Risk-adapted Therapy in HPV-positive Oropharyngeal Cancer Using Circulating Tumor (ct) HPV DNA Profiling (ReACT 2.0)

The purpose of this study is to assess risk for HPV driven oropharyngeal cancers by using HPV blood tests and clinical features (such as tumor stage and smoking status) to determine appropriate treatment to improve survival outcomes in participants with stage I, II, or III, HPV-associated oropharyngeal (tongue base or tonsil) squamous cell carcinoma,.

Study Overview

• Status: Not yet recruiting
• Conditions: Oropharyngeal Squamous Cell Carcinoma; HPV-positive Oropharyngeal Squamous Cell Carcinoma
• Intervention / Treatment: Drug: Pembroluzimab; Other: Observation

Detailed Description

This is a phase 2 randomized, open-label clinical trial to evaluate risk for HPV driven oropharyngeal cancers by using HPV blood tests and clinical features (such as tumor stage and smoking status) to determine appropriate treatment to improve survival outcomes for participants with stage I, II, or III, HPV-associated oropharyngeal (tongue base or tonsil) squamous cell carcinoma,.

Participants will be randomized 2:1 into one of two study arms: Arm 1 Pembroluzimab vs. Arm 2 Observation. Randomization is stratified by NavDx detectability at 6 weeks post curative intent therapy: yes/no.

The U.S. Food and Drug Administration (FDA) has not approved NavDx® as a method for guiding treatment decision-making for human papillomavirus (HPV)-driven oropharyngeal cancers. The U.S. Food and Drug Administration (FDA) has approved pembrolizumab as a treatment option for human papillomavirus (HPV)-driven oropharyngeal cancers.

The research study procedures include screening for eligibility, in-clinic visits, urine tests, questionnaires, tumor assessment by one or more of the following standard assessment tools: X-ray, CT (Computerized Tomography) scan, MRI (Magnetic Resonance Imaging) or PET (Positron Emission Tomography) scans, blood tests (including NavDx TTMV-HPV DNA Testing), biobanking, Electrocardiogram (ECG), and tumor tissue biopsy.

It is expected that about 116 people will take part in this research study.

• Study Type: Interventional
• Enrollment (Estimated): 116
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Glenn Hanna, MD; Phone Number: 617-632-3779; Email: Gjhanna@partners.org

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
      • Principal Investigator: Glenn Hanna, MD
      • Contact: Glenn Hanna, MD; Phone Number: 617-632-3779; Email: Gjhanna@partners.org
    • Boston, Massachusetts, United States, 02215
      • Brigham and Women's Hospital
      • Principal Investigator: Glenn Hanna, MD
      • Contact: Glenn Hanna, MD; Phone Number: 617-632-3779; Email: Gjhanna@partners.org

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Participants must have histologically or cytologically confirmed, stage I, II, or III, HPV-associated oropharyngeal (tongue base or tonsil) squamous cell carcinoma, as defined by 2017 American Joint Committee on Cancer (AJCC), 8th edition staging. Participants with HPV-associated disease of unknown primary (cT0) are eligible.

  • Participants who undergo upfront surgery are permitted to enroll if their post-operative pathology necessitates that they receive adjuvant therapy.
  • Participants who undergo upfront induction chemotherapy with platinum-based therapy are eligible if they have less than a complete clinical or radiologic response to induction as judged by the treating investigator(s).
  • Participants with locoregionally recurrent disease are eligible if they completed definitive or curative-intent treatment and meet criteria 3.1, 6e below.
• HPV status should be confirmed on tissue biopsy or cytologic sample by any of the following: (a) IHC staining for p16 with ≥70% expression, and/or (b) DNA testing (PCR or ISH) for high-risk subtypes 16, 18, 31, 33, or 35.
• Tumor tissue available for PD-L1 CPS testing.
• Age 18 years or older at the time of informed consent.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤1.

• Intermediate or high-risk HPV+ disease defined by any one of the following:

  • TTMV-HPV DNA score >200 at baseline and failure to clear by >95% by week 4-5 of treatment
  • undetectable or low (≤200) TTMV-HPV DNA at baseline prior to treatment with clinical or pathologic T3-4 or N2-3 disease
  • known HPV subtypes 18, 31, 33, or 35 (but excluding cT1-2N0 participants)
  • known N3 disease or fixed neck nodes as judged by the treating investigator(s)
  • any stage disease with known detectable TTMV-HPV DNA 6 weeks or onward from completion of definitive or curative-intent therapy without clinical or radiographic disease and with no additional intervening therapy administered.

• Participants should have adequate organ and marrow function to receive adjuvant immunotherapy as outlined below:

  • Absolute neutrophil count (ANC) ≥1500/µL
  • Platelets > 100,000/µL
  • Hemoglobin ≥9.0g./dL or ≥5.6 mmol/La
  • Creatinine OR Measured or calculated b creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤1.5 × ULN OR ≥30 mL/min for participant with creatinine levels >1.5 × institutional ULN
  • Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with total bilirubin levels >1.5 × ULN
  • AST (SGOT) and ALT (SGPT) ≤2.5 × ULN (≤5 × ULN for participants with liver metastases)
  • International normalized ratio (INR) OR prothrombin time (PT) Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants
  • Ability to understand and the willingness to sign a written informed consent document.
  • Participants or persons of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of therapy. Note: Contraception requirements should conform with CTFG guidelines. The pembrolizumab standard for use of highly effective contraceptive methods for POCBP is 120 days (5 half-lives) after the last dose. Abstaining from breastfeeding after study intervention is at least 5 half-lives or 120 days.

