Phase II Trial of Immunotherapeutic HPV Vaccine PRGN-2009 With Pembrolizumab Before Standard Treatment in Subjects With Newly Diagnosed HPV-Associated Oropharyngeal Cancer

Background:

Cancers in and around the mouth associated with human papilloma virus (HPV) are common. Two treatments (the drug pembrolizumab and the HPV vaccine PRGN-2009) have been shown to work well when used individually against these cancers. Researchers want to find out if they might work better when used together.

Objective:

To test pembrolizumab combined with PRGN-2009 in people with HPV-positive cancers in and around the mouth.

Eligibility:

Adults aged 18 and older newly diagnosed with HPV-positive cancers in and around the mouth.

Design:

Participants will be screened. They will have a physical exam with blood tests. They will have imaging scans. They may need to have a biopsy: A sample of tissue will be taken from the tumor.

PRGN-2009 is given as an injection under the skin. Pembrolizumab is given through a tube attached to a needle inserted into a vein in the arm.

Participants will have at least 3 clinic visits: At the first, they will receive both the drug and the vaccine; 15 days later, they will receive a second shot of the vaccine. At the third visit, about 1 week after the second, they will have follow-up tests.

During these visits, participants will give samples of blood, urine, and saliva. Imaging scans and biopsies will be repeated. They will have tests of their heart function.

Participants may opt to return for another follow-up visit about 1 month after their second dose of the vaccine.

Participants will have follow-up contacts by phone 3 and 6 months after starting the study. The calls will continue once a year for 5 years.

Study Overview

• Status: Active, not recruiting
• Conditions: Oropharyngeal Squamous Cell Carcinoma (SCC)
• Intervention / Treatment: Biological: PRGN-2009; Drug: Pembrolizumab; Diagnostic test: EKG; Diagnostic test: CT; Diagnostic test: PET scan; Diagnostic test: MRI; Procedure: Biopsy

Detailed Description

Background

-Human papilloma virus-associated oropharyngeal cancer (HPV-OPC) is the most common HPV-associated malignancy in the United States, with an increasing incidence. Although the prognosis for stage I HPV-OPC is favorable, about 20 percent of patients with stage II

disease and 35 percent of patients with stage III disease will die within four years.

• The standard-of-care primary treatment for HPV-OPC without distant metastasis is definitive concurrent chemoradiotherapy (primarily) or surgery (which may be followed by adjuvant chemoradiotherapy).
• Neoadjuvant/induction immunotherapy is in clinical trials aiming to induce antigen-specific immunity prior to primary treatment and to reduce the risk of disease relapse. Pembrolizumab, an anti-PD-1 monoclonal antibody that is Food and Drug Administration (FDA)-approved for first-line treatment of recurrent/metastatic head and neck squamous cell cancer (HNSCC) has been used in these trials and shown to be safe and active.
• PRGN-2009 is an anti-HPV immunotherapeutic vaccine. It has demonstrated induction of HPV antigen-specific responses and tumor growth inhibition in pre-clinical models of HPV-associated malignancy, with improved anti-tumor efficacy upon addition of T-cell immune checkpoint blockade. In a Phase I/II trial at the National Cancer Institute (NCI) it has demonstrated excellent safety and tolerability as monotherapy or in combination with checkpoint blockade in recurrent/metastatic disease but also as monotherapy in neoadjuvant/induction context for HPV-OPC.

Objective:

-To determine if the use of PRGN-2009 with pembrolizumab in participants with p16-positive OPC can result in a >= 2-fold increase in cluster of differentiation 3 (CD3+) tumor infiltrating T cells post treatment compared with pre-treatment.

Eligibility:

• Age >= 18 years.
• Pathologically confirmed newly diagnosed Stage I (T1, T2; N1), II or III p16-positive OPC.

Design:

• This is a Phase II study to evaluate the effect of PRGN-2009 and pembrolizumab before definitive treatment in subjects with p16-positive OPC.
• Participants will receive PRGN-2009 and pembrolizumab prior to definitive treatment.
• Participants will receive two doses of PRGN-2009 5x10^11 viral particles (VP) subcutaneously (SC) approximately two weeks apart, and one dose of pembrolizumab 200 mg intravenously (IV) concurrently with the first vaccine dose.
• Up to 20 evaluable participants will be enrolled.

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

• INCLUSION CRITERIA:
• Subjects must have cytologically or histologically confirmed newly diagnosed stage I (T1,2 N1), II or III p16-positive oropharyngeal squamous cell carcinoma (SCC) planned for definitive therapy (surgery or chemoradiotherapy).
• Subjects must have measurable disease, per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
• Age >=18 years.
• Eastern Cooperative Oncology Group [ECOG] performance status <= 2.

• Adequate hematologic function at screening, as follows:

  • Absolute neutrophil count (ANC) >=1 x 10^9/L;
  • Hemoglobin (Hgb) >= 9 g/dL;
  • Platelets >= 75,000/microliter.

