Phase 2 Study (With Safety Lead in) of the Safety, Tolerability and Efficacy of Anti-CTLA4 (Ipilimumab) and Anti-PD-1 (Nivolumab) in Combination With Radiation Therapy to 50-66 Gy in Low-Intermediate Volume, Local-Regionally Advanced HPV-Positive Oropharyngeal Squamous Cell Carcinoma (OPSCC)
Phase: PHASE2
Conditions: Clinical Stage I HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Clinical Stage II HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Human Papillomavirus Positive Oropharyngeal Squamous Cell Carcinoma, Oropharyngeal Basaloid Carcinoma, Pathologic Stage I HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Pathologic Stage II HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Posterior Tongue Squamous Cell Carcinoma, Soft Palate Squamous Cell Carcinoma, Stage III Oropharyngeal Squamous Cell Carcinoma AJCC v7, Stage IVA Oropharyngeal Squamous Cell Carcinoma AJCC v7, Tonsillar Squamous Cell Carcinoma
Sponsor: M.D. Anderson Cancer Center

 
 
MD Anderson IND Sponsor Cover Sheet 
 
Protocol ID 
2018-0381 
Protocol Title 
Phase 2 study (with safety lead in) of the safety, tolerability and efficacy 
of anti-CTLA4 (ipilimumab) and anti-PD-1 (nivolumab) in combination 
with radiation therapy to 50-66 Gy in low- intermediate volume, local-
regionally advanced HPV-positive  oropharyngeal squamous  cell 
carcinoma (OPSCC) 
Protocol Phase 
II 
Protocol Version 
8.0 
Version Date 
07/21/2025 
 
Protocol PI 
 Renata Ferrarotto, MD 
Department 
Thoracic Head and Neck 
 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
142403 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol # 2018-0381 
Ipilumumab and Nivolumab 
 
 
 
 
 
 
Clinical Protocol 
 
Phase 2 study (with safety lead in) of the safety, tolerability and efficacy of anti-CTLA4 (ipilimumab) 
and anti-PD-1 (nivolumab) in combination with radiation therapy to 50-66 Gy in low- intermediate 
volume, local-regionally advanced HPV-positive  oropharyngeal squamous  cell carcinoma (OPSCC) 
 
 
 
 
Principal Investigator: Renata Ferrarotto, MD, PhD 
 
Radiation Oncology: Jack Phan, MD, PhD; Adam Garden, MD  
 
Radiology: Maria Gule-Monroe, MD 
 
Head and Neck Surgery: Neil Gross, MD; Ryan Goepfert, MD 
 
Speech and Swallowing Therapy: Kate Hutcheson, PhD  
 
Interventional Radiology: Sanjay Gupta, MD 
 
Statistics: J. Jack Lee, PhD 
 
Pathology: Diana Bell, MD 
 
Thoracic and Head and Neck Medical Oncology: Ignacio Wistuba, MD 
 
Version 0, date 08/01/2018 
 
Version 1, date 10/22/2018 
 
Version 2, date 04/24/2019 
 
Version 3, date 07/15/2019 
 
Version 4, date 08/27/2019 
 
Version 5, date 4/06/2020 
 
Version 6, date 11/2/2020 
 
Version 7, date 3/2/2021 
 
Version 8, date 07/21/2025 

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Protocol # 2018-0381 
Ipilumumab and Nivolumab 
 
 
 
 
 
SYNOPSIS 
 
Title of Study: Phase 2 study (with safety lead in) of the safety, tolerability and efficacy of anti- 
CTLA4 (ipilimumab) and anti-PD-1 (nivolumab) in combination radiation therapy to 50-66 Gy in 
low- intermediate volume, local-regionally advanced HPV-positive orpharyngeal squamous cell 
carcinoma (OPSCC). 
 
Investigational Product: Each subject will be administered two six week cycles of intravenous 
(IV) ipilimumab 1 mg/kg on day 1 and nivolumab 3 mg/kg on day 1, 15, and 29. 
 
Study phase: 2 
 
Research Hypothesis: The combination of ipilimumab, nivolumab and concurrent intensity 
modulated photon therapy (IMRT) with reduced field will demonstrate adequate safety, tolerability 
and clinical efficacy for treatment of subjects with low-intermediate volume, local-regionally 
advanced HPV-positive OPSCC. 
 
Primary Objective 1: To evaluate the safety, tolerability and feasibility of ipilimumab and nivolumab 
when administered concurrently with reduced-field IMRT. 
 
Primary Objective 2: To evaluate the clinical complete response rate to ipilimumab, nivolumab 
and IMRT with reduced field at six months as indicated by FDG-PET/CT post completion of RT. 
 
Primary Objective 3: To evaluate the 2-year progression-free survival (PFS) rate of subjects with 
low-intermediate volume, local-regionally advanced, HPV-positive SCCHN treated with ipilimumab, 
nivolumab and reduced-field IMRT. 
 
Principal Secondary Objectives: 
To evaluate overall response rate to six weeks of induction immunotherapy (IO). 
 
To evaluate the frequency of pharyngeal dysphasia as measured by DIGEST grade on modified 
barium swallow (MBS) and patient-reported symptoms (MDADI) at 6 months and 2 years after 
radiotherapy [IMRT]. 
 
Additional Secondary Objectives: 
To measure acute and chronic toxicities per CTCAE v4; 
To measure acute toxicity profiles at the end of radiation therapy and IO and at 6 months;  
To measure late toxicity profiles at 1 and 2 years; 
To determine local and regional control at 6 and 12 months; 
To determine patterns of failure (local-regional relapse vs. distant) at 1 and 2 years;  
To determine overall survival (OS) at 1 and 2 years; 
 
Principal Correlative Objectives: 
To evaluate associations between total mutational load, IFNƴ score, T cell clonality at diagnosis 
with clinical response to induction, combination CTLA-4 PD-1 checkpoint blockade. 
 
To evaluate changes in the tumor immune microenvironment (CD8 + IFN gamma score, T cell 
clonality, in tumor biopsy specimens pre and post induction immunotherapy (IO); 
 
To evaluate dynamic changes in and clearance of oral HPV and cfDNA viral load during therapy 

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Protocol # 2018-0381 
Ipilumumab and Nivolumab 
 
 
 
and to investigate associations with PFS and OS. 
Additional Exploratory Objectives: 
 
To evaluate changes in peripheral blood lymphocyte phenotypes and serum cytokine profiles before 
and after induction IO; 
 
To evaluate changes in the T cell receptor repertoire in TIL and the peripheral blood in tumor biopsy 
specimens pre and post induction IO; 
 
To determine the NPV and PPV of FDG-PET/CT 12-14 weeks after end of RT for 1 year and 2 year 
PFS and OS. 
  
Study Design: 
This is a phase II, open label, single arm study. The study is designed to evaluate the safety,  
feasibility and clinical efficacy of a treatment strategy of combination anti-CTLA4 (ipilimumab) and 
anti-PD-1 (nivolumab) IO with reduced dose and field radiation therapy to 50-66 Gy for patients with 
low-intermediate volume, local-regionally advanced HPV-positive OPSCC (AJCC 7th edition 
T1N2a-N2c, T3N0, T2-T3N1-N2C; AJCC 8th edition stage 1-2, excluding T1N0-1, T2N0). The 
primary objective of this study is to establish the efficacy of the new immunotherapy regimen such 
that it is non-inferior to the current standard therapy. Two co-primary endpoints are specified: (1) 
the complete response (CR) rate at 6 months and (2) the two-year progression-free survival (PFS) 
rate. 
 
Based on the available data, the standard therapy yields a 6-month CR rate of 0.87 and a two- year 
PFS of 0.91. The non-inferiority margin is set at 0.05 for the 6-month CR rate and at 0.06 for the 2-
year PFS. Thus, the new treatment is considered non-inferior to the standard therapy if the 6-month 
CR rate is at least 0.82 and the two-year PFS is at least 0.85. Otherwise, the new treatment is 
considered inferior to the standard therapy. The study comprises a three-year accrual period with 
5 patient enrolled per month and additional two years of follow up. The maximum total sample size 
is 180 and the total study duration is up to 5 years. Assume that the 6-month response rate follows 
a binomial distribution and the PFS follows a Weibull distribution, given the parameters specified 
above, the study will have 82% power of establishing the non-inferiority if the efficacy of the new 
treatment is as good as the standard treatment. On the other hand, if the new treatment yields a 6-
month response rate of 0.75 and a two-year PFS of 0.85, the early stopping probability is 0.93 with 
an average sample size of 127.6. The probability of claiming non-inferiority is 0.06 (type I error). 
 
Interim Analysis: 
Futility early stopping rule will be implemented monthly starting month 7 after 35 patients are 
enrolled to protect patients from receiving inferior therapy. In order to assure that the new regimen 
is safe and efficacious, patient accrual will be paused after 35 patients are enrolled. After the toxicity 
data and the 6-month CR status are available, study statistician will perform the first interim 
analysis. The study PI will discuss with sponsor and make a decision to either resume accrual and 
expand the study size beyond 35 patients if the new regimen is deemed to be safe and efficacious 
or close the study otherwise. If the trial is not stopped early after the first interim analysis, patient 
accrual will resume and additional interim monitoring will be performed monthly. The non-inferiority 
boundary is evaluated at the end of study if the study is not stopped early. Patients in the lead in 
portion of the trial will be included in the phase 2. The maximum total sample size is 180 and the 
total study duration is up to 5 years.  
 
