Circulating Tumor DNA-Informed Adjuvant Therapy for Intermediate-Risk Head and Neck Cancer

Phase II Trial of Drain Fluid Circulating Tumor DNA-Informed Adjuvant Therapy for Intermediate-Risk Head and Neck Cancer

This study is being done to determine whether an assay called LymphDetect™ Head and Neck is a useful tool to help guide treatment decisions for patients with head and neck cancer. The LymphDetect™ assay works to detect a certain kind of DNA that is released by tumors called circulating tumor DNA or ctDNA for short. In this study, the presence of ctDNA will be assessed in fluid collected from the surgical drain that will be placed during curative-intent surgical procedure performed as a part of patient standard care. Treatment after surgery is determined by a patient's disease risk category (low-risk, intermediate-risk, or high-risk). Having intermediate-risk with detection of ctDNA in the surgical drain fluid (SDF+) may mean that a patient is at greater risk of their cancer coming back. To reduce this risk, treatment will be more intensive than if ctDNA in the surgical drain fluid (SDF-) was not found.

Study Overview

• Status: Not yet recruiting
• Conditions: Head and Neck Cancer
• Intervention / Treatment: Diagnostic test: LymphDetect assay; Procedure: Surgery +/- neoadjuvant pembrolizumab; Radiation: Intensity-modulated radiation therapy (IMRT) or Intensity-modulated proton therapy (IMPT); Drug: Pembrolizumab; Drug: Cisplatin or carboplatin

Detailed Description

Patients who are Surgical Drain Fluid (SDF) positive have a more than eight-fold higher risk of Head and Neck Squamous Cell Carcinoma disease recurrence. Whether these pathologically intermediate-risk patients benefit from the addition of concurrent cisplatin to adjuvant radiotherapy is unknown. Various prognostic biomarkers have been proposed to identify patients at high risk of recurrence. Tissue-based biomarkers may be less prognostic after successful tumor extirpation. Several plasma-based ctDNA assays measuring treatment response in HPV- HNSCC are under investigation. However, data is limited on the role of such assays for the detection of molecular residual disease (MRD) after surgery, particularly for risk-informed adjuvant treatment decision making. Tumor-informed ctDNA from postoperative SDF, taken 24 hours after surgery, has been shown to be a promising biomarker for individualizing recurrence risk. The LymphDetect™ Head & Neck system, will be used to measure circulating tumor DNA (ctDNA) in surgical drain fluid, the most proximal biofluid to a recently resected tumor, to assess cancer recurrence risk at the source of potential spread - before it can travel to other parts of the body. There is a critical need to improve recurrence risk estimates for patients with HPV- HNSCC to inform the extent of adjuvant management, improve oncologic outcomes, and limit unnecessary treatment morbidity and mortality.

• Study Type: Interventional
• Enrollment (Estimated): 140
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jennifer Ruth, RN, BSN; Phone Number: 412-623-8963; Email: ruthj2@upmc.edu
• Study Contact Backup: Name: Mel J Mendez, RN, BSN; Phone Number: 878-261-6071; Email: mendezmj@upmc.edu

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • UPMC Hillman Cancer Center
      • Contact: Jennifer Ruth, RN, BSN; Phone Number: 412-623-8963; Email: ruthj2@upmc.edu
      • Contact: Mel J Mendez, RN, BSN; Phone Number: 878-261-6071; Email: mendezmj@upmc.edu
      • Principal Investigator: Kevin J Contrera, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Must have histologically or cytologically confirmed newly diagnosed mucosal HNSCC (i.e., oral cavity, oropharynx, hypopharynx, or larynx).

   o Patients with intermediate-risk disease (stage cT2N0 with adverse pathologic features OR stage cT3-4Nany OR stage cTanyN1-3a) will be preferentially enrolled.

2. Must have received no prior therapies for current malignancy, except for neoadjuvant pembrolizumab.

3. Must be able to undergo curative-intent surgical resection with neck dissection and placement of a drain.

4. Patient is considered a candidate for adjuvant chemotherapy (cisplatin) and radiation based on the clinical judgment of the treating investigator. This decision should be made based upon the patient's pre-operative assessment performed as part of the standard of care.

5. Age ≥18 years.

6. Performance status ECOG 0-2

7. Sexually active, fertile subjects and their partners must agree to use highly effective methods of contraception prior to study entry, during the course of the study, and for 30 days after the last dose of chemotherapy and/or radiation (whichever is later). In addition, men must agree not to donate sperm and women must agree not to donate eggs (ova, oocyte) for the purpose of reproduction during these same periods.

8. Female subjects of childbearing potential must not be pregnant or breastfeeding at screening. Female subjects are considered to be of childbearing potential unless one of the following criteria is met:

   o Permanent sterilization (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or documented postmenopausal status (defined as 12 months of amenorrhea in a woman > 45 years of age in the absence of other biological or physiological causes). Note: Documentation may include review of medical records, medical examination, or medical history interview by study site staff.