• Adequate renal and hepatic function at screening, as follows:

  • Serum creatinine <= 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance >= 40 mL/min for participant with creatinine levels > 1.5 x ULN (glomerular filtration rate [GFR] can also be used in place of creatinine or CrCl);
  • Total bilirubin <= 1.5 x ULN OR in subjects with Gilbert's syndrome, a total bilirubin <= 3.0 x ULN;
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <= 2.5 x ULN, unless liver metastases are present, then values must be <= 3 x ULN.
• Participants serologically positive for human immunodeficiency virus (HIV) Hepatitis B, or Hepatitis C are eligible if the viral loads are undetectable by quantitative polymerase chain reaction (PCR). Note: HIV positive participants must have CD4 count >= 200 cells/mm^3 at enrollment, be on stable antiretroviral therapy for at least 4 weeks and have no reported opportunistic infections or Castleman's disease within 12 months prior to enrollment.
• Women of child-bearing potential (WOCBP) must agree to use effective contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation and for at least 4 months following the last dose of pembrolizumab.
• Participants must be willing to undergo two research biopsies on this study.
• Ability of participant to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

• Participants with prior investigational drug, live vaccine, chemotherapy, immunotherapy, or any prior radiotherapy (except for palliative bone directed therapy) within the past 4 weeks prior to the first drug administration. Participants may continue adjuvant hormonal therapy in the setting of a definitively treated cancer (e.g., breast).
• Major surgery within 28 days prior to the first drug administration (minimally invasive procedures such as diagnostic biopsies are permitted).
• Pregnant individuals as evaluated by a positive serum or urine Beta-human chorionic gonadotropin (hCG) at screening

• Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent with the exception of:

  • Diabetes type I, eczema, vitiligo, alopecia, psoriasis, hypo- or hyperthyroidism or other mild autoimmune disorders not requiring immunosuppressive treatment.
  • Administration of glucocorticoids through a route known to result in a minimal systemic exposure (topical, intranasal, intraocular, or inhalation).
• Systemic (intravenous or oral) glucocorticoid (except for physiologic doses of corticosteroids, i.e., <= the equivalent of prednisone 10 mg/day) or other immunosuppressors such as azathioprine or cyclosporin A, are excluded because of potential immune suppression. These treatments must be discontinued at least 1 week prior to enrollment for recent short course use (<= 14 days). Glucocorticoids as premedication for contrast-enhanced studies is allowed prior to enrollment and on study.
• Participants with a prior or concurrent malignancy whose natural history or treatment that has potential to interfere with the safety or efficacy assessment of the regimen.
• Prior allogenic tissue/solid organ transplant.
• Participants with pulse oximetry < 92% on room air at screening.
• Uncontrolled intercurrent illness that would limit compliance with study requirements suggested by medical history, physical examination or standard clinical assessments such as imaging and laboratory studies.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Arm 1/PRGN 5x10^11 Viral Particles Subcutaneously Plus Pembrolizumab 200mg Intravenous; PRGN 5x10^11 Viral Particles (VP) subcutaneous (SC) plus pembrolizumab 200mg intravenous (IV) as induction/ neoadjuvant therapy

Biological: PRGN-2009; PRGN-2009 5x10^11 viral particles (VP) subcutaneously (SC) approximately two weeks apart; Drug: Pembrolizumab; Pembrolizumab 200 mg intravenously (IV) concurrently with the first vaccine dose; Other Names: Keytruda; Diagnostic test: EKG; Baseline, completion visit, and safety follow-up visit.; Other Names: Electrocardiogram; Diagnostic test: CT; Screening and baseline (neck and chest), and completion visit (neck).; Other Names: Computed tomography; Diagnostic test: PET scan; Screening and baseline (neck and chest).; Other Names: Positron emission tomography; Diagnostic test: MRI; Screening and baseline (neck and chest), and completion visit (neck).; Other Names: Magnetic resonance imaging; Procedure: Biopsy; Baseline and completion visit.; Other Names: Bx