Study Conduct: 
 
Eligible subjects will include patients with newly diagnosed, low-intermediate volume local- 

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Protocol # 2018-0381 
Ipilumumab and Nivolumab 
 
 
 
regionally advanced (AJCC 7th edition T1N2A-N2C, T2-T3N1-N2C, T3N0 or AJCC 8th edition stage 
T1 N2; T2 N1-N2 or T3 N0-N2), HPV-positive OPSCC. The study will be divided into four phases, 
including screening, treatment, clinical follow-up and survival follow-up. Patients will undergo 
screening (up to 1 month), treatment (12 weeks), clinical follow up (100 days) and survival follow-
up (up to five years). The treatment period will include two, six-week cycles of ipilmumab 1 mg/kg 
day 1 and nivolumab 3 mg/kg on days 1, 15, and 29 starting six weeks before start of radiation 
therapy (50-66Gy) , equivalent to cycle 2 day 1 of the IO. On days when ipilimumab and nivolumab 
are given on the same day, nivolumab will be infused first over 30 minutes. A minimum of 30 minutes 
is required between infusions. Clinical response to induction therapy will be evaluated by repeat 
imaging after six weeks of IO and before start of radiotherapy. In the phase II trial, clinical response 
to treatment will be evaluated by physical exam and CT neck (or MRI) at eight-10 weeks and FDG-
PET/CT at 12-14 weeks post completion of radiation therapy. For the first co-primary endpoint, the 
outcome of interest will be the proportion of patients who have a clinical complete response to 
therapy. Criteria for a clinical complete response include: (1) a metabolic complete response by 
FDG-PET/CT on week 12-14 post RT or (2) an indeterminant response by FDG-PET/CT on week 
12-14 post RT followed by a complete metabolic response on week 24-28 or (3) an indeterminant 
or residual tumor FDG-PET/CT with no evidence of viable tumor on pathology from a salvage 
surgical procedure. The second co-primary endpoint of interest is 2-year progression-free survival, 
defined as the time from start of therapy to progression of disease or death from any cause. 
 
Study Schema 
.
 
 
1. RATIONALE 
Platinum-based chemo-RT is the current standard of care for local-regionally advanced HPV- 
positive OPSCC and results in an approximate 8-year OS of 70.9% (Nguyen-Tan et al. 2014). 
Although platinum-based chemo-RT improves local-regional control and OS for SCCHN, acute and 
long-term toxicities (Trotti et al. 2007; Bentzen et al. 2007) as well as non-cancer associated deaths 
are increased (Kang et al. 2016). Accounting for total toxicity burden, concurrent chemo- RT has 
been estimated to increase the acute toxicity experienced by patients by 500% in comparison to 

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Protocol # 2018-0381 
Ipilumumab and Nivolumab 
 
 
 
radiation therapy alone (Trotti et al. 2007). Given patients with HPV-positive OPSCC have a high 
probability of long-term survival, late toxicities of therapy are an increasing concern. Several recent 
trials have demonstrated that local-regional control (Chera et al. 2015) or progression-free survival 
(Marur et al, abstract 6005, ASCO 2016) may be maintained with reductions in intensity (e.g. total 
dose) of RT among patients with HPV-positive OPSCC. However, these studies maintained 
platinum chemotherapy (CT). In Checkmate 141, anti-PD1 (nivolumab) monotherapy reduced the 
risk of death by half in comparison to single-agent CT among patients with platinum-refractory, 
recurrent and metastatic HPV-positive OPSCC. This demonstrated clinical activity together with in 
vivo models of combination immunotherapy (IO)-RT support a hypothesis that neoadjuvant anti-
CTLA4 and anti-PD1 IO followed by concurrent administration with RT would have substantial anti-
cancer activity for patients with HPV-positive OPSCC. Therefore, we designed a phase 1/2 clinical 
trial to investigate combination IO-RT with anti-PD1 (Nivolumab) and anti-CTLA4 (Ipilimumab) with 
reduce field and dose of IMRT in patients with low-intermediate volume, local-regionally advanced 
HPV-positive OPSCC. 
 
1.1 Head and neck cancer 
Squamous cell carcinoma of the head and neck (SCCHN) is a major cause of cancer-associated 
morbidity, with 600,000 cases diagnosed annually worldwide (Ferlay et al. 2013). In the United 
States in 2013, there were 53,640 new cases and 11,520 deaths from SCCHN (Siegel et al 2013). 
Traditional risk factors include tobacco and alcohol use. However, HPV infection is now a major 
cause of OPSCC (Gillison et al. 2008; De Martel et al. 2012). Indeed, incidence rates for HPV-
positive SCCHN increased by 225% (Chaturvedi et al. 2011) from 1988-2004 and are projected to 
continue to increase through 2060 (Maura L. Gillison et al. 2015) 
 
 
1.2 HPV-positive oropharyngeal squamous cell carcinoma  
In comparison to its HPV-negative counterpart, HPV-positive SCCHN is unique with regard to risk-
factor profiles, clinical-pathological features, treatment response, prognosis and genetic profiles 
(Gillison et al. 2012; Gillison et al. 2015). It is now clear that tumor HPV status is a strong 
independent determinant of OS. Across numerous clinical trials, patients with HPV-positive SCCHN 
have been shown to have at least half the risk of death when compared to HPV-negative SCCHN 
(Ang et al. 2010). HPV-positive SCCHN has an improved response to platinum-based induction 
chemotherapy (Fakhry et al. 2008), RT (Gillison et al. 2015) and chemo-RT (Ang KK et al. 2010; 
Rischin et al. 2010) when compared to HPV-negative SCCHN. In an analyses of RTOG 0129, a 
combination of tumor HPV status, tobacco pack-years (<10 or ≥ 10), and T and N stage classified 
patients into low, intermediate, or high-risk of death (three-year OS rates 93% [95%CI, 88.3-97.7], 
70.8% [95%CI 60.7-80.8] and 46.2% [95%CI 34.7-57.5], respectively) (Gillison et al. 2012). Notably, 
all HPV-positive SCCHN patients were included in the low-risk group (including T4 and N3), with 
the exception of those with the combination of >10 pack-years and N2b-N3 disease. This model 
was subsequently validated in RTOG 9003 and 0522 and O’Sullivan and colleagues confirmed the 
excellent 3-year local-regional and distant control rates of 93-95% for the low-risk subset (O’Sullivan 
et al. 2013). As a consequence, alternative pathways for clinical therapeutics for HPV-positive 
SCCHN have evolved, taking advantage of the increased sensitivity of the disease to chemotherapy 
and RT. Numerous clinical trials of reduce intensity of chemotherapy and/or RT are completed or 
ongoing, with a goal to reduce long-term toxicities while preserving disease control. 
 
The current AJCC TNM staging system accurately discriminates subgroups of patients with HPV- 
negative, but not HPV-positive OPSCC (Maura L. Gillison 2016). Analyses of large datasets at 
Princess Margaret (O’Sullivan et al. 2013), MD Anderson (Sturgis et al. 2016) and additional 
institutions (O’Sullivan et al. 2016) have resulted in proposals for a new staging system specific to 
HPV-positive SCCHN. Across these analyses is a consistent pattern of high local-regional disease 
control and survival among patients with low-intermediate volume, HPV-positive SCCHN (<T4 and 

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Protocol # 2018-0381 
Ipilumumab and Nivolumab 
 
 
 
<N3). In a Princess Margaret series, patients with <T4, <N3 HPV-positive OPSCC had 3-year 
disease control rate of 93% (95%CI, 89-95) and local-regional control of 95% (95%CI 91- 97%) 
(O’Sullivan et al. 2013). In a follow-up study, tobacco smoking was found to significantly affect OS 
for patients with low-intermediate volume HPV-positive OPSCC, with a cut-point of 20 pack-years. 
Five-year OS was 89% (95%CI, 85-93%) among those with ≤20 pack-years and 64% (95%CI 56-
73%) for >20 pack-years (Huang et al. 2015). In the MD Anderson series, patients with low-
intermediate volume HPV-positive SCCHN were classified as Stage 1A (T1<N3) and 1B (T2<N3) 
and had a 5-year survival of 94% (95%CI 87-97%) and 87% (95%CI 79-92%), respectively. Notably, 
5-year survival for T1-T2N3 or T3N0-N3 was 76% (95%CI 65-84%). We note that, in contrast to 
prior models, smoking was not included in the final model. In the recent ICON-S stage validation 
analysis reported by O’Sullivan et al (O’Sullivan et al. 2016), five-year OS for patients with ICON-S 
stage 1 (T1-T2N0-N2b) was 85% (95% CI 81-90) and for ICON-S stage 2 (T1-T3N2c) was 78% 
(95%CI 73-84%). For patients who meet the specific eligibility criteria for this trial in the ICON-S 
dataset treated with chemoRT, 2-year PFS was 91%, local- regional control 97%, and distant 
control rate 94%. Notably, none of these ICON-S models included smoking history. Thus, patient 
with low-intermediate volume HPV-positive SCCHN (<T4,<N3) are an excellent clinical subgroup 
for treatment de-intensification strategies, given the consistently favorable outcomes across these 
studies. 
 
1.3 De-escalation protocols and reduced dose RT. 
Given patients with HPV-positive OPSCC are young and likely to survive, the long-term morbidity 
(i.e. xerostomia, dysphagia, hypothyroidism, atherosclerosis, radiation fibrosis, dental loss) 
associated with standard-of-care, high dose cisplatin-based chemo-RT to 70Gy has a significant 
clinical and economic impact (Gillison et al. 2012; Ang et al. 2010). “De-escalation” treatment 
strategies are therefore designed to investigate whether or not intensity of chemotherapy, 
radiotherapy or both can be reduced while preserving disease control and reducing long-term 
toxicities for the patient with HPV-positive SCCHN (Masterson et al. 2014). 
 
