Adjuvant De-Escalated Radiation + Adjuvant Nivolumab for Intermediate-High Risk P16+ Oropharynx Cancer

Study Overview
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Brief Summary
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This clinical trial will evaluate a new combination of treatments for Oropharyngeal Squamous Cell cancers (OPSCC), and compare it to the current standard of care (concurrent, platinum-based chemoradiotherapy). Chemoradiotherapy is efficacious, but also associated with significant toxicities and is only suitable for patients with good performance status and without severe comorbidities. The purpose of this trial is to demonstrate equivalent oncologic outcome with fewer adverse effects and improved quality of life when compared to the standard of care.

Detailed Description
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This study aims to enroll 135 patients (male and female, age 18+) who are newly diagnosed with resectable, squamous cell carcinoma or undifferentiated carcinoma of the oropharynx. Survival rate and treatment response of OPSCC varies based on HPV infection status and genotype; therefore, in this study, only patients who are HPV seropositive and have HPV type 16 will be enrolled. All patients will receive the same treatment, i.e. there is no active control group. In this trial, patients will undergo transoral surgery followed by de-intensified adjuvant radiotherapy plus nivolumab. The radiotherapy will consist of 45 or 50 Gy (depending on tumor volume) in 25 daily fractions, 6 fractions per week. Nivolumab will be administered at a fixed dose of 240 mg over 30 minutes IV every 2 weeks during radiotherapy, and at 480 mg over 60 minutes IV every 4 weeks for 6 doses after radiotherapy. The first dose will be given prior to the first fraction of radiation (Day 1) on Day -3 (+/- 2 days), and continued every 2 weeks (+/- 2 days). Nivolumab will thus be given in weeks 2 and 4 of radiotherapy. Adjuvant nivolumab will then be given for a total of 6 additional doses after the completion of radiotherapy every 4 weeks (+/- 7 days), starting in the second or third week after the completion of radiotherapy. Doses of nivolumab may be interrupted, delayed, or discontinued depending on how well the subject tolerates the treatment. Relevant outcome measures include disease free survival (2 year post surgery); percutaneous gastronomy dependence (1-year postsurgery); acute and late toxicity; patient-reported Quality of Life measures, locoregional control and distant metastatic control.

Official Title
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Phase II Trial of Adjuvant De-Escalated Radiation + Concurrent and Adjuvant Nivolumab for Intermediate-High Risk P16+ Oropharynx Cancer

Conditions
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Carcinoma, Squamous Cell of Head and Neck, Oropharynx Squamous Cell Carcinoma

