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) (SAVED)

February 10, 2026 updated by: Jason Molitoris, MD PhD, University of Maryland, Baltimore

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.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

This research study is designed for people with HPV-related head and neck cancer who are being treated with either surgery followed by radiation or radiation as their first treatment. Patients with this type of cancer generally have excellent outcomes, but the treatments can cause significant short- and long-term side effects. Because cancer control is often very good regardless of the specific treatment approach, this study focuses on whether radiation doses can be safely reduced to lessen side effects while still effectively controlling the cancer.

Most patients receive either surgery or radiation as their initial treatment, based on discussions with their medical team. For patients who have surgery first, radiation is often recommended afterward to the surgical area and nearby lymph nodes in the neck. Traditionally, this includes radiation to lymph nodes on both sides of the neck, even the side opposite the tumor. This study will evaluate whether lowering the radiation dose to low-risk lymph nodes on the side opposite the tumor can reduce side effects without compromising cancer control. This approach is called reduced lymph node radiation (Method A).

For patients who receive radiation as their first treatment, radiation is typically given to both the tumor and lymph nodes on both sides of the neck. In these patients, the study will evaluate one or two radiation-reduction strategies. In addition to reduced lymph node radiation (Method A), the study will also examine tumor dose reduction (Method B), which lowers the amount of radiation delivered directly to the tumor itself. Some patients may receive one of these approaches, while others may be eligible for both. Eligibility for these radiation-reduction approaches is based on individual cancer characteristics, such as tumor size, the number of involved lymph nodes, and risk factors like smoking history.

For patients who may qualify for tumor dose reduction (Method B), an additional blood test called a circulating tumor DNA (ctDNA) test is used. This test measures small amounts of tumor DNA in the blood. Studies suggest that patients whose ctDNA levels are negative after treatment are less likely to have their cancer return. In this study, ctDNA testing before treatment and partway through radiation will help identify patients who may be able to safely stop radiation earlier than usual (Method B).

Participants in the study are followed closely as part of their routine cancer care. This includes regular clinic visits, imaging, and physical exams. This also includes research procedures such as questionnaires about symptoms and quality of life. Some participants will also provide additional research-related blood samples to help researchers better understand which factors may predict treatment response and long-term outcomes in the future.

Up to 132 patients will take part in this study at the University of Maryland Medical System. Participation is voluntary, and treatment decisions-such as whether to have surgery or radiation and whether to receive chemotherapy-are made by the patient and their medical team, not determined by the study. However, the study procedures will determine participants' eligibility for and use of one or both of the two radiation reduction approaches.

The goal of this research is to improve future care by identifying safe ways to reduce radiation and treatment-related side effects while maintaining excellent cancer control.

Study Type

Interventional

Enrollment (Estimated)

132

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

4.1 Step 1 Registration 4.1.1 Step 1 Inclusion

(Y) 1. Is there pathologically (histologically or cytologically) proven diagnosis of squamous cell carcinoma (including the histological variants papillary squamous cell carcinoma and basaloid squamous cell carcinoma) of the oropharynx or squamous cell carcinoma unknown primary? Note: specimen from cervical lymph nodes with a well-defined primary site documented clinically or radiologically is acceptable; in patients with carcinoma of unknown primary this will be sufficient for pathologic confirmation without a clinically or radiographically defined primary site.

(Y) 2. Is the patient ≥ 18 years of age?

(Y) 3. Did the patient provide study specific informed consent prior to study entry, including consent for mandatory submission of tissue for required p16 review?

(Y) 4. Clinical TNM staging criteria by cohort (AJCC 8th edition):

TORS candidate patients must be:

• cT0-4 and N0, N1, N3

Non-TORS candidate patients must be either:

  • cT1-4 N0, N1, N3
  • cT1-3 N2 with < 10 pack years

4.1.2 Step 1 Exclusion

(N) 1. Patient who are clinical N2 and have ≥10 pack years smoking history

(N) 2. Patients who are clinical T4N2

(N) 3. Patients with distant metastasis (M1)

4.2 Step 2 Registration 4.2.1 Step 2 inclusion

(Y) 1. Does the patient have pathologically (histologically or cytologically) proven P16+ status?

(Y) 2. Does the patient have appropriate imaging (PET/CT preferred, CT neck with IV contrast and CT chest without contrast as recommended alternative to PET/CT) completed within 90 days of enrollment?

(Y) 3. Does the patient have clinical or pathological M0 staging? (Y) 4. Patients who have undergone TORS must have pathological stage pT1-4 N0, N1 or N3. TORS patients found to be clinical N2 post TORS or have contralteral neck dissection and positive nodes will be excluded.

