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

Phase 2

Completed

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

Interventions: Drug: Nivolumab Injection
Radiation: Radiotherapy (RT)

Registration Number: NCT03715946

Lead Sponsor: Robert L. Ferris, MD, PhD

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 40

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Radiotherapy (RT) + Nivolumab Injection	Nivolumab Injection	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.
Radiotherapy (RT) + Nivolumab Injection	Radiotherapy (RT)	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.

Primary Outcome Measures

Name	Time	Method
One-year Progression-free Survival (PFS)	At 1 year post start of treatment	The probability of PFS measured from of beginning of study treatment, without local, regional or distant disease recurrence (appearance of new metastatic lesions). Measurement/determination of disease progression (recurrence) by CT and MRI, Chest X-Ray (Lesions acceptable as measurable when clearly defined and surrounded by an aerated lung), Tumor Markers, Clinical Examination (Clinically detected lesions will only be considered measurable when they are superficial (e.g., skin nodules and palpable lymph nodes). For skin lesions, documentation by color photography, including a ruler to estimate size of the lesion, Cytology and Histology (Cytologic confirmation of the neoplastic nature of any effusion that appears or worsens during treatment is required when the measurable tumor has met response or stable disease criteria, Ultrasound (Ultrasound may be used only as an alternative to clinical measurements for superficial palpable lymph nodes, subcutaneous lesions and thyroid nodules.
Two-year Progression-free Survival (PFS)	At 2 years post start of treatment	The probability of PFS measured from of beginning of study treatment, without local, regional or distant disease recurrence (appearance of new metastatic lesions). Measurement/determination of disease progression (recurrence) by CT and MRI, Chest X-Ray (Lesions acceptable as measurable when clearly defined and surrounded by an aerated lung), Tumor Markers, Clinical Examination (Clinically detected lesions will only be considered measurable when they are superficial (e.g., skin nodules and palpable lymph nodes). For skin lesions, documentation by color photography, including a ruler to estimate size of the lesion, Cytology and Histology (Cytologic confirmation of the neoplastic nature of any effusion that appears or worsens during treatment is required when the measurable tumor has met response or stable disease criteria, Ultrasound (Ultrasound may be used only as an alternative to clinical measurements for superficial palpable lymph nodes, subcutaneous lesions and thyroid nodules.
PEG Tube Dependence	At 1-year post-surgery	Presence /absence of enteral feeding tube.

Secondary Outcome Measures

Name	Time	Method
Worst Grade of Adverse Events Related to Treatment	Up to 24 months	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
Local Recurrence-free Survival (RFS) at One Year	At 1-year post-surgery	Probability of patients with disease growth that is not present within the area in which disease was first located. Measurement/determination of disease progression (recurrence) by CT and MRI, Chest X-Ray (Lesions acceptable as measurable when clearly defined and surrounded by an aerated lung), Tumor Markers, Clinical Examination (Clinically detected lesions will only be considered measurable when they are superficial (e.g., skin nodules and palpable lymph nodes). For skin lesions, documentation by color photography, including a ruler to estimate size of the lesion, Cytology and Histology (Cytologic confirmation of the neoplastic nature of any effusion that appears or worsens during treatment is required when the measurable tumor has met response or stable disease criteria, Ultrasound (Ultrasound may be used only as an alternative to clinical measurements for superficial palpable lymph nodes, subcutaneous lesions and thyroid nodules.
Local Recurrence-free Survival (RFS) at Two Years	At 2-years post-surgery	Probability of patients with disease growth that is not present within the area in which disease was first located. Measurement/determination of disease progression (recurrence) by CT and MRI, Chest X-Ray (Lesions acceptable as measurable when clearly defined and surrounded by an aerated lung), Tumor Markers, Clinical Examination (Clinically detected lesions will only be considered measurable when they are superficial (e.g., skin nodules and palpable lymph nodes). For skin lesions, documentation by color photography, including a ruler to estimate size of the lesion, Cytology and Histology (Cytologic confirmation of the neoplastic nature of any effusion that appears or worsens during treatment is required when the measurable tumor has met response or stable disease criteria, Ultrasound (Ultrasound may be used only as an alternative to clinical measurements for superficial palpable lymph nodes, subcutaneous lesions and thyroid nodules.
Regional Recurrence-free Survival (RFS)	At two years post-surgery	Probability of patients with disease growth that is not present within the anatomical region in which disease was first located. Measurement/determination of disease progression (recurrence) by CT and MRI, Chest X-Ray (Lesions acceptable as measurable when clearly defined and surrounded by an aerated lung), Tumor Markers, Clinical Examination (Clinically detected lesions will only be considered measurable when they are superficial (e.g., skin nodules and palpable lymph nodes). For skin lesions, documentation by color photography, including a ruler to estimate size of the lesion, Cytology and Histology (Cytologic confirmation of the neoplastic nature of any effusion that appears or worsens during treatment is required when the measurable tumor has met response or stable disease criteria, Ultrasound (Ultrasound may be used only as an alternative to clinical measurements for superficial palpable lymph nodes, subcutaneous lesions and thyroid nodules.
Distant Recurrence-free Survival (RFS) at One Year	At one year post-surgery	Probability of patients with disease that has spread (metastasized) to areas farther away from where disease was first located. Measurement/determination of disease progression (recurrence) by CT and MRI, Chest X-Ray (Lesions acceptable as measurable when clearly defined and surrounded by an aerated lung), Tumor Markers, Clinical Examination (Clinically detected lesions will only be considered measurable when they are superficial (e.g., skin nodules and palpable lymph nodes). For skin lesions, documentation by color photography, including a ruler to estimate size of the lesion, Cytology and Histology (Cytologic confirmation of the neoplastic nature of any effusion that appears or worsens during treatment is required when the measurable tumor has met response or stable disease criteria, Ultrasound (Ultrasound may be used only as an alternative to clinical measurements for superficial palpable lymph nodes, subcutaneous lesions and thyroid nodules.
Distant Recurrence-free Survival (RFS)	At 2 years post-surgery	Percentage of patients with disease that has spread (metastasized) to areas farther away from where disease was first located. Measurement/determination of disease progression (recurrence) by CT and MRI, Chest X-Ray (Lesions acceptable as measurable when clearly defined and surrounded by an aerated lung), Tumor Markers, Clinical Examination (Clinically detected lesions will only be considered measurable when they are superficial (e.g., skin nodules and palpable lymph nodes). For skin lesions, documentation by color photography, including a ruler to estimate size of the lesion, Cytology and Histology (Cytologic confirmation of the neoplastic nature of any effusion that appears or worsens during treatment is required when the measurable tumor has met response or stable disease criteria, Ultrasound (Ultrasound may be used only as an alternative to clinical measurements for superficial palpable lymph nodes, subcutaneous lesions and thyroid nodules.
Overall Survival (OS) at One Year	At one year	The probability of survival from the start of treatment.
Overall Survival (OS) at Two Years	At two years	The probability of survival from the start of treatment.
MD Anderson Dysphagia Inventory (MDADI)	At 30 months after start of treatment	The MDADI measures swallowing-related quality of life (QOL) in patients with swallowing dysfunction in a 20 - item written questionnaire. Each item is scored on a 5-point Likert scale (scoring is 5-strongly disagree, 4-disagree, 3-no opinion, 2-agree, 1-strongly agree). Subscales evaluate the patient's physical (P), emotional (E) and functional (F) perceptions of swallowing dysfunction. A composite score is generated by calculating the mean response for the 19 items (excluding the global question) making up the emotional, functional and physical subscales and multiplying the result by 20, resulting in a score ranging from 20 representing a low QOL function to 100 indicating high QOL. Higher scores indicate better perception of swallowing function.
MD Anderson Dysphagia Inventory (MDADI) (Total - Overall Score)	Up to 30 months after start of treatment	Total scores including all time-points for the MDADI measures swallowing-related quality of life (QOL) in patients with swallowing dysfunction in a 20 - item written questionnaire. Each item is scored on a 5-point Likert scale (scoring is 5-strongly disagree, 4-disagree, 3-no opinion, 2-agree, 1-strongly agree). Subscales evaluate the patient's physical (P), emotional (E) and functional (F) perceptions of swallowing dysfunction. A composite score is generated by calculating the mean response for the 19 items (excluding the global question) making up the emotional, functional and physical subscales and multiplying the result by 20, resulting in a score ranging from 20 representing a low QOL function to 100 indicating high QOL. Higher scores indicate better perception of swallowing function. Scores taken at month 3, 6, 12, 24 and 30 months after completion of treatment were averaged for the population and reported below.
Performance Status Scale (PSS-HN)	At 3, 6, 12 and 24 months after completion of treatment	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.
Voice Handicap Index-10 (VHI-10)	At 30 months after completion of treatment	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. Scores for the VHI-10 range from zero-to-40, with higher scores indicating a greater voice-related handicap.
Voice Handicap Index-10 (VHI-10) (Total)	Calculated at 30 months after completion of treatment	Total scores are a mean average of time-points for 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. Scores for the VHI-10 range from zero-to-40, with higher scores indicating a greater voice-related handicap.
Functional Assessment of Cancer Therapy - Head and Neck Cancer (FACT-H&N) Score	At 30 months after start of treatment	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 the statements are for them for the past 7 days. Subscale responses range from not at all (0), to very much (4) on a 5-point scale. Total scores range from 0 to 108, with higher scores indicating better quality of life.
Functional Assessment of Cancer Therapy - Head and Neck Cancer (FACT-H&N) Score (Total)	Calculated at 30 months after start of treatment	Total scores as mean average of the combined timepoint values for 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 the statements are for them for the past 7 days. Subscale responses range from not at all (0), to very much (4) on a 5-point scale. Total scores range from 0 to 108, with higher scores indicating better quality of life.
MD Anderson Symptom Inventory for Head and Neck Cancer (MDASI-HN)	At 30 months after start of treatment	MDASI-HN is a 28 symptom items questionnaire of 13 general cancer-related symptoms, such as pain, fatigue and nausea; 9 HNC-related symptoms, such as problems with mucus in the mouth and difficulty in swallowing or chewing; 6 items to evaluate the effects of symptoms on daily life, including mood and enjoyment of life. Each item/subscale is rated on a 11-point scale from 0 (not at all) to 10 (as bad as you can imagine), while the items that assess the interference of symptoms on daily activities are rated from 0 (does not interfere) to 10 (interfered completely). When calculating any subscale score (arithmetic mean of items in the subscale), a majority of the subscale's items must have been responded to (ie, 7 of the 13 core symptom severity items or 4 of the 6 interference items would represent the majority of the items for the subscale). Total scores range from 0 to 280, with higher scores indicating better quality of life/lesser impairment.
MD Anderson Symptom Inventory for Head and Neck Cancer (MDASI-HN) (Total)	Calculated at 30 months after start of treatment	Total scores as mean average of the combined timepoint values. Includes all time-points for MDASI-HN is a 28 symptom items questionnaire of 13 general cancer-related symptoms, such as pain, fatigue and nausea; 9 HNC-related symptoms, such as problems with mucus in mouth and difficulty swallowing or chewing; 6 items to evaluate the effects of symptoms on daily life, including mood and enjoyment of life. Each item/subscale is rated on a 11-point scale from 0 (not at all) to 10 (as bad as you can imagine), while the items that assess the interference of symptoms on daily activities are rated from 0 (does not interfere) to 10 (interfered completely). When calculating any subscale score (arithmetic mean of items in the subscale), a majority of the subscale's items must have been responded to (7 of the 13 core symptom severity items or 4 of the 6 interference items would represent the majority of the items for the subscale).Total scores range 0-280;higher scores mean better life quality.
Modified Barium Swallow (MBS) Rating	At 6 and 24 months after completion of treatment	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.
EuroQoL-5D Questionnaire	At 30 months after start of treatment	EQ-5D is an instrument which evaluates the generic quality of life developed in Europe and widely used. The EQ-5D descriptive system is a preference-based HRQL measure with one question for each of the five dimensions that include mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. A value set consists of weights that can convert each EQ-5D health profile into a value on a scale anchored at 1 (meaning full health) and 0 (meaning a state as bad as being dead). The scale allows negative values to be assigned to health states that are considered worse than dead. EQ-5D-5L index scores range from -0.59 to 1, where 1 is the best possible health state; EQ VAS scores range from 0 to 100, where 100 is the best possible health state.
EuroQoL-5D Questionnaire (Total)	Calculated at 30 months after start of treatment	Total scores as mean average of the combined timepoint values for the EQ-5D is an instrument which evaluates the generic quality of life developed in Europe and widely used. The EQ-5D descriptive system is a preference-based HRQL measure with one question for each of the five dimensions that include mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. A value set consists of weights that can convert each EQ-5D health profile into a value on a scale anchored at 1 (meaning full health) and 0 (meaning a state as bad as being dead). The scale allows negative values to be assigned to health states that are considered worse than dead. EQ-5D-5L index scores range from -0.59 to 1, where 1 is the best possible health state; EQ VAS scores range from 0 to 100, where 100 is the best possible health state.

Trial Locations

Locations (3): Winship Cancer Institute @ Emory University Hospital Midtown
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Atlanta, Georgia, United States
UPMC Hillman Cancer Center
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Pittsburgh, Pennsylvania, United States
Providence Cancer Institute
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Portland, Oregon, United States