Basaloid Squamous Cell Carcinoma, Clinical Stage I HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Clinical Stage II HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Oropharyngeal Squamous Cell Carcinoma, Papillary Squamous Cell Carcinoma, Pathologic Stage I HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Pathologic Stage II HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Squamous Cell Carcinoma
Conditions
Brief summary
This phase II/III trial studies how well a reduced dose of radiation therapy works with nivolumab compared to cisplatin in treating patients with human papillomavirus (HPV)-positive oropharyngeal cancer that is early in its growth and may not have spread to other parts of the body (early-stage), and is not associated with smoking. Radiation therapy uses high-energy x-rays to kill tumor cells and shrink tumors. Chemotherapy drugs, such as cisplatin, 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. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. This trial is being done to see if a reduced dose of radiation therapy and nivolumab works as well as standard dose radiation therapy and cisplatin in treating patients with oropharyngeal cancer.
Detailed description
PRIMARY OBJECTIVES: I. To demonstrate non-inferiority in terms of progression-free survival (PFS) of concurrent reduced-dose radiation therapy (RT) with cisplatin or concurrent reduced-dose radiation therapy with nivolumab to the current standard of care (standard-dose RT with cisplatin). (Phase II) (Arm 2 \[concurrent reduced-dose RT with cisplatin\] was dropped after interim futility analysis in phase II.) II. To demonstrate non-inferiority in terms of progression-free survival (PFS) of concurrent reduced-dose radiation therapy (RT) with nivolumab to the current standard of care (standard-dose RT with cisplatin). (Phase II) III. To demonstrate co-primary endpoints of non-inferiority of PFS and superiority of quality of life (QOL) as measured by the MD Anderson Dysphagia Inventory (MDADI) of concurrent reduced-dose radiation with cisplatin or concurrent reduced-dose radiation with nivolumab to the current standard of care (standard-dose RT with cisplatin). (Phase III) (Arm 2 \[concurrent reduced-dose RT with cisplatin\] was dropped after interim futility analysis in phase II.) IV. To demonstrate co-primary endpoints of non-inferiority of PFS and superiority of quality of life (QOL) as measured by the MD Anderson Dysphagia Inventory \[MDADI\] of concurrent reduced-dose radiation with nivolumab to the current standard of care (standard-dose RT with cisplatin). (Phase III) SECONDARY OBJECTIVES: I. To compare patterns of failure (local and regional relapse versus distant) and overall survival between the experimental arm and the control arm. II. To assess long term PFS, overall survival, and toxicity between the experimental arm and the control arm. III. To determine acute and late toxicity profiles as measured by the Common Terminology Criteria for Adverse Events (CTCAE). IV. To explore the symptomatic adverse events (AEs) for tolerability of each treatment arm as measured by the Patient-Reported Outcomes (PRO)-CTCAE. V. To compare changes in patient-reported outcomes (Hearing Handicap Inventory for Adults-Screening \[HHIA-S\], European Organization for Research and Treatment of Cancer \[EORTC\]-Quality of Life Questionnaire \[QLQ\]30) between the experimental arm and the control arm. VI. To assess the association of fludeoxyglucose F-18 (FDG)-positron emission tomography (PET)/computed tomography (CT) at baseline with locoregional control and PFS. VII. To estimate the negative predictive value of the 12-14 weeks post-radiation therapy (RT) FDG-PET/CT in terms of locoregional control rates and PFS rates at 1 and 2 years. EXPLORATORY OBJECTIVES: I. To collect blood and tissue specimens for future translation research. II. To optimize radiotherapy treatment plan quality assurance methodology for radiotherapy planning and imaging. III. To compare changes in patient-reported outcomes (European Quality of Life Five Dimension Five Level Scale \[EQ-5D-5L\]) between the experimental arm and the control arm. IV. To collect Modified Barium Swallow (MBS) data for future review and analysis. OUTLINE: PHASE II: Patients are randomized to 1 of 3 arms. ARM I: Patients undergo standard dose RT as 70 Gy intensity modulated radiation therapy (IMRT) or image-guided radiation therapy (IGRT) over 6 fractions per week and receive 100 mg/m\^2/day cisplatin intravenously (IV) over 30-60 minutes on days 1 and 22. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients receive fludeoxyglucose F-18 (FDG) and undergo positron emission tomography (PET)/computed tomography (CT) or CT during screening and during follow up, and undergo magnetic resonance imaging (MRI) during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study. ARM II (CLOSED TO ACCRUAL 03-FEB-2023): Patients undergo reduced dose RT as 60 Gy IMRT or IGRT once daily (QD) over 5 fractions per week and receive 100 mg/m\^2/day cisplatin IV over 30-60 minutes on days 1 and 22. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study. ARM III: Beginning 1 week prior to radiation, patients receive 240 mg fixed dose nivolumab IV over 30 minutes on day 1. Treatment repeats every 2 weeks (14 days) for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo reduced dose RT as 60 Gy IMRT or IGRT over 6 fractions per week for 5 weeks in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study. PHASE III: Patients are randomized to Arm I and/or Arm III. After completion of study treatment, patients are followed up at 12-14 weeks, every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.