Results of several of these trials have been reported. Based upon the increased response to 
induction chemotherapy for HPV-positive SCCHN demonstrated in a prospective ECOG trial 
(Fakhry et al. 2008), ECOG 1308 investigated reduced dose radiation to 54Gy among patients 
treated with three cycles of platinum-based induction chemotherapy (Cmelak et al. 2014). Sixty- 
seven of 80 patients received induction chemotherapy followed by reduced dose IMRT to 54Gy in 
27 fractions concurrent with cetuximab. After a median follow-up of 35.4 months, 2-year PFS and 
OS were 81% and 93% for all patients treated with ≤54Gy and 96% for 27 patients with <T4, <N2C, 
<10 pack-years. Given the small subset, it could not be determined which of these factors (T4, N2C-
N3, ≥ 10 pack-years) was most influential for the less successful disease control. Chen and 
colleagues reported similarly high 2-year PFS of 92% among patients with Stage 3-4 HPV- positive 
OPC when treated with two cycles of paclitaxel/carboplatin followed by 54 Gy IMRT with weekly 
paclitaxel among complete or partial responders (Chen AM 2017). Three of 4 patients with 
progression received standard dose RT due to a best response of stable disease during induction. 
A similar treatment algorithm is being investigated in the Quarterback Trial, a phase III clinical trial 
comparing induction chemotherapy followed by reduced dose chemo-RT in responding patients vs. 
standard dose RT. 
 
Chera and colleagues reported the results of a phase II trial among 43 patients with low- volume 
HPV-positive SCCHN (<T4, <N3) treated with cisplatin 30 mg/m2/week X 6 and 60Gy IMRT, 
representing a 16% reduction in RT and a 60% reduction in cisplatin dose (Chera et al. 2015). The 
principal outcome of interest was pathological complete response (pCR) at a planned neck 
dissection nine weeks after RT. The pCR rate was 86%, just below the estimated 87% 3- year local-
regional control rate achieved in RTOG 0129 with high-dose cisplatin and IMRT 70Gy. These 
results are encouraging, and the completed NRG-HN002 trial will be a more robust evaluation of a 

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Protocol # 2018-0381 
Ipilumumab and Nivolumab 
 
 
 
similar approach. In that trial, patients with HPV-positive SCCHN (<T4, <N2C, <10 pack- years) 
were treated with cisplatin at 40/mg/m2/week X 6 and 60 Gy/30 fractions/6 weeks or accelerated 
reduced dose radiation therapy (60 Gy/30 fractions/5 weeks). The primary objective for this trial is 
to select the arm(s) achieving a 2-year PFS rate of ≥ 85% without unacceptable swallowing toxicity 
at 1 year (ClinicalTrials.gov NCT: 02254278). 
 
The radiation therapy alone arm in HN002 is based upon high rates of local-regional control for low 
volume OPSCC with IMRT given as a single modality. RTOG 0022 was a phase II of 69 patients 
with T1-2 N0-N1 M0 OPSCC. The protocol specified a prescribed dose to the high-dose planning 
target volume of 66 Gy at 2.2 Gy/fraction in 30 fractions delivered over 6 weeks. With a median 
follow up of 2.8 years, the 2-year local-regional failure rate was 9% (95% Cl, 2.1-15.9), the disease-
free survival (DFS) was 82% (95% Cl, 72.7-91.2), and the OS was 95.5% (95% CI, 90.6-100.0). 
Notably, all cases of local-regional failure, metastasis, or second primary cancer occurred among 
patients identifiable as current or former smokers (54% of all enrolled), and no such events were 
seen among reported nonsmokers (defined as < 5 packs per lifetime, with a prevalence of 34% in 
this study) (Eisbruch et al. 2010) 
 
A clinical precedent exists for treatment of HPV-positive OPSCC with reduced dose radiation to 60 
Gy over five weeks. In the Princess Margaret Hospital series, 449 OPSCC were treated with RT 
alone on a variety of schedules (60-70 Gy over 4-7 weeks). Among 148 patients with p16-positive 
OPSCC, 82% were stage III-IVB. Three-year outcomes for disease, local and regional control were 
92%, 93% and 88%, respectively. Patients with p16-positive OPSCC who had ≤10 pack-years (n = 
37) had 3-year OS, cause-specific survival, local control, and regional control rates of 86%, 92%, 
95% and 97%, with distant control rates of 92% (O’Sullivan et al. 2013) Additional analyses 
indicated high volume disease (T4 or N3) had a high-risk of disease progression, even if tobacco 
exposure is <10 pack-years (O’Sullivan et al. 2013). In a case series from Princess Margaret 
Hospital from 1985-1991, 228 patients with tonsillar cancer were treated with ipsilateral RT to a 
total dose of 50 Gy in 4 weeks (Withers et al, 1995) (O’Sullivan et al. 2001). The majority of patients 
had low-intermediate volume disease (<T4 and <N2C). Five-year local and nodal control rates were 
77% and 81% overall. 
 
Several trials of reduced dose RT for HPV-positive OPSCC in additional clinical settings are 
ongoing. This includes ECOG 3311, in which post-operative patients with intermediate risk features 
are randomized to adjuvant IMRT of 50Gy vs. 60Gy. A phase II clinical trial is ongoing in which 
post-operative adjuvant RT is reduced to 30 Gy. At Memorial Sloan Kettering, patients with early 
stage HPV-positive OPSCC without evidence of significant tumor hypoxia by FDG-PET/CT are 
undergoing TORS resection of the primary followed by IMRT 30 Gy to involved nodes and selective 
neck dissection. To date, 4 of 4 patients enrolled have had a pathological complete response to 30 
Gy of RT (personal communication, Nancy Lee). 
 
A common alternative de-escalation approach to RT dose reduction is replacement of cisplatin by 
cetuximab concurrent with IMRT to 68-72 Gy. Given cetuximab-RT did not increase acute toxicities 
over RT alone in the seminal trial led by Bonner and colleagues, three ongoing trials are based 
upon the hypothesis that cetuximab-RT will reduce acute and late toxicities in comparison to 
cisplatin-RT while preserving disease control. RTOG1016 is a non-inferiority study design, whereas 
the TROG-12.01 and De-Escalate trials have principal outcomes of acute and late toxicities. Results 
of RTOG1016 and De-Escalate trials identified similar rates of toxicity with cetuximab and cisplatin 
and inferior disease control with cetuximab (Gillison et al. 2019; Mehanna et al. 2019). 
 
A radiation-based alternative to de-intensification of treatment is the use of proton beam therapy in 
OPC patients. An MD Anderson led multi-institution randomized Phase II/III radiation de- 
intensification trial (Frank-PI) is currently underway testing concurrent chemoraditation strategies 

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Protocol # 2018-0381 
Ipilumumab and Nivolumab 
 
 
 
with IMRT vs. IMPT for patients with locally advanced head and neck cancer. IMPT significantly 
reduces the bystander radiation to non-clinical target volume structures in the head and neck that 
results in a decrease in acute and chronic toxicity without compromising disease control outcomes 
(Frank et al. 2012, Holliday et al. 2014, Gunn et al. 2016, McKeever et al. 2016, Blanchard et al. 
2016, Leeman et al. 2017). 
 
However, all the trials above treat the entire neck comprehensively, which may affect the lymphoid 
organs involved in priming and enhancing immune response. A differential radiation sensitivity of 
immune cells may have an effect on the anti-cancer response. T helper, T cytotoxic and monocytes 
have a radiation sensitive phenotype whereas regulatory T cells, macrophages, dendritic cells and 
NK cells have a relative radiation resistance (Heylmann et al. 2014) The University of Chicago has 
conducted a trial called Response Adapted Volume De-escalation (RAVD), wherein 2 cycles of TPC 
(cisplatin, paclitaxel and cetuximab) induction chemotherapy is followed by reduced radiation 
volume to treat mainly the gross disease with margins in patients with good response and to treat 
the neck comprehensively in nonresponders. For HPV-positive patients, this was associated with a 
3-year local-regional control rate of 100% and 87%, respectively in good responders and non-
responders. Reduced field in responders was associated with less long-term gastrostomy tube 
dependence (Melotek JM et al, Arizona meeting 2, 2016). Therefore, the combination of reduced-
total dose RT and RT field size is expected to diminish both acute and long-term toxicity and 
maintain survival outcomes. In this trial there is interest in pursuing reduced field radiation therapy 
in combination with IO as a viable treatment option to offer to selected “low risk” oropharyngeal 
cancer patients. 
 
 
1.4 Head and neck cancer and immunity 
Cancer IO is based on the premise that tumors can be recognized as foreign rather than as self 
and can be effectively attacked by an activated immune system. Pathogenesis and progression of 
SCCHN may therefore be facilitated by local immunosuppressive alterations in the tumor 
microenvironment. Down-regulation of T cell function has been reported in SCCHN, and is mediated 
by multiple mechanisms including: reduced expression of co-stimulating molecules of the B7-CD28 
family (Albers et al. 2005); increased expression of PD-L1 in tumor cells and tumor associated 
fibroblasts; and loss of HLA-class I and selective down-regulation of HLA-A, B, C locus expression 
resulting in defective antigen presentation (López-Albaitero et al. 2006; Leibowitz et al. 2013). 
Additionally, HPV-positive SCCHN patients have expanded populations of virus-specific T cells with 
an ineffective antitumor phenotype (Albers et al. 2005). 
 