Exclusion Criteria:

• Participants with AJCC 2017 8th edition stage IV (M1, metastatic) disease.
• Pregnant or lactating women.
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or another stimulatory or co-inhibitory T-cell receptor treatment.
• Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of pembrolizumab.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic corticosteroid therapy (in doses exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days of first pembrolizumab dosing.
• Has active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. levothyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed. Participants with a history of allogeneic tissue/solid organ transplant are excluded.
• Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
• Has an active infection requiring systemic therapy.
• Has a known history of uncontrolled human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority. Well-controlled typically includes a CD4+ T-cell count ≥350 cells/mm3 at the time of screening and achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 or the LLOQ (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks before screening.
• Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
• Has a known additional malignancy that is progressing or requires active treatment. Exceptions: include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer, and low-risk prostate adenocarcinoma being managed with active surveillance. A history of another separate malignancy in remission without evidence of active disease is permitted if chance of recurrence is thought to be low (in discussion with the Sponsor-investigator).
• ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper limit of normal.

a Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks.

b Creatinine clearance (CrCl) should be calculated per institutional standard.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Adjuvant Pembroluzimab; Cycle 1 through Cycle 9 (42-day cycles); Days 1-378: Predetermined dose of Pembrolizumab once every 6 weeks, up to 9 cycles; Follow up for up to 2 years	Drug: Pembroluzimab; monoclonal antibody, single-dose vial via intravenous (through the arm) infusion, per protocol; Other Names: Keytruda; MK-3475
Active Comparator: Observation; Cycle 1 through Cycle 9 (42-day cycles) Days 1-378: Standard of care observation Device: NavDx® TTMV-HPV DNA testing (used for risk stratification and treatment assignment) Follow up for up to 2 years	Other: Observation; Standard of care observation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival at 2 Years (PFS2)	PFS2 is the percent probability estimate at 2 years based on the Kaplan-Meier method. PFS is defined as the time from the date of randomization to first invasive local, regional, distant progression, invasive second head and neck primary, or death due to any cause. Participants alive without progression are censored at date of last disease evaluation. Progression should be confirmed by biopsy or lymph node removal when feasible, but may also be determined based on clinical or pathologic evidence at the discretion of the treating investigator.	2 years
Grade 3 or 4 Adverse Event (AE) Rate	Grade 3 or 4 AE rate is defined as the proportion of participants who experience grade 3 or 4 adverse events during study treatment. AEs are summarized and graded based on CTCAE 5.0.	Treatment duration is up to 54 weeks, and adverse events will be collected through 30 days following the end of treatment.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Median Progression-free Survival (PFS)	PFS is defined as the time from the date of randomization to first invasive local, regional, distant progression, invasive second head and neck primary, or death due to any cause. Participants alive without progression are censored at date of last disease evaluation. Progression should be confirmed by biopsy or lymph node removal when feasible, but may also be determined based on clinical or pathologic evidence at the discretion of the treating investigator.	Tumor assessments will be performed every 12 weeks (±2 weeks) for up to 2 years following randomization.
Median Overall Survival (OS)	OS based on Kaplan-Meier method is defined as the time from randomization to death due to any cause or censored at date last known alive.	Survival will be monitored every 12 weeks (±2 weeks) for up to 2 years following randomization.
Median Distant Metastatic-free Survival (DMFS)	DMFS based on Kaplan-Meier method is defined as the time from randomization to the earlier of the first occurrence of distant or metastatic disease, or death due to any cause. Confirmation of distant metastasis should be obtained via pathologic evaluation (biopsy or lymph node removal) when feasible, by imaging evidence (CT, MRI, or PET-CT) using RECIST-style lesion measurement criteria, or by clinical judgment if pathologic or imaging confirmation is not possible. Progression limited to the primary site or regional lymph nodes is not considered an event for DMFS. Suspicion of distant metastasis based solely on indeterminate or positive PET-CT findings should be confirmed with continued clinical follow-up or pathologically.Participants alive without distant or metastatic recurrence are censored at date of last disease evaluation.	Tumor assessments will be performed every 12 weeks (±2 weeks) for up to 2 years following randomization.

Collaborators and Investigators

• Sponsor: Dana-Farber Cancer Institute
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Glenn Hanna, MD, Dana-Farber Cancer Institute

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2026
• Primary Completion (Estimated): January 1, 2028
• Study Completion (Estimated): January 1, 2030

Study Registration Dates

• First Submitted: April 1, 2026
• First Submitted That Met QC Criteria: April 6, 2026
• First Posted (Actual): April 7, 2026

Study Record Updates

• Last Update Posted (Actual): April 7, 2026
• Last Update Submitted That Met QC Criteria: April 6, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Oropharyngeal squamous cell carcinoma; HPV-positive oropharyngeal squamous cell carcinoma
• 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; Methods; Observation; pembrolizumab
• Other Study ID Numbers: 25-742

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The Harvard Cancer Consortium encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: [contact information for Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
• IPD Sharing Time Frame: Data can be shared no earlier than 1 year following the date of publication
• IPD Sharing Access Criteria: Contact the Belfer office for Dana -Farber Innovations (BODFI) at innovations@dfci.harvard.edu
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

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