Decitabine in Combination With Standard of Care Therapy for the Treatment of Surgically Resectable HPV-Negative Head and Neck Cancer

Phase 1

Not yet recruiting

• Conditions: Human Papillomavirus-Negative Neck Squamous Cell Carcinoma; Resectable Head and Neck Squamous Cell Carcinoma; Resectable Human Papillomavirus-Independent Head and Neck Mucosal Squamous Cell Carcinoma; HPV-Negative Squamous Cell Carcinoma; Resectable Head and Neck Squamous-cell Carcinoma
• Interventions: Procedure: Biospecimen Collection; Drug: Chemotherapy; Drug: Decitabine; Radiation: External Beam Radiation Therapy; Other: Questionnaire Administration; Procedure: Surgical Procedure

• Registration Number: NCT06997094
• Lead Sponsor: Mayo Clinic

Brief Summary

This phase I trial tests the safety, side effects, and best dose of decitabine in combination with standard of care surgery, radiation, and/or chemotherapy and the effectiveness of the combination in treating patients with head and neck squamous cell cancers that are not caused by human papilloma virus (HPV-negative) and that can be removed by surgery (resectable). Decitabine, an antimetabolite, stops cells from making deoxyribonucleic acid (DNA) and may kill tumor cells. Studies have shown that medications like decitabine can make some types of solid tumors more sensitive to chemotherapy. This allows the chemotherapy to be more effective, with slower progression and longer survival. Decitabine is also a clinically active demethylating agent, and may help make tumor cells more sensitive to radiation therapy. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill tumor cells and shrink tumors. External beam radiation therapy (EBRT) is a type of radiation that uses a machine to aim high-energy rays at the tumor from outside the body. Chemotherapy drugs work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving decitabine in combination with standard of care surgery, radiation and/or chemotherapy may be safe, tolerable, and/or effective in treating patients with surgically resectable HPV-negative head and neck squamous cell cancers.

Detailed Description

PRIMARY OBJECTIVE:

I. To prospectively evaluate maximum tolerated dose of decitabine with standard-of-care therapy surgery and/or radiation/chemotherapy for HPV-negative head and neck cancers.

SECONDARY OBJECTIVES:

I. 1-year overall survival. (Stratified by methylation status) II. 1-year progression free survival. (Stratified by methylation status) III. Acute/late Common Terminology Criteria for Adverse Events (CTCAE) toxicity. (Stratified by methylation status)

CORRELATIVE RESEARCH OBJECTIVES:

I. In vivo methylation response to preoperative decitabine. II. Pharmacokinetics of decitabine. III. Exploratory circulating biomarkers.

OUTLINE: This is a dose-escalation study followed by a dose-expansion study.

PREOPERATIVE PHASE: Patients receive decitabine intravenously (IV) over 1 hour once daily (QD) for 3 days and undergo standard of care surgery within 28 days of receiving decitabine.

ADJUVANT TREATMENT: Patients receive decitabine IV over 1 hour QD for 3 days every 3 weeks during radiation therapy in the absence of disease progression or unacceptable toxicity. Patients also undergo EBRT QD on 5 days per week for up to 5-35 treatments per standard of care. Patients may receive concurrent chemotherapy of choice per standard of care.

Patients also undergo blood sample collection throughout the study.

After completion of study treatment, patients are followed up at 30 days, every 4-6 months for 2 years and then every 12 months for up to 5 years.

