HPV-Negative Squamous Cell Carcinoma, Human Papillomavirus-Negative Neck Squamous Cell Carcinoma, Resectable Head and Neck Squamous-cell Carcinoma, Resectable Head and Neck Squamous Cell Carcinoma, Resectable Human Papillomavirus-Independent Head and Neck Mucosal Squamous Cell Carcinoma
Conditions
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 the maximum tolerated dose (MTD) of decitabine, in both the preoperative and adjuvant phases of treatment, combined with standard-of-care therapy including surgery +/- chemoradiation for HPV-negative head and neck cancers. SECONDARY OBJECTIVES: I. Evaluation of acute (early onset) toxicities. (Stratified by methylation status) II. Evaluation of late onset toxicities. (Stratified by methylation status) III. Evaluation of event-free survival (EFS). (Stratified by methylation status) IV. Evaluation of overall survival (OS). (Stratified by methylation status) V. Evaluation of quality of life (QOL). (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.
Interventions
PROCEDUREBiospecimen Collection
Undergo blood sample collection
DRUGChemotherapy
Given concurrent chemotherapy
DRUGDecitabine
Given IV
RADIATIONExternal Beam Radiation Therapy
Undergo EBRT
OTHERQuestionnaire Administration
Ancillary studies
PROCEDURESurgical Procedure
Undergo standard of care surgery
Sponsors
Mayo Clinic
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum tolerated dose (MTD) of preoperative decitabine | From first dose of preoperative decitabine to the first dose of adjuvant decitabine | MTD will be selected based on the rate of grade 4 toxicity and correlative methylation response data. |
| MTD of adjuvant decitabine | From first dose of adjuvant decitabine to 28 days after the end of treatment | MTD will be selected based on the rate of grade 4 toxicity and correlative methylation response data. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of acute (early onset) adverse events | Up to 90 days | Defined as toxicities which begin during the start of adjuvant therapy until 90 days post end of treatment. Will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The maximum grade for each type of acute AE will be recorded for each patient. |
| Incidence of late onset adverse events | From 91 days to 2 years | 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. The maximum grade for each type of acute AE will be recorded for each patient. |
| Event-free survival | 1 year, 2 years, 5 years | Defined as the interval from registration to last follow-up without an event, defined to include 1) recurrence of disease, 2) progression of disease, or 3) death. |
| Overall survival | 1 year, 2 years, 5 years | Defined as the interval from registration to last follow-up or death from any cause. |
| Quality of Life - EORTC QLQ-H&N35 | Baseline, at end of treatment, every 4-6 months post end of treatment for up to 2 years | Assessed using the EORTC (European Organization for Research and Treatment of Cancer) QLQ (Quality of Life) - Head \& Neck 35 (H\&N35) inventory, a 35-item questionnaire that assesses symptoms encountered specifically by patients with head and neck cancer. This measure generates 7 multiple-item scales (Pain, Swallowing, Senses, Speech, Social eating, Social contact, and Sexuality), in addition to 11 single items (e.g., opening mouth, sticky saliva, dry mouth). Scales range in score from 0 to 100. A high score for a functional scale represents a high/healthy level of functioning whereas a high score for a symptom scale or item represents a high level of symptomatology or problems. |
Countries
United States
Contacts
CONTACTClinical Trials Referral Office
PRINCIPAL_INVESTIGATORAdam L. Holtzman, MD
Mayo Clinic
Outcome results
None listed