A Single Arm Phase II Trial in p16-positive Oropharynx Cancer of Selective Dose De-escalation of nodAl VolumEs at Minimal Risk and Primary Site Disease (SAVED)

Summary

Patients with human papillomavirus (HPV)-related oropharyngeal cancer generally have very good outcomes. Patients' treatment responses depend more on their individual cancer characteristics and personal risk factors than on the specific type of treatment they receive. However, the different treatments used for this cancer can cause significant side effects. Because outcomes are often favorable regardless of treatment type, reducing treatment-related side effects should be a priority when choosing care.

Studies have reported that lowering radiation doses for some patients can reduce side effects while still effectively controlling the cancer.

Patients with this type of head and neck cancer typically receive either surgery or radiation as their first treatment.

For patients who receive surgery first, radiation to the surgical area and nearby neck lymph nodes is often recommended afterward. In these patients, the study will test whether lowering the radiation dose to low-risk lymph nodes on the side of the neck opposite the tumor can reduce side effects while still effectively controlling the cancer (Method A).

For patients who receive radiation as their first treatment, the study will test one or both of two radiation approaches aimed at reducing both short-term and long-term side effects. These approaches include reduced lymph node radiation (Method A, described above) and a tumor dose reduction approach (Method B), which lowers the radiation dose delivered directly to the tumor.

Information such as tumor size, the number of cancerous or suspicious lymph nodes, and risk factors like smoking history will be used to determine which patients may be eligible for reduced lymph node radiation (Method A), reduced tumor radiation (Method B), or both. Patients who may qualify for tumor dose reduction (Method B), either alone or combined with Method A, will need an additional blood test called a circulating tumor DNA (ctDNA) test to determine eligibility.

The ctDNA test measures small amounts of tumor-related DNA in the blood, which are often elevated at the time of diagnosis. Studies have shown that cancer is more likely to return when ctDNA levels remain positive after treatment. This study will evaluate whether ctDNA levels measured before and during treatment can help identify patients who can safely receive lower radiation doses to the tumor (Method B).

Overall, this study aims to safely evaluate two radiation de-escalation approaches in order to lessen short- and long-term side effects while maintaining excellent cancer control.

Conditions

• Head and Neck Cancer
• Head and Neck Squamous Cell Cancer
• Head and Neck Squamous Cell Carcinoma
• Oropharyngeal Carcinoma
• Oropharyngeal Squamous Cell Carcinoma (OPSCC)
• Oropharyngeal Human Papillomavirus-Positive Squamous Cell Carcinoma
• Oropharyngeal Squamous Cell Carcinoma
• Oropharyngeal Squamous Cell Carcinoma (SCC)
• Oropharyngeal Squamous Cell Carcinoma (OPSCCA)
• Oropharyngeal Cancer
• Oropharyngeal Squamous Cell Cancer
• HPV Positive Oropharyngeal Squamous Cell Carcinoma
• HPV (Human Papillomavirus)-Associated Carcinoma
• HPV 16 Positive Oropharyngeal Tumors (OPC)

Interventions

RADIATION

Dose de-escalation to contralateral neck.

Dose de-escalation of elective treatment volumes including the SAVER-defined volume reduction in the contralateral neck. These patients can be treated in the definitive or adjuvant setting, and have c/pT1-4, N0-1,3 (AJCC 8th ed) disease with a recommendation to treat the contralateral neck. They will undergo treatment with sequential planning of 30Gy to the gross disease and elective neck volumes (using SAVER defined volumes of the contralateral neck) and a subsequent boost to 70Gy for definitive treatment and 50Gy for adjuvant treatment. Chemotherapy will be incorporated per SOC guidelines and based on multi-disciplinary recommendations.

RADIATION

Dose de-escalation to gross disease to contralateral neck

Dose de-escalation to gross disease for patients treated with definitive chemoRT who meet eligibility for NRG HN 005 (cT1-2N0-2, cT3N0-1 \[AJCC 8th ed\], ≤ 10 Smoking Pack years). Additionally, these patients will require pre-treat positive ctDNA. They will undergo treatment with sequential planning of 30Gy to gross disease and elective neck volumes (using SAVER defined volumes of the contralateral neck). A subsequent boost will be initiated to gross disease. At 4 weeks of treatment, patients will undergo ctDNA analysis. If a patient's ctDNA decreases by ≥95%, final dose will be decreased from SOC dosing for 70Gy to 60Gy (HN-002 dosing). If ctDNA dosing is not resulted by the time patients reach 60Gy, they will continue SOC treatment up to a maximum of 70Gy or until the ctDNA results are available. If there is a ≥95% reduction in ctDNA, treatment will be stopped prior to 70Gy.

RADIATION

Dose de-escalation to gross disease

Dose de-escalation to the gross disease for patients treated with definitive chemoRT who meet eligibility criteria for NRG HN 005 (cT1-2N0-2, cT3N0-1 \[AJCC 8th ed\], ≤ 10 Smoking Pack years). Additionally, these patients will require pre-treatment positive ctDNA levels. At 4 weeks of treatment (after fraction 19 and before fraction 22), patients will undergo ctDNA analysis. If a patient's ctDNA decreases by ≥95%, final dose will be decreased from SOC dosing for 70Gy to 60Gy (HN-002 dosing). If ctDNA dosing is not resulted by the time patients reach 60Gy, they will continue SOC treatment up to a maximum of 70Gy or until the ctDNA results are available. If there is a ≥95% reduction in ctDNA, treatment will be stopped prior to 70Gy.

DIAGNOSTIC_TEST

Circulating Tumor DNA test (ctDNA test)

Blood test for diagnostic and surveillance purposes measuring expression of Cell free HPV tumor DNA (ctDNA) in the blood. Patients who are eligible for dose de-escalation to gross disease, whether they are also eligible for dose de-escalation of contralateral neck or not, will undergo ctDNA evaluation pretreatment, at 4 weeks of treatment, and then at 3, 6, and 12 months post treatment.

Sponsors & Collaborators

• University of Maryland, Baltimore

  lead OTHER

Principal Investigators

• Jason K Molitoris · University of Maryland/Maryland Proton Treatment Center

Study Design

Allocation

NA

Purpose

TREATMENT

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2026-05-31

Primary Completion

2031-05-31

Completion

2033-05-31