5-Fluorouracil Response and Optimization STudy (The FROST Trial)

The 5-Fluorouracil Response and Optimization STudy (The FROST Trial): A Randomized Phase II Trial of Two Dosage Regimens (2D-Q2W vs 4D-Q3W) of 5-Fluorouracil (5-FU) in Patients With Platinum and PD-1 Inhibitor Pre-treated Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

This randomized phase II trial will characterize the efficacy, adverse event (AE) profile, and safety of two regimens of 5-FU given as 2L+ treatment to patients with RM-HNSCC. Eligible patients for this trial will have previously received platinum and PD-1 inhibitor therapy. The experimental regimen (Arm 1) will comprise the two days every two weeks (2D-Q2W) regimen of 5-FU. The standard regimen (Arm 2) will consist of the four days every three weeks (4D-Q3W) regimen of 5-FU. The primary hypotheses is that each regimen of 5-FU will result in an ORR of 10% of greater assessed by RECIST v1.1 criteria. The study will also describe treatment-related AEs assessed by CTCAE v5.0, dose interruptions, discontinuations, and modifications in each regimen.

Study Overview

• Status: Recruiting
• Conditions: Squamous Cell Carcinoma of Head and Neck; Recurrent Squamous Cell Carcinoma of the Head and Neck; Metastatic Squamous Cell Carcinoma
• Intervention / Treatment: Drug: 5-Fluorouracil

• Study Type: Interventional
• Enrollment (Estimated): 46
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Christine Auberle, MD; Phone Number: 314-747-1459; Email: auberlec@wustl.edu

Study Locations

• United States
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Recruiting
      • Washington University School of Medicine
      • Sub-Investigator: Peter Oppelt, MD
      • Sub-Investigator: Esther Lu, PhD
      • Contact: Christine Auberle, MD; Phone Number: 314-747-1459; Email: auberlec@wustl.edu
      • Principal Investigator: Christine Auberle, MD
      • Sub-Investigator: Douglas Adkins, MD
      • Sub-Investigator: Brendan Knapp, MD
      • Sub-Investigator: Jesse Zaretsky, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Histologically or cytologically confirmed:

  • RM-HNSCC of the oral cavity, oropharynx, larynx, or hypopharynx, OR
  • p16+ (HPV-related) level 2-3 neck node and unknown primary site, OR
  • Second primary HNSCC in a previously radiated field not amenable to curative-intent surgery and/or re-radiation.
• Measurable disease per RECIST 1.1.
• Previously treated with platinum-based chemotherapy, RM disease within 6 months of definitive cisplatin + radiation therapy (DCisRT) or post-operative adjuvant cisplatin + radiation therapy (POACisRT) OR progressive disease on or after or intolerance to platinum agent given for RM disease.
• Previously treated with PD-1 inhibitor, RM disease within 6 months of PD-1 inhibitor given as part of curative-intent therapy OR progressive disease on or after PD-1 inhibitor given for RM disease OR intolerance to prior PD-1 inhibitor in the curative or metastatic setting.
• At least 18 years of age
• ECOG performance status ≤ 2

• Adequate bone marrow and organ function as defined below:

  • Absolute neutrophil count ≥ 1.0 K/cumm
  • Platelets ≥ 100 K/cumm
  • Hemoglobin ≥ 8.0 g/dL
  • Total bilirubin ≤ 1.5 x IULN (for subjects with Gilbert's disease ≤ 3 x IULN)
  • AST(SGOT)/ALT(SGPT)/Alkaline Phosphatase (ALP) ≤ 3.0 x IULN. For subjects with documented bone metastasis, ALP ≤ 5.0 x IULN.
  • Serum creatinine <3 mg/dL or creatinine clearance > 30 mL/min by Cockcroft- Gault.
• The effects of 5-FU on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 30 days after last dose of 5-FU
• Recovery to baseline or ≤ grade 1 from AEs due to prior therapy, unless AEs are clinically nonsignificant and/or stable on supportive therapy (e.g., physiological replacement of corticosteroid). Low-grade or controlled toxicities such as alopecia, ≤ grade 2 hypomagnesemia, or ≤ grade 2 neuropathy are permitted.
• Ability to understand and willingness to sign an IRB approved written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.

Exclusion Criteria:

