc.

Must not be taking: Bevacizumab, Corticosteroids, Anticoagulants, others

Disqualifiers: Uncontrolled disease, Autoimmune, Organ transplant, others

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

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 13

Duration: 76 weeks

34 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the safety and effectiveness of a new combination of treatments for individuals with glioblastoma, an aggressive brain cancer that has returned or worsened. The trial tests a mix of drugs, including N-803 (an IL-15 superagonist complex), PD-L1 t-haNK (PD-L1 CAR-NK cells), and bevacizumab (also known as Avastin). In some cases, it includes a device called TTFields, which sends low-intensity electric fields to the brain. Individuals whose glioblastoma has recurred after initial treatments like surgery and radiation, and who can manage the daily use of a device on their head, might be suitable candidates. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you are on chronic daily treatment with high-dose systemic corticosteroids or if you are receiving therapeutic anticoagulation. 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 the treatments tested in this trial have been safe in earlier studies. For N-803, a drug that boosts the immune system, evidence suggests it can do so without causing serious side effects. Patients who received more than four doses experienced fewer instances of disease recurrence, indicating good tolerance.

PD-L1 t-haNK, a therapy using natural killer cells, was also found to be safe and generally well-tolerated. Most side effects were mild, such as minor adverse events. Importantly, there were no reports of serious issues like cytokine release syndrome (CRS) or nerve damage, which can be concerns with some cancer treatments.

Bevacizumab, already approved by the FDA for treating recurrent glioblastoma, has a known safety record. While it can cause serious side effects, such as stomach problems, it generally has fewer adverse effects compared to some other glioblastoma treatments.

Overall, past research indicates that the treatments studied here have been relatively well-tolerated, offering reassurance about their safety for those considering joining this trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for glioblastoma because they offer innovative approaches compared to traditional therapies like surgery, radiation, and standard chemotherapy. Unlike typical treatments, the combination of N-803, PD-L1 t-haNK, and Bevacizumab targets the immune system to fight cancer more effectively. N-803 boosts immune cell activity, while PD-L1 t-haNK enhances the body's immune response against tumor cells. Bevacizumab helps by blocking blood supply to the tumor. Additionally, the use of TTFields technology, which involves continuous application of electric fields to the brain, offers a novel way to disrupt cancer cell division. These treatments, together, provide a multi-pronged strategy that may improve outcomes for patients with this aggressive brain cancer.

What evidence suggests that this trial's treatments could be effective for glioblastoma?

In earlier studies, N-803 has shown promise in managing glioblastoma, a type of brain cancer. For example, research indicated that it helped reduce tumor size and improved survival in animals. Another study found that 100% of patients had their disease under control, with some almost free of tumors. In this trial, participants in the Single Arm will receive a combination of N-803, PD-L1 t-haNK, and Bevacizumab. PD-L1 t-haNK therapy, another part of this trial, also showed 100% disease control in a small group of glioblastoma patients. Bevacizumab, a drug already used for glioblastoma, has been effective in slowing tumor growth and improving survival for some patients. Each treatment shows potential, and when combined, they may offer even better results for those with recurring glioblastoma. ^{3 6 7 8 9}

Are You a Good Fit for This Trial?

This trial is for adults over 18 with glioblastoma that's worsened after initial treatments. They should have a life expectancy of more than 12 weeks, be able to consent, and have had prior therapy including radiotherapy and temozolomide. Participants need a performance status score indicating they can carry out daily activities and must agree to use effective contraception.

Inclusion Criteria

I've had radiotherapy and temozolomide as my first treatment and it's been at least 28 days since my last treatment.

I agree to use effective birth control during and up to 6 months after treatment.

Life expectancy > 12 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive N-803 subcutaneously, PD-L1 t-haNK intravenously, and Bevacizumab intravenously in 28-day cycles for a maximum of 76 weeks

76 weeks

Visits on days 1 and 15 of each 28-day cycle

Follow-up

Participants are monitored for survival status every 12 weeks for the first 2 years, then yearly thereafter

2 years

Every 12 weeks (± 2 weeks) for the first 2 years, then yearly

What Are the Treatments Tested in This Trial?

Interventions

• Bevacizumab
• N-803
• PD-L1 t-haNK

Trial Overview

The study tests the combination of N-803 (given under the skin), PD-L1 t-haNK (given into the vein), and Bevacizumab (also IV) in patients with recurrent or progressive glioblastoma. Treatments are given in cycles every two weeks up to 76 weeks unless side effects become too severe or disease progresses.