Interventions
PROCEDUREBiopsy Procedure
Undergo tissue biopsy
PROCEDUREBiospecimen Collection
Undergo blood sample collection
DRUGCisplatin
Given IV
PROCEDUREComputed Tomography
Undergo CT
OTHERFludeoxyglucose F-18
Receive FDG
RADIATIONImage Guided Radiation Therapy
Undergo IGRT
RADIATIONIntensity-Modulated Radiation Therapy
Undergo IMRT
PROCEDUREMagnetic Resonance Imaging
Undergo MRI
BIOLOGICALNivolumab
Given IV
PROCEDUREPositron Emission Tomography
Undergo PET
OTHERQuality-of-Life Assessment
Ancillary studies
OTHERQuestionnaire Administration
Ancillary studies
Sponsors
National Cancer Institute (NCI)
NRG Oncology
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Pathologically (histologically or cytologically) proven diagnosis of squamous cell carcinoma (including the histological variants papillary squamous cell carcinoma and basaloid squamous cell carcinoma but not neuroendocrine phenotype) of the oropharynx (tonsil, base of tongue, soft palate, or oropharyngeal walls); cytologic diagnosis from a cervical lymph node is sufficient in the presence of clinical evidence of a primary tumor in the oropharynx. Clinical evidence should be documented, may consist of palpation, imaging, or endoscopic evaluation, and should be sufficient to estimate the size of the primary (for T stage) * Patients must have clinically or radiographically evident measurable disease at the primary site or at nodal stations. Simple tonsillectomy or local excision of the primary without removal of nodal disease is permitted, as is excision removing gross nodal disease but with intact primary site. Limited neck dissections retrieving =\< 4 nodes are permitted and considered as non-therapeutic nodal excisions * P16-positive based on local site immunohistochemical tissue staining (defined as greater than 70% strong diffuse nuclear or nuclear and cytoplasmic staining of tumor cells). Fine needle aspiration (FNA) biopsy specimens may be used as the sole diagnostic tissue. Centers are encouraged to contact the pathology chair for clarification * Note: Institutions must screen patients, whose tumors must be p16-positive by immunohistochemistry (IHC) in order to be eligible for the trial using a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. A rigorous laboratory accreditation process similar to the United States (U.S.) CLIA certification, such as the provincial accreditation status offered by the Ontario Laboratory Accreditation (OLA) Program in Canada, the College of American Pathologists (CAP), or an equivalent accreditation in other countries, is acceptable. The p16-positive results must be reported on the pathology report being submitted * Note: If p16 result is equivocal, positive HPV deoxyribonucleic acid (DNA) test of tumor specimen is acceptable and fulfills the eligibility criteria * Clinical stage T1-2, N1, M0 (American Joint Committee on Cancer \[AJCC\], 8th edition \[ed.\]) or T3, N0-N1, M0 (AJCC, 8th ed.) including no distant metastases based on the following diagnostic workup: * General history and physical examination within 56 days prior to registration; * Exam with laryngopharyngoscopy (mirror or in office direct procedure acceptable) within 70 days prior to registration; * One of the following imaging studies is required within 56 days prior to registration: * FDG-PET/CT of the neck and chest (with or without contrast); FDG-PET/CT scan is strongly preferred and highly recommended to be used for eligibility OR * Chest CT (with or without contrast) * One of the following imaging studies is required within 28 days prior to registration: * A diagnostic CT scan of neck (with contrast and of diagnostic quality) OR * An magnetic resonance imaging (MRI) of the neck (with contrast and of diagnostic quality) * Note: A diagnostic quality CT or MRI with contrast or FDG-PET/CT scan of neck performed for the purposes of radiation planning may serve as both staging and planning tools * Patients must provide their personal smoking history prior to registration. The lifetime cumulative history cannot exceed 10 pack-years. The following formula is used to calculate the pack-years during the periods of smoking in the patient's life; the cumulative total of the number of pack-years during each period of active smoking is the lifetime cumulative history * Number of pack-years = \[Frequency of smoking (number of cigarettes per day) x duration of cigarette smoking (years)\] / 20 * Note: Twenty cigarettes is considered equivalent to one pack. The effect of non-cigarette tobacco products on the survival of patients with p16-positive oropharyngeal cancers is undefined. While there are reportedly increased risks of head and neck cancer associated with sustained heavy cigar and pipe use (Wyss 2013), such sustained use of non-cigarette products is unusual and does not appear to convey added risk with synchronous cigarette smoking. Cigar and pipe tobacco consumption is therefore not included in calculating the lifetime pack-years. Marijuana consumption is likewise not considered in this calculation. There is no clear scientific evidence regarding the role of chewing tobacco-containing products in this disease, although this is possibly more concerning given the proximity of the oral cavity and oropharynx. In any case, investigators are discouraged from enrolling patients with a history of very sustained use (such as several years or more) of non-cigarette tobacco products alone * Zubrod performance status of 0-1 within 14 days prior to registration * Age \>= 18 * Absolute neutrophil count \>= 1,500/mcL (within 14 days