Programmed death receptor-1 (PD-1, CD279), a 55 kD type I transmembrane protein, is a member 
of the CD28 family of T-cell co-stimulatory receptors primarily expressed on activated T cells, B 
cells, and myeloid cells. Two ligands specific for PD-1 have been identified: PD-L1 (B7- H1/CD274) 
and PD-L2 (B7-DC/CD273). PD-L1 and PD-L2 have been shown to down-regulate T- cell activation 
upon binding to PD-1. PD-1 delivers a negative signal, suppressing the immune response away 
from a beneficial “type 1” response (Li et al. 2014). Existing literature supports a prevalence of PD-
L1 expression in SCCHN of ~50-60% overall, with a slightly higher prevalence in HPV-positive 
SCCHN (Lyford-Pike et al. 2013). Ukpo and colleagues analyzed 181 OPSCC samples, 138 were 
HPV E6/E7 positive, and from those 68 (49.2%) expressed PD-L1. The authors found a correlation 
between the intensity of expression of PD-L1 and the development of distance metastasis (p=0.03) 
(Ukpo et al, 2013). More recently, Kim and colleagues evaluated 133 OPSCC, finding that the 71% 
of HPV-positive cases expressed PD-L1 (Kim et al. 2016). Concha-Benavente and colleagues 
studied 127 SCCHN for both HPV status and PD-L1 expression and observed PD-L1 expression 
to be more frequent in HPV-positive specimens (70% vs 43.3%) (Concha-Benavente et al. 2016). 
PD-L1 expression on tumor cells has been correlated with increased tumor aggressiveness and 
decrease survival (Cho et al. 2011). Additionally, tumor infiltration by PD-1+ Treg is more common 

10 
Protocol # 2018-0381 
Ipilumumab and Nivolumab 
 
 
 
for HPV-positive than HPV-negative SCCHN (Badoual et al. 2013). Jie and colleagues observed 
higher expression of immune-checkpoint receptors (CTLA-4 and PD-1) in intratumoral Treg cells 
than on matched peripheral blood samples from 27 patients with SCCHN (H-B Jie et al. 2013). 
 
CTLA-4 is a member of the immunoglobulin superfamily of receptors that is expressed on CTLs 
and Tregs. CTLA-4 is a co-inhibitory receptor that competes with the co-stimulatory molecule CD28 
on CD8+ T cells to prevent binding to CD80 and CD86 on antigen presenting cells, thus suppressing 
the critical second signal and decreasing activation and proliferation of CTL. Montler and colleagues 
have reported co-expression of CTLA-4 and PD-1 in the Treg subset of TIL isolated from HNSCC 
(Montler et al. 2016) 
 
In an analysis of transcriptome data from 280 HNSCC in TCGA, Mandal et al evaluated the immune 
landscape of HPV-positive vs. negative tumors (Mandal et al. 2016). Expression profiles were 
consistent with higher T cell infiltration in HPV-positive tumors, including both CD8+CTL and Tregs. 
Expression of negative regulators of both CD8+CTL (CTLA-4) and NK (Kir2DL1 and 3) function 
was higher in HPV-positive vs. negative HNSCC. Patients with high TIL had significantly improved 
OS. In a retrospective analysis published by Wad et al, 270 OPSCC the levels of tumor infiltrating 
lymphocytes (TILs) were dichotomized into two categories. Three-year survival in HPV-
positive/high-TIL tumors was 96% vs. 59% in HPV-positive/low-TILs tumors (Ward et al. 2014). 
Circulating levels of T cells and NK cells that express detectable co-inhibitory checkpoint receptors 
may also correlate with disease stage and status (Badoual et al. 2013; H-B Jie et al. 2013; Hyun-
Bae Jie et al. 2015; Lyford-Pike et al. 2013). In conclusion, HPV-positive HNSCC has a higher 
infiltration by TIL, consistent with an immunologically “hot” tumor indicative of likely benefit from IO. 
 
 
1.5 Clinical trials of checkpoint inhibitors in SCCHN 
Strome and colleagues originally demonstrated in animal models that PD-L1 blockade had 
therapeutic activity against PD-L1 positive SCCHN (Strome et al. 2003). Several clinical trials of 
single agent anti-PD1 or anti-PD-L1 therapy have demonstrated clinical activity of immunotherapy 
in patients with heavily pre-treated, recurrent/metastatic (R/M) SCCHN. A phase 1b clinical trial 
(Keynote 12) of single agent pembrolizumab (anti-PD1) demonstrated an ORR of 18% among 192 
patients and 1-year OS of 38%. Response rates were slightly higher in HPV-positive vs negative 
patients (24 vs 16%) (Chow et al. 2016). A combined measure of PD-L1 expression in the tumor 
and inflammatory infiltrate identified a subset of patients with higher ORR (23% vs. 10%). 
Preliminary results of Keynote 55 including 92 of 171 patients with platinum- and cetuximab-
refractory R/M SCCHN demonstrated an ORR of 18%, 22% in HPV-positive and 16% in HPV-
negative SCCHN. ORR was also higher in PD-L1>1% vs. <1% (17% vs. 8%). Single- agent therapy 
with an anti-PD-L1 monoclonal (durvalumab) leads to an estimated ORR of 11% in RM SCCHN. 
 
Importantly, data from a phase III trial (CheckMate 141) demonstrated that nivolumab improved 
survival of patients with platinum-refractory recurrent or metastatic SCCHN in comparison to 
standard of care therapy. Nivolumab monotherapy reduced the risk of death by 30% (HR 0,70, 
96%CI 0.51-0.96) in comparison to single-agent methotrexate, docetaxel or cetuximab of 
investigator’s choice (IC). Notably, one-year OS was more than doubled with nivolumab vs. IC (37% 
vs 17%) (Ferris et al. 2016). In a subset analysis, the risk of death was reduced by half (HR 0.56, 
95% CI 0.32-0.99) with nivolumab vs. IC for patients with p16-positive (a surrogate for HPV) tumors, 
regardless of tumor PD-L1 expression. Similar to SCCHN, single agent nivolumab therapy has been 
shown to improve OS in patients with previously treated advanced non-small cell lung carcinoma 
(NSCLC) vs. docetaxel. In SQ-NSCLC, nivolumab therapy reduced the risk of death by 41% (HR 
0.59, 95%CI 0.44-0.79). Keynote40 demonstrated similar results with single agent pembrolizumab 
(Cohen E et al. 2019). 
 

11 
Protocol # 2018-0381 
Ipilumumab and Nivolumab 
 
 
 
 
1.6 Rationale for combination of Nivolumab and Ipilimumab 
The combination of PD-1 and CTLA-4 receptor blockade has demonstrated improved clinical 
antitumor activity than either drug alone in clinical trials for patients with melanoma and lung cancer. 
The synergy between combined checkpoint inhibitor therapy is attributed to CTLA4 acting at early 
time points during T cell priming, activation and expansion versus PD-1 reactivation of exhausted 
T cells. In a phase II trial (CA209069), ORR for patients with BRAF wild type melanoma was 
improved with ipilimumab and nivolumab combination IO (ORR 61%, with 22% complete responses 
[CR]) in comparison to ipilimumab alone (ORR 11%, 0 CRs). In a subsequent randomized phase 3 
trial (Checkmate 067), PFS was 11.5 months (95% CI, 8.9 to 16.7) in the nivolumab-plus-ipilimumab 
group, 6.9 months (95% confidence interval [CI], 4.3 to 9.5) in the nivolumab group, and 2.9 months 
(95% CI, 2.8 to 3.4) in the ipilimumab group. The PFS hazard ratio for the comparison between the 
nivolumab-plus-ipilimumab group and the nivolumab group was 0.74 (95% CI, 0.60 to 0.92) (Larkin 
et al. 2015). Notably, the combination lead to deep and durable responses in patients with 
melanoma with as estimated 2-year OS of 79%. 
 
The clinical activity of nivolumab and ipilimumab combinations has been evaluated in patients with 
stage IIB-IV NSCLC as first line treatment in CheckMate 12 (ClinicalTrials.gov Identifier: 
NCT01454102) (Gettinger et al. 2012). Cohorts that evaluated nivolumab 1 mg/kg with ipilimumab 
3 mg/kg every 3 weeks or nivolumab 3 mgs/kg with ipilimumab 1 mg/kg every 3 weeks resulted in 
ORR of 13-20% and 1-year OS of 44-65% but had significant toxicity in the non-small cell lung 
cancer (NSCLC) population (grade 3-4 treatment related adverse events (TRAEs) 44-58%), with 
37% of patients discontinuing treatment due to a treatment-related adverse event. Thus, additional 
combination cohorts were initiated using lower doses of both nivolumab and ipilimumab, or the 
approved dose of nivolumab 3 mg/kg with less frequent dosing of ipilimumab. Numerically higher 
response rates were observed in cohorts evaluating the approved dose of nivolumab 3 mg/kg (with 
ipilimumab 1 mg/kg every 6 or 12 weeks), with confirmed response rates 38-47%. Median time to 
response was 8 weeks, and median number of doses was 8 for nivolumab and 2 for ipilimumab. 
Importantly, TRAEs grades 3-4 were reduced to ~28%, with treatment discontinuation of 10%. Most 
frequent TRAE of any grade were skin, gastrointestinal (diarrhea) and endocrine. Every six week 
ipilimumab 1 mg/kg scheduling thus improved ORR in comparison to nivolumab alone in SQ 
NSCLC and was more tolerable than every 3 week dosing. A phase 1-2 trial (Checkmate 032) 
among small cell lung cancer (SCLC) patients with progression after platinum chemotherapy 
investigated several combinations of nivolumab and ipilimumab (1mg/kg plus 1 mg/kg, 1 mg/kg plus 
3 mg/kg or 3 mg/kg plus 1 mg/kg) every 3 weeks for 4 cycles, followed by nivolumab 3 mg/kg every 
2 weeks. Among the 54 patients in the nivolumab 3 mg/kg and ipilimumab 1 mg/kg arm the 7% 
discontinued treatment because of toxicity related to the study drug (Helloman et al. 2017, Antonia 
et al. 2016). 
 