How Is the Trial Designed?

Group I: Single Arm Experimental Treatment 3 Interventions

Phase 2 Participants will receive N-803 1 mg subcutaneously (SC), PD-L1 t-haNK (\~2 × 10\^9 cells/infusion) intravenously (IV), and Bevacizumab (10 mg/kg IV) combination therapy during 28-day cycles on days 1 and 15 of each cycle. Maximum treatment period is 76 weeks, 19 cycles.

Group II: Experiment Treatment Arm B Experimental Treatment 4 Interventions

Participants will be randomized 1:1 to 1 of 2 experimental arms (Arm A or Arm B). Treatment for all enrolled participants will consist of repeated 8-week cycles for a maximum treatment period of up to 80 weeks (10 cycles). Every 2 weeks (Days 1, 15, 29, and 43 of an 8-week cycle): PD-L1 t-haNK, 2 × 109 cells per infusion IV NAI, 1 mg SC Bevacizumab, 10 mg/kg IV Plus - Continuous application (≥ 18 hours/day) to the brain: TTFields, 200 kHz

Group III: Experiment Treatment Arm A Experimental Treatment 3 Interventions

Phase 2B: Participants will be randomized 1:1 to 1 of 2 experimental arms (Arm A or Arm B). Treatment for all enrolled participants will consist of repeated 8-week cycles for a maximum treatment period of up to 80 weeks (10 cycles). Experimental Arm (A): Every 2 weeks (Days 1, 15, 29, and 43 of an 8-week cycle): N-803, 1 mg SC Bevacizumab, 10 mg/kg IV Continuous application (≥ 18 hours/day) to the brain: TTFields, 200 kHz

Bevacizumab is already approved in European Union, United States, Japan, Canada for the following indications:

Approved in European Union as Avastin for:

• Colorectal cancer
• Breast cancer
• Non-small cell lung cancer
• Renal cell carcinoma
• Ovarian cancer

Approved in United States as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Glioblastoma
• Renal cell carcinoma
• Cervical cancer
• Ovarian cancer

Approved in Japan as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Breast cancer
• Renal cell carcinoma
• Ovarian cancer

Approved in Canada as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Breast cancer
• Renal cell carcinoma
• Ovarian cancer

Who Is Running the Clinical Trial?

ImmunityBio, Inc.

Lead Sponsor

Trials

75

Recruited

5,000+

Richard Adcock

ImmunityBio, Inc.

Chief Executive Officer since 2024

Information not available

Dr. Patrick Soon-Shiong

ImmunityBio, Inc.

Chief Medical Officer since 2021

MD

Published Research Related to This Trial

Bevacizumab (Bev) treatment in glioblastoma patients leads to a significant decrease in immunosuppressive markers (PD-L1 and PD-1) and an increase in T cell infiltration, suggesting a shift towards a more supportive immune environment.

The study analyzed 47 glioblastoma tissues and found that the positive effects of Bev on the tumor microenvironment persist even during long-term therapy, indicating its potential to enhance anti-tumor immunity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Persistent restoration to the immunosupportive tumor microenvironment in glioblastoma by bevacizumab. Tamura, R., Tanaka, T., Ohara, K., et al.[2021]

The combination of bevacizumab (BEV) and vorinostat (VOR) was well tolerated in patients with recurrent glioblastoma, with a 6-month progression-free survival (PFS6) rate of 30% and a median overall survival (OS) of 10.4 months based on a study of 40 patients.

Despite being well tolerated, the combination therapy did not show an improvement in PFS6 or median OS compared to BEV alone, indicating that adding VOR may not enhance the effectiveness of BEV in treating recurrent glioblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Study of Bevacizumab and Vorinostat for Patients with Recurrent World Health Organization Grade 4 Malignant Glioma. Ghiaseddin, A., Reardon, D., Massey, W., et al.[2019]

Natural killer (NK) cells, which are often suppressed by glioblastoma (GB) tumors, can be activated ex vivo with cytokines to restore their ability to attack GB cells, suggesting their potential for immunotherapy.

Current research includes a phase I clinical trial using CAR-NK cells targeting the ErbB2 (HER2) antigen in glioblastoma patients, highlighting a promising approach to enhance NK cell specificity and efficacy against this aggressive cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-Engineered NK Cells for the Treatment of Glioblastoma: Turning Innate Effectors Into Precision Tools for Cancer Immunotherapy. Burger, MC., Zhang, C., Harter, PN., et al.[2020]

Olaparib, an FDA-approved drug for certain cancers, shows promise as a safe and effective enhancer of NK cell responses in glioblastoma multiforme (GBM), a type of brain cancer with poor survival rates.