prior to registration) * Platelets \>= 100,000/mcL (within 14 days prior to registration) * Hemoglobin \>= 8.0 g/dL (within 14 days prior to registration) (Note: use of transfusion or other intervention to achieve hemoglobin \[Hgb\] \>= 8.0 g/dL is acceptable) * Total bilirubin =\< 1.5 x institutional upper limit of normal (ULN) (within 14 days prior to registration) * Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase \[SGOT\]) or alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase \[SGPT\]) =\< 3.0 x institutional ULN (within 14 days prior to registration) * Serum creatinine =\< 1.5 x ULN OR creatinine clearance (CrCl) \>= 50 mL/min (if using the Cockcroft-Gault formula) (within 14 days prior to registration) * Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial * For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated * Note: Known positive test for hepatitis B virus surface antigen (HBV sAg) indicating acute or chronic infection would make the patient ineligible unless the viral load becomes undetectable on suppressive therapy. Patients who are immune to hepatitis B (anti-hepatitis B surface antibody positive) are eligible (e.g. patients immunized against hepatitis B) * Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment for the hepatitis, they are eligible if they have an undetectable HCV viral load. * Note: Known positive test for hepatitis C virus ribonucleic acid (HCV RNA) indicating acute or chronic infection would make the patient ineligible unless the viral load becomes undetectable on suppressive therapy * For women of childbearing potential (WOCBP), negative serum or urine pregnancy test within 24 hours prior to registration * Women of childbearing potential (WOCBP) is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes. In addition, women under the age of 55 must have a documented serum follicle stimulating hormone (FSH) level less than 40 mIU/mL * Women of childbearing potential (WOCBP) and men who are sexually active with WOCBP must be willing to use an adequate method of contraception during and after treatment * The patient or a legally authorized representative must provide study-specific informed consent prior to study entry * Only English, Spanish, or French speaking patients are eligible to participate as these are the only languages for which the mandatory dysphagia-related patient reported instrument (MDADI) is available
Exclusion criteria
* Clinical stages T0; T4; T1-2, N0; or any N2 (AJCC, 8th ed) * Recurrent disease * Definitive clinical or radiologic evidence of metastatic disease or adenopathy below the clavicles * Cancers considered to be from an oral cavity site (oral tongue, floor mouth, alveolar ridge, buccal or lip), or the nasopharynx, hypopharynx, or larynx, even if p16-positive, or histologies of adenosquamous, verrucous, or spindle cell carcinomas * Carcinoma of the neck of unknown primary site origin (T0 is ineligible, even if p16-positive) * Radiographically matted nodes, defined as 3 abutting nodes with loss of the intervening fat plane * Supraclavicular nodes, defined as nodes centered below the level of the cricoid cartilage * Gross total excision of both primary and nodal disease; this includes tonsillectomy, local excision of primary site, and nodal excision that removes all clinically and radiographically evident disease. In other words, to participate in this protocol, the patient must have clinically or radiographically evident gross disease for which disease response can be assessed * Patients with simultaneous primary cancers or separate bilateral primary tumor sites are excluded with the exception of patients with bilateral tonsil cancers * Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 1095 days (3 years) (of note, the exclusion applies only for invasive cancers such that carcinoma in situ of the breast, oral cavity, or cervix are all permissible) * Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable * Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields * 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 * History of severe hypersensitivity reaction to any monoclonal antibody. * 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 within 30 days of registration * Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects * Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition with immune compromise greater than that noted; note, however, that HIV testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive. Protocol-specific requirements may also exclude immuno-compromised patients * Condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of registration. Inhaled or topical steroids and adrenal replacement doses \< 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease * Patients with active autoimmune disease requiring systemic treatment (i.e. disease modifying agents, corticosteroids, or immunosuppressive drugs) should be excluded. These include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), rheumatoid arthritis, connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded because of the risk of recurrence or exacerbation of disease * Note: Patients are permitted to enroll if they have 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 (precipitating event) * Patients who are pregnant, nursing, or expecting to conceive or father children * Prior allergic reaction to cisplatin