(Y) 5. Is the patient a candidate for bilateral radiation based on evaluation by ENT, Rad Onc, or Med Onc and review at multi-disciplinary tumor board?

(Y) 6. Non-TORS patients who are cT1-3 N0, N1, N2 and have <10 PY must have completed a ctDNA evaluation prior to Step 2 enrollment.

(Y) 7. Non-TORS patients who are cT1-3 N2 must have a positive ctDNA result prior to Step 2 enrollment.

(Y) 8. Was a general history and physical examination performed by a radiation oncologist, medical oncologist, or head and neck surgeon within 60 days prior to registration?

(Y) 9. Was the patient's Zubrod Performance Status 0-1 within 30 days prior to registration?

(Y) 10. If a woman of child-bearing potential or sexually active male, is the patient willing to use effective contraception throughout their participation in the treatment phase of the study and at least 180 days following the last study treatment.

4.2.2 Step 2 Exclusion

(N) 1. Does the patient have cancer considered to be from an oral cavity site (oral tongue, floor mouth, alveolar ridge, buccal or lip), nasopharynx, hypopharynx, or larynx?

(N) 2. Does the patient have distant metastasis?

(N) 3. Does the patient have prior invasive malignancy (except non-melanomatous skin cancer and low/intermediate risk prostate cancer) unless disease free for a minimum of 3 years?

(N) 4. Did the patient have prior systemic chemotherapy for the study cancer (prior chemotherapy for a different cancer is allowable)?

(N) 5. Did the patient have prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields?

(N) 6. Did the patient have prior cancer-related surgeries of curative intent of the head and neck excluding superficial removal of cutaneous skin malignancies?

(N) 7. Does the patient have any co-morbid condition or concern that may interfere with follow up per experimental arm?

(N) 8. Does the patient have an active drug or alcohol dependency that in the opinion of the investigator would limit compliance with study requirements?

(N) 9. Is the patient pregnant or nursing (an exception will be made for nursing patients that are not receiving chemotherapy)?

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Selective dose de-escalation of nodAl VolumEs at minimal Risk and primary site Disease
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.
Other Names:
  • SAVER volume reduction
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Freedom From Regional Failures (FFRF)
Time Frame: 2 years post treatment
The efficacy of dose de-escalation to the elective nodal regions will be evaluated by ensuring a 93% freedom from regional failures (FFRF) at 2 years.
2 years post treatment
Freedom From Local Recurrence (FFLR)
Time Frame: 2 years post treatment
The efficacy of de-escalation of dose to gross disease in patients who clear ctDNA will be evaluated by ensuring a 93% Freedom From Local Recurrence (FFLR) at 2 years.
2 years post treatment

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
PEG-tube rate
Time Frame: 2-year following completion of treatment
Percutaneous endoscopic gastrostomy (PEG)-tube rate
2-year following completion of treatment
Progression-free Survival (PFS)
Time Frame: 2 year post treatment
Percent PFS at 2 year post treatment
2 year post treatment
Overall Survival (OS)
Time Frame: 2 year post treatment
2 year post treatment
Freedom from Distant Metastases (FFDM)
Time Frame: 2 years post treatment
Freedom from Distant Metastases (FFDM) at 2 years post last treatment
2 years post treatment
Number of participants with grade 2/3 xerostomia
Time Frame: [Time Frame: 1-year following completion of treatment]
defined by PRO-CTCAE (patient-reported outcome (PRO) measurement system - Common Terminology Criteria for Adverse Events (CTCAE))
[Time Frame: 1-year following completion of treatment]
Patient scores from the questionnaire called The Monroe Dunaway Anderson Dysphagia Inventory (MDADI)
Time Frame: 1-year following completion of treatment

The M.D. Anderson Dysphagia Inventory is a self-administered questionnaire designed specifically for evaluating the impact of dysphagia on the Quality of Life (QOL) of patients with head and neck cancer.

Two scores are obtained: a Global Score and a Composite Score.

Global Score ranges from 1 (extremely low functioning) to 5 (high functioning)

Composite Score ranges from 20 (extremely low functioning) to 100 (high functioning)
1-year following completion of treatment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Maryland, Baltimore

Investigators

  • Principal Investigator: Jason K Molitoris, University of Maryland/Maryland Proton Treatment Center

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

May 1, 2026

Primary Completion (Estimated)

May 1, 2031

Study Completion (Estimated)

May 1, 2033

Study Registration Dates

First Submitted

February 10, 2026

First Submitted That Met QC Criteria

February 10, 2026

First Posted (Actual)

February 18, 2026

Study Record Updates

Last Update Posted (Actual)

February 18, 2026

Last Update Submitted That Met QC Criteria

February 10, 2026

Last Verified

February 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • HP-00116955

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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