9. Must have the ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

1. HPV-related oropharyngeal cancer
2. Nasopharyngeal cancer
3. Sinonasal cancer
4. Prior or recurrent HNSCC
5. Distant metastasis
6. Other active malignancy, other than nonmetastatic skin, prostate, or thyroid malignancy
7. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low-Risk	Diagnostic test: LymphDetect assay; A tumor-informed ctDNA assay that uses Surgical Drain Fluid (SDF) collected 24 hours after the end of surgery to direct therapeutic intervention.; Procedure: Surgery +/- neoadjuvant pembrolizumab; Performed within 28 days after baseline assessment to remove Head and Neck Cancer tumor(s).
Experimental: Intermediate Risk - Surgical Drain Fluid (negative); IMRT or IMPT to 60 Gy in 30 fractions (2Gy/FX) ± Pembrolizumab - 200 mg q3w - Restart post-surgery (can begin prior to or at the same time as radiation therapy) and continue for up to 17 cycles (including neoadjuvant cycles). [IMRT / IMPT Schedule to be determined by radiation oncologist, should be completed within 42 days of start date]	Diagnostic test: LymphDetect assay; A tumor-informed ctDNA assay that uses Surgical Drain Fluid (SDF) collected 24 hours after the end of surgery to direct therapeutic intervention.; Procedure: Surgery +/- neoadjuvant pembrolizumab; Performed within 28 days after baseline assessment to remove Head and Neck Cancer tumor(s).; Radiation: Intensity-modulated radiation therapy (IMRT) or Intensity-modulated proton therapy (IMPT); Advanced type of radiation therapy that uses powerful energy beams to kill cancer cells. The energy can come from X-rays, protons or other sources, in which the beams of radiation are carefully customized.; Drug: Pembrolizumab; Humanized monoclonal antibody and a PD-1 inhibitor used in cancer immunotherapy that differs from chemotherapy as it does not directly kill cancer cells but stimulates the immune system, particularly T-cells, to recognize and attack cancer cells more effectively.; Other Names: Keytruda®
Experimental: Intermediate Risk - Surgical Drain Fluid (positive); IMRT or IMPT to 60 Gy in 30 fractions (2Gy/FX) with concurrent cisplatin 40 mg/m^2 weekly for 6 doses or 3-weekly 100mg/m2 dose for 3 doses ± Pembrolizumab - 200 mg q3w - Restart post-surgery (can begin prior to or at the same time as radiation therapy) and continue for up to 17 cycles (including neoadjuvant cycles). [Cisplatin: 40 mg/m^2 weekly (6 total doses) - Day 1, 8, 15, 22, 29, and 36 of radiation therapy or Cisplatin: 100 mg/m^2 q3w (3 total doses) - Day 1, 22, and 43 of radiation therapy (last dose of cisplatin may be after the last dose of radiation)] (If Cisplatin is not tolerated, Carboplatin AUC 2 weekly for 6 doses may be given.)	Diagnostic test: LymphDetect assay; A tumor-informed ctDNA assay that uses Surgical Drain Fluid (SDF) collected 24 hours after the end of surgery to direct therapeutic intervention.; Procedure: Surgery +/- neoadjuvant pembrolizumab; Performed within 28 days after baseline assessment to remove Head and Neck Cancer tumor(s).; Radiation: Intensity-modulated radiation therapy (IMRT) or Intensity-modulated proton therapy (IMPT); Advanced type of radiation therapy that uses powerful energy beams to kill cancer cells. The energy can come from X-rays, protons or other sources, in which the beams of radiation are carefully customized.; Drug: Pembrolizumab; Humanized monoclonal antibody and a PD-1 inhibitor used in cancer immunotherapy that differs from chemotherapy as it does not directly kill cancer cells but stimulates the immune system, particularly T-cells, to recognize and attack cancer cells more effectively.; Other Names: Keytruda®; Drug: Cisplatin or carboplatin; An alkylating agent that contains platinum, which binds to DNA in cancer cells, causing cross-links that prevent DNA replication and repair, leading to cell death, particularly in rapidly dividing cancer cells.; Other Names: Platinol®
Experimental: High Risk; IMRT or IMPT to 60 Gy in 30 fractions (2Gy/FX) with concurrent cisplatin 40 mg/m^2 weekly for 6 doses or 3-weekly 100mg/m2 dose for 3 doses ± Pembrolizumab - 200 mg q3w - Restart post-surgery (can begin prior to or at the same time as radiation therapy) and continue for up to 17 cycles (including neoadjuvant cycles). [Cisplatin: 40 mg/m^2 weekly (6 total doses) - Day 1, 8, 15, 22, 29, and 36 of radiation therapy or Cisplatin: 100 mg/m^2 q3w (3 total doses) - Day 1, 22, and 43 of radiation therapy (last dose of cisplatin may be after the last dose of radiation)] (If Cisplatin is not tolerated, Carboplatin AUC 2 weekly for 6 doses may be given.)	Diagnostic test: LymphDetect assay; A tumor-informed ctDNA assay that uses Surgical Drain Fluid (SDF) collected 24 hours after the end of surgery to direct therapeutic intervention.; Procedure: Surgery +/- neoadjuvant pembrolizumab; Performed within 28 days after baseline assessment to remove Head and Neck Cancer tumor(s).; Radiation: Intensity-modulated radiation therapy (IMRT) or Intensity-modulated proton therapy (IMPT); Advanced type of radiation therapy that uses powerful energy beams to kill cancer cells. The energy can come from X-rays, protons or other sources, in which the beams of radiation are carefully customized.; Drug: Pembrolizumab; Humanized monoclonal antibody and a PD-1 inhibitor used in cancer immunotherapy that differs from chemotherapy as it does not directly kill cancer cells but stimulates the immune system, particularly T-cells, to recognize and attack cancer cells more effectively.; Other Names: Keytruda®; Drug: Cisplatin or carboplatin; An alkylating agent that contains platinum, which binds to DNA in cancer cells, causing cross-links that prevent DNA replication and repair, leading to cell death, particularly in rapidly dividing cancer cells.; Other Names: Platinol®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
2-year Locoregional Control (LRC): SDF+ intermediate risk	Proportion of patients without locoregional recurrence (growth or recurrence of the primary tumor or other nearby structures within the same anatomical region or nearby regional lymph nodes) at 2 years from the initiation of study treatment in patients who are SDF+ intermediate risk.	At 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
2-year Locoregional Control (LRC): SDF- intermediate risk	Proportion of patients without locoregional recurrence (growth or recurrence of the primary tumor or other nearby structures within the same anatomical region or nearby regional lymph nodes) at 2 years from the initiation of study treatment in patients who are SDF-intermediate risk.	At 2 years
2-year Locoregional Control (LRC)	Proportion of all patients without disease recurrence (growth or recurrence of the primary tumor or other nearby structures within the same anatomical region or nearby regional lymph nodes) at 2 years from the initiation of study treatment.	At 2 years
2-year Event-free Survival (EFS): SDF+ intermediate risk	Proportion of patients without disease recurrence (growth or recurrence of the primary tumor and nearby regional lymph nodes or other nearby structures within the same anatomical region), progression, or death from any cause in SDF+ intermediate risk patients at 2 years from the initiation of study treatment.	At 2 years
2-year Event-free Survival (EFS): SDF- intermediate risk	Proportion of patients without disease recurrence (growth or recurrence of the primary tumor and nearby regional lymph nodes or other nearby structures within the same anatomical region), progression, or death from any cause in SDF- intermediate risk patients at 2 years from the initiation of study treatment.	At 2 year
2-year Event-free Survival (EFS)	Proportion of all patients without disease recurrence (growth or recurrence of the primary tumor and nearby regional lymph nodes or other nearby structures within the same anatomical region), progression, or death from any cause at 2 years from the initiation of study treatment.	At 2 years
2-year Overall Survival (OS): SDF+ intermediate risk	Proportion of SDF+ intermediate risk patients alive at 2 years from the initiation of study treatment.	At 2 years
2-year Overall Survival (OS): SDF- intermediate risk	Proportion of SDF- intermediate risk patients alive at 2 years from the initiation of study treatment.	At 2 years
2-year Overall Survival (OS)	Proportion of all patients alive at 2 years from the initiation of study treatment.	At 2 year
Incidence of Grade ≥ 3 Treatment-related Adverse Events (AE)	Number of (distinct) HNSCC patients with grade ≥ 3 Treatment-related Adverse Events (AE)s per CTCAE v5.0.	up to 30 days post-treatment