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) (Phase II) (Percentage of Participants Alive Without Progression) | From randomization to first progression or last follow-up. Maximum follow-up at the time of analysis was 4.6 years. The 1- and 2-year estimates are reported. | Progression is defined as local-regional progression or recurrence, distant metastasis, death due to any reason, salvage surgery of primary with tumor present/unknown, salvage neck dissection with tumor present/unknown, \> 20 weeks from end of radiation therapy. Progression-free survival rates are estimated using the Kaplan-Meier method, censoring participants alive at time of analysis. The primary phase IIR endpoint is tested using a confidence interval (CI) approach with each experimental arm compared to the standard arm (Arm 1). |
| Progression-free Survival (Phase III) (Percentage of Participants Alive Without Progression) | From randomization to first progression or last follow-up. Maximum follow-up was 4.6 years. | Progression is defined as local-regional progression or recurrence, distant metastasis, death due to any reason, salvage surgery of primary with tumor present/unknown, salvage neck dissection with tumor present/unknown, \> 20 weeks from end of radiation therapy. Progression-free survival rates are estimated using the Kaplan-Meier method, censoring participants alive at time of analysis. |
| MD Anderson Dysphagia Inventory (MDADI) Global Quality of Life (QOL) Score | Baseline to two years | The M. D. Anderson Dysphagia Inventory (MDADI) assesses how patients view their swallowing ability as a result of treatment and how this affects their QOL. It consists of a global quality of life question and a functional, emotional, and physical subscale. The global QOL question ranges from 1 to 5 and multiplied by 20 to obtain a score with a range of 0 to 100. Higher scores indicate better functioning. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Locoregional Failure (Percentage of Participants With Locoregional Failure) | From randomization to first failure, competing event, or last known follow-up, whichever occurs first. Maximum follow-up at the time of analysis was 4.6 years. The 1- and 2-year estimates are reported. | Locoregional failure is defined as local-regional progression or recurrence, death due to study cancer or unknown causes, salvage neck dissection with tumor present/unknown. Locoregional failure rates are estimated the cumulative incidence method, treating distant metastasis and death due to any reason other than study cancer or unknown as competing risks, and otherwise censoring participants alive at time of analysis. Each experimental arm is compared to the standard arm (Arm I). |
| Distant Failure (Percentage of Participants With Distant Failure) | From randomization to first failure, competing event, or last known follow-up, whichever occurs first. Maximum follow-up at the time of analysis was 4.6 years. The 1- and 2-year estimates are reported. | Distant failure is defined as the occurrence of distant metastasis. Distant failure rates are estimated the cumulative incidence method, treating local-regional progression or recurrence, death due to any reason, salvage neck dissection with tumor present/unknown as competing risks, and otherwise censoring participants alive at time of analysis. Each experimental arm is compared to the standard arm (Arm I). |
| Overall Survival (Percentage of Participants Alive) | From randomization to death from any cause or last follow-up. Maximum follow-up at the time of analysis was 4.6 years. The 1- and 2-year estimates are reported. | Survival rates are estimated using the Kaplan-Meier method, censoring participants alive at time of analysis. |
| Number of Participants by Highest Grade Adverse Event Reported | From randomization to last known follow-up. Maximum follow-up at the time of analysis was 4.6 years. | Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grades adverse event severity as follows: 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, 5 = death related to adverse event. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data. |
| Hearing | Baseline up to 24 months from end of radiation therapy (RT) | Measured as Hearing Handicap Inventory for Adults-Screening (HHIA-S). |
| Quality of Life | Baseline up to 24 months from end of RT | Measured by the European Organization for Research and Treatment of Cancer (EORTC)-Quality of Life Questionnaire (QLQ)30. |
| Fludeoxyglucose F-18 (FDG)-Positron Emission Tomography (PET)/Computed Tomography (CT) Locoregional Control | Up to 6 years | Will be associated with PFS. |
| Negative Predictive Value of Post-RT FDG-PET/CT for Locoregional Control | At 1 and 2 years | The negative predictive value of FDG-PET/CT for locoregional control will be estimated using binomial proportions and confidence intervals based on normal approximation. |
| Negative Predictive Value of Post-RT FDG-PET/CT for PFS | At 1 and 2 years | The negative predictive value of FDG-PET/CT PFS will be estimated using binomial proportions and confidence intervals based on normal approximation. |
| Incidence of Adverse Events | Up to 6 years | Measured using Patient-Reported Outcomes (PRO)-CTCAE. For each symptom, counts and frequencies will be provided for the worst score experienced by the patient by treatment arm. The proportion of patients with scores \>= 1 and \>= 3 will be compared between groups using a Chi-square test, or Fisher's exact test if cell frequencies are \< 5, using a significance level of 0.05. Analysis of changes in patient reported outcomes over time will analyzed by fitting generalized estimating equations (GEE) models using a logit link (dichotomizing the symptom scores as 0 vs. \> 1 and 0-2 vs. 3-4) with time of assessment, treatment arm, and treatment-by-time interaction terms in the model. |