There is an enlarging body of evidence of increased clinical benefit from dual PD-1/PD-L1 and 
CTLA-4 checkpoint blockade in comparison to either agent alone. Dual checkpoint blockade is 
now a SOC for patients with melanoma, renal cell carcinoma and non-small cell lung cancer 
(NSCLC, with high TMB). In NSCLC, dual checkpoint blockade significantly prolonged PFS and 
duration of response (DOR) in comparison to platinum-doublet chemotherapy in patients with high 
TMB, regardless of PD-L1 TPS (Hellmann et al. NEJM 2018). In metastatic melanoma, long-term 
follow up data from CheckMate 67 revealed dual checkpoint blockade significantly prolonged PFS 
versus nivolumab alone and also lead to numerically higher median and 4-year OS rates (Hodi et 
al. 2018). Benefit of the combination appeared independent of tumor PD-L1 status. Dual 
checkpoint blockade improved OS, PFS, ORR and DOR versus SOC sunitinib in patients with 
intermediate and high-risk renal cell carcinoma (Motzer et al. 2018). Relative to single agent 
checkpoint blockade, dual checkpoint blockade enhanced outcomes in small cell carcinoma high 
TMB (Hellmann et al. Cancer Cell 2018), improved ORR versus nivolumab in treatment-refractory 

12 
Protocol # 2018-0381 
Ipilumumab and Nivolumab 
 
 
 
sarcoma (D’Angelo et al. 2018), and in DNA mismatch repair-deficient/microsatellite-high 
colorectal cancer (Overman et al. 2018). Preliminary results of clinical trials of the combination of 
durvalumab and tremelimumab in recurrent and metastatic head and neck cancer have been 
disappointing (Liu S. et al ASTRO/HNS/ASCO 2018), however, there is some concern regarding 
dose and efficacy of tremelimumab relative to ipilimumab. The synergy with dual checkpoint 
blockade is thought to be multifactorial, including induction of novel responses to neoantigens, 
decreased activity of Tregs, improved motility and cytotoxicity of activated CD8+ T cells and 
enhanced immunological memory (Grosso et al. 2013; Zhao et al. 2018). 
 
Given the responses rates and toxicity profile, nivolumab 3 mg/kg every 2 weeks and ipilimumab 1 
mg/kg every 6 weeks will be the treatment regimen chosen for this study. 
 
In SCCHN, several ongoing phase 2 trials are investigating anti-PD1 or anti-PD-L1 in combination 
with anti-CTLA4 in patients with platinum-refractory R/M SCCHN or in first line. In the R/M SCCHN 
setting in first line (CheckMate 651) or platinum-refractory settings (CheckMate 714), the dose and 
schedule of nivolumab 3 mg/kg (or fixed dose equivalent) Q2w and ipilimumab 1 mg/kg Q6w is 
being utilized. Several phase 3 trials are comparing PFS and OS of anti-PD1 (or PD-L1) with or 
without anti-CTLA4 to standard of care platinum/5-FU/cetuximab (“extreme regimen”). A recent 
press release of Keynote 048 has reported that single agent pembrolizumab led to superior overall 
survival in comparison to triple agent platinum based chemotherapy in first line recurrent metastatic 
disease in patients with a CPS score of >20%, thus immediately changing the standard of care. A 
single, three-arm phase 3 trial is comparing anti-PD-1 + anti-CTLA4 (Checkmate 651) met accrual 
goals in December 2018. 
 
A window of opportunity trial in patients with early stage, resectable oropharynx cancer at MDA has 
randomized 28 patients to anti-PD-L1 +/- anti-CTLA has demonstrated very strong activity in this 
patient population with the majority of patients experiencing a response at the primary site, and 
complete responses have been observed. No safety concerns have arisen. These data provide 
strong preliminary safety and efficacy data. In yet another window of opportunity trial of single agent 
anti_PD1 in 37 patients with advanced resectable oral cavity cancer has demonstrated a high 
pathological response rate to a single dose of pembrolizumab and safety of the addition of this 
agent to adjuvant (chemo)radiotherapy post-operative. All of these studies are currently undergoing 
intensive biomarker analysis and preparation for submission for publication. 
 
In summary, in SQ-NSCLC the combination of nivolumab 3 mg/kg every two weeks and ipilimumab 
1 mg/kg every six weeks led to grade 3-4 TRAE of ~28% with a median number of cycles similar to 
that proposed in this trial. However, it should be noted that standard of care cisplatin-based chemo-
RT to ~70Gy is associated with grade 3-5 TRAE of 77-82% (Nguyen-Tan et al. 2014). IO and RT 
have minimal overlapping toxicities, with the exception of rash and hypothyroidism, and a total dose 
of RT to 60 Gy with reduced RT fields would be expected to significantly reduce mucosal and skin 
inflammation in comparison to 70Gy. 
 
 
1.7 Checkpoint Inhibitors and RT 
RT induces DNA damage and ER stress via reactive oxygen species (ROS), resulting in cell cycle 
arrest (Derer, Frey, et al. 2015). In addition to direct cytotoxic effects, RT may induce an immune 
effect important to tumor cell death (Demaria et al. 2005). RT can result in expression of activating 
cytokines and chemokines that may facilitate CD4+ and CD8+ T cell infiltration into the tumor as 
well as activation of dendritic cells, stimulating an immune response to the tumor. RT induced 
necroptosis of tumor may increase the immunogenicity of tumor cells. RT alone does not, however, 
induced anti-tumor immune responses outside of the radiation field. However, preclinical data 
support synergy between checkpoint inhibitors and RT (Table 1). Mouse models of poorly 

13 
Protocol # 2018-0381 
Ipilumumab and Nivolumab 
 
 
 
immunogenic tumors have demonstrated that concomitant administration of anti-CTLA- 4 
antibodies and RT results in antitumor T cell responses both in the radiation field as well as outside 
of it (an abscopal effect) (Demaria et al. 2005; Dewan et al. 2009). PD-1 blockade after completion 
of RT also has been shown to induce rejection of persistent tumors in mouse models (Deng et al. 
2014). Combination PD-1 blockade and anti-CD137 stimulation increased response to RT in a 
mouse model of triple negative breast cancer (Verbrugge et al. 2012) and PD-L1 blockade 
concomitant with RT improved survival in comparison to either therapy alone in mouse models of 
glioma (Zeng et al. 2013). Activation of dendritic cells (DCs) in response to radiation- induced tumor 
cell death may initiate innate and adaptive immune responses (Derer, Frey, et al. 2015).These data 
support a hypothesis that RT-induced cell death may result in alterations in the tumor immune 
environment (via upregulation of MHC class I, ICAM-1, CD80) as well as presentation of novel 
tumor antigens and generation of anti-tumor immune responses (Teng et al. 2015). 
 
In addition to novel antigen presentation, recent in vivo data indicate that RT can induce increased 
PD-L1 expression in tumors and thereby inhibit activation of cytotoxic CD8+ T cell responses, thus 
reducing the efficacy of RT. Concurrent administration of anti-PD1 antibodies improved response 
to RT and survival in mouse models whereas sequential therapy did not (Dovedi et al. 2014). 
 
There is preclinical and clinical data to support initiation of IO prior to RT for maximal synergy. In 
vivo models of sequencing of anti-PD-1 and RT have observed maximal anti-tumor effect when 
anti-PD-1 therapy is administered prior to and during RT (RL Ferris et al, personal communication 
2016). In mouse models of colon and breast carcinoma, sequential (i.e. adjuvant) administration of 
anti-CTLA4 and radiation had reduced therapeutic efficacy relative to concurrent therapy (Dewan 
et al. 2009). More recent in vivo data support substantial synergy between the combination of anti-
PD-1, anti-CTLA4 and RT. Tumor expression of PD-L1 was found to be a mechanism of resistance 
to anti-CTLA-4 and RT. Twyman-Saint Victor and colleagues demonstrated that genetic elimination 
of PD-L1 expression by CRISPR technology restored response to tumors that relapsed after RT 
and anti-CTLA4 therapy (Res 499 and Res 177). (Victor et al. 2015) Notably, in treatment-naïve 
tumors the combination of anti-PD-1/anti-CTLA4/RT markedly improved response and survival over 
anti-CTLA-4/RT. In this model, combination immunotherpy was administered prior, during and 
subsequent to RT. Each modality had a unique effect within the tumor microenvironment. Anti-
CTLA4 reduced Tregs and reversed exhaustion of T cells, increasing Ki67+GzmB+CD8+ TIL 
whereas anti-PD-1 expanded CD8+ T cells in the tumor microenvironment and peripheral blood. 
Additionally, RT increased the the diversity of the TCR repertoire of TILs in un-irradiated tumors 
(Victor et al. 2015). The results support combination IO with anti PD-1 and anti-CTLA4 together with 
RT as is proposed in this trial. 
 
In human subjects, case-reports support the existence of a clinically significant abscopal effect for 
patients with melanoma who have received ipilimumab prior to RT (Grimaldi et al. 2014; Stamell et 
al. 2013; Postow et al. 2012). Moreover, induction IO with INF-alfa(2b) and immune- RT 
demonstrated efficacy in locally advance melanomas (Hazard, Sause, and Noyes 2002; Conill et 
al. 2007) and neoadjuvant evaluation revealed a significant immunomodulating role for ipilimumab 
on Treg, MDSC and effector T cells in the circulation and tumor microenvironment in melanoma 
patients (Tarhini et al. 2014). 
 