Study Timeline

• Status Verified: 2025-05
• Study First Submitted: 2025-05-21
• Study First Submitted QC: 2025-05-21
• Last Update Submitted: 2025-05-21
• Study First Posted: 2025-05-30
• Last Update Posted: 2025-05-30
• Study Start: 2025-07-08
• Primary Completion: 2027-07-08
• Study Completion: 2027-07-08

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 24

Inclusion Criteria

• Age ≥ 18 years

• Histologic confirmation of HPV-negative, squamous cell carcinoma of the head and neck that is surgically resectable. HPV-status confirmation by p16, circulating tumor DNA or in-situ hybridization is only required for oropharyngeal primaries

  • Includes mucosal and non-mucosal subsites
  • Includes head and neck of unknown primary origin

• Measurable disease preoperatively, as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or equivalent criteria

  • NOTE: Tumor lesions in a previously irradiated area are not considered measurable disease; disease that is measurable by physical examination only is not eligible

• Absence of distant metastases on standard diagnostic work-up ≤ 16 weeks prior to registration. [Chest computed tomography (CT) or positron emission tomography (PET)/CT]

• Negative pregnancy test done ≤ 7 days prior to registration, for women of childbearing potential only

  • NOTE: If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1

• Hemoglobin ≤ 9.0 g/dL (obtained ≤ 14 days prior to registration)

• Absolute neutrophil count (ANC) ≥ 1500/mm^3 (obtained ≤ 14 days prior to registration)

• Platelet count ≥ 100,000/mm^3 (obtained ≤ 14 days prior to registration)

• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (obtained ≤ 14 days prior to registration)

• Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤ 3 x ULN (≤ 5 x ULN for patients with liver involvement) (obtained ≤ 14 days prior to registration)

• Prothrombin time (PT)/international normalized ratio (INR)/activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN (obtained ≤ 14 days prior to registration) OR if patient is receiving anticoagulant therapy and INR or aPTT is within target range of therapy

• Provide written informed consent

• Ability to complete questionnaire(s) by themselves or with assistance

• Willingness to provide mandatory blood specimens for correlative research

• Willingness to provide mandatory tissue specimens for correlative research

• Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)

Exclusion Criteria

• Any of the following:

  • Pregnant women
  • Nursing women
  • Men or women who are of childbearing potential who are unwilling to employ adequate contraception

• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens

• Immunocompromised patients and patients known to be HIV positive and currently receiving antiretroviral therapy

  • NOTE: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial

• Failure to recover from acute, reversible effects of prior therapy regardless of interval since last treatment

  • EXCEPTION: Grade 1 peripheral (sensory) neuropathy that has been stable for at least 3 months since completion of prior treatment

• Uncontrolled intercurrent illness including, but not limited to:

  • Ongoing or active infection
  • Symptomatic congestive heart failure
  • Unstable angina pectoris
  • Cardiac arrhythmia
  • Or psychiatric illness/social situations that would limit compliance with study requirements
  • Dyspnea at rest due to complications of advanced malignancy or other disease that requires continuous oxygen therapy

• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm

• Other active malignancy ≤ 5 years prior to registration

  • EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix
  • NOTE: If there is a history of prior malignancy, they must not be receiving other specific treatment for their cancer

• History of myocardial infarction ≤ 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias

• Prior history of radiation therapy to the affected site

• Prior systemic chemotherapy ≤ 5 years prior to registration for other diagnosis not related to study disease

