BCG + N-803 for Bladder Cancer

Recruiting at 68 trial locations

Overseen By Jayson Garmizo

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: ImmunityBio, Inc.

Must be taking: BCG therapy

Must not be taking: Chronic steroids

Disqualifiers: Muscle-invasive cancer, HIV, CHF, others

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

Compensation: Varies

Number of Visits: Unknown

596 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of combining two treatments, N-803 (an experimental treatment also known as Nogapendekin alfa inbakicept) and BCG, compared to BCG alone for individuals with high-grade non-muscle invasive bladder cancer (NMIBC). Researchers aim to determine if adding N-803 can improve outcomes for those who have not previously received BCG treatment. Suitable candidates for this trial have been diagnosed with high-grade NMIBC and have not undergone BCG treatment. As a Phase 1, Phase 2 trial, this research seeks to understand how the treatment works in people and measure its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking cancer treatment advancements.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, if you are on chronic systemic steroid therapy or investigational agents, you may need to stop those before participating.

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

Research has shown that using N-803 with BCG has been safe in past studies. In one study with bladder cancer patients unresponsive to BCG alone, 77 patients received N-803 plus BCG. Only 10% of these patients experienced cancer progression, indicating the treatment is generally well-tolerated.

The combination of N-803 and BCG has also been studied and approved for another bladder cancer condition, supporting its safety. While some risks may exist, previous research and approval for similar conditions suggest that the treatment is generally safe for people. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about N-803 combined with BCG for bladder cancer because it introduces a unique approach to enhancing the immune response. While BCG alone is a standard treatment that stimulates the immune system to attack cancer cells, the addition of N-803, an interleukin-15 superagonist, aims to amplify this immune activation even further. This combination could potentially lead to a more robust and sustained attack on bladder cancer cells, offering hope for improved outcomes compared to BCG alone.

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

Research has shown that combining N-803 with BCG may help treat bladder cancer. In this trial, one group of participants will receive the combination of N-803 and BCG. A study found that this combination resulted in 58.2% of patients being disease-free after 12 months. On average, patients remained disease-free for 25.3 months, with many staying healthy for over two years. The treatment was generally well-tolerated, with most side effects being mild, such as tiredness and nausea. These findings suggest that adding N-803 to BCG could be more effective than using BCG alone, which is another treatment arm in this trial, for some patients. ^{4 5 6 7 8}

Who Is on the Research Team?

Bobby Reddy, MD

Principal Investigator

ImmunityBio, Inc.

Are You a Good Fit for This Trial?

This trial is for adults with high-grade non-muscle invasive bladder cancer who haven't had BCG treatment before. They should be in good enough health to undergo the therapy, with specific blood counts and organ functions within set limits. Women of childbearing age must use birth control, as must men, to prevent pregnancy during the study.

Inclusion Criteria

You had an imaging test of your upper body within the last 6 months, and it did not show signs of cancer in that area.

Laboratory tests performed within 21 days of treatment start: Absolute neutrophil count (AGC/ANC) ≥ 1,000/µL, Platelets ≥ 100,000/µL, Hemoglobin ≥ 8 g/dL, Calculated glomerular filtration rate (GFR*) >40 mL/min or Serum creatinine ≤ 1.5 x ULN, Total bilirubin ≤ 2.0 X ULN, AST, ALT, ALP ≤ 3.0 X ULN, Adequate pulmonary function without any clinical sign of severe pulmonary dysfunction, Negative serum pregnancy test if female and of childbearing potential, Female participants of childbearing potential must adhere to using a medically accepted method of birth control prior to screening and agree to continue its use during the study or be surgically sterilized, Male participants must agree to use barrier methods of birth control while on study, Provide signed informed consent and HIPPA authorization and agree to comply with all protocol-specified procedures and follow-up evaluations

My bladder cancer is confirmed to be high-grade and not muscle-invasive.

Exclusion Criteria

You have been diagnosed with HIV.

You are not using any other experimental drugs at the same time.

I haven't had bladder or any cancer except specific cases in the last 5 years.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation (Phase Ib)

Patients are treated with intravesical N-803 in combination with BCG to evaluate safety and determine the Maximum Tolerated Dose (MTD) and Recommended Dose (RD) level.

6 months

Expansion (Phase IIb)

Patients are randomized to receive either intravesical N-803 in combination with BCG or BCG alone to evaluate treatment efficacy.

36 months

Follow-up

Participants are monitored for safety and effectiveness after treatment, including long-term follow-up data collection.

10 years

What Are the Treatments Tested in This Trial?

