Phase I/ II Trial Combining PD-1 Inhibition and Neoadjuvant Proton or Photon Radiation Therapy in Recurrent Head and Neck Squamous Cell Carcinoma

NCT07213934 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: UCCC-HN-24-01
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of the Phase I study is to see if it is safe to use X-ray photon radiation (XRT) and proton radiation (PT) before surgery in patients with recurrent head and neck squamous cell carcinoma (rHNSCC). The purpose of the Phase II study is to see if using XRT or PT before immunotherapy (pembrolizumab) prior to surgery benefits patients with recurrent head and neck squamous cell carcinoma (rHNSCC).

Conditions

Head and Neck Cancer; Recurrent Head and Neck Squamous Cell Carcinoma

Outcome Measures

Primary Outcomes (2)

• Dose Limiting Toxicity (DLT) Evaluation defined as the number of subjects experiencing a major, non-grade 5 adverse event as defined by CTCAE v6 or a grade 5 adverse event as defined by CTCAE 6.

  To determine DLTs during Phase I to determine the recommended Phase 2 dose. A DLT is defined as experiencing ≥ Gr 4 AEs prior to surgery, a delay in surgery past 5 wks from RT, or ≥ Gr 4 surgical complications or Grade 5 adverse events are defined as deaths occurring during the study period, regardless of attribution, as assessed using CTCAE v6.0 criteria.

  From the initiation of study treatment to 28 days post resection.

• Major Pathologic Response (MPR) defined as less than 10% viable tumor on resected tumor specimen.

  To determine the major pathological response (MPR) in patients undergoing neoadjuvant X-ray photon radiation (XRT) or proton radiation (PT) with pembrolizumab followed by surgical salvage compared to a historical control group undergoing salvage surgery with PD-1 alone.

  Surgery - Week 4

Secondary Outcomes (2)

• Disease Free Survival as measured from time of surgery until either disease recurrence or death from any cause.

  Surgery - Week 4 through 5 years

• Safety using CTCAE v6.0 and toxicity evaluation.

  5 years

Other Outcomes (3)

• Percent immune cell infiltration in tumors or microenvironment in patients undergoing neoadjuvant XRT or PT followed by surgical salvage determined by IHC and/or IF and/or Flow Cytometry.

  Baseline (prior to radiotherapy) Cycle 1, Day 1 (Phase 1, post-radiotherapy) Cycle 1, Day 1 (Phase 2, post-radiotherapy and pembrolizumab initiation) Cycle 1, Day 22 Cycle 2, Day 1 Note: Neoadjuvant cycles are 28 days; adjuvant cycles are 42 days.

• Overall survival (OS)

  5 years

• Overall response rate measured by RECIST criteria.

  Week 4

Study Arms (2)

Standard Radiation Therapy

ACTIVE COMPARATOR

XRT followed by PD-1 inhibition

Drug: Pembrolizumab

Photon Therapy

EXPERIMENTAL

PT followed by PD-1 inhibition

Radiation: Proton therapy; Drug: Pembrolizumab

Interventions

Proton therapy RADIATION

Proton therapy is a type of radiation therapy that uses protons rather than x-rays. It painlessly delivers radiation to treat some types of cancer.

Photon Therapy

Pembrolizumab DRUG

PDL-1 immunotherapy drug

Photon Therapy; Standard Radiation Therapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have histologically or cytologically confirmed recurrent head and neck squamous cell carcinoma including oral cavity, laryngeal, hypopharyngeal, or oropharyngeal (HPV-) SCC.
• Patients must be a candidate for salvage surgical resection.
• Patients must have failed prior RT \>6 months prior to recurrence with at least 30 Gy delivered to the current target volume.
• Disease must be limited to a single site or adjacent sites that can be treated in a single contiguous target volume for which the maximum total tumor dimension (GTV) must be \<7 cm.
• Patients must have a CPS PD-L1 of ≥1%. This may be tested on a new biopsy or archival tissue.
• Age ≥18 years.
• ECOG performance status ≤1 (or Karnofsky ≥70%, see Appendix A).
• Patients must have adequate organ and marrow function as defined below:
• Platelets ≥100,000/mcL Total bilirubin ≤ institutional upper limit of normal (ULN) AST(SGOT)/ALT(SGPT) ≤3 × institutional ULN Creatinine ≤ 1.5x institutional upper limit of normal (ULN) OR glomerular filtration rate (GFR) ≥30 mL/min/1.73 m2 (see Appendix B).
• Archival tissue must be available for baseline analysis. Either a tumor block or at least 20 slides must be available.
• Known human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with known HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better.

You may not qualify if:

• Patients who have metastatic disease.
• Patients who have ongoing adverse events from prior anti-cancer therapy that would preclude completion of the proposed study treatment at the opinion of the treating investigators.
• Patients who are receiving any other investigational agents. Patients who have received other investigational agents previously who are no longer receiving these investigational agents may be eligible at the discretion of the PI.
• Prior treatment with PD-1 inhibitors in the last 6 months or progression on a PD-1 inhibitor at any time.
• Autoimmune disease or other pro-inflammatory conditions other than treated stable asthma, minor allergies (such as seasonal allergies), vitiligo or hypothyroidism.
• Active and ongoing steroid use \>10 mg prednisone, except for non-systemically absorbed treatments (such as inhaled or topical steroid therapy for asthma, COPD, allergic rhinitis).
• Patients with uncontrolled intercurrent illness or any other significant condition(s) that would make participation in this protocol unreasonably hazardous, in the opinion of the Investigator.
• Pregnant women are excluded from this study. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with breastfeeding should be discontinued if the mother is treated with pembrolizumab.

Sponsors & Collaborators

• University of Cincinnati: lead

Study Sites (1)

University of Cincinnati Medical Center

Cincinnati, Ohio, 45219, United States

RECRUITING

MeSH Terms

Conditions

Head and Neck Neoplasms; Squamous Cell Carcinoma of Head and Neck

Interventions

Proton Therapy; pembrolizumab

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Carcinoma, Squamous Cell; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type

Intervention Hierarchy (Ancestors)

Heavy Ion Radiotherapy; Radiotherapy; Therapeutics

Central Study Contacts

UCCC Clinical Trials Office

CONTACT

513-584-7698; cancer@uchealth.com

Trisha Wise-Draper, MD

CONTACT

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: September 30, 2025
• First Posted: October 9, 2025
• Study Start: October 8, 2025
• Primary Completion (Estimated): December 1, 2030
• Study Completion (Estimated): December 1, 2031
• Last Updated: April 15, 2026

Record last verified: 2026-04

Locations

US (1)