• Contraindication to radiation therapy as determined by the treating team

• Contraindication to decitabine as determined by the treating team

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (decitabine, surgery, radiation)	Biospecimen Collection	PREOPERATIVE PHASE: Patients receive decitabine IV over 1 hour QD for 3 days and undergo standard of care surgery within 28 days of receiving decitabine. ADJUVANT TREATMENT: Patients receive decitabine IV over 1 hour QD for 3 days every 3 weeks during radiation therapy in the absence of disease progression or unacceptable toxicity. Patients also undergo EBRT QD on 5 days per week for up to 5-35 treatments per standard of care. Patients may receive concurrent chemotherapy of choice per standard of care. Patients also undergo blood sample collection throughout the study.
Treatment (decitabine, surgery, radiation)	Chemotherapy	PREOPERATIVE PHASE: Patients receive decitabine IV over 1 hour QD for 3 days and undergo standard of care surgery within 28 days of receiving decitabine. ADJUVANT TREATMENT: Patients receive decitabine IV over 1 hour QD for 3 days every 3 weeks during radiation therapy in the absence of disease progression or unacceptable toxicity. Patients also undergo EBRT QD on 5 days per week for up to 5-35 treatments per standard of care. Patients may receive concurrent chemotherapy of choice per standard of care. Patients also undergo blood sample collection throughout the study.
Treatment (decitabine, surgery, radiation)	Decitabine	PREOPERATIVE PHASE: Patients receive decitabine IV over 1 hour QD for 3 days and undergo standard of care surgery within 28 days of receiving decitabine. ADJUVANT TREATMENT: Patients receive decitabine IV over 1 hour QD for 3 days every 3 weeks during radiation therapy in the absence of disease progression or unacceptable toxicity. Patients also undergo EBRT QD on 5 days per week for up to 5-35 treatments per standard of care. Patients may receive concurrent chemotherapy of choice per standard of care. Patients also undergo blood sample collection throughout the study.
Treatment (decitabine, surgery, radiation)	External Beam Radiation Therapy	PREOPERATIVE PHASE: Patients receive decitabine IV over 1 hour QD for 3 days and undergo standard of care surgery within 28 days of receiving decitabine. ADJUVANT TREATMENT: Patients receive decitabine IV over 1 hour QD for 3 days every 3 weeks during radiation therapy in the absence of disease progression or unacceptable toxicity. Patients also undergo EBRT QD on 5 days per week for up to 5-35 treatments per standard of care. Patients may receive concurrent chemotherapy of choice per standard of care. Patients also undergo blood sample collection throughout the study.
Treatment (decitabine, surgery, radiation)	Questionnaire Administration	PREOPERATIVE PHASE: Patients receive decitabine IV over 1 hour QD for 3 days and undergo standard of care surgery within 28 days of receiving decitabine. ADJUVANT TREATMENT: Patients receive decitabine IV over 1 hour QD for 3 days every 3 weeks during radiation therapy in the absence of disease progression or unacceptable toxicity. Patients also undergo EBRT QD on 5 days per week for up to 5-35 treatments per standard of care. Patients may receive concurrent chemotherapy of choice per standard of care. Patients also undergo blood sample collection throughout the study.
Treatment (decitabine, surgery, radiation)	Surgical Procedure	PREOPERATIVE PHASE: Patients receive decitabine IV over 1 hour QD for 3 days and undergo standard of care surgery within 28 days of receiving decitabine. ADJUVANT TREATMENT: Patients receive decitabine IV over 1 hour QD for 3 days every 3 weeks during radiation therapy in the absence of disease progression or unacceptable toxicity. Patients also undergo EBRT QD on 5 days per week for up to 5-35 treatments per standard of care. Patients may receive concurrent chemotherapy of choice per standard of care. Patients also undergo blood sample collection throughout the study.

Primary Outcome Measures

Name	Time	Method
Maximum tolerated dose (MTD) of decitabine with standard-of-care therapy surgery and/or radiation/chemotherapy for human papillomavirus negative head and neck cancers	From initiation of decitabine up to 28-30 days after each infusion	MTD will be selected based on the rate of grade 4 toxicity and correlative methylation response data.

Secondary Outcome Measures

Name	Time	Method
Overall survival	Up to 1 year	Defined as the time from study enrollment until death from any cause
Incidence of early onset (acute) adverse events	Up to 90 days post radiation therapy	Defined as toxicities which begin during the start of adjuvant therapy upwards to 90 days post radiation therapy. Will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Incidence of acute and late adverse events	Up to 2 years post radiation therapy	Defined as toxicities which begin from 91 days to two years post radiation therapy. Early onset toxicities can also be considered late toxicities if they persist for at least one day beyond the 90 days used to define late onset toxicities. Will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Progression-free survival	Up to 1 year	Defined as the time from study enrollment to disease progression or death from any cause

Trial Locations

Locations (1)

Mayo Clinic in Florida; 🇺🇸 Jacksonville, Florida, United States