NBTXR3 + Radiation + Pembrolizumab for Head and Neck Cancer

Overseen by Jay Reddy, MD, PHD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Autoimmune disease, CNS metastases, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Approved in 3 Jurisdictions

Trial Summary

What is the purpose of this trial?

This phase II trial investigates the effect of NBTXR3, radiation therapy, and pembrolizumab in treating patients with head and neck squamous cancer that has come back (recurrent) or has spread to other places in the body (metastatic). NBTXR3 may cause cell destruction when activated by radiation. Radiation therapy, such as stereotactic body radiation therapy, uses special equipment to position a patient and deliver radiation to tumors with high precision. This method may kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. And hypofractionated radiation therapy delivers higher doses of radiation therapy over a shorter period of time and may kill more tumor cells and have fewer side effects. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving NBTXR3, radiation therapy, and pembrolizumab may kill more tumor cells.

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.

What data supports the effectiveness of the treatment NBTXR3 + Radiation + Pembrolizumab for Head and Neck Cancer?

Research shows that pembrolizumab, when used with radiation, can enhance the immune response against head and neck cancer, especially in patients with high PD-L1 levels. Additionally, combining pembrolizumab with radiation has been found to be safe and feasible, suggesting potential benefits in treating locally advanced head and neck cancer. ^{1 2 3 4 5}

Is the combination of NBTXR3, radiation, and pembrolizumab safe for head and neck cancer treatment?

Pembrolizumab, when used with radiation therapy, has been shown to be generally safe in patients with head and neck cancer, although some serious side effects like pneumonia and thyroid disorders have been reported. The combination of pembrolizumab with radiation is considered acceptable in terms of safety for this patient group. ^{1 3 5 6 7}

What makes the NBTXR3 + Radiation + Pembrolizumab treatment unique for head and neck cancer?

This treatment is unique because it combines NBTXR3, a novel radio-enhancer, with pembrolizumab, an immune checkpoint inhibitor, and radiation therapy to potentially enhance the immune response against head and neck cancer, offering a new approach compared to traditional treatments like cetuximab with radiation. ^{1 3 8 9 10}

Research Team

Jay Reddy, MD, PHD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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.

Trial Timeline

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)

Treatment Details

Interventions

• Hypofractionated Radiation Therapy (Radiation)
• NBTXR3 (Nanoparticles)
• Pembrolizumab (PD-1 Inhibitor)
• Stereotactic Body Radiation Therapy (Radiation)

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.

Participant Groups

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.

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Dr. Peter WT Pisters

M.D. Anderson Cancer Center

Chief Executive Officer since 2017

MD from University of Western Ontario

Dr. Jeffrey E. Lee

M.D. Anderson Cancer Center

Chief Medical Officer

MD from Stanford University School of Medicine

Findings from Research

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]

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 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 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, 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 (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]

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]

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]

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]

References

1. England 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. [2023]

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

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

3. England 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. [2021]

4. England 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. [2021]

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

Concurrent Definitive Immunoradiotherapy for Patients with Stage III-IV Head and Neck Cancer and Cisplatin Contraindication. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab and its use in the treatment of recurrent or metastatic head and neck cancer. [2019]

7. England 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. [2019]

8. Switzerland 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. [2023]

9. Greece pubmed.ncbi.nlm.nih.gov

Efficacy of Nivolumab and Pembrolizumab in Platinum-sensitive Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma. [2023]

10. New Zealand pubmed.ncbi.nlm.nih.gov

Potential of Pembrolizumab in Metastatic or Recurrent Head and Neck Cancer: Evidence to Date. [2020]