Pembrolizumab plus short-course proton or X‑ray radiation before salvage surgery for recurrent head and neck cancer

WOPPPR: Window of Opportunity Phase I and Phase II Trial Combining PD-1 Inhibition and Neoadjuvant Proton or Photon Radiation Therapy in Recurrent Head and Neck Squamous Cell Carcinoma

This study will try short-course proton or X‑ray radiation followed by pembrolizumab before salvage surgery in adults with recurrent head and neck squamous cell carcinoma who previously received radiation.

Quick facts

• Phase: PHASE1; PHASE2
• Study type: Interventional
• Enrollment: 40 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: University of Cincinnati (other)
• Drugs / interventions: pembrolizumab, prednisone, immunotherapy, radiation
• Locations: 1 site (Cincinnati, Ohio)
• Trial ID: NCT07213934 on ClinicalTrials.gov

What this trial studies

Phase I uses sequential cohorts of 3–6 patients receiving three fractions of photon (XRT) or proton (PT) radiation prior to salvage surgery with dose escalation/de‑escalation based on toxicity up to 28 days after resection to establish a recommended phase II dose (RP2D). The RP2D for XRT will be determined first and then used as the starting dose for PT to confirm safety for both modalities. Phase II is a randomized, two‑arm Simon two‑stage design comparing PT plus pembrolizumab versus XRT plus pembrolizumab, with the primary endpoint of major pathological response (MPR) and a target MPR of 35% versus a historical 10% for PD‑1 alone. Forty patients will be screened and randomized across the two arms with nine patients required in stage I of each arm before potential expansion to stage II.

Who should consider this trial

Good fit: Adults (≥18) with histologically confirmed recurrent head and neck squamous cell carcinoma who are candidates for salvage surgery, had prior radiotherapy >6 months earlier with ≥30 Gy to the current target, have disease limited to a single contiguous target with GTV <7 cm, CPS PD‑L1 ≥1%, ECOG ≤1, and adequate organ and marrow function are ideal candidates.

Not a fit: Patients with widespread or multi‑site disease not treatable in a single contiguous volume, GTV ≥7 cm, PD‑L1 CPS <1%, poor performance status, inadequate organ function, or those not eligible for salvage surgery are unlikely to receive benefit from this protocol.

Why it matters

Potential benefit: If successful, this approach could raise the rate of major pathological response before surgery and potentially improve local control and longer‑term outcomes for patients with recurrent HNSCC.

How similar studies have performed: Neoadjuvant PD‑1 therapy and combinations of radiation with immunotherapy have shown promising pathological responses in HNSCC, but the specific approach of short-course preoperative proton versus photon radiation combined with pembrolizumab remains exploratory.

Eligibility criteria

Inclusion Criteria (Both Phase I and Phase II)

1. Patients must have histologically or cytologically confirmed recurrent head and neck squamous cell carcinoma including oral cavity, laryngeal, hypopharyngeal, or oropharyngeal (HPV-) SCC.
2. Patients must be a candidate for salvage surgical resection.
3. Patients must have failed prior RT \>6 months prior to recurrence with at least 30 Gy delivered to the current target volume.
4. 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.
5. Patients must have a CPS PD-L1 of ≥1%. This may be tested on a new biopsy or archival tissue.
6. Age ≥18 years.
7. ECOG performance status ≤1 (or Karnofsky ≥70%, see Appendix A).
8. 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).
9. Archival tissue must be available for baseline analysis. Either a tumor block or at least 20 slides must be available.
10. Known human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
11. For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
12. 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.
13. 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.
14. 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.
15. Women of child-bearing potential and men must agree to use adequate contraception (e.g., hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and for 4 months after completion of pembrolizumab administration.
16. Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.

Exclusion Criteria (Phase I \& II)

1. Patients who have metastatic disease.
2. 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.
3. 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.
4. Prior treatment with PD-1 inhibitors in the last 6 months or progression on a PD-1 inhibitor at any time.
5. Autoimmune disease or other pro-inflammatory conditions other than treated stable asthma, minor allergies (such as seasonal allergies), vitiligo or hypothyroidism.
6. 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).
7. 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.
8. 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.

Where this trial is running

Cincinnati, Ohio

• University of Cincinnati Medical Center — Cincinnati, Ohio, United States (RECRUITING)

Study contacts

• Study coordinator: UCCC Clinical Trials Office

Conditions: Head and Neck Cancer, Recurrent Head and Neck Squamous Cell Carcinoma