P53 Mutational Status and cf HPV DNA for the Management of HPV-associated OPSCC

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate whether genomic based risk-stratification can be used in deciding whether to de-intensify in patients with Human Papillomavirus (HPV)-associated Oropharyngeal Squamous Cell Carcinoma (OPSCC) with > 10 pack years smoking history. Hypothesis: Patients with HPV-associated OPSCC, > 10 pack years smoking history, and non-mutated p53 will have similar 2 year progression-free survival (PFS) as patients with < 10 pack years smoking history.

Detailed Description
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The proposed study is a follow-up study to LCCC 1120 and 1413. The investigators have shown that de-intensification is efficacious in these two phase II studies. A major question is whether the investigators can de-intensify in patients with HPV-associated oropharyngeal cancer who have smoking histories. The investigators' hypothesis is that genomic profiling of patients' tumors (specifically for p53 mutations) will help in triaging patients to de-intensification versus standard of care. Patients with HPV-associated OPSCC will be enrolled regardless of smoking history and p53 mutational status will be assessed in patients with a smoking history. The investigators will use the same de-intensification chemoradiotherapy regimen already evaluated in LCCC 1120 and 1413 in patients with HPV-associated OPSCC who have a minimal smoking history and in patients with a smoking history but with wild-type p53. Patients with a smoking history who have mutated p53 will not receive de-intensified chemoradiotherapy, but instead will receive standard doses. The hypothesis is that by using genomics in the patients with a significant smoking history, the investigators will better select those who can be safely de-intensified. Circulating free HPV DNA (cf-HPV-DNA) will also be prospectively assessed from blood samples.

Official Title
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LCCC 1612: P53 Mutational Status and Circulating Free HPV DNA for the Management of HPV-associated Oropharyngeal Squamous Cell Cancers

Conditions
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Carcinoma, Squamous Cell, Head and Neck Neoplasms, Oropharyngeal Neoplasms