Moreover, two trials have recently investigated the safety of anti-CTLA-4 (ipilimumab) in 
combination with cetuximab-IMRT to 68-70Gy (NCT01935921) or of anti-PD-1 (pembrolizumab) in 
combination with weekly cisplatin-IMRT to 70Gy in local-regionally advanced SCCHN 
(NCT02586207). In the former trial, the dose of ipilimumab was de-escalated from 3 to 1mg/kg for 
four doses Q3 weeks starting week 5 of RT. Two patients experienced a DLT of grade 4 radiation 
dermatitis at the dose of ipilimumab 3 mg/kg (J Bauman, personal communication). The dose of 
ipilimumab 1 mg/kg was recommended for future study. In the latter study, fixed-dose 

14 
Protocol # 2018-0381 
Ipilumumab and Nivolumab 
 
 
 
pembrolizumab 200 mgs was started 7 days prior to RT and continued for 8 doses. Thirty patients 
have been enrolled to date and no unexpected toxicities have been observed (Powell J Clin Oncol 
34, 2016, abstract TPS6107). A complete response rate of 100% has been observed in this study 
(J Lee, personal communication). Additionally, a recently completed safety evaluation trial (RTOG 
3504) includes 4 treatment arms designed to evaluate the safety of nivolumab concurrent with 
cetuximab-IMRT 68-70Gy, high-dose cisplatin 100 mgs/m2 X 3-IMRT 68-70 Gy, weekly cisplatin 
40 mg/m2/week X 7 and IMRT 68-70GY and IMRT 68-70Gy. No DLTs or other safety concerns 
were identified. Disease control has also been excellent with a median follow-up of over 12 months. 
 
Johnson and colleagues at Jefferson University presented safety data of the combination of 
nivolumab, ipilimumab and radiotherapy at ASCO 2019. Eligible patients included those with 
local-regionally very advanced Stage IVA-B HNSCC and ECOG PS 0-1. Patients received 
nivolumab 3 mgs/kg every 2 weeks for 17 doses and ipilimumab 1 mg/kg every 6 weeks for 6 
doses, starting 14 days prior to start of 70Gy RT (2 Gy per fraction/35 fractions). DLT was 
defined as any grade >3 in radiation field toxicity within two weeks after completion of 
radiotherapy. Safety data for a total of 12 patients were presented. Three of 12 patients 
experienced grade 3 immune mediated events, including colitis,  lipase increase or 
hyperglycemia. Rates of grade 3 dysphagia (4 of 12), oral mucositis (3 of 12), odynophagia (2 of 
12) and radiation dermatitis (1 of 12) were similar to that expected with radiotherapy alone. No 
DLT events were observed. However, 2 of 12 patients had radiation ulcer with or without 
bleeding more than three months after completion of RT. In one patient, the bleeding event was 
fatal (carotid rupture). Ten of 12 patients are alive without evidence of disease after 10 to 21 
months of follow-up. To date, no emergent safety signals have been observed and disease 
control is very promising. Accrual of an additional 12 patients is ongoing. 
 
Table 1: Systemic effects observed in preclinical studies after multimodal treatment of RT 
and anti-PD1/PDL-1 or anti-CTLA4 (Modified from Derer et al, Frontiers in Immunology 2015) 
(Derer, Deloch, et al. 2015) 
Checkpoint 
Tumor type 
Treatment 
Systemic effect 
PD-1 
Melanoma (B16), 
renal cortical 
adenocarcinoma 
(RENCA)1 
SABR (15Gy) + 
anti-PD-1 mAb (5x) 
Near complete-regression of 
primary tumor, 66% size 
reduction of non-irradiated tumor, 
increase CD8+ CTLs 
Glioma ( GL261)2 
RT (10Gy)+ anti- 
PD-1 mAb i.p. 
Tumor regression and long-term 
survival, decrease Tregs, 
increase CD8+ CTLs and 
INFgamma 
Melanoma (B16), 
Breast carcinoma 
(4T1-HA)3 
RT (12Gy)+ anti- 
PD-1 mAb i.p. 
(x3) 
Tumor regression and tumor 
control, decrease Tregs, 
increase CD8+ CTLs 
PD-L1 
Mammary 
Carcinoma 
(TUBO)4 
SABR (12Gy) + 
anti-PD-L1 mAb (4x) 
Side reduction of primary and 
abscopal tumors, decrease 
MDCS, increase CD8+ CTLs 
PD-1 and 
CD137 
Triple negative 
breast Cancer: AT-
3 tumors 5 
RT (4 X 4 Gy or 4 X 
5 Gy)+ anti PD-1 + 
anti-(α)-CD137 
Therapy in combination with either 
4 X 4 Gy or 4 X 5 Gy was more 
effective in controlling tumor 
outgrowth than either treatment 
alone; achieving 
rejection rates of 40% and 80%, 
respectively, increase CD8+ CTLs 

15 
Protocol # 2018-0381 
Ipilumumab and Nivolumab 
 
 
 
CTLA4 
Metastatic 
mammary 
carcinoma6 
RT (2x12 Gy) 
primary tumor + 
anti-CTLA4 (x3) 
Inhibition of lung metastases, 
increase CD8+ CTLs 
B16-F10 melanoma 
mouse model7 
Anti-CTLA4 (before 
or concurrent) + RT 
Complete responses were CD8 T-
cell-dependent. 
Cell lines that 
relapse after RT+ 
anti-CTLA4 (Res 
499 and Res 177) 7 
Resistance study 
Best predictor of resistance 
CD8/Treg ratio. 
Genetic elimination of PD-L1 on 
Res 499 by CRISPR restored 
response by increasing survival 
from 0 to 60% 
1.Park SS et al, Cancer Immunol Res 2015. 2. Zenj J et al, Int J Radiat Oncol Biol Phys 2013 3. 
Sharabi AB et al, Cancer Immunol Res 2015 4. Deng L et al, J Clin invest 2014 5. Verbrugge et al, 
Cancer Research 2012. 6. Demaria S, Clin Cancer Res 2005. 7. Twyman-Saint Victor, Nature 2015. 
 
 
These data support a hypothesis that combination IO concurrent with RT will be safe, feasible and 
synergistic and will induce clinically significant anti-tumor immune responses induced by 
“vaccination” to tumor-specific antigens exposed during radiation-induced cell death (Demaria and 
Formenti 2012). Such a phenomenon may be particularly relevant to viral-induced tumors, such as 
HPV-positive SCCHN. An advantage of “neoadjuvant” or “induction” IO is the ability to perform 
tumor biopsy before and after exposure in previously untreated patients in order to perform 
exploratory biomarker studies to identify immunological and histological correlates of tumor 
response. 
 
 
Table 2: Systemic effects observed in clinical trials after multimodal treatment of RT and 
anti-CTLA4 (Modified from Derer et al, Frontiers in Immunology 2015) (Derer, Deloch, et al. 
2015) 
Checkpoint 
Tumor type 
Treatment 
Systemic effect 
CTLA4 
Melanoma with brain 
metastasis (n=21)1 
Ipilimumab x4 + loco-
regional RT 
13/21 local responses, 11/21 local 
responses with abscopal effect and 
2/21 stable disease 
Metastatic 
castration-resistant 
prostate cancer 
(n=799) 
(NCT00861614)2 
RT (1x8Gy) per 
lesion =1-4 doses of 
ipilimumab (n=399) or 
placebo (n=400) 
Improve median OS 
Metastatic 
melanoma (phase I) 
(NCT01497808)3 
SBRT plus 
Ipilimumab 
(Escalating dose) 
Major tumor regressions 
1.Grimaldi AM, Oncoimmunology 2014. 2. Known ED, Lancet Oncol 2014. 3. Twyman-Saint Victor 
C, Nature 2015. 
 
 
1.8 Rationale for using the FDG-PET/CT as a predictive imaging marker in HPV-positive OPSCC. 
In this trial we will monitor FDG-PET CT response at 12-14 weeks after completion of radiotherapy 
as an early surrogate of long-term disease control in the study population. This FDG-PET/CT 
evaluation is included in the National Comprehensive Cancer Center Guidelines and is considered 
within the standard of care. This evaluation is utilized to guide need for salvage surgical resection 
of persistent disease (Loo et al. 2011; Nayak et al. 2007; Martin et al. 2009). A recently reported 

16 
Protocol # 2018-0381 
Ipilumumab and Nivolumab 
 
 
 
randomized clinical trial (PET-NECK) demonstrated equivalent OS for FDG- PET/CT surveillance 
vs. planned neck dissection after chemo-RT for local-regionally advanced SCCHN. 
 
The literature provides criteria for interpretation and estimates for FDG-PET/CT metabolic complete 
response (CR) rates obtained for HPV-positive oropharyngeal cancer patients when treated with 
standard of care chemoradiotherapy. Marcus et al have developed and validated a 5-point scoring 
system for PET-CT interpretation that has high inter-reader agreement and that strongly stratifies 
risk for cancer progression (Marcus et al. 2014). Among 123 HPV-positive cases, the metabolic CR 
by PET at ~12 weeks was 87%. Investigators at the University of Michigan reported an analysis of 
FDG-PET/CT response among 101 patients with Stage 3-4 (94% stage 4) HPV-positive 
oropharyngeal cancer treated with chemoradiation (Vainshtein JM Oral Oncol 2014). SUVmax 
thresholds of 6.5 for the primary tumor and 2.8 for the lymph nodes were used as cut-points to 
distinguish metabolic CR from less than CR, a cut-point established by discrimination of patients 
who had subsequent disease progression (Moeller B et al J Clin Oncol 2009). At 3-months, 92% of 
cases achieved a CR. Chen and colleagues utilized a lower threshold of SUVmax of 2.0 among 67 
patients with HPV-positive oropharynx cancer treated with chemoradiotherapy. The lower threshold 
resulted in a lower metabolic CR rate of 70% (Chen JY Arch Otolaryngol Head Neck Surg 2012). 
 
In the PET NECK trial, 75% of patients enrolled in the trial had HPV-positive OPSCC (Mehanna et 
al. 2016). A metabolic CR (interpreted per local practice without central review) was documented 
in 69% of patients, however, 25% of patients had FDG-PET/CT performed 10 or fewer weeks post 
completion of RT. The sensitivity and specificity of FDG-PET/CT for persistent disease after chemo-
RT strongly depend upon the time interval between the completion of therapy and FDG-PET/CT, 
with both improved when performed at least 12 weeks from RT (Yao et al. 2009; Sandro V. 
Porceddu et al. 2011). Residual uptake prior to 12 weeks is attributable to treatment-related 
inflammation. 
 
