NBTXR3 + Radiation and Immunotherapy for Metastatic Lung Cancer

Overseen By Nathan Comeaux

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: CNS metastases, Autoimmune disease, others

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

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

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 2 years

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination of treatments to manage cancer that has spread to the lungs or liver. It includes an experimental treatment, NBTXR3 (Hafnium Oxide nanoparticles), designed to increase cancer cells' sensitivity to radiation, combined with radiation therapy and immunotherapy. Researchers aim to understand the safety and effectiveness of this approach in controlling the disease. This trial suits individuals whose cancer has spread to the lungs or liver and who have previously tried other treatments without success. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

Do I need to stop my current medications for this trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have received any anti-cancer treatments, except for anti-PD-1/L1 therapy, within 2 weeks before the NBTXR3 injection. 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 NBTXR3, when combined with radiation, is generally safe. Past studies found it well-tolerated without major safety issues, and it helped destroy more cancer cells than radiation alone.

Immunotherapy treatments like nivolumab and ipilimumab have a strong safety record. Studies have found these treatments generally safe for patients with advanced lung cancer. They are widely used and help the immune system fight cancer. Recent studies have documented their safety, with no new safety concerns.

Overall, previous research has shown the treatments in this trial to be generally safe. However, individual experiences may vary, so discussing possible side effects with healthcare professionals is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment because it combines a novel particle-based therapy, NBTXR3, with radiation and immunotherapy to target metastatic lung cancer. Unlike standard treatments, which typically involve chemotherapy and traditional radiation, NBTXR3 is injected directly into tumors, enhancing the effects of radiation by making cancer cells more sensitive to it. This approach could potentially boost the immune system's ability to attack cancer cells, especially when paired with immunotherapies like nivolumab and ipilimumab, which are designed to help the body recognize and destroy cancer cells. Additionally, the use of innovative radiation techniques, like Abscopal and RadScopal, might trigger systemic anti-tumor responses, offering hope for more effective and comprehensive cancer control.

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

Research has shown that NBTXR3, which participants in this trial may receive, can make cancer cells more sensitive to radiation, aiding in their destruction. Studies have found that combining NBTXR3 with radiation controls tumor growth more effectively than radiation alone, potentially leading to a stronger attack on the cancer.

Participants in this trial will also receive Nivolumab, which has improved survival rates in patients with advanced non-small cell lung cancer. When combined with Ipilimumab, another treatment option in this trial, these treatments have demonstrated long-term benefits for individuals with this type of cancer. Together, these treatments may enhance the body's immune response against the cancer. ^{1 2 3 4 6}

Who Is on the Research Team?

Saumil Gandhi, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

Adults with advanced solid tumors that have spread to the lungs or liver may join this trial. They should have tried anti-PD-1/L1 therapy before, be in a decent physical state (ECOG 0-2), and not be pregnant or breastfeeding. Participants need functioning major organs and can't have had certain recent treatments or live vaccines, active infections, severe heart conditions, psychiatric illnesses, or specific allergies.

Inclusion Criteria

I have had one previous treatment with an anti-PD-1 or PD-L1 therapy.

I have received a specific high dose radiation treatment.

My cancer has spread to my lung, liver, or soft tissue and cannot be cured with surgery or radiation.

Exclusion Criteria

I am not pregnant or breastfeeding.

I have been treated for an autoimmune disease in the last 2 years.

My targeted lesion has been treated with high-dose radiation before.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive NBTXR3 intratumorally on day 1, followed by Anti PD-1/L-1 intravenously on day 8. Radiation therapy (Abscopal or RadScopal) begins on day 15 and lasts 1-2 weeks. Cycles with Anti PD-1/L-1 repeat every 3-6 weeks up to 2 years.

Up to 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up every 12 weeks for up to 2 years post-radiation therapy.

Up to 2 years

What Are the Treatments Tested in This Trial?

Interventions

• Ipilimumab
• NBTXR3
• Nivolumab
• Radiation Therapy

Trial Overview The study is testing NBTXR3 nanoparticles activated by radiation along with immunotherapy drugs against cancer that has spread to the lung/liver. It aims to see if making tumor cells more sensitive to radiation improves treatment outcomes when combined with immune system-boosting drugs.