The study found that Olaparib does not reduce the susceptibility of GBM cells to NK cells, suggesting it could be effectively combined with NK cell therapies to improve treatment outcomes for patients with GBM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Investigating the Effects of Olaparib on the Susceptibility of Glioblastoma Multiforme Tumour Cells to Natural Killer Cell-Mediated Responses. Moran, J., Mylod, E., Kane, LE., et al.[2023]

The study demonstrated that injecting HER2-targeted CAR-NK cells into patients with recurrent glioblastoma is safe, with no dose-limiting toxicities or severe side effects like cytokine release syndrome observed in the nine patients treated.

Five out of nine patients experienced stable disease for 7 to 37 weeks after treatment, indicating potential efficacy, while the median overall survival was 31 weeks, suggesting that this approach could be a promising option for managing recurrent glioblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intracranial injection of natural killer cells engineered with a HER2-targeted chimeric antigen receptor in patients with recurrent glioblastoma. Burger, MC., Forster, MT., Romanski, A., et al.[2023]

Blocking the PD-1/B7H1 pathway enhances the ability of natural killer (NK) cells to kill glioblastoma stem cells (GL261GSCs), showing a significant increase in cytotoxicity in vitro and improved tumor control in vivo.

In a mouse model, treatment with PD-1 inhibited NK cells resulted in a median survival of 44 days, compared to 29 days in the control group, indicating that this combination therapy could be a promising immunotherapeutic strategy for glioblastoma multiforme.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The PD-1/B7-H1 pathway modulates the natural killer cells versus mouse glioma stem cells. Huang, BY., Zhan, YP., Zong, WJ., et al.[2023]

In a study using a murine glioblastoma model, single-agent therapies targeting PD-1, PD-L1, and CTLA-4 showed varying efficacy, with anti-PD-1 achieving a 50% tumor-free survival rate, while anti-CTLA-4 had a 15% rate.

Combination therapy using anti-CTLA-4 and anti-PD-1 resulted in a remarkable 75% cure rate, indicating that targeting multiple immune checkpoints can significantly enhance treatment outcomes and promote long-term immune memory against tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glioblastoma Eradication Following Immune Checkpoint Blockade in an Orthotopic, Immunocompetent Model. Reardon, DA., Gokhale, PC., Klein, SR., et al.[2022]

The EvCAR-KHYG-1 NK cell line, designed to target the EGFRvIII variant in glioblastoma, successfully produced immune-related cytokines in response to GBM cells, indicating a potential for immune activation.

However, in vivo studies showed that while EvCAR-KHYG-1 cells did not reduce tumor size in xenograft models, they did decrease tumor cell occupancy, suggesting that further research is needed to understand their role in tumor progression and to optimize treatment conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

KHYG-1 Cells With EGFRvIII-specific CAR Induced a Pseudoprogression-like Feature in Subcutaneous Tumours Derived from Glioblastoma-like Cells. Nakazawa, T., Murakami, T., Natsume, A., et al.[2020]

In a study involving 40 newly diagnosed and 86 recurrent glioblastoma patients, PD-L1 blockade with durvalumab did not meet primary efficacy endpoints, indicating it was ineffective in improving outcomes compared to standard treatments.

Recurrent glioblastoma patients exhibited significantly lower levels of circulating immune cell subsets, and the use of dexamethasone was associated with a reduction in these immune cells, suggesting that immune suppression may hinder treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Circulating Immune Cell and Outcome Analysis from the Phase II Study of PD-L1 Blockade with Durvalumab for Newly Diagnosed and Recurrent Glioblastoma. Nayak, L., Standifer, N., Dietrich, J., et al.[2023]

PD-L1 overexpression in glioblastoma patients is linked to poorer outcomes, especially in those not treated with chemo-radiotherapy, indicating that the CD8+ T-cell/PD-L1 interaction plays a significant role in tumor progression.

Exposure to anti-cancer therapies can increase inhibitory immune checkpoints in CD8+ T-cells, leading to worse prognoses; thus, using single-cell sequencing to tailor immune checkpoint inhibitor treatments may enhance patient responses and reduce adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Systematic Review of the Tumor-Infiltrating CD8+ T-Cells/PD-L1 Axis in High-Grade Glial Tumors: Toward Personalized Immuno-Oncology. Shadbad, MA., Asadzadeh, Z., Hosseinkhani, N., et al.[2021]

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