Importantly, a negative FDG-PET/CT at 12-14 weeks has a very high negative predictive value 
(NPV) for the presence of persistent disease (S Porceddu et al. 2014; Sandro V. Porceddu et al. 
2011). A meta-analysis of 2335 patients estimated post-treatment FDG-PET/CT >12 weeks post 
RT to have a 91.9% sensitivity and 86.7% specificity for residual disease at the primary site and 
90.4% and 94.3% for nodal disease (Gupta et al. 2011). 
 
Several studies have indicated that a negative FDG-PET/CT post RT has a high predictive value 
for long-term local-regional disease control. Bird and colleagues recently reported performance 
characteristics of FDG-PET/CT for residual disease in 146 OPSCC patients, the majority (92%) of 
which were treated with platinum or cetuximab together with IMRT 65Gy in 30 fractions. A positive 
post-treatment FDG-PET/CT was vaguely defined as “suspicious for residual or regional tumor”. In 
this study, sensitivity, specificity, positive predictive-value (PPV) and NPV for detection of residual 
disease were estimated as 92%, 85%, 56% and 98%, respectively. Only 9.6% of patients in this 
study underwent neck dissection as a result of an abnormal FDG-PET/CT, and 36% were positive 
for cancer. Thus, only 5 (3.4%) of 146 patients had pathologically confirmed persistent disease. 
Most importantly, the investigators observed a 92% 3-year DFS among patients with HPV-positive 
OPSCC who had a 12 week FDG-PET/CT with either a complete metabolic response (CMR) or an 
equivocal metabolic response followed by a CMR at a repeat FDG-PET/CT 12 weeks later. 
Additional studies have reported NPV of ~98% associated with negative FDG-PET/CT scans post 
treatment (Yao et al. 2009; Ryan et al. 2005; Moeller et al. 2009). Therefore, in HPV-positive 
OPSCC, a CR on FDG-PET/CT is a reasonable surrogate biomarker for 3-year local-regional and 
overall disease control. 
 
Residual treatment-related inflammatory response is thought to account for the reduced specificity 
of FDG-PET/CT scans performed prior to 12 weeks after RT. In this trial it is possible that the 

17 
Protocol # 2018-0381 
Ipilumumab and Nivolumab 
 
 
 
performance characteristics of post-treatment FDG-PET/CT could be altered by immunotherapy. 
No formal studies have yet evaluated this concern in any tumor type, including melanoma. However, 
FDG-PET/CT is commonly utilized to assess treatment response to immune modulation and used 
for follow-up to detect recurrence in melanoma (Perng, Marcus, and Subramaniam 2015). It has 
been noted, however, that pseudo progression, immune-related toxicities (e.g. colitis, hypophysitis), 
and mild inflammatory FDG uptake in lymph nodes can be detectable by FDG-PET/CT in patients 
on IO. In the latter case, SUV uptake is generally equivocal and is noted to resolve on repeat FDG-
PET/CT. 
 
As noted above, a scoring system for post-treatment FDG-PET/CT for SCCHN patients was 
recently validated by Marcus et al (The Hopkins Criteria). The five-point scoring system indicated 
in the Table below had high inter-rater agreement (kappa ~0.70) and high AUC (0.98) in comparison 
to 6 month clinical follow-up for local-regional disease progression (Marcus et al. 2014). To align 
with NRG HN002 interpretation, a score of 1 or 2 will be considered negative, a score of 3 
indeterminate, and a score of 4 or 5 will be positive. The standard of care for individuals with a 
positive FDG-PET/CT is further evaluation with ultrasound and fine needle aspiration biopsy 
followed by salvage surgery at the primary site and/or lymph nodes. Because of moderate PPV and 
sensitivity of FDG-PET/CT for residual disease, however, histopathological confirmation of residual 
disease is considered necessary for documentation of treatment “failure.” 
 
 
Five-Point Qualitative Post therapy Assessment Scoring System (Hopkins Criteria) for 
Head and Neck FDG-PET/CT/CT (Marcus et al. 2014) 
 
Score FDG uptake pattern 
Response category 
1 
FDG uptake at the primary site and nodes less than 
IJV. 
Complete metabolic 
response 
2 
Focal F-FDG uptake at the primary site and nodes 
greater than IJV but less than liver. 
Likely complete metabolic 
response 
3 
Diffuse F-FDG uptake at the primary site or nodes is 
greater than IJV or liver. 
Likely post-radiation 
inflammation 
4 
Focal F-FDG uptake at the primary site or nodes 
greater than liver. 
Likely residual tumor 
5 
Focal and intense F-FDG uptake at the primary site or 
nodes. 
Residual tumor 
IJV: Internal Jugular Vein. Scores 1, 2, and 3, which represent complete metabolic response, likely 
complete metabolic response, and likely post-radiation inflammation, respectively, were considered 
negative for tumor. Note, a score of 3 requires repeat PET in 12 weeks per protocol. Scores 4 and 
5, which represent likely residual tumor and residual tumor, respectively, were considered positive 
for tumor. New lesion would be considered as progressive disease. 
 
 
In summary, in this trial we will monitor metabolic CR rate as measured by FDG-PET/CT at 12- 14 
weeks post treatment as defined by the Hopkins Criteria and validated by Marcus et al. Prospective 
studies have established that a metabolic CR has a high predictive value (~95%) for 3-year 
progression-free survival. An overall metabolic CR rate of 87% would be expected in the patient 
population when treated by standard chemoradiotherapy. 
 

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Protocol # 2018-0381 
Ipilumumab and Nivolumab 
 
 
 
 
1.9 Rationale for assessment of tumor HPV status by p16 IHC and HPV DNA in situ hybridization 
detection for HPV Testing. 
Tumor p16 expression as measured by immunohistochemistry (IHC) is a common clinical surrogate 
for tumor HPV status and is scored as positive if strong and diffuse nuclear and cytoplasmic staining 
is present in ≥ 70% of tumor cells (Jordan et al. 2012). The p16 IHC assay is readily available, 
inexpensive, and has excellent interrater agreement on interpretation (Jordan et al. 2012). 
Moreover, the laboratory methods used for p16 IHC and HPV16 ISH have demonstrated good 
prognostic value on formalin fixed, paraffin-embedded (FFPE) material (Ang KK et al. 2010). 
 
When restricted to testing of OPSCC, the assay has high sensitivity (≥90%) but only moderate 
(>80%) specificity when compare to the gold standard of high-risk HPV mRNA expression (Thavaraj 
et al. 2011). Despite being the gold standard for causality, HPV E6/E7 RNA detection is difficult to 
reproduce on a clinical setting. Therefore, to improve specificity of testing a common algorithm 
recommends p16 IHC as a first step due to its high sensitivity, follow by HPV DNA ISH methods for 
use as confirmation of the viral aetiology, leading to less equivocal molecular classification (Smeets 
et al. 2007). The combination of p16 IHC and HPV DNA ISH has demonstrated 98% specificity in 
comparison to HPV mRNA expression (Jordan et al. 2012)(Thavaraj et al. 2011). 
 
An alternative to confirmation with HPV DNA ISH is HPV RNA ISH with the RNAscope HPV test. 
High concordance between RNA ISH and p16 IHC of 96.4% or DNA ISH of 83.5% has been 
observed (Ukpo et al. 2011; Bishop et al. 2012). In comparison to the gold standard of HPV E6/E7 
mRNA by reverse transcriptase PCR, RNAscope had a sensitivity of 93-97%, specificity of 93- 94%, 
positive predictive-value of 91-96% and negative predictive value of 88-98% (Mirghani H. et al. 
2015; Schache et al. 2013). 
 
Clinical trials investigating “de-intensification” strategies for patients with HPV-positive OPSCC 
should require high specificity to avoid false positives and consequent under treatment of patients 
with true HPV-negative OPSCC. Therefore combined positivity for both p16 IHC and HPV ISH is 
necessary to provide the high specificity required (Jordan et al. 2012). The combination of p16 IHC 
and RNAscope is a reasonable clinical alternative to p16 IHC and HPV DNA ISH. 
 
Rationale for Principal Secondary Outcome of Pharyngeal Dysphagia 
 
Fortunately, survival rates from HPV-positive oropharyngeal cancer are high, but as a consequence 
long-term toxicities of radiotherapy in this patient population have become problematic. The most 
frequent high-grade (CTCAE grade 3-4) long-term toxicity reported with standard of care 
chemoradiotherapy is dysphagia, traditionally measured by g-tube dependence. G tube 
dependence at 1 and 5 years is ~26-28% and 6-13% with cisplatin-based chemoradiotherapy 
(Nguyen_tan JCO 2014). Rates appear slightly lower among p16-positive patients (~17% and 5%), 
likely due to lower T stage and thus treatment volumes to the oropharynx. However, the effect on 
quality of life for patients from chronic swallowing dysfunction is underrepresented by g-tube 
dependence alone and should include dysphagia that can result in life threatening complications 
(aspiration pneumonia), nutritional deficiencies, and psychosocial morbidity. Hutcheson and 
colleagues at MD Anderson have developed and validated a 5-point grading system (dynamic 
imaging grade of swallowing toxicity or DIGEST) for interpretation of modified barium swallow 
studies that combines an assessment of safety and efficiency of swallowing function (Hutcheson 
Cancer 2017). Additionally, pharyngeal dysphagia DIGEST grade inversely correlated with patient 
perception of swallowing dysfunction as measured by MDADI. Approximately 31% of patients with 
any stage oropharynx cancer treated with IMRT experience Grade 2 or greater dysphagia 3-6 
months after radiotherapy as measured by DIGEST (Kamal 2018). Sixteen percent (16%) of low to 
intermediate risk oropharyngeal carcinoma patients (AJCC 7th ed. T1-2 N0-2b, T3N0) treated with 

19 
Protocol # 2018-0381 
Ipilumumab and Nivolumab 
 
 
 
primary displayed pharyngeal dysphagia DIGEST grade 2 or higher (Hutcheson, manuscript under 
review). Rates of pharyngeal dysphagia are affected by the total dose of radiotherapy (in particular 
to laryngeal, submental and pharyngeal constrictors), field size and exacerbated by concurrent 
chemotherapy. Alterations in radiation dose to 55-60 Gy and to treatment volume as proposed in 
this trial have the potential to reduce the frequency and severity of pharyngeal dysphagia as 
measured by DIGEST by ~25% (from 40% to 30%). 
 