Countries
Canada, United States
Contacts
PRINCIPAL_INVESTIGATORSue S Yom
NRG Oncology
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm I (Standard RT + Cisplatin) Patients undergo standard dose RT as 70 Gy IMRT or IGRT over 6 fractions per week and receive 100 mg/m\^2/day cisplatin IV over 30-60 minutes on days 1 and 22. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study. | 136 |
| Arm II (Reduced RT+ Cisplatin) Patients undergo reduced dose RT as 60 Gy IMRT or IGRT QD over 5 fractions per week and receive 100 mg/m\^2/day cisplatin IV over 30-60 minutes on days 1 and 22. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study. | 116 |
| Arm III (Reduced RT + Nivolumab) Beginning 1 week prior to radiation, patients receive 240 mg fixed dose nivolumab IV over 30 minutes on day 1. Treatment repeats every 2 weeks (14 days) for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo reduced dose RT as 60 Gy IMRT or IGRT over 6 fractions per week for 5 weeks in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study. | 132 |
| Total | 384 |
Baseline characteristics
| Characteristic | Total | Arm III (Reduced RT + Nivolumab) | Arm II (Reduced RT+ Cisplatin) | Arm I (Standard RT + Cisplatin) |
|---|---|---|---|---|
| Age, Continuous | 60 years | 60.5 years | 61 years | 60 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 20 Participants | 7 Participants | 9 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 348 Participants | 120 Participants | 104 Participants | 124 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 16 Participants | 5 Participants | 3 Participants | 8 Participants |
| M stage M0, clinical (AJCC 8) | 384 Participants | 132 Participants | 116 Participants | 136 Participants |
| N stage, clinical (AJCC 8) N0 | 13 Participants | 4 Participants | 4 Participants | 5 Participants |
| N stage, clinical (AJCC 8) N1 | 369 Participants | 126 Participants | 112 Participants | 131 Participants |
| N stage, clinical (AJCC 8) N2 | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| N stage, clinical (AJCC 8) N3 | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| p16-positive status | 384 Participants | 132 Participants | 116 Participants | 136 Participants |
| Pack-years 0 | 306 Participants | 104 Participants | 93 Participants | 109 Participants |
| Pack-years >0 to ≤10 | 78 Participants | 28 Participants | 23 Participants | 27 Participants |
| Primary tumor site Base of tongue | 151 Participants | 54 Participants | 46 Participants | 51 Participants |
| Primary tumor site Oropharynx NOS | 38 Participants | 10 Participants | 12 Participants | 16 Participants |
| Primary tumor site Pharyngeal oropharynx | 7 Participants | 3 Participants | 3 Participants | 1 Participants |
| Primary tumor site Tonsillar fossa, tonsil | 188 Participants | 65 Participants | 55 Participants | 68 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants | 1 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 9 Participants | 3 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 16 Participants | 6 Participants | 6 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 19 Participants | 5 Participants | 4 Participants | 10 Participants |
| Race (NIH/OMB) White | 336 Participants | 116 Participants | 102 Participants | 118 Participants |
| Sex: Female, Male Female | 36 Participants | 13 Participants | 11 Participants | 12 Participants |
| Sex: Female, Male Male | 348 Participants | 119 Participants | 105 Participants | 124 Participants |
| Smoking history Current | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Smoking history Former | 78 Participants | 28 Participants | 22 Participants | 28 Participants |
| Smoking history Never | 305 Participants | 104 Participants | 93 Participants | 108 Participants |
| Stage group, clinical (AJCC 8) III (T0-3, N3, M0) | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Stage group, clinical (AJCC 8) II (T0-2,N2,M0 or T3,N0-2,M0) | 57 Participants | 20 Participants | 20 Participants | 17 Participants |
| Stage group, clinical (AJCC 8) I (T0-2,N0-1,M0) | 326 Participants | 111 Participants | 96 Participants | 119 Participants |
| T stage, clinical (AJCC 8) T0 | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| T stage, clinical (AJCC 8) T1 | 140 Participants | 51 Participants | 39 Participants | 50 Participants |
| T stage, clinical (AJCC 8) T2 | 186 Participants | 61 Participants | 57 Participants | 68 Participants |
| T stage, clinical (AJCC 8) T3 | 57 Participants | 20 Participants | 20 Participants | 17 Participants |
| Zubrod performance status 0 | 337 Participants | 117 Participants | 102 Participants | 118 Participants |
| Zubrod performance status 1 | 47 Participants | 15 Participants | 14 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 136 | 6 / 116 | 5 / 132 |
| other Total, other adverse events | 123 / 123 | 111 / 112 | 122 / 123 |
| serious Total, serious adverse events | 49 / 123 | 32 / 112 | 34 / 123 |
Outcome results
Primary
MD Anderson Dysphagia Inventory (MDADI) Global Quality of Life (QOL) Score
The M. D. Anderson Dysphagia Inventory (MDADI) assesses how patients view their swallowing ability as a result of treatment and how this affects their QOL. It consists of a global quality of life question and a functional, emotional, and physical subscale. The global QOL question ranges from 1 to 5 and multiplied by 20 to obtain a score with a range of 0 to 100. Higher scores indicate better functioning.