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants That Had a 2-fold Increase of Cluster of Differentiation 3 (CD3+) Tumor Infiltrating T Cells in Biopsies Performed Post-treatment Compared to Pre-treatment.	CD3+ tumor infiltrating T cells post treatment compared with pre-treatment reported with a 95% confidence interval assessed by multiplex CD3+ tumor infiltrating lymphocytes assessed by multiplex immunofluorescence from the surgical/ biopsy tissue collected pre- and post-treatment. The percentage of participants with doubling of baseline CD3+ tumor infiltrating lymphocytes will be provided as well as the 95% confidence interval. The CD3 cells are assessed by multiplex immunofluorescence in the biopsies. Doubling is the desired outcome.	Pre-Treatment (Baseline) and anytime between Week 4-5 post treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival at 3 Years Compared With Historical Cohort	Assess if PRGN-2009 plus pembrolizumab results in significantly prolonged survival at three years as compared to the expected 80% three-year historical survival in p16-positive oropharyngeal cancer (OPC) participants. Three-year overall survival will be measured using a Kaplan-Meier curve and will be compared descriptively with the historical benchmark. Participants who receive two doses of PRGN-2009 and the single dose of pembrolizumab and go on to receive standard definitive therapy will be evaluable for overall survival assessment.	3 years
Overall Survival at 3 Years	Overall survival was assessed using the Kaplan-Meier method and is defined as the time from the date of first treatment to the date of death (any cause). Participants who receive two doses of PRGN-2009 and the single dose of pembrolizumab and go on to receive standard definitive therapy will be evaluable for overall survival assessment.	3 years
Number of Treatment-related Serious Adverse Events (AE) of Grades 1, 2, 3, 4 and/or 5 Along With the AE Term	Number of treatment-related serious adverse events of Grades 1, 2, 3, 4 and/or 5 along with the AE term. Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe. Grade 4 is life-threatening. Grade 5 is death related to adverse event. All participants who receive any investigational treatment will be evaluable for safety and toxicity evaluations.	From baseline up to 28 days after last treatment, up to 2 months.
Percentage of 2-fold Increase in Cluster of Differentiation (CD3+) Tumor Infiltrating Lymphocytes (TILs) Post-treatment Compared to Pre-treatment in This Trial Compared to Participants Receiving PRGN2009 in Study NCT04432597	Percentage of 2-fold increase in CD3+ Tumor Infiltrating Lymphocytes (TILs) by multiplex immunofluorescence post-treatment compared to pre-treatment in participants receiving PRGN2009 plus pembrolizumab in this trial as compared to that in participants receiving PRGN2009 monotherapy in study NCT04432597. Results of the primary endpoint of this study (Proportion of 2-fold increase in CD3+ Tumor Infiltrating Lymphocytes (TILs) by multiplex immunofluorescence post-treatment compared to pre-treatment) were compared with the same in participants in trial NCT04432597 (PRGN-2009 monotherapy). The two percentages will be compared descriptively and reported with a 95% confidence interval.	Pre-Treatment (Baseline) and anytime between Week 4 to 5 post treatment
Relapse Free Survival (RFS) Rate at 3 Years	Relapse free survival was assessed using the Kaplan-Meier method and is defined as the time from completion of standard chemoradiation to the date of disease recurrence or death (any cause) whichever comes first. Participants who receive two doses of PRGN-2009 and the single dose of pembrolizumab and go on to receive standard definitive therapy will be evaluable for relapse-free-survival assessment.	3 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)	Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. All participants who receive any investigational treatment will be evaluable for safety and toxicity evaluations.	Adverse Events were monitored/assessed from the time of first drug administration through 28 days after the last drug administration up to 2 months

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Charalampos Floudas, M.D., National Cancer Institute (NCI)

Publications and helpful links

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): November 7, 2023
• Primary Completion (Actual): May 22, 2025
• Study Completion (Estimated): July 16, 2030

Study Registration Dates

• First Submitted: August 16, 2023
• First Submitted That Met QC Criteria: August 16, 2023
• First Posted (Actual): August 18, 2023

Study Record Updates

• Last Update Posted (Actual): June 23, 2026
• Last Update Submitted That Met QC Criteria: June 1, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Monoclonal Antibody; PD-1 inhibitor; HPV16/18
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Head and Neck Neoplasms; Neoplasms, Glandular and Epithelial; Carcinoma; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Investigative Techniques; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Surgical Procedures, Operative; Cytological Techniques; Cytodiagnosis; Diagnostic Techniques, Surgical; Tomography; Diagnostic Imaging; Diagnostic Techniques, Cardiovascular; Radiography; Heart Function Tests; Electrodiagnosis; Image Interpretation, Computer-Assisted; Radiographic Image Enhancement; Image Enhancement; Photography; Tomography, X-Ray; Tomography, Emission-Computed; Radionuclide Imaging; Diagnostic Techniques, Radioisotope; Biopsy; Magnetic Resonance Imaging; pembrolizumab; Electrocardiography; Tomography, X-Ray Computed; Positron-Emission Tomography
• Other Study ID Numbers: 10001536; 001536-C

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All collected individual participant data (IPD) will be shared. All IPD recorded in the medical record will be shared with intramural investigators upon request. In addition, all large-scale genomic sequencing data will be shared with subscribers to the database of Genotypes and Phenotypes (dbGaP).
• IPD Sharing Time Frame: Data from this study may be requested from other researchers no sooner than 3 years after the completion of the primary endpoint. Genomic data is available once genomic data is uploaded per protocol Genomic Data Sharing (GDS) plan for as long as database is active.
• IPD Sharing Access Criteria: Data from this study may be requested by contacting the principal investigator (PI). Genomic data is made available via the database of Genotypes and Phenotypes (dbGaP) through requests to the data custodians.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No