How Is the Trial Designed?

Group I: Cohort II (NBTXR3, RadScopal, Anti PD-1 / PD-L1 Experimental Treatment 2 Interventions

COHORT II: Patients receive NBTXR3 intratumorally on day 1. Patients also receive ( anti-PD-1/L-1) IV on day 8. Beginning day 15, patients undergo RadScopal radiation therapy over 1-2 weeks. Cycles with ( anti-PD-1/L-1)repeat every 3-6 weeks per standard of care up to 2 years in the absence of disease progression or unacceptable toxicity.

Group II: Cohort I (NBTXR3, Abscopal, Anti PD-1 / PD-L1 Experimental Treatment 2 Interventions

COHORT I: Patients receive NBTXR3 intratumorally on day 1. Patients also receive ( anti-PD-1/L-1) intravenously (IV) on day 8. Beginning day 15, patients undergo Abscopal radiation therapy over 1-2 weeks. Cycles with ( anti-PD-1/L-1) repeat every 3-6 weeks per standard of care up to 2 years in the absence of disease progression or unacceptable toxicity.

Ipilimumab is already approved in United States, European Union for the following indications:

Approved in United States as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Approved in European Union as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Recent advancements in lung cancer treatment highlight the potential synergy between radiotherapy (RT) and immunotherapy, particularly immune checkpoint inhibitors (ICIs), which may enhance antitumor immune responses in non-small cell lung cancer (NSCLC).

Ongoing clinical trials are exploring the combination of RT and immunotherapy, raising important questions about the safety and toxicity risks for patients, as well as strategies to address mixed responses to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Combination of Radiation Therapy and Immunotherapy for Non-small Cell Lung Cancer: Peer Exchange on Frontier Academic Topics]. Ai, X., Cai, Y., Chu, Q., et al.[2021]

The combination of NBTXR3 nanoparticles with immunoradiotherapy (anti-PD1 and anti-CTLA4) significantly enhanced antitumor immune responses and reduced immune suppression in a mouse model of metastatic lung cancer, leading to the eradication of both primary and secondary tumors.

This treatment approach resulted in a 75% survival rate among the mice, with survivors showing a long-lasting antitumor memory immune response, suggesting potential for effective clinical applications in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NBTXR3 improves the efficacy of immunoradiotherapy combining nonfucosylated anti-CTLA4 in an anti-PD1 resistant lung cancer model. Hu, Y., Paris, S., Bertolet, G., et al.[2022]

In a study of 21 patients with extensive stage small cell lung cancer, the addition of ipilimumab (IPI) and nivolumab (NIVO) after consolidative thoracic radiation therapy (TRT) resulted in a 12-month overall survival rate of 48%, which is higher than historical expectations for this patient group.

While the treatment did not significantly improve progression-free survival (PFS), it was associated with a notable toxicity profile, with 52% of patients experiencing grade 3 to 4 immune-related adverse events, indicating that while the treatment may be beneficial, it also carries significant risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prospective Single-Arm Phase 1 and 2 Study: Ipilimumab and Nivolumab With Thoracic Radiation Therapy After Platinum Chemotherapy in Extensive-Stage Small Cell Lung Cancer. Perez, BA., Kim, S., Wang, M., et al.[2022]

The FORCE study is a phase II trial involving 130 patients with stage IV non-squamous non-small cell lung cancer, investigating the effects of nivolumab combined with hypofractionated palliative radiotherapy, aiming to assess its safety and efficacy in improving response rates and survival outcomes.

Preliminary data suggest that combining nivolumab with radiation therapy may enhance immune responses against tumors, potentially leading to better treatment outcomes compared to nivolumab alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fostering efficacy of anti-PD-1-treatment: Nivolumab plus radiotherapy in advanced non-small cell lung cancer - study protocol of the FORCE trial. Bozorgmehr, F., Hommertgen, A., Krisam, J., et al.[2020]

NBTXR3 nanoparticle injection is a new radioenhancer that shows promise in enhancing the effectiveness of radiation therapy for head and neck squamous cell carcinoma, as observed in CT scans of metastatic lymph nodes.

