Response-Adaptive Chemoradiation after Induction Therapy for the Treatment of Patients with Locally Advanced Head and Neck Squamous Cell Cancer

Status: active

This phase II trial evaluates whether response-adaptive chemoradiation therapy after induction therapy (paclitaxel, carboplatin, cetuximab) is safe and effective in treating patients with human papillomavirus negative head and neck squamous cell cancer that has spread to nearby tissue or lymph nodes (locally advanced). Paclitaxel is in a class of medications called antimicrotubule agents. It stops cancer cells from growing and dividing and may kill them. Carboplatin is in a class of medications known as platinum-containing compounds. It works in a way similar to the anticancer drug cisplatin, but may be better tolerated than cisplatin. Carboplatin works by killing, stopping or slowing the growth of cancer cells. Cetuximab is in a class of medications called monoclonal antibodies. It binds to a protein called EGFR, which is found on some types of cancer cells. This may help keep cancer cells from growing. In this study, imaging scans are used to assess a patient's response to induction therapy and assign them to a response-adaptive chemoradiation regimen with standard fractionated radiation or de-escalated hyperfractionated radiation and chemotherapy (cisplatin or paclitaxel, fluorouracil, and hydroxyurea). Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. Hyperfractionated radiation therapy delivers smaller doses of radiation therapy over time and may kill more tumor cells and have fewer side effects. Cisplatin is in a class of medications known as platinum-containing compounds. It works by killing, stopping or slowing the growth of cancer cells. Chemotherapy drugs, such as fluorouracil and hydroxyurea, 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. Response-adaptive chemoradiation therapy after induction may be effective at treating patients with locally advanced head and neck squamous cell cancer while reducing the amount of radiation and/or chemotherapy a patient receives.

Inclusion Criteria

Patients must have pathologically confirmed locally advanced, non-metastatic, head and neck squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, nasopharynx, larynx, or sinuses. Pathological P16/HPV testing to confirm HPV negative disease is required for oropharyngeal subtypes
Stage III or IV disease based on American Joint Committee on Cancer (AJCC) staging 8th edition
If a primary oropharyngeal squamous cell carcinoma is diagnosed, HPV must be ruled out by immunohistochemistry
Patients must be at least 18 years of age
Measurable disease (either primary site and/or nodal disease) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
No previous radiation or chemotherapy for a head and neck cancer
No complete surgical resection for a head and neck cancer within 8 weeks of enrollment (although lymph node biopsy including excision of an individual node with presence of residual nodal disease, or surgical biopsy/excision of the tumor with residual measurable disease is acceptable.) No surgical procedures or core-needle or excisional biopsies will occur after baseline scans are performed and measurable lesions are identified. Fine-needle aspiration can be performed (i.e. to confirm extent of baseline lymph node involvement) following discussion with principal investigator (PI) if not performed on a target lesion
Eastern Cooperative Oncology Group (ECOG) performance status 0-1
Leukocytes ≥ 3000/mm^3
Platelets ≥ 100,000/mm^3
Absolute neutrophil count ≥ 1,500
Hemoglobin ≥ 9.0 gm/dL
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x upper limit of normal
Alkaline phosphatase ≤ 2.5 x upper limit of normal
Albumin > 2.9 gm/dL
Total bilirubin ≤ 1.5 mg/dL
Creatinine clearance > 45 mL/min, normal within 2 weeks prior to start of treatment (Of note, the standard Cockcroft and Gault formula must be used to calculate creatinine clearance [CrCl] for enrollment or dosing)
Patients must sign a study-specific informed consent form prior to study entry. Patients should have the ability to understand and the willingness to sign a written informed consent document
Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 24 hours prior to the start of study drug
Women must not be breastfeeding
Women of childbearing potential must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s) plus 5 months after completing chemoradiation or receiving the last dose of chemoradiation, whichever occurs latest
Men who are sexually active with women of childbearing potential must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s) plus 5 months after completing chemoradiation or receiving the last dose of chemoradiation, whichever occurs latest

Exclusion Criteria

Unequivocal demonstration of distant metastatic disease (M1 disease)
Unidentifiable primary site
Intercurrent medical illnesses which would impair patient tolerance to therapy or limit survival. This includes but is not limited to ongoing or active infection, immunodeficiency, symptomatic congestive heart failure, pulmonary dysfunction, cardiomyopathy, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance. Patients with clinically stable and/or chronically managed medical illnesses that are not symptomatic and/or are not expected to impact treatment on protocol are still eligible (conditions to be reviewed by the PI to confirm eligibility)
Prior surgical therapy other than incisional/excisional biopsy or organ-sparing procedures such as debulking of airway-compromising tumors. Residual measurable tumor is required for enrollment as discussed above
Patients receiving other investigational agents
Diagnosis of immunodeficiency or is receiving systemic steroid therapy in excess of physiologic dose or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
Known history of active tuberculosis (Bacillus Tuberculosis infection)
Hypersensitivity to cetuximab or any other drug used in this protocol
Prior systemic anti-cancer treatment within the last 8 weeks
Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer or any tumors that are not likely to influence life expectancy in the subsequent 3 years without active treatment
Has a history of HIV
Has known active hepatitis B or hepatitis C. If eradicated, patient is eligible
Has received a live vaccine within 28 days of planned start of study therapy

PRIMARY OBJECTIVES:

I. To assess feasibility of measuring serial quantitative circulating tumor deoxyribonucleic acid (DNA) (ctDNA) in patients undergoing induction therapy followed by response adaptive treatment for locoregionally advanced (LA) human papillomavirus (HPV) negative (-) head and neck squamous cell carcinoma (HNSCC).