Summary of Rationale 
• 
Long-term toxicities of platinum-based chemo-RT are a concern for patients with HPV- 
positive OPSCC given they are young at diagnosis and have high survival rates. 
• 
Recent trials have demonstrated that local-regional control and progression-free survival 
can be maintained with CT and reduced dose IMRT among patients with low-intermediate 
volume (T4, <N3) HPV-positive OPSCC. 
• 
Anti-PD1 therapy with nivolumab reduced the risk of death by ~50% in patients with 
platinum-refractory HPV-positive OPSCC in comparison to standard of care single agent 
chemotherapy, regardless of PD-L1 expression, indicating responsiveness to IO even when 
refractory to CT and RT. 
• 
Combination IO with anti-CLTA4 (ipilimumab) and anti-PD1 (nivolumab) increases durable 
response rates in patients with melanoma and NSCLC in comparison to anti-PD-1 therapy 
along and is currently under investigation in phase 3 trials for first line therapy of R/M 
SCCHN. 
• 
Ongoing clinical trials of the addition of anti-PD1 (Pembrolizumab) to platinum-based 
chemo-RT and anti-CTLA4 to cetuximab-based chemo-RT for patients with local- regionally 
advanced SCCHN have demonstrated no safety concerns to date. 
• 
Preclinical models demonstrate substantial synergy between anti-PD-1 and anti-CTLA-4 
and RT. 
• 
HPV-positive OPSCC is an excellent candidate for IO given higher TIL, higher interferon- 
associated inflammation gene signature and higher PD-L1 expression in comparison to 
HPV-negative SCCHN. 
• 
Therefore, we designed a phase 1/2 clinical trial to investigate combination immuno-RT with 
anti-PD1 (Nivolumab) and anti-CTLA4 (Ipilimumab) with reduce field and dose of intensity 
modulated radiation therapy (IMRT) in patients with low-volume (T1 N2, T2 N1- 2, T3 N0-
2), local-regionally advanced HPV-positive OPSCC. 
 
 
2. PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILTY CRITERIA 
 
2.1 Patient Selection Guidelines 
Investigators should consider all relevant medical and non-medical factors and the risks and 
benefits of study therapy when deciding if a patient is an appropriate candidate for this trial. 
 
Patients must have the psychological ability and general health that permits completion of the study 
requirements and required follow up. 
 
Women of childbearing potential and men who are sexually active should be willing and able to use 
medically acceptable forms of contraception throughout the treatment phase of the trial and until at 
least 23 weeks (161 days) for women and 31 weeks (217 days) for men following the last dose of 
study treatment (nivolumab or ipilimumab). 
 
Submission of biospecimens (tumor) is mandatory for this trial. Therefore, investigators should 
consult with pathology departments about availability and release of specimens before discussing 
enrollment with a patient. 

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Protocol # 2018-0381 
Ipilumumab and Nivolumab 
 
 
 
 
Subjects must have signed and dated the approved written informed consent form in accordance 
with regulatory and institutional guidelines. This must be obtained before the performance of any 
protocol related procedures that are not part of normal subject care. 
 
 
 
2.2 Eligibility Criteria 
 
2.2.1 
Histologically or cytologically newly confirmed diagnosis of squamous cell carcinoma (including the 
histological variants of papillary or basaloid) of the oropharynx (tonsil, base of tongue, soft palate, 
or oropharyngeal walls). 
2.2.2 
Clinical AJCC 7th edition stage T1N2a-N2cM0, T2N1-N2cM0, T3N0-N2cM0, excluding T1N0-N1 
and T2N0, equivalent to AJCC 8th edition stage 1 and 2 (T1 N1-N2, T2 N1-N2, T3 N0-N2) (Brian 
O’Sullivan et al. 2016). 
2.2.3 
Tumor positive for p16 IHC (defined as greater than 70% strong nuclear or nuclear and cytoplasmic 
staining of tumor cells) (Jordan et al. 2012) and HPV DNA in situ hybridization or HPV mRNA 
RNAScope. Repeat samples may be required if adequate diagnostic tissue is unavailable for 
testing.  
Note: Although confirmation of tumor HPV-positive status via DNA ISH or RNAScope is preferred, 
cobas HPV testing may be performed for patients who only have banked tissue from FNA biopsy. 
2.2.4 
PD-L1-positive status as determined by an immunohistochemistry assay. 
2.2.5 
Zubrod Performance Status of 0-1 
2.2.6 
Age ≥ 18 years 
2.2.7 
Patients must have radiographically evident measurable disease at the primary site or at nodal 
stations per RECIST 1.1 documented by diagnostic quality CT or MRI of the neck with contrast 
within 28* days prior to registration; a FDG-PET/CT of the neck performed for the purposes of 
radiation planning is acceptable as a substitute if the CT is of diagnostic quality 
2.2.8 
Diagnostic quality cross sectional imaging of the thorax within 28* days prior to registration. A 18- 
FDG-PET/CT or conventional CT are acceptable. 
2.2.9 
FDG-PET/CT of the neck is required within 28* days prior to registration for comparison to post 
treatment FDG-PET/CT. Note: Repeat imaging for variability within 96 hours of this time frame 
should be allowed to avoid unnecessary re-imaging and its financial potential physical 
consequences for patients. 
2.2.10 
History and physical exam within 1 month prior to registration. 
2.2.11 
Fiberoptic exam with laryngopharyngoscopy (mirror and/or fiberoptic and/or direct procedure) by 
Radiation Oncologist, Medical Oncologist or ENT/Head and neck surgeons within 28 days prior to 
registration; 
2.2.12 
Adequate hematologic function within 2 weeks prior to registration, defined as follows: 
• 
Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3; 
• 
Platelets ≥ 100,000 cells/mm3; 
• 
Hemoglobin ≥ 8.0 g/dl; Note: The use of transfusion or other intervention to achieve Hgb ≥ 
8.0 g/dl is acceptable. 
 
2.2.13 
Adequate renal function within 2 weeks prior to registration, defined as follows: 
 
• 
Serum creatinine < 1.5 mg/dl or creatinine clearance (CC) ≥ 50 ml/min determined by 24- 
hour collection or estimated by Cockcroft-Gault formula: 
 
CCr male  = [(140 – age) x (wt in kg)] 
[(Serum Cr mg/dl) x (72)] 
 

21 
Protocol # 2018-0381 
Ipilumumab and Nivolumab 
 
 
 
CCr female = 0.85 x (CrCl male) 
 
2.2.14 
Adequate hepatic function within 2 weeks prior to registration defined as follows: 
 
• 
Bilirubin < 2 mg/dl; 
• 
AST or ALT < 3 x the upper limit of normal 
 
2.2.15 
Na, K, Cl, glucose, Ca, Mg, albumin, amylase, lipase, TSH within 2 weeks prior to registration 
2.2.16 
Negative serum pregnancy test within 2 weeks prior to registration for women of childbearing 
potential; 
2.2.17 
Seronegative for active Hepatitis-B or hepatitis-C infection and seronegative for HIV. 
2.2.18 
Mandatory submission of hematoxylin and eosin (H&E) and paraffin-embedded tumor block or 
unstained slides. 
*Note: 4 day window allowed for the 28 day-window assessments 
  
2.3 Exclusion Criteria 
 
2.3.1 
Cancers of the oral cavity (oral tongue, floor mouth, alveolar ridge, buccal or lip), or the 
nasopharynx, hypopharynx, or larynx, even if p16 positive; 
2.3.2 
Carcinoma of the neck of unknown primary site origin (even if p16 positive); 
2.3.3 
Definitive clinical or radiologic evidence of metastatic disease or adenopathy below the clavicles; 
2.3.4 
Gross total excision of both primary and nodal disease with curative intent; this includes 
tonsillectomy, local excision of primary site, and nodal excision that removes all clinically and 
radiographically evident disease; 
2.3.5 
Simultaneous primary cancers or separate bilateral primary tumor sites; 
2.3.6 
Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a 
minimum of 1095 days (3 years) (for example, carcinoma in situ of the breast, oral cavity, or cervix 
are all permissible); 
2.3.7 
Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different 
cancer is allowable; patients who have received PD-1/PD-L1 or CTLA4 therapy for a previous 
malignancy are not eligible; 
2.3.8 
Prior RT to the region of the study cancer that would result in overlap of radiation therapy fields; 
2.3.9 
Severe, active co-morbidity defined as any of the following: 
• 
Unstable angina and/or congestive heart failure requiring hospitalization 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; 
• 
A diagnosis of immunodeficiency or use of any form of systemic immunosuppressive therapy. 
The use of physiologic doses of corticosteroids may be approved after consultation with the 
Sponsor. 
2.3.10 Active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of 
disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy 
(e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) is not considered a form of systemic treatment. Steroid premedications for 
contrast allergy allowed (see below). 
2.3.11 Has evidence of active, non-infectious pneumonitis. 
2.3.12 Has received a live vaccine within 30 days of planned start of study therapy. 
 
2.3.13 Pregnancy or breast-feeding; this exclusion is necessary because the treatment involved in this 
study may be significantly teratogenic. