Vaccines + Pembrolizumab for Oropharyngeal Cancer

Overseen By Vanderbilt-Ingram Services for Timely Access

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Michael K. Gibson

Must be taking: Pembrolizumab

Must not be taking: Live vaccines, Immunosuppressive drugs

Disqualifiers: Pregnancy, Immunodeficiency, Active autoimmune, 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

Compensation: Varies

Number of Visits: 3

Duration: Up to approximately 1 year

54 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial tests how well pB1-11 and human papillomavirus tumor antigen (TA-HPV) vaccines in combination with pembrolizumab work in treating patients with oropharyngeal cancer that has come back (recurrent) or that has spread from where it first started (primary site) to other places in the body (metastatic) and that is PD-L1 and human papillomavirus (HPV) positive. Oropharyngeal cancer is a type of head and neck cancer involving structures in the back of the throat (the oropharynx), such as the non-bony back roof of the mouth (soft palate), sides and back wall of the throat, tonsils, and back third of the tongue. Scientists have found that some strains or types of a virus called HPV can cause oropharyngeal cancer. pBI-11 is a circular deoxyribonucleic acid (DNA) (plasmid) vaccine that promotes antibody, cytotoxic T cell, and protective immune responses. TA-HPV is an investigational recombinant vaccina virus derived from a strain of the vaccina virus which was widely used for smallpox vaccination. Vaccination with this TA-HPV vaccine may stimulate the immune system to mount a cytotoxic T cell response against tumor cells positive for HPV, resulting in decreased tumor growth. 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 by inhibiting the PD-1 receptor. These investigational vaccines could cause or enhance an immune response in the body against HPV, during which time the activity of pembrolizumab against oropharyngeal cancer associated with HPV may be strengthened. These drugs in combination may be more effective in increasing the ability of the immune system to fight oropharyngeal cancer than pembrolizumab alone.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are on immunosuppressive drugs or have received a live vaccine recently, you may need to stop or adjust those treatments before participating.

What data supports the effectiveness of the treatment for oropharyngeal cancer?

Pembrolizumab, a part of the treatment, is approved for head and neck cancers, but only a limited number of patients benefit. Combining vaccines with PD-1 inhibitors like pembrolizumab may enhance immune response and improve outcomes, as seen in similar treatments. ^{1 2 3 4 5}

Is the combination of vaccines and pembrolizumab generally safe for humans?

Pembrolizumab has been evaluated for safety in patients with head and neck cancer, showing some serious side effects like pneumonia, breathing difficulties, and immune-related issues such as skin and thyroid problems. However, its overall safety profile was considered acceptable for these patients. ^{3 6 7 8 9}

How is the treatment with vaccines and pembrolizumab for oropharyngeal cancer different from other treatments?

This treatment is unique because it combines a DNA vaccine targeting HPV (human papillomavirus) with pembrolizumab, an immune checkpoint inhibitor that helps the immune system attack cancer cells, offering a novel approach for oropharyngeal cancer, especially in cases linked to HPV. ^{3 10 11 12 13}

Research Team

Michael Gibson

Principal Investigator

Vanderbilt University/Ingram Cancer Center

Eligibility Criteria

Adults (18+) with recurrent or metastatic PD-L1 CPS≥1, hrHPV+ oropharyngeal cancer who haven't been treated for this advanced stage. They must have a good performance status, adequate organ function, and not be pregnant or breastfeeding. Participants should agree to use contraception and not donate blood/sperm during the trial.

Inclusion Criteria

Calcium =< 11.5 mg/dL or =< 2.9 mmol/L

Able to father children and sexually active with a WOCBP must agree to use acceptable contraception

aPTT or PTT =< 1.5 times institutional ULN

Exclusion Criteria

My condition can be treated with the goal of curing it.

Pregnant or breastfeeding

My side effects from previous treatments are not severe.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive pBI-11 vaccine IM, TA-HPV vaccine IM, and pembrolizumab IV. Patients undergo CT or MRI and blood sample collection.

Up to approximately 1 year

Regular visits for treatment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-8 weeks

2 visits (in-person)

Treatment Details

Interventions

• pBI-11
• Pembrolizumab
• TA-HPV

Trial Overview The trial is testing pBI-11 & TA-HPV vaccines combined with pembrolizumab against HPV-positive oropharyngeal cancer. It aims to see if these treatments together boost the immune system more effectively than pembrolizumab alone in fighting cancer.

Participant Groups

Group I: Treatment (pBI-11, TA-HPV, pembrolizumab) Experimental Treatment 7 Interventions

Patients receive pBI-11 vaccine IM, TA-HPV vaccine IM, and pembrolizumab IV on study. Patients undergo CT or MRI and blood sample collection during screening and on study. Patients may undergo tumor biopsy during screening and on study.

Who Is Running the Clinical Trial?

Michael K. Gibson

Lead Sponsor

Trials

2

Recruited

50+

Findings from Research

In a preclinical model of HPV+ oropharyngeal cancer, combining PD-1 blockade with CTLA-4 inhibition resulted in a remarkable 93.3% survival rate in mice with tongue tumors over a 100-day study, indicating a highly effective immunotherapy strategy.

The addition of a STING agonist to the treatment regimen not only enhanced the efficacy of PD-1 and CTLA-4 blockade but also led to sustained tumor regression in 71% of mice with metastatic disease, highlighting a promising approach for patients who do not respond to standard PD-1 therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting interferon signaling and CTLA-4 enhance the therapeutic efficacy of anti-PD-1 immunotherapy in preclinical model of HPV+ oral cancer. Dorta-Estremera, S., Hegde, VL., Slay, RB., et al.[2020]

Pembrolizumab, an FDA-approved monoclonal antibody for recurrent or metastatic head and neck cancers, has shown limited efficacy, highlighting the need for alternative treatments.

Therapeutic vaccination is emerging as a promising strategy in head and neck cancers, with ongoing research into its potential synergistic effects when combined with anti-PD(L)1 therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vaccine-Based Immunotherapy for Head and Neck Cancers. Beyaert, S., Machiels, JP., Schmitz, S.[2021]

In a study of 257 patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) treated with pembrolizumab, biomarkers such as tumor mutational burden (TMB), PD-L1 expression, and T-cell-inflamed gene expression profile (Tcellinf GEP) were found to be significantly associated with overall response rates (ORR) to the treatment.

The study indicated that higher levels of these biomarkers correlated with better treatment responses, suggesting that they could be useful in predicting how well patients will respond to pembrolizumab therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biomarkers predictive of response to pembrolizumab in head and neck cancer. Pfister, DG., Haddad, RI., Worden, FP., et al.[2023]

In a phase Ib/IIa study involving 35 patients with recurrent/metastatic HPV-16/18-associated head and neck cancer, the combination of the DNA vaccine MEDI0457 and the PD-L1 inhibitor durvalumab showed an objective response rate of 27.6%, indicating some effectiveness in enhancing HPV-specific T-cell responses.

The treatment was generally well tolerated, with 80% of patients experiencing treatment-related adverse events, mostly mild to moderate, and a median overall survival of 29.2 months, suggesting potential clinical benefit despite not meeting the primary efficacy endpoint.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of MEDI0457 plus Durvalumab in Patients with Human Papillomavirus-Associated Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma. Aggarwal, C., Saba, NF., Algazi, A., et al.[2023]

HPV-positive tumors account for a significant portion of oropharyngeal squamous cell carcinomas (OSCC), with HPV-16 being the most common high-risk genotype, highlighting the importance of HPV in the development of these cancers.

Current treatment strategies for HPV-induced head and neck squamous cell carcinomas are shifting towards de-escalation, and new immunotherapy approaches are being explored to enhance the immune response against these tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An updated overview of HPV-associated head and neck carcinomas. Zaravinos, A.[2022]

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 of 36 patients with resectable HPV-unrelated head and neck squamous-cell carcinoma, neoadjuvant pembrolizumab was found to be safe, with no serious adverse events reported during treatment.

The treatment resulted in a pathologic tumor response in 44% of patients, and the one-year relapse rate for those with high-risk pathology was significantly lower at 16.7%, compared to the historical rate of 35%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant and Adjuvant Pembrolizumab in Resectable Locally Advanced, Human Papillomavirus-Unrelated Head and Neck Cancer: A Multicenter, Phase II Trial. Uppaluri, R., Campbell, KM., Egloff, AM., et al.[2021]

Pembrolizumab has been approved by the FDA as the first-line treatment for both HPV-positive and HPV-negative recurrent head and neck squamous cell carcinoma, marking it as a significant advancement in immunotherapy for this cancer type.

The approval allows pembrolizumab to be used either alone for tumors expressing PD-L1 or in combination with chemotherapy, highlighting the need for healthcare providers to be aware of and manage potential immune-related toxicities such as dermatitis and mucositis associated with this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of Immune-Related Dermatitis and Mucositis Associated With Pembrolizumab in Metastatic Human Papillomavirus-Associated Squamous Cell Carcinoma of the Oropharynx. Fazer, C., Price, KA.[2021]

Pembrolizumab, an immune checkpoint inhibitor, can cause pneumonitis in 1%-5% of patients, and this case report highlights an atypical presentation of this side effect in a patient with metastatic squamous cell carcinoma.

The patient was successfully treated with steroid therapy after ruling out other potential causes, leading to complete resolution of the pneumonitis, emphasizing the importance of recognizing and managing atypical cases of checkpoint inhibitor-pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. Jeon, WJ., Nguyen, J., Castillo, DR., et al.[2023]

In a study of 38 patients with p16+ oropharyngeal squamous cell carcinoma, there was a 76% agreement in PD-L1 combined positive scores (CPS) between primary tumors and lymph node metastases, indicating variability in scoring between these specimens.

The interobserver agreement for CPS scoring was fair to substantial, suggesting that additional evaluations may be necessary to ensure accurate scoring, especially for patients who might benefit from immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Programmed Death Ligand-1 Combined Positive Score Concordance and Interrater Reliability in Primary Tumors and Synchronous Lymph Node Metastases in Resected Cases of p16+ Oropharyngeal Squamous Cell Carcinoma. Kaur, A., Kuchta, K., Watkin, W., et al.[2023]

In a phase IB study involving 59 patients with locally advanced head and neck squamous cell carcinoma, the combination of pembrolizumab with cisplatin-based chemoradiotherapy was found to be safe, with a high completion rate of treatment and only 8.8% of patients experiencing immune-related adverse events.

The treatment showed promising efficacy, with complete response rates of 85.3% for HPV-positive and 78.3% for HPV-negative patients, suggesting that this combination warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Pembrolizumab With Chemoradiotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma: A Phase IB Study. Powell, SF., Gold, KA., Gitau, MM., et al.[2022]

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 with 882 patients over a median follow-up of 45 months, pembrolizumab and pembrolizumab-chemotherapy showed significant improvements in overall survival compared to cetuximab-chemotherapy for recurrent/metastatic head and neck squamous cell carcinoma, particularly in patients with high PD-L1 expression (CPS ≥ 20).

The analysis also indicated that patients who received pembrolizumab-based therapies had favorable outcomes in subsequent treatments, with improved progression-free survival on next-line therapies, highlighting the long-term efficacy of pembrolizumab in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab With or Without Chemotherapy in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Updated Results of the Phase III KEYNOTE-048 Study. Harrington, KJ., Burtness, B., Greil, R., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Targeting interferon signaling and CTLA-4 enhance the therapeutic efficacy of anti-PD-1 immunotherapy in preclinical model of HPV+ oral cancer. [2020]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Vaccine-Based Immunotherapy for Head and Neck Cancers. [2021]

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

Biomarkers predictive of response to pembrolizumab in head and neck cancer. [2023]

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

Safety and Efficacy of MEDI0457 plus Durvalumab in Patients with Human Papillomavirus-Associated Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma. [2023]

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

An updated overview of HPV-associated head and neck carcinomas. [2022]

6. 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]

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

Neoadjuvant and Adjuvant Pembrolizumab in Resectable Locally Advanced, Human Papillomavirus-Unrelated Head and Neck Cancer: A Multicenter, Phase II Trial. [2021]

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

Management of Immune-Related Dermatitis and Mucositis Associated With Pembrolizumab in Metastatic Human Papillomavirus-Associated Squamous Cell Carcinoma of the Oropharynx. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. [2023]

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

Programmed Death Ligand-1 Combined Positive Score Concordance and Interrater Reliability in Primary Tumors and Synchronous Lymph Node Metastases in Resected Cases of p16+ Oropharyngeal Squamous Cell Carcinoma. [2023]

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

Safety and Efficacy of Pembrolizumab With Chemoradiotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma: A Phase IB Study. [2022]

12. 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]

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

Pembrolizumab With or Without Chemotherapy in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Updated Results of the Phase III KEYNOTE-048 Study. [2023]