Time frame: Baseline to two years
Population: Randomized phase III participants. (Phase III component did not and will not open.)
Primary
Progression-free Survival (PFS) (Phase II) (Percentage of Participants Alive Without Progression)
Progression is defined as local-regional progression or recurrence, distant metastasis, death due to any reason, salvage surgery of primary with tumor present/unknown, salvage neck dissection with tumor present/unknown, \> 20 weeks from end of radiation therapy. Progression-free survival rates are estimated using the Kaplan-Meier method, censoring participants alive at time of analysis. The primary phase IIR endpoint is tested using a confidence interval (CI) approach with each experimental arm compared to the standard arm (Arm 1).
Time frame: From randomization to first progression or last follow-up. Maximum follow-up at the time of analysis was 4.6 years. The 1- and 2-year estimates are reported.
Population: Randomized phase II participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I (Standard RT + Cisplatin) | Progression-free Survival (PFS) (Phase II) (Percentage of Participants Alive Without Progression) | 1 year | 99.1 percentage of participants |
| Arm I (Standard RT + Cisplatin) | Progression-free Survival (PFS) (Phase II) (Percentage of Participants Alive Without Progression) | 2 years | 98.1 percentage of participants |
| Arm II (Reduced RT+ Cisplatin) | Progression-free Survival (PFS) (Phase II) (Percentage of Participants Alive Without Progression) | 1 year | 96.4 percentage of participants |
| Arm II (Reduced RT+ Cisplatin) | Progression-free Survival (PFS) (Phase II) (Percentage of Participants Alive Without Progression) | 2 years | 88.6 percentage of participants |
| Arm III (Reduced RT + Nivolumab) | Progression-free Survival (PFS) (Phase II) (Percentage of Participants Alive Without Progression) | 1 year | 96.6 percentage of participants |
| Arm III (Reduced RT + Nivolumab) | Progression-free Survival (PFS) (Phase II) (Percentage of Participants Alive Without Progression) | 2 years | 90.3 percentage of participants |
Comparison: The null hypothesis (H0) for each comparison in phase II will be rejected if the 90% upper confidence of the hazard ratio (HR) (experimental arm / standard arm) is less than HR=2.4.
Comparison: The null hypothesis (H0) for each comparison in phase II will be rejected if the 90% upper confidence of the hazard ratio (HR) (experimental arm / standard arm) is less than HR=2.4.
Primary
Progression-free Survival (Phase III) (Percentage of Participants Alive Without Progression)
Progression is defined as local-regional progression or recurrence, distant metastasis, death due to any reason, salvage surgery of primary with tumor present/unknown, salvage neck dissection with tumor present/unknown, \> 20 weeks from end of radiation therapy. Progression-free survival rates are estimated using the Kaplan-Meier method, censoring participants alive at time of analysis.
Time frame: From randomization to first progression or last follow-up. Maximum follow-up was 4.6 years.
Population: Randomized phase III participants. (Phase III component did not and will not open.)
Secondary
Distant Failure (Percentage of Participants With Distant Failure)
Distant failure is defined as the occurrence of distant metastasis. Distant failure rates are estimated the cumulative incidence method, treating local-regional progression or recurrence, death due to any reason, salvage neck dissection with tumor present/unknown as competing risks, and otherwise censoring participants alive at time of analysis. Each experimental arm is compared to the standard arm (Arm I).