Intervention / Treatment
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* Drug: Nivolumab Injection
* Radiation: Radiotherapy (RT)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >/= 18 years. ECOG performance status of 0 or 1. Patients must have newly diagnosed, histologically or cytologically confirmed squamous cell carcinoma or undifferentiated carcinoma of the oropharynx. Patients must have been determined to have resectable oropharyngeal disease. Patients with primary tumor or nodal metastasis fixed to the carotid artery, skull base or cervical spine are not eligible. Patients must have intermediate risk factors, as described below as determined by imaging studies (performed < 45 days prior to registration) and complete neck exam, from the skull base to the clavicles. The following imaging is required: CT scan of neck only with IV contrast or MRI. PET scan of HN and chest with IV contrasted CT correlation is encouraged prior to enrollment. Intermediate risk features: Tobacco <10 pk-yr: T0-3 plus any one of the following: >N2b (> 5 LN's +), N2c/N3, +ENE >1 mm, or + margin (if approved by surgical chair) OR Tobacco >10 pk-yr: T0-3 plus any one of the following: any N2, N3, +ENE >1 mm, or + margin (if approved by surgical chair) Patients must have no evidence of distant metastases (M0) Patients must have biopsy-proven p16+ oropharynx cancer; the histologic evidence of invasive squamous cell carcinoma may have been obtained from the primary tumor or metastatic lymph node. It is required that patients have a positive p16 IHC (as surrogate for HPV) status from either the primary tumor or metastatic lymph node. Carcinoma of the oropharynx associated with HPV as determined by p16 protein expression using immunohistochemistry (IHC) performed by a CLIA approved laboratory. No prior radiation above the clavicles. Patients with a history of a curatively treated malignancy must be disease-free for at least two years except for carcinoma in situ of cervix, differentiated thyroid cancer, melanoma in-situ (if fully resected), and/or non-melanomatous skin cancer, or clinically negligible in judgement of investigator. Patients with the following within the last 6 months prior to registration must be evaluated by a cardiologist and / or neurologist prior to entry into the study. Congestive heart failure > NYHA Class II CVA / TIA Unstable angina Myocardial infarction (with or without ST elevation) Patients must have acceptable renal and hepatic function within 4 weeks prior to registration as defined below: Absolute neutrophil count ≥1,500/mm3 Platelets ≥ 100,000/mm3 Total bilirubin ≤ the upper limit of normal (ULN) Calculated creatinine clearance must be > 60 ml/min using the Cockcroft-Gault formula: (140-age)*wt(kg)/([Cr]*72). For women the calculation should be multiplied by 0.85 Women must not be pregnant or breast-feeding. All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy. A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). Patient without intercurrent illness likely to interfere with protocol therapy. Patients must not have uncontrolled diabetes, uncontrolled infection despite antibiotics or uncontrolled hypertension within 30 days prior to registration. Exclusion Criteria: Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results. Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways. Treatment with any chemotherapy, radiation therapy, biologics for cancer, or investigational therapy within 30 days of first administration of study treatment (subjects with prior radiation, cytotoxic or investigational products < 4 weeks prior to treatment might be eligible after discussion between investigator and sponsor, if toxicities from the prior treatment have been resolved to Grade 1 (NCI CTCAE version 4). Known positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection. Subjects who test positive for HCV antibody but negative for HCV ribonucleic acid are permitted to enroll. Known history of testing positive for human immunodeficiency virus (HIV) and CD4 count < 200 or known acquired immunodeficiency syndrome (AIDS). Any Grade 4 laboratory abnormalities. History of allergy to study drug components. History of severe hypersensitivity reaction to any human monoclonal antibody. Prisoners or subjects who are involuntarily incarcerated. Subjects compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Radiotherapy (RT) + Nivolumab Injection<br>RT of 45 or 50 Gy in 25 daily fractions, 6 fractions per week. Nivolumab will be administered at 240 mg every 2 weeks during radiotherapy, and at 480 mg every 4 weeks for 6 doses after radiotherapy. | Drug: Nivolumab Injection<br>* A fully human anti-programmed death 1 (PD-1) monoclonal antibody<br>* Other names: BMS-936558;Radiation: Radiotherapy (RT)<br>* 45-50 Gy accelerated fractionation in 25 daily fractions, 6 fractions per week<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | The length of time (months) from of beginning of study treatment without local, regional or distant disease recurrence until the appearance of new metastatic lesions. | From beginning of study treatment (post surgery) up to 3-years | 
| PEG tube dependence | Presence /absence of enteral feeding tube | At 1-year post-surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Functional Assessment of Cancer Therapy - Head and Neck Cancer (FACT-H&N) Score | The FACT-H&N (version 4)17 consists of a cancer-specific questionnaire, FACT-G, in addition to 12 H&N cancer-specific items (the HN subscale). FACT-G is a 27-item measure that assesses general cancer quality of life. The FACT-G contains 4 subscales: physical, social/family, emotional, and functional well-being. Individuals are asked to indicate how true 27 statements are for them, using the past 7 days as the timeframe. Responses range from not at all (0), to very much (4) on a 5-point scale. | At 3, 6, 12 and 24 months after completion of treatment | 
| Locoregional control (LRC) | Identification of disease growth that is present within the area in which it was first located. | At 1-year and at 2-year post surgery | 
| Distant disease recurrence | Identification of disease that has spread (metastasized) to areas farther away from where it was first located. | At 1-year and at 2 year post-surgery | 
| MD Anderson Symptom Inventory for head and neck cancer (MDASI-HN) | MDASI-HN measures treatment related symptom burden in head and neck cancer patients. The 20-item MDASI measures both severity and burden of symptoms and their effect on patients' daily activities, using a numeric rating scale of 0-10. This instrument includes 13 core symptoms and 9 head and neck specific items. Higher scores indicate superior perception of function. | At 3, 6, 12 and 24 months after completion of treatment | 
| MD Anderson Dysphagia Inventory (MDADI) | The MDADI measures swallowing-related quality of life (QOL) in patients with swallowing dysfunction in a 20 - item written questionnaire. It evaluates the patient's physical (P), emotional (E) and functional (F) perceptions of swallowing dysfunction. This instrument has been psychometrically validated in head and neck cancer patients. Higher scores indicate superior perception of swallowing function. | At 3, 6, 12 and 24 months after completion of treatment | 
| Voice Handicap Index-10 (VHI-10) | The VHI-10 is a patient self-assessment instrument that quantifies patients' perception of their voice handicap. It evaluates patient's physical (P), emotional (E), and functional (F) perceptions of voice and has shown to be highly reliable for internal consistency and test-retest stability. The VHI-10 utilizes a 10-item questionnaire in which the patient circles the response that most accurately reflects his or her own experience on a linear scale (from never to always). Always response is scored 4 points, a Never response is scored 0. The remaining options are scored between 1 and 3 points. The tallied number of points for each of the subscales is computed to a total composite score. The patient's values are compared to published norms. | At 3, 6, 12 and 24 months after completion of treatment | 
| Performance Status Scale (PSS-HN) | The Performance Status Scale (PSS-HN) is a clinician-rated instrument consisting of 3 questions: normalcy of diet, public eating/swallowing, and understandability of speech subscales in patients with head and neck cancer. Each subscale is rated from 0 to 100, with higher scores indicating better performance. | At 3, 6, 12 and 24 months after completion of treatment | 
| Modified Barium Swallow (MBS) rating | Three swallowing outcomes will be rated by the SLP conducting the MBS study and reported by research staff: 1) laryngeal penetration (yes, no); 2) aspiration (no, sensate, silent), and 3) pharyngeal residue (no, < 50%, > 50%). These have been selected as universal items generally reported by swallowing clinicians that have been shown to significantly predict pneumonia in patients with oropharyngeal cancers. Prevalence of these dysphagia endpoints will be estimated at each time point. | At 6 and 24 months after completion of treatment | 
| Overall Survival (OS) | The length of time (in months) from the start of treatment patients remain alive. | From beginning of study treatment (post surgery) up to 3-years | 
| Adverse Events Related to Treatment | Number of patients experiencing Adverse Events and Serious Adverse Events (SAE) related to study treatment per Common Terminology Criteria for Adverse Events (CTCAE) v4.0 | Up to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Oropharynx Cancer, OPSCC, Nivolumab, Adjuvant therapy, De-Escalated Radiation, Squamous cell carcinoma, P16+, Head and Neck cancer, Oropharynx Squamous Cell Carcinoma, Carcinoma, Squamous Cell of Head and Neck, Transoral surgery, Radiotherapy