• Prior 5-FU given to treat RM-HNSCC.
• Prior or concurrent malignancy whose natural history has the potential to interfere with the safety or efficacy assessment of the investigational regimen. Patients with prior or concurrent malignancy that does NOT meet that definition are eligible for this trial.
• Currently receiving any other investigational agents.
• RM or incurable second primary SCC of cutaneous, nasopharynx, paranasal/nasal/sinus origin.
• DPYD deficiency (poor or intermediate metabolizer) as determined by next generation sequencing through blood or saliva (results of historical testing are accepted).
• Severe hepatic impairment (Child-Pugh C) or history of hepatitis B or C.
• Patients with untreated brain metastases. Patients with treated brain metastases are allowed if post-treatment brain-imaging after CNS-directed therapy shows no evidence of progression.
• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to 5-FU or other agents used in the study.
• Pregnant and/or breastfeeding. Women of childbearing potential must have a negative urine pregnancy test within 14 days of study registration.
• HIV-infected if not on effective anti-retroviral therapy with undetectable viral load for 6 months. Patients with HIV who are receiving effective anti-retroviral therapy and have had an undetectable viral load for at least 6 months are eligible. HIV testing not required in the absence of known history of infection.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1: 5-Fluorouracil (5-FU) 2D-Q2W; Patients randomized to Arm 1 will receive 5-FU as a 400mg/m2 bolus followed by 2,400 mg/m2 continuous intravenous infusion (CIVI) over a 46 hour time period every 2 weeks on Day 1-2 and Days 15-16. Each cycle is 28 days.	Drug: 5-Fluorouracil; Dose modifications or reductions are determined by patient's tolerability to the drug.; Other Names: 5-FU; Adrucil
Active Comparator: Arm 2: 5-Fluorouracil (5-FU) 4D-Q3W; Patients randomized to Arm 2 will receive 5-FU as a 1000g/m2/day continuous intravenous infusion (CIVI) over 4 days every 3 weeks on Day 1-4. Each cycle is 21 days.	Drug: 5-Fluorouracil; Dose modifications or reductions are determined by patient's tolerability to the drug.; Other Names: 5-FU; Adrucil

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate (ORR)	ORR, defined as CR and PR per RECIST v1.1.; Complete Response (CR): Disappearance of all target lesions. Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis).; Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.	Start of treatment through completion of treatment (estimated time up to 4 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of patients requiring a dose reduction due to treatment related adverse events (TRAEs)		Start of treatment through completion of treatment (estimated time up to 4 months)
Incidence of patients requiring a dose interruption or delay due to treatment related adverse events (TRAEs)		Start of treatment through completion of treatment (estimated time up to 4 months)
Incidence of patients requiring treatment discontinuation due to treatment related adverse events (TRAEs)		Start of treatment through completion of treatment (estimated time up to 4 months)
Daily dose intensity	Daily dose intensity will be measured as the average daily dose/m2 of 5-FU administered in the treatment interval for each regimen (Days 1-2 and Days 15-16 for Arm 1 and Days 1-4 for Arm 2).	Start of treatment through completion of treatment (estimated time up to 4 months)
Overall Adverse Events (AEs) by grade (3, 4, and 5) and type	Adverse events are classified and graded by CTCAE v5.0.	Start of treatment to 28 days after completion of treatment (estimated time up to 5 months)
Number of adverse events of specific interest (AESI)	Adverse events of special interest are as follows: diarrhea, mucositis, palmar-plantar erythrodysesthesia (Hand-Foot Syndrome) (PPE/HRS), neutropenia, and thrombocytopenia. Adverse events are classified by CTCAE v5.0.	Start of treatment through 28 days after completion of treatment (estimated time up to 5 months)
Number of treatment-related deaths		Start of treatment through 28 days after completion of treatment (estimated time up to 5 months)
Duration of Response (DoR)	DoR is defined as the duration from the onset of first response (CR + PR) to disease progression or death for any reason; Complete Response (CR): Disappearance of all target lesions. Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis).; Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.	From time criteria is met for CR or PR through 3 years after completion of treatment (up to 3 years and 4 months)
Progression-free survival (PFS)	PFS is defined as the time from the date of treatment start to progression or death, which occurs first. The alive patients without progression are censored at the last follow-up.	Start of treatment through 3 years after completion of treatment (up to 3 years and 4 months)
Overall survival (OS)	OS is defined as the time from the start of treatment to the date of death, censored at the last follow-up otherwise.	Start of treatment through 3 years after completion of treatment (up to 3 years and 4 months)

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: The Joseph Sanchez Foundation
• Investigators: Principal Investigator: Christine Auberle, MD, Washington University School of Medicine

Publications and helpful links

Helpful Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): April 21, 2026
• Primary Completion (Estimated): July 31, 2028
• Study Completion (Estimated): July 31, 2031

Study Registration Dates

• First Submitted: February 11, 2026
• First Submitted That Met QC Criteria: February 11, 2026
• First Posted (Actual): February 19, 2026

Study Record Updates

• Last Update Posted (Actual): April 27, 2026
• Last Update Submitted That Met QC Criteria: April 21, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: HNSCC; Larynx; 5-FU; Hypopharynx; Oropharynx; Oral cavity; RM-HNSCC
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Neoplasms by Histologic Type; Head and Neck Neoplasms; Neoplasms, Glandular and Epithelial; Carcinoma; Neoplasms, Squamous Cell; Otorhinolaryngologic Diseases; Squamous Cell Carcinoma of Head and Neck; Carcinoma, Squamous Cell; Laryngeal Diseases; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines; Uracil; Pyrimidinones; Fluorouracil
• Other Study ID Numbers: 202603057

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.: Yes