Interventions

• ALT-803
• BCG

Trial Overview The study compares two treatments: one group receives a combination of an immune response booster called N-803 plus BCG (a type of immunotherapy), while another group gets only BCG. It's designed to see if adding N-803 improves outcomes for patients who are new to this kind of treatment.

How Is the Trial Designed?

Group I: N-803+BCG Experimental Treatment 1 Intervention

(Phase Ib and IIb) for BCG-naive patients

Group II: BCG alone Active Control 1 Intervention

(Phase IIb) for BCG-naive patients

ALT-803 is already approved in United States for the following indications:

Approved in United States as Anktiva for:

• Non-muscle invasive bladder 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

BCG-IL-15 treatment significantly improved survival rates in mice with bladder cancer compared to standard BCG treatment, indicating enhanced efficacy in cancer therapy.

The BCG-IL-15 strain increased neutrophil infiltration and elevated chemokine levels in the bladder, suggesting that it may enhance the immune response against bladder tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor activity of recombinant Bacille Calmette-Guérin secreting interleukin-15-Ag85B fusion protein against bladder cancer. Takeuchi, A., Eto, M., Tatsugami, K., et al.[2017]

In a phase 1b clinical trial involving 9 patients with non-muscle invasive bladder cancer (NMIBC), the combination of intravesical N-803 and BCG showed promising results, with all participants remaining disease-free for 6 years after treatment.

The treatment was well-tolerated, with no dose-limiting toxicities and manageable adverse events, indicating a favorable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, Tolerability, and Long-Term Clinical Outcomes of an IL-15 analogue (N-803) Admixed with Bacillus Calmette-Guérin (BCG) for the Treatment of Bladder Cancer. Rosser, CJ., Tikhonenkov, S., Nix, JW., et al.[2022]

IL-15 superagonists, created by combining IL-15 with its receptor, show enhanced efficacy in stimulating natural killer (NK) and CD8+ T cells, which are crucial for fighting cancer, and have demonstrated tumor regression in animal studies.

Currently, there are fourteen ongoing phase I/II clinical trials investigating the safety and efficacy of IL-15 superagonists in cancer patients, with results on toxicity and effectiveness eagerly anticipated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunobiology of the IL-15/IL-15Rα complex as an antitumor and antiviral agent. Guo, Y., Luan, L., Patil, NK., et al.[2018]

N-803, a chimeric IL-15 superagonist, has a significantly longer half-life (approximately 20 hours) compared to regular IL-15, which enhances its potential as an immunotherapy for cancer.

The phase 1 study demonstrated that N-803 is safe and well-tolerated in healthy volunteers, with no serious adverse events reported, and it effectively increased levels of immune cells like NK cells and CD8+ T cells, suggesting it could boost antitumor immunity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Trial Characterizing the Pharmacokinetic Profile of N-803, a Chimeric IL-15 Superagonist, in Healthy Volunteers. Rubinstein, MP., Williams, C., Mart, C., et al.[2023]

The novel IL-15 superagonist F4RLI significantly enhances the half-life and stability of IL-15, extending its exposure in mice by approximately 28- and 200-fold compared to the standard IL-15 monomer, which could improve its effectiveness in cancer treatment.

F4RLI not only stimulates the proliferation of key immune cells like CD8+ T cells and NK cells but also shows promising synergistic effects when combined with immune checkpoint inhibitors and angiogenesis inhibitors, leading to significant tumor growth suppression in mouse models.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A homodimeric IL-15 superagonist F4RLI with easy preparation, improved half-life, and potent antitumor activities. Lv, L., Wang, H., Shi, W., et al.[2022]

IL-15SA/IL-15RαSu-Fc significantly expanded natural killer (NK) and CD8+ T cells in tumor-bearing mice, enhancing their anti-tumor functions and leading to prolonged survival.

The treatment showed notable anti-tumor activity against metastases in breast and colon cancer models, especially when combined with checkpoint inhibitors, indicating its potential as an effective immunotherapy strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

IL-15 superagonist/IL-15RαSushi-Fc fusion complex (IL-15SA/IL-15RαSu-Fc; ALT-803) markedly enhances specific subpopulations of NK and memory CD8+ T cells, and mediates potent anti-tumor activity against murine breast and colon carcinomas. Kim, PS., Kwilas, AR., Xu, W., et al.[2021]

In a phase 1 study involving 11 patients with CD52-positive mature T-cell malignancies, IL-15 was safely administered without severe adverse events, leading to significant increases in NK cells (7.2-fold) and CD8+ T cells (2.5-fold).

