Decitabine plus standard surgery, radiation, and chemotherapy for HPV-negative operable head and neck cancer

Phase I Decitabine Dose-Tolerance in Surgically Resectable HPV-Negative Head and Neck Cancer

This trial will test whether adding decitabine to standard surgery and radiation/chemotherapy helps people with HPV-negative head and neck cancers that can be removed by surgery.

Quick facts

• Phase: PHASE1
• Study type: Interventional
• Enrollment: 24 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Mayo Clinic (other)
• Drugs / interventions: chemotherapy, radiation
• Locations: 1 site (Jacksonville, Florida)
• Trial ID: NCT06997094 on ClinicalTrials.gov

What this trial studies

This Phase 1, dose-escalation and expansion trial gives short courses of intravenous decitabine before surgery and again during adjuvant radiation (with or without chemotherapy) to find a safe dose and schedule. The primary goal is to determine the maximum tolerated dose of decitabine when combined with standard-of-care surgical and post-operative treatments. Secondary endpoints include early and late toxicities, event-free survival, overall survival, and quality of life, with analyses stratified by tumor methylation status. Correlative work includes measuring in vivo methylation changes, decitabine pharmacokinetics, and exploratory circulating biomarkers.

Who should consider this trial

Good fit: Adults with HPV-negative, surgically resectable head and neck squamous cell carcinoma with measurable disease who are candidates for surgery and post-operative radiation (with or without chemotherapy) are best suited for this protocol.

Not a fit: Patients with HPV-positive tumors, distant metastases, unresectable disease, or who are not fit for surgery or radiotherapy are unlikely to benefit from this approach.

Why it matters

Potential benefit: If successful, adding decitabine could make tumors more sensitive to chemotherapy and radiation, potentially slowing progression and improving survival.

How similar studies have performed: Demethylating agents like decitabine have proven activity in blood cancers and preclinical and early clinical data suggest they may sensitize some solid tumors to chemo and radiation, but this specific combination in resectable HPV-negative head and neck cancer remains early-phase and not yet established.

Eligibility criteria

Inclusion Criteria:

* REGISTRATION: Age ≥ 18 years
* REGISTRATION: 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 REGISTRATION: 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
* REGISTRATION: Absence of distant metastases on standard diagnostic work-up ≤ 16 weeks prior to registration. (chest computed tomography \[CT\] or positron emission tomography \[PET\]/CT)
* REGISTRATION: 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
* REGISTRATION: Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
* REGISTRATION: Hemoglobin ≤ 9.0 g/dL (obtained ≤ 14 days prior to registration)
* REGISTRATION: Absolute neutrophil count (ANC) ≥ 1500/mm\^3 (obtained ≤ 14 days prior to registration)
* REGISTRATION: Platelet count ≥ 100,000/mm\^3 (obtained ≤ 14 days prior to registration)
* REGISTRATION: Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (obtained ≤ 14 days prior to registration)
* 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)
* 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
* REGISTRATION: Provide written informed consent
* REGISTRATION: Ability to complete questionnaire(s) by themselves or with assistance
* REGISTRATION: Willingness to provide mandatory blood specimens for correlative research
* REGISTRATION: Willingness to provide mandatory tissue specimens for correlative research
* REGISTRATION: Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)
* RE-REGISTRATION FOR ADJUVANT DOSE ASSIGNMENT: Patient received pre-operative decitabine dose
* RE-REGISTRATION FOR ADJUVANT DOSE ASSIGNMENT: The patient had study-specific surgery
* RE-REGISTRATION FOR ADJUVANT DOSE ASSIGNMENT: Patient meets adjuvant radiation criteria based on investigator choice

Exclusion Criteria:

* REGISTRATION: Any of the following:

  * Pregnant women
  * Nursing women
  * Men or women who are of childbearing potential who are unwilling to employ adequate contraception
* REGISTRATION: 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
* REGISTRATION: 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
* REGISTRATION: 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
* REGISTRATION: 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
* REGISTRATION: Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm
* REGISTRATION: 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
* REGISTRATION: History of myocardial infarction ≤ 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
* REGISTRATION: Prior history of radiation therapy to the affected site
* REGISTRATION: Prior systemic chemotherapy ≤ 5 years prior to registration for other diagnosis not related to study disease
* REGISTRATION: Contraindication to radiation therapy as determined by the treating team
* REGISTRATION: Contraindication to decitabine as determined by the treating team
* RE-REGISTRATION FOR ADJUVANT DOSE ASSIGNMENT: Experienced a dose limiting toxicity (DLT) during pre-operative decitabine therapy

Where this trial is running

Jacksonville, Florida

• Mayo Clinic in Florida — Jacksonville, Florida, United States (RECRUITING)

Study contacts

• Principal investigator: Adam L. Holtzman, MD — Mayo Clinic
• Study coordinator: Clinical Trials Referral Office

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