NBTXR3 + Radiation + Pembrolizumab for Head and Neck Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Autoimmune disease, CNS metastases, 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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 9

Duration: 24 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment combination for head and neck cancer that has recurred or spread. It includes NBTXR3 (a type of hafnium oxide nanoparticle), radiation therapy, and pembrolizumab (an immunotherapy) to determine if this combination can more effectively destroy cancer cells. The goal is to assess whether this combo can kill more cancer cells and reduce side effects compared to current treatments. Individuals with head and neck cancer that cannot be cured with standard treatments and who have at least two tumors might be suitable for this trial. As a Phase 2 trial, the 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 protocol does not specify if you need to stop taking your current medications. However, you cannot have received any approved or investigational anti-cancer treatments within 4 weeks before starting the trial, except for certain cases. 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 used with radiation, is generally easy for patients to handle. One study found it safe for people with head and neck cancer, with no severe side effects reported. Another study demonstrated that NBTXR3, combined with radiation, effectively destroyed cancer cells, highlighting its potential benefits.

Pembrolizumab, another part of the treatment, also has a strong safety record. It is already approved for treating head and neck cancer. Studies indicate it does not cause unexpected harm to patients. While serious side effects can occur, healthcare professionals manage them.

In summary, previous studies have found both NBTXR3 and pembrolizumab to be safe. They are generally well-tolerated by patients, though, like any treatment, they can have side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for head and neck cancer, which often include surgery, chemotherapy, and conventional radiation therapy, the combination of NBTXR3 with radiation and pembrolizumab introduces a novel approach. NBTXR3 consists of hafnium oxide-containing nanoparticles injected directly into the tumor, enhancing the local effects of radiation therapy. Researchers are excited about this because it could amplify the cancer-killing power of radiation while pembrolizumab, an immunotherapy, helps the body's immune system recognize and attack cancer cells. This dual approach could potentially improve outcomes by making tumors more responsive to treatment and by harnessing the body's own defenses against cancer.

What evidence suggests that this trial's treatments could be effective for head and neck cancer?

Research has shown that NBTXR3, when combined with radiotherapy, may destroy cancer cells more effectively, particularly in head and neck cancers. Studies have found that NBTXR3 controls tumor growth better than radiotherapy alone. In this trial, participants will receive a combination of NBTXR3, radiotherapy, and pembrolizumab. Pembrolizumab, a type of immunotherapy, has improved survival rates for patients with recurring or spreading head and neck cancer. Combining these treatments could provide a stronger approach to fighting this type of cancer. ^{1 2 3 4 5}

Who Is on the Research Team?

Jay Reddy, MD, PHD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

Adults with recurrent or metastatic head and neck squamous cell cancer, who can undergo specific radiation therapy and have at least two measurable lesions. They must be in good enough health for the trial, not pregnant, willing to use contraception, and have stable oxygen needs if they require supplemental oxygen.

Inclusion Criteria

Leukocytes >= 1500/mm^3

My lung function is good enough for treatment, based on recent tests.

Absolute neutrophil count (ANC) >= 1,000/mm^3

Exclusion Criteria

I still have side effects from cancer treatment that are not mild.

Women of child-bearing potential and their male partners who are unwilling or unable to use an acceptable method of birth control to avoid pregnancy for the entire study period and up to 6 months, for females, and 220 days for males after the last dose of anti-PD-1

I do not have an active, uncontrolled HIV or hepatitis B/C infection.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive NBTXR3 via injection, undergo radiation therapy, and receive pembrolizumab IV every 3 weeks for up to 24 months

24 months

Every 3 weeks (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Every 6 weeks (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Hypofractionated Radiation Therapy
• NBTXR3
• Pembrolizumab
• Stereotactic Body Radiation Therapy

Trial Overview The trial is testing a combination of NBTXR3 nanoparticles with high-precision radiation therapy and pembrolizumab (an immunotherapy drug) to see if this trio is more effective in treating head and neck cancer that has returned or spread.

How Is the Trial Designed?