Collaborators and Investigators

• Sponsor: Kevin Contrera
• Collaborators: Droplet Biosciences, Inc.
• Investigators: Principal Investigator: Kevin J Contrera, MD, UPMC Cancer Center Hillman

Study record dates

Study Major Dates

• Study Start (Estimated): November 15, 2026
• Primary Completion (Estimated): November 15, 2028
• Study Completion (Estimated): November 15, 2030

Study Registration Dates

• First Submitted: October 27, 2026
• First Submitted That Met QC Criteria: October 27, 2026
• First Posted (Actual): November 12, 2026

Study Record Updates

• Last Update Posted (Actual): November 12, 2026
• Last Update Submitted That Met QC Criteria: October 27, 2026
• Last Verified: October 1, 2026

More Information

Terms related to this study

• Keywords: tumor-informed plasma-based ctDNA assay; circulating Tumor DNA (ctDNA); molecular residual disease (MRD)
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Head and Neck Neoplasms; Organic Chemicals; Therapeutics; Inorganic Chemicals; Chlorine Compounds; Nitrogen Compounds; Coordination Complexes; Platinum Compounds; Radiotherapy; Radiotherapy, Conformal; Radiotherapy, Computer-Assisted; Carboplatin; Cisplatin; pembrolizumab; Radiotherapy, Intensity-Modulated
• Other Study ID Numbers: HCC 26-056

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No