The injected NBTXR3 material appears hyperattenuating on CT scans, with a mean attenuation of 1516 HU, indicating its presence and potential leakage beyond tumor margins, which may impact treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Imaging Features of Intratumoral Injection of NBTXR3 for Head and Neck Squamous Cell Carcinoma Lymph Node Metastases. Ginat, DT., Juloori, A., Vivar, OI., et al.[2022]

NBTXR3 nanoparticles can be effectively taken up by various human cancer cell lines, with their uptake and clustering in cells depending on the concentration and type of cancer cells, indicating potential for targeted cancer therapy.

The study suggests that the radioenhancement effect of NBTXR3 nanoparticles can be predicted based on the concentration of nanoparticles and the radiation dose, which could help optimize treatment strategies for different types of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hafnium oxide nanoparticles: toward an in vitro predictive biological effect? Marill, J., Anesary, NM., Zhang, P., et al.[2021]

NBTXR3, a novel radioenhancer made of hafnium oxide nanoparticles, significantly enhances the effectiveness of radiotherapy in treating various solid tumors by improving cancer cell destruction and tumor growth control.

The study demonstrated that NBTXR3 is internalized by cancer cells and remains in tumor tissue during treatment, and it also improves the efficacy of cisplatin-based chemoradiotherapy, suggesting its potential as a universal treatment option for solid cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NBTXR3 Radiotherapy-Activated Functionalized Hafnium Oxide Nanoparticles Show Efficient Antitumor Effects Across a Large Panel of Human Cancer Models. Zhang, P., Marill, J., Darmon, A., et al.[2022]

The combination of NBTXR3, high-dose radiation, low-dose radiation, and immune checkpoint inhibitors significantly improved survival rates in a mouse model of anti-PD1-resistant metastatic lung cancer, increasing survival from 0% to 50%.

This treatment enhanced the immune response by increasing CD8 T-cell infiltration and reducing regulatory T cells in the tumors, suggesting that NBTXR3 may help overcome resistance to anti-PD1 therapy by promoting a stronger antitumor immune response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A radioenhancing nanoparticle mediated immunoradiation improves survival and generates long-term antitumor immune memory in an anti-PD1-resistant murine lung cancer model. Hu, Y., Paris, S., Barsoumian, H., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9937094/

Five-Year Survival Outcomes With Nivolumab Plus Ipilimumab ... Patients with metastatic non–small-cell lung cancer (mNSCLC) have historically had a 5-year survival rate of only 7%, but more recently, immune check point ...

2. nejm.org nejm.org/doi/full/10.1056/NEJMoa1910231

Nivolumab plus Ipilimumab in Advanced Non–Small-Cell ... Among all the patients in the trial, the median duration of overall survival was 17.1 months (95% CI, 15.2 to 19.9) with nivolumab plus ipilimumab and 13.9 ...

3. esmoopen.com esmoopen.com/article/S2059-7029(25)00992-5/fulltext

final, 6-year outcomes from CheckMate 9LA The 6-year DOR rate was 19% with nivolumab plus ipilimumab with chemotherapy; all patients in the chemotherapy arm were censored or stopped ...

4. opdivohcp.com opdivohcp.com/efficacy/nsclc/opdivo-yervoy

OPDIVO® (nivolumab) + YERVOY® (ipilimumab) Efficacy ... Five-year survival outcomes with nivolumab plus ipilimumab versus chemotherapy as first-line treatment for metastatic non-small cell lung cancer in CheckMate ...

5. jto.org jto.org/article/S1556-0864(24)02355-4/fulltext

Long-Term Survival Outcomes With First-Line Nivolumab ... In patients with squamous NSCLC, median OS was 16.2 versus 8.2 months with nivolumab plus ipilimumab with or without chemotherapy versus ...

6. ejcancer.com ejcancer.com/article/S0959-8049(24)00952-3/fulltext

Five-year outcomes with first-line nivolumab plus ... Five-year progression-free survival and DOR rates in 5-year survivors were 55% versus 38% and 59% versus 46%, respectively. No new safety ...