Intervention / Treatment
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* Radiation: Intensity Modulated Radiotherapy (IMRT) - deintensified
* Radiation: Intensity Modulated Radiotherapy (IMRT) - standard
* Drug: Cisplatin (or alternative) - deintensified
* Drug: Cisplatin (or alternative) - standard
* Procedure: Assessment for surgical evaluation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥ 18 years of age (no upper age limit) T0-3, N0 to N2c, M0 squamous cell carcinoma of the oropharynx Biopsy proven squamous cell carcinoma that is HPV and/or p16 positive Radiologic confirmation of the absence of hematogenous metastasis within 12 weeks prior to treatment ECOG Performance Status 0-1 CBC/differential obtained within 8 weeks prior to treatment, with adequate bone marrow function defined as follows: Platelets ≥ 100,000 cells/mm3; Hemoglobin ≥ 8.0 g/dl Adequate renal and hepatic function within 4 weeks prior to treatment, defined as follows: Serum creatinine < 2.0 mg/dl; Total bilirubin < 2 x the institutional ULN; AST or ALT < 3 x the institutional ULN Negative pregnancy test within 2 weeks prior to treatment for women of childbearing potential Women of childbearing potential and male participants who are sexually active must practice adequate contraception during treatment and for 6 weeks following treatment. Patients must be deemed able to comply with the treatment plan and follow-up schedule. Patients must provide study specific informed consent prior to study entry Exclusion Criteria: Prior history of radiation therapy to the head and neck Prior history of head and neck cancer. Unresectable disease (e.g. immobile node on physical exam, nodal disease that radiographically involves the carotid arteries, nerves) Currently taking Disease Modifying Rheumatoid Drugs (DMRDs) Severe, active co-morbidity, defined as follows: Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months; Transmural myocardial infarction within the last 6 months; Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration; Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration; Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects (Note, however, coagulation parameters are not required for entry into this protocol); Pre-existing ≥ grade 2 neuropathy; Prior organ transplant; Systemic lupus; Psoriatic arthritis Known HIV positive.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ≤ 10 pack years smoking history<br> | Radiation: Intensity Modulated Radiotherapy (IMRT) - deintensified<br>* 60 Gy at 2 Gy/fx<br>Drug: Cisplatin (or alternative) - deintensified<br>* The acceptable weekly chemotherapy regimens are Cisplatin 30 to 40 mg/m2 (first choice), Cetuximab 250mg/m2 (second choice), Carboplatin AUC 1.5 and paclitaxel 45 mg/m2 (third choice), Carboplatin AUC 3 (fourth choice). Chemotherapy will be given intravenously weekly during IMRT, 6 total doses.<br>Procedure: Assessment for surgical evaluation<br>* Decision for surgical evaluation will be based on the results of the PET/CT and clinical exam 10-16 weeks after CRT. Patients with a positive PET/CT scan will undergo surgical evaluation at the discretion of the surgeon. Patients with a negative PET/CT scan will be observed.<br>|
| Experimental: > 10 py smoking history, no p53 mutation<br> | Radiation: Intensity Modulated Radiotherapy (IMRT) - deintensified<br>* 60 Gy at 2 Gy/fx<br>Drug: Cisplatin (or alternative) - deintensified<br>* The acceptable weekly chemotherapy regimens are Cisplatin 30 to 40 mg/m2 (first choice), Cetuximab 250mg/m2 (second choice), Carboplatin AUC 1.5 and paclitaxel 45 mg/m2 (third choice), Carboplatin AUC 3 (fourth choice). Chemotherapy will be given intravenously weekly during IMRT, 6 total doses.<br>Procedure: Assessment for surgical evaluation<br>* Decision for surgical evaluation will be based on the results of the PET/CT and clinical exam 10-16 weeks after CRT. Patients with a positive PET/CT scan will undergo surgical evaluation at the discretion of the surgeon. Patients with a negative PET/CT scan will be observed.<br>|
| Active Comparator: > 10 py smoking history, p53 mutation<br> | Radiation: Intensity Modulated Radiotherapy (IMRT) - standard<br>* 70 Gy at 2 Gy/fx<br>Drug: Cisplatin (or alternative) - standard<br>* The acceptable weekly chemotherapy regimens are Cisplatin 30 to 40 mg/m2 (first choice), Cetuximab 250mg/m2 (second choice), Carboplatin AUC 1.5 and paclitaxel 45 mg/m2 (third choice), Carboplatin AUC 3 (fourth choice). Chemotherapy will be given intravenously weekly during IMRT, 7 total doses.<br>Procedure: Assessment for surgical evaluation<br>* Decision for surgical evaluation will be based on the results of the PET/CT and clinical exam 10-16 weeks after CRT. Patients with a positive PET/CT scan will undergo surgical evaluation at the discretion of the surgeon. Patients with a negative PET/CT scan will be observed.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 2 year Progression Free Survival after de-intensified chemoradiation therapy (CRT) in HPV-associated OPSCC |  | Two years after completion of CRT on last enrolled patient | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in plasma circulating free HPV DNA during and after treatment as related to clinical outcomes in patients with HPV-associated OPSCC |  | Two years after completion of CRT on last enrolled patient | 
| Local control rate |  | 2 years post-CRT | 
| Regional control rate |  | 2 years post-CRT | 
| Local-regional control rate |  | 2 years post-CRT | 
| Distant metastasis free survival |  | 2 years post-CRT | 
| Overall survival rate |  | 2 years post-CRT | 
| Head and neck quality of life assessments |  | From date of study enrollment to last follow-up as long as patient continues seeing study doctor, up to 30 years | 
| Speech and swallowing function via penetration-aspiration scale (PAS) and EAT-10 survey assessments |  | From date of study enrollment to last follow-up as long as patient continues seeing study doctor, up to 30 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Human Papillomavirus, Oropharynx, Oropharyngeal Squamous Cell Carcinoma, Squamous Cell Carcinoma, Radiation Therapy, Chemotherapy, p16