Time frame: From randomization to first failure, competing event, or last known follow-up, whichever occurs first. Maximum follow-up at the time of analysis was 4.6 years. The 1- and 2-year estimates are reported.
Population: Randomized participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I (Standard RT + Cisplatin) | Distant Failure (Percentage of Participants With Distant Failure) | Year 2 | 1.9 percentage of participants |
| Arm I (Standard RT + Cisplatin) | Distant Failure (Percentage of Participants With Distant Failure) | Year 1 | 0.9 percentage of participants |
| Arm II (Reduced RT+ Cisplatin) | Distant Failure (Percentage of Participants With Distant Failure) | Year 1 | 0.0 percentage of participants |
| Arm II (Reduced RT+ Cisplatin) | Distant Failure (Percentage of Participants With Distant Failure) | Year 2 | 4.1 percentage of participants |
| Arm III (Reduced RT + Nivolumab) | Distant Failure (Percentage of Participants With Distant Failure) | Year 1 | 0.8 percentage of participants |
| Arm III (Reduced RT + Nivolumab) | Distant Failure (Percentage of Participants With Distant Failure) | Year 2 | 2.9 percentage of participants |
95% CI: [0.34, 9.46]
95% CI: [0.24, 8.45]
Secondary
Fludeoxyglucose F-18 (FDG)-Positron Emission Tomography (PET)/Computed Tomography (CT) Locoregional Control
Will be associated with PFS.
Time frame: Up to 6 years
Secondary
Hearing
Measured as Hearing Handicap Inventory for Adults-Screening (HHIA-S).
Time frame: Baseline up to 24 months from end of radiation therapy (RT)
Secondary
Incidence of Adverse Events
Measured using Patient-Reported Outcomes (PRO)-CTCAE. For each symptom, counts and frequencies will be provided for the worst score experienced by the patient by treatment arm. The proportion of patients with scores \>= 1 and \>= 3 will be compared between groups using a Chi-square test, or Fisher's exact test if cell frequencies are \< 5, using a significance level of 0.05. Analysis of changes in patient reported outcomes over time will analyzed by fitting generalized estimating equations (GEE) models using a logit link (dichotomizing the symptom scores as 0 vs. \> 1 and 0-2 vs. 3-4) with time of assessment, treatment arm, and treatment-by-time interaction terms in the model.
Time frame: Up to 6 years
Secondary
Locoregional Failure (Percentage of Participants With Locoregional Failure)
Locoregional failure is defined as local-regional progression or recurrence, death due to study cancer or unknown causes, salvage neck dissection with tumor present/unknown. Locoregional failure rates are estimated the cumulative incidence method, treating distant metastasis and death due to any reason other than study cancer or unknown as competing risks, and otherwise censoring participants alive at time of analysis. Each experimental arm is compared to the standard arm (Arm I).
Time frame: From randomization to first failure, competing event, or last known follow-up, whichever occurs first. Maximum follow-up at the time of analysis was 4.6 years. The 1- and 2-year estimates are reported.
Population: Randomized participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I (Standard RT + Cisplatin) | Locoregional Failure (Percentage of Participants With Locoregional Failure) | 1 year | 0.0 percentage of participants |
| Arm I (Standard RT + Cisplatin) | Locoregional Failure (Percentage of Participants With Locoregional Failure) | 2 years | 0.0 percentage of participants |
| Arm II (Reduced RT+ Cisplatin) | Locoregional Failure (Percentage of Participants With Locoregional Failure) | 1 year | 2.7 percentage of participants |
| Arm II (Reduced RT+ Cisplatin) | Locoregional Failure (Percentage of Participants With Locoregional Failure) | 2 years | 6.5 percentage of participants |
| Arm III (Reduced RT + Nivolumab) | Locoregional Failure (Percentage of Participants With Locoregional Failure) | 1 year | 1.7 percentage of participants |
| Arm III (Reduced RT + Nivolumab) | Locoregional Failure (Percentage of Participants With Locoregional Failure) | 2 years | 5.0 percentage of participants |
95% CI: [1.05, 403.31]
95% CI: [0.58, 287.93]
Secondary
Negative Predictive Value of Post-RT FDG-PET/CT for Locoregional Control
The negative predictive value of FDG-PET/CT for locoregional control will be estimated using binomial proportions and confidence intervals based on normal approximation.
Time frame: At 1 and 2 years
Secondary
Negative Predictive Value of Post-RT FDG-PET/CT for PFS
The negative predictive value of FDG-PET/CT PFS will be estimated using binomial proportions and confidence intervals based on normal approximation.
Time frame: At 1 and 2 years
Secondary
Number of Participants by Highest Grade Adverse Event Reported
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grades adverse event severity as follows: 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, 5 = death related to adverse event. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data.