II. To assess the correlation between ctDNA clearance and volumetric radiographic response following induction therapy in LA HPV(-) HNSCC.

SECONDARY OBJECTIVES:

I. Assess toxicity and tolerability in patients undergoing induction therapy followed by response adaptive treatment for LA HPV(-) HNSCC.

II. Assess progression free survival, overall survival, locoregional control, and distant control of HPV(-) LA HNSCC receiving treatment with induction chemotherapy followed by risk and response-stratified de-escalated therapy.

EXPLORATORY OBJECTIVES:

I. Assess correlation of serial plasma ctDNA during response-adaptive chemoradiotherapy and following treatment during surveillance with volumetric radiographic tumor burden.

II. Assess long-term/late toxicities including enteral tube dependence between standard dose and de-escalated chemoradiotherapy (CRT).

III. Evaluate quality of life and late toxicity in patients who receive dose-reduced chemoradiotherapy after a deep response to induction therapy.

IV. Correlate plasma ctDNA with sputum ctDNA in patients with LA HPV(-) HNSCC receiving treatment with induction therapy followed by response-adaptive treatment for HPV(-) HNSCC.

OUTLINE:

INDUCTION: Patients receive paclitaxel intravenously (IV) on days 1, 8, and 15 of each cycle, carboplatin IV on day 1 of each cycle, and cetuximab IV on days 1, 8, and 15 of each cycle. Treatment repeats every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients with oral cavity cancer and stable disease, partial response, or complete response after induction may undergo surgical resection. Patients undergo computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and/or PET/CT at screening and during week 9 for response stratification. Patients also undergo collection of blood samples at screening and during induction and may undergo biopsy at screening.

RESPONSE STRATIFIED GROUPING: Patients with < 50% reduction in the sum of diameters of target lesions are assigned at the discretion of the treating physician to Arm I or Arm II. Patients with >= 50% reduction in the sum of diameters of target lesions are assigned at the discretion of the treating physician to Arm III or Arm IV. Patients with progressive disease are assigned to Arm V or Arm VI.

ARM I: Patients undergo standard fractionated image-guided radiation therapy (IGRT) once daily (QD) Monday through Friday for 7 weeks (or 6-6.5 weeks for patients with resected disease) and receive concurrent cisplatin IV over 1-2 hours once weekly (QW) for 7 weeks (or 6 weeks in patients with resected disease). Patients also undergo collection of blood samples during CRT and follow up and undergo CT, MRI, PET, and/or PET/CT during follow up.

ARM II: Patients undergo standard fractionated IGRT twice daily (BID) Monday through Friday every other week for 10 weeks. Patients receive paclitaxel IV over 60 minutes on day 1 of each cycle, fluorouracil (5-FU) IV over 120 hours (days 1-5), and hydroxyurea orally (PO) every 12 hours for 6 days (days 0-6). Cycles repeat every 14 days until the completion of standard fractionated IGRT (up to 5 cycles or 10 weeks). Patients also undergo collection of blood samples during CRT and follow up and undergo CT, MRI, PET, and/or PET/CT during follow up.

ARM III: Patients undergo de-escalated hyperfractionated IGRT QD Monday through Friday for 6.5 weeks (or 5-6 weeks in patients with resected disease) and receive concurrent cisplatin IV over 1-2 hours QW for 7 weeks (or 5-6 weeks in patients with resected disease). Patients also undergo collection of blood samples during CRT and follow up and undergo CT, MRI, PET, and/or PET/CT during follow up.

ARM IV: Patients undergo de-escalated hyperfractionated IGRT BID Monday through Friday every other week for 8-9 weeks. Patients receive paclitaxel IV over 60 minutes on day 1 of each cycle, 5-FU IV over 120 hours (days 1-5), and hydroxyurea PO every 12 hours for 6 days (days 0-6). Cycles repeat every 14 days until the completion of de-escalated hyperfractionated IGRT (up to 4.5 cycles or 8-9 weeks). Patients also undergo collection of blood samples during CRT and follow up and undergo CT, MRI, PET, and/or PET/CT during follow up.

ARM V: Patients undergo standard fractionated IGRT for 7 weeks and receive concurrent cisplatin IV over 1-2 hours QW for 7 weeks. Patients also undergo collection of blood samples during CRT and follow up and undergo CT, MRI, PET, and/or PET/CT during follow up.

ARM VI: Patients undergo standard fractionated IGRT BID every other week. Patients receive paclitaxel IV over 60 minutes on day 1 of each cycle, 5-FU IV over 120 hours (days 1-5), and hydroxyurea PO every 12 hours for 6 days (days 0-6). Cycles repeat every 14 days for up to 5 cycles. Patients also undergo collection of blood samples during CRT and follow up and undergo CT, MRI, PET, and/or PET/CT during follow up.

After completion of study treatment, patients are followed up in weeks 4 and 12, then every 3 months in year 1, every 6 months in years 2 and 3, and yearly in years 4 and 5.

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Response-Adaptive Chemoradiation after Induction Therapy for the Treatment of Patients with Locally Advanced Head and Neck Squamous Cell Cancer

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Response-Adaptive Chemoradiation after Induction Therapy for the Treatment of Patients with Locally Advanced Head and Neck Squamous Cell Cancer

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