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

Recruiting at 1 trial location

Overseen By Deana Martz

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

20 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a phase 2 open-label study to evaluate the safety and efficacy of N-803 and PD-L1 t-haNK when combined with Bevacizumab in subjects with recurrent or progressive GBM. Participants will receive N-803 subcutaneously (SC), PD-L1 t-haNK intravenously (IV), and Bevacizumab IV combination therapy. Treatment for all enrolled participants will consist of repeated cycles of 28 days for a maximum treatment period of 76 weeks (19 cycles). Treatment will be administered on days 1 and day 15 of each cycle. Treatment will be discontinued if the participant reports unacceptable toxicity (not corrected with dose reduction), withdraws consent, if the Investigator feels it is no longer in the participant's best interest to continue treatment, or the participant has confirmed progressive disease by iRANO, unless the participant is potentially deriving benefit per Investigator's assessment. Participants will be followed for collection of survival status every 12 weeks (± 2 weeks) for the first 2 years, then yearly thereafter.

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.

What data supports the effectiveness of the treatment N-803 + PD-L1 t-haNK + Bevacizumab for Glioblastoma?

Research shows that blocking PD-L1, a protein that helps tumors hide from the immune system, can lead to long-term survival in some glioblastoma models. Bevacizumab, another part of the treatment, has been shown to change the tumor environment in a way that might help the immune system fight the cancer more effectively. ^{1 2 3 4 5}

Is the combination of N-803, PD-L1 t-haNK, and Bevacizumab safe for humans?

Bevacizumab (also known as Avastin) has been used in various treatments and is generally considered safe, though it can have side effects like high blood pressure and increased risk of bleeding. The safety of PD-L1 t-haNK and N-803 (IL-15 superagonist complex) in humans is still being studied, but early trials suggest they can be used safely, although more research is needed to fully understand their safety profiles. ^{1 2 6 7 8}

What makes the N-803 + PD-L1 t-haNK + Bevacizumab treatment unique for glioblastoma?

This treatment is unique because it combines an immune system booster (N-803), engineered immune cells (PD-L1 t-haNK), and a drug that inhibits blood vessel growth (Bevacizumab) to target glioblastoma, a brain cancer with limited treatment options. The combination aims to enhance the immune response against the tumor, which is a novel approach compared to traditional therapies. ^{1 7 8 9 10}

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

Group I: Pilot Combination Therapy Experimental Treatment 3 Interventions

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.

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

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

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

Glioblastoma Eradication Following Immune Checkpoint Blockade in an Orthotopic, Immunocompetent Model. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Persistent restoration to the immunosupportive tumor microenvironment in glioblastoma by bevacizumab. [2021]

3. United States 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. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Phase II Study of Bevacizumab and Vorinostat for Patients with Recurrent World Health Organization Grade 4 Malignant Glioma. [2019]

5. Switzerland 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. [2021]

6. Switzerland pubmed.ncbi.nlm.nih.gov

CAR-Engineered NK Cells for the Treatment of Glioblastoma: Turning Innate Effectors Into Precision Tools for Cancer Immunotherapy. [2020]

7. Greece 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. [2020]

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

Intracranial injection of natural killer cells engineered with a HER2-targeted chimeric antigen receptor in patients with recurrent glioblastoma. [2023]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Investigating the Effects of Olaparib on the Susceptibility of Glioblastoma Multiforme Tumour Cells to Natural Killer Cell-Mediated Responses. [2023]

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

The PD-1/B7-H1 pathway modulates the natural killer cells versus mouse glioma stem cells. [2023]