The combination of IL-15 and alemtuzumab resulted in an overall response rate of 45%, with 3 partial and 2 complete responses, indicating that IL-15 may enhance the effectiveness of antibody therapies by improving immune cell activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interleukin-15 augments NK cell-mediated ADCC of alemtuzumab in patients with CD52+ T-cell malignancies. Miljkovic, MD., Dubois, SP., Müller, JR., et al.[2023]

Intravesical ALT-803, when used alone, reduced bladder tumor burden by 35%, while BCG alone only achieved a 15% reduction; however, their combination resulted in a significant 46% reduction, indicating enhanced efficacy.

The combination treatment not only improved tumor reduction but also led to a 76% decrease in angiogenesis, suggesting a strong immunologic response linked to the activation of NK cells and the production of specific cytokines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravesical ALT-803 and BCG treatment reduces tumor burden in a carcinogen induced bladder cancer rat model; a role for cytokine production and NK cell expansion. Gomes-Giacoia, E., Miyake, M., Goodison, S., et al.[2022]

The study highlights the importance of the IL-15 pathway in enhancing the effectiveness of CD40 agonist antibodies in treating bladder cancer, showing that this combination can lead to increased activation of CD8 T cells and improved antitumor responses.

Using humanized models, the research demonstrates that combining anti-CD40 agonist antibodies with exogenous IL-15 can optimize therapeutic outcomes, suggesting a promising new strategy for bladder cancer treatment that warrants further clinical investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

IL-15 synergizes with CD40 agonist antibodies to induce durable immunity against bladder cancer. Wong, JL., Smith, P., Angulo-Lozano, J., et al.[2023]

The study highlights the critical role of the IL-15 pathway in enhancing the effectiveness of CD40 agonist antibodies in treating bladder cancer, particularly by increasing the activation of CD8 T cells in the tumor environment.

Combining anti-CD40 agonist antibodies with exogenous IL-15 significantly boosts anti-tumor activity and promotes long-term immune memory, suggesting a promising new strategy for bladder cancer treatment that warrants further clinical investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

IL-15 synergizes with CD40 agonist antibodies to induce durable immunity against bladder cancer. Wong, JL., Smith, P., Angulo-Lozano, J., et al.[2023]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40824697/

Nogapendekin Alfa Inbakicept-pmln with BCG for ... Substantial evidence of effectiveness for this application was obtained from Cohort A of the single-arm, multicenter QUILT-3.032 trial. Patients ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38226931/

Quality of Life in the Phase 2/3 Trial of N-803 Plus Bacillus ... The overall stability of PROs scores, taken together with the efficacy findings, indicates a favorable risk-benefit ratio and quality of life following N-803 ...

3. immunitybio.com immunitybio.com/unmatched-long-term-bladder-preservation-for-36-months-in-over-80-percent-of-responders-with-anktiva-plus-bcg-in-bcg-unresponsive-nmibc-cis-and-papillary-disease-alone-best-in-disease/

Unmatched Long-Term Bladder Preservation for 36 Months ... ANKTIVA plus BCG demonstrated a 58.2% disease-free survival (DFS) rate at 12 months (primary endpoint), with a median DFS of 25.3 months.

4. fda.gov fda.gov/media/188893/download?attachment

ANKTIVA | Promotional Material Clinically relevant adverse reactions in <15% of patients who received ANKTIVA with BCG included fatigue (14%), nausea (14%), bladder irritation ...

5. urotoday.com urotoday.com/library-resources/anktiva-library-resources/156331-a-new-horizon-in-bcg-unresponsive-non-muscle-invasive-bladder-cancer-anktiva-n-803-bcg.html

A New Horizon in BCG Unresponsive Non-Muscle ... Intravesical Bacillus Calmette-Guerin (BCG) currently remains the standard of care, guideline recommended treatment of choice in the adjuvant setting for ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12363661/

FDA Approval Summary: Nogapendekin Alfa Inbakicept ... Of the 77 evaluable patients with BCG-unresponsive CIS treated in Cohort A of QUILT-3.032, 8 (10%) of progressed to muscle-invasive bladder ...

7. fda.gov fda.gov/drugs/resources-information-approved-drugs/fda-approves-nogapendekin-alfa-inbakicept-pmln-bcg-unresponsive-non-muscle-invasive-bladder-cancer

FDA approves nogapendekin alfa inbakicept-pmln for BCG ... FDA approves nogapendekin alfa inbakicept-pmln for BCG-unresponsive non-muscle invasive bladder cancer · Efficacy and Safety · Expedited Programs.

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8096327/

Safety, Tolerability, and Long-Term Clinical Outcomes of an IL ... Intravesical BCG is active against non-muscle invasive bladder cancer (NMIBC), but bladder cancer will recur and even progress in a significant ...