Group I: Treatment (NBTXR3, RT, pembrolizumab) Experimental Treatment 4 Interventions

Patients receive hafnium oxide-containing nanoparticles NBTXR3 via injection intratumorally or intranodally on day 1. Beginning as early as day 3 and within 8 days of NBTXR3 injection, patients undergo SBRT QOD or hypofractionated RT QD over 1-2 weeks at the discretion of the treating radiation oncologist. Starting on the same day as radiation therapy, patients also receive pembrolizumab IV over 30 minutes every 3 weeks for up to 24 months in the absence of disease progression or unacceptable toxicity.

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

Approved in United States as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in European Union as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in United Kingdom as KEYTRUDA for:

• Untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Published Research Related to This Trial

In a study involving 882 participants with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), pembrolizumab alone significantly improved overall survival compared to cetuximab with chemotherapy, especially in patients with high PD-L1 expression (CPS of 20 or more).

Pembrolizumab combined with chemotherapy also showed improved overall survival compared to cetuximab with chemotherapy across all populations, indicating that pembrolizumab is an effective first-line treatment option for HNSCC, particularly for those with PD-L1 positivity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Burtness, B., Harrington, KJ., Greil, R., et al.[2021]

In a study of platinum-sensitive recurrent or metastatic head and neck squamous cell carcinomas involving 36 patients, both nivolumab and pembrolizumab showed effectiveness, with median overall survival of 16.9 months for nivolumab and 19.2 months for pembrolizumab, indicating similar efficacy between the two treatments.

The median progression-free survival was 4.8 months for nivolumab and 9.3 months for pembrolizumab, with objective response rates of 38% and 47%, respectively, suggesting that both drugs are viable options for treatment in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Nivolumab and Pembrolizumab in Platinum-sensitive Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma. Yamashita, G., Okamoto, I., Ito, T., et al.[2023]

The Phase III trial KEYNOTE-412 is designed to evaluate the efficacy and safety of pembrolizumab, an immune checkpoint inhibitor, when used alongside chemoradiation therapy (CRT) in patients with locally advanced head and neck squamous cell carcinoma (HNSCC).

Previous Phase Ib studies have indicated that combining pembrolizumab with CRT is safe and feasible, supporting its potential use in this larger trial to improve treatment outcomes for patients with locally advanced HNSCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab given concomitantly with chemoradiation and as maintenance therapy for locally advanced head and neck squamous cell carcinoma: KEYNOTE-412. Machiels, JP., Tao, Y., Burtness, B., et al.[2021]

In a study involving 133 patients with locally advanced squamous cell carcinoma of the head and neck, pembrolizumab combined with radiotherapy did not show a significant improvement in locoregional control or survival compared to the standard treatment of cetuximab with radiotherapy.

However, patients receiving pembrolizumab experienced significantly lower toxicity, with only 74% reporting severe adverse events compared to 92% in the cetuximab group, suggesting it may be a safer option for patients unfit for high-dose cisplatin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab versus cetuximab concurrent with radiotherapy in patients with locally advanced squamous cell carcinoma of head and neck unfit for cisplatin (GORTEC 2015-01 PembroRad): a multicenter, randomized, phase II trial. Tao, Y., Biau, J., Sun, XS., et al.[2023]

In a study involving 25 patients with locally advanced or recurrent/metastatic head and neck squamous cell carcinoma, the addition of immune-checkpoint blockade (ICB) therapies like nivolumab or pembrolizumab to standard treatments did not show systematic overall survival differences, but certain cytokine levels were linked to patient outcomes.

Specifically, lower pre- and post-ICB levels of interferon-gamma (IFN-γ) were associated with better outcomes, while increases in interleukin-6 (IL-6), IL-8, and vascular endothelial growth factor A (VEGF) correlated with poorer survival, suggesting that cytokine expression patterns could help identify patients likely to benefit from ICB.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune checkpoint blockade induced shifts in cytokine expression patterns in peripheral blood of head and neck cancer patients are linked to outcome. Röhl, L., Wellhausen, J., Berszin, M., et al.[2023]

Pembrolizumab, an immune checkpoint inhibitor, has been approved by the FDA for treating platinum-refractory recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC), offering a new option with potentially improved efficacy compared to traditional chemotherapy and EGFR inhibitors.

This review discusses the pharmacology and tolerability of pembrolizumab, emphasizing its mechanism of action by blocking the PD-1 receptor, which may enhance the immune response against HNSCC tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab and its use in the treatment of recurrent or metastatic head and neck cancer. Sheth, S., Weiss, J.[2019]

Pembrolizumab, an immune checkpoint inhibitor, has shown significantly improved overall survival in patients with relapsed and/or metastatic head and neck squamous cell carcinoma compared to the standard EXTREME regimen, indicating a promising shift in treatment options.

This review highlights the importance of understanding the mechanisms of immune checkpoint inhibitors, including their interaction with the immune system and the challenges posed by tumor heterogeneity and PD-L1 expression, which are crucial for optimizing patient selection for treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Potential of Pembrolizumab in Metastatic or Recurrent Head and Neck Cancer: Evidence to Date. McCusker, MG., Orkoulas-Razis, D., Mehra, R.[2020]

In a phase III trial, pembrolizumab, a single-agent treatment, showed significant effectiveness in patients with head and neck tumors that had high PD-L1 expression, leading to deep and lasting responses.

This study highlights the potential of pembrolizumab as a first-line therapy for this specific group of cancer patients, suggesting a targeted approach based on PD-L1 levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembro Ups Survival in PD-L1-positive HNSCC. [2019]

In a phase II study involving 29 patients with locally advanced head and neck squamous cell carcinoma who were ineligible for cisplatin, the combination of pembrolizumab and radiotherapy showed promising efficacy, with a 24-month progression-free survival rate of 71%.

The treatment was generally well-tolerated, although a significant number of patients experienced grade 3/4 lymphopenia (58.6%), indicating the need for monitoring immune cell changes during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concurrent Definitive Immunoradiotherapy for Patients with Stage III-IV Head and Neck Cancer and Cisplatin Contraindication. Weiss, J., Sheth, S., Deal, AM., et al.[2023]

Pembrolizumab (KEYTRUDA) received accelerated FDA approval for treating recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) based on a study of 174 patients, showing an objective response rate of 16% and a duration of response ranging from 2.4 to 27.7 months.

The safety profile included serious adverse reactions such as pneumonia and respiratory failure, but the overall benefit-risk assessment was deemed acceptable, marking pembrolizumab as the first new treatment option for HNSCC since 2006.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for the Treatment of Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma with Disease Progression on or After Platinum-Containing Chemotherapy. Larkins, E., Blumenthal, GM., Yuan, W., et al.[2019]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.e18041

PEP503 (NBTXR3), a radioenhancer, in combination with ... Adding PEP503, a radioenhancer, via a single intratumoral injection to weekly cisplatin-containing CCRT was feasible and safe for patients with locally ...

2. ir.nanobiotix.com ir.nanobiotix.com/news-releases/news-release-details/nanobiotix-announces-first-data-phase-1-study-evaluating-jnj

NANOBIOTIX Announces First Data From Phase 1 Study ... Radiotherapy-activated JNJ-1900 (NBTXR3) is being evaluated across multiple solid tumor indications as a single agent or combination therapy.

3. targetedonc.com targetedonc.com/view/nbtxr3-well-tolerated-in-r-m-hnscc-with-early-efficacy-signals

NBTXR3 Well Tolerated in R/M HNSCC, With Early Efficacy ... Innovative NBTXR3 shows promise in enhancing radiotherapy for recurrent head and neck cancer, potentially transforming treatment options for ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8052129/

NBTXR3 Radiotherapy-Activated Functionalized Hafnium ... NBTXR3 activated by radiotherapy was also more effective in destroying cancer cells and in controlling tumor growth than radiotherapy alone.

5. asco.org asco.org/abstracts-presentations/ABSTRACT362356

Dose-finding of a phase 1b/2 trial. PEP503 nanoparticles plus RT has been tested in elderly HNSCC patients and has demonstrated a good safety profile. The phase 1b part of the study aimed to test ...