Time frame: From randomization to last known follow-up. Maximum follow-up at the time of analysis was 4.6 years.
Population: Randomized and started protocol treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm I (Standard RT + Cisplatin) | Number of Participants by Highest Grade Adverse Event Reported | Grade 4 | 15 Participants |
| Arm I (Standard RT + Cisplatin) | Number of Participants by Highest Grade Adverse Event Reported | Grade 3 | 68 Participants |
| Arm I (Standard RT + Cisplatin) | Number of Participants by Highest Grade Adverse Event Reported | Grade 2 | 37 Participants |
| Arm I (Standard RT + Cisplatin) | Number of Participants by Highest Grade Adverse Event Reported | Grade 1 | 3 Participants |
| Arm II (Reduced RT+ Cisplatin) | Number of Participants by Highest Grade Adverse Event Reported | Grade 3 | 66 Participants |
| Arm II (Reduced RT+ Cisplatin) | Number of Participants by Highest Grade Adverse Event Reported | Grade 2 | 27 Participants |
| Arm II (Reduced RT+ Cisplatin) | Number of Participants by Highest Grade Adverse Event Reported | Grade 1 | 4 Participants |
| Arm II (Reduced RT+ Cisplatin) | Number of Participants by Highest Grade Adverse Event Reported | Grade 4 | 15 Participants |
| Arm III (Reduced RT + Nivolumab) | Number of Participants by Highest Grade Adverse Event Reported | Grade 2 | 38 Participants |
| Arm III (Reduced RT + Nivolumab) | Number of Participants by Highest Grade Adverse Event Reported | Grade 1 | 4 Participants |
| Arm III (Reduced RT + Nivolumab) | Number of Participants by Highest Grade Adverse Event Reported | Grade 4 | 8 Participants |
| Arm III (Reduced RT + Nivolumab) | Number of Participants by Highest Grade Adverse Event Reported | Grade 3 | 72 Participants |
Secondary
Overall Survival (Percentage of Participants Alive)
Survival rates are estimated using the Kaplan-Meier method, censoring participants alive at time of analysis.
Time frame: From randomization to death from any cause or last follow-up. Maximum follow-up at the time of analysis was 4.6 years. The 1- and 2-year estimates are reported.
Population: Randomized participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I (Standard RT + Cisplatin) | Overall Survival (Percentage of Participants Alive) | 1 year | 100 Percent of participants |
| Arm I (Standard RT + Cisplatin) | Overall Survival (Percentage of Participants Alive) | 2 year | 99.0 Percent of participants |
| Arm II (Reduced RT+ Cisplatin) | Overall Survival (Percentage of Participants Alive) | 1 year | 99.1 Percent of participants |
| Arm II (Reduced RT+ Cisplatin) | Overall Survival (Percentage of Participants Alive) | 2 year | 98.0 Percent of participants |
| Arm III (Reduced RT + Nivolumab) | Overall Survival (Percentage of Participants Alive) | 1 year | 99.2 Percent of participants |
| Arm III (Reduced RT + Nivolumab) | Overall Survival (Percentage of Participants Alive) | 2 year | 96.1 Percent of participants |
95% CI: [0.67, 46.41]
95% CI: [0.57, 41.74]
Secondary
Quality of Life
Measured by the European Organization for Research and Treatment of Cancer (EORTC)-Quality of Life Questionnaire (QLQ)30.
Time frame: Baseline up to 24 months from end of RT
Other Pre-specified
Locoregional Control for Patients With Post-RT FDG-PET/CT
Locoregional control rates will be compared between negative and positive/undetermined patients. Cox proportional hazards models will be used to determine whether there are differences between these two groups, while adjusting for treatment arm and other covariates (cause-specific Cox models for locoregional failure).
Time frame: At 12-14 weeks post-RT
Other Pre-specified
PFS for Patients With Post-RT FDG-PET/CT
PFS rates will be compared between negative and positive/undetermined patients. Cox proportional hazards models will be used to determine whether there are differences between these two groups, while adjusting for treatment arm and other covariates (cause-specific Cox models for locoregional failure).
Time frame: At 12-14 weeks post-RT
Other Pre-specified
Quality of Life
Measured by EuroQol-5 Dimensional- 5 Level (EQ-5D-5L).
Time frame: Baseline up to 24 months from end of RT
Other Pre-specified
Swallowing Physiology
Measured by a Modified Barium Swallow (MBS) test. The proportion of aspiration for each arm will be estimated assuming a binomial distribution and between arm comparison will be performed using a Fisher's exact test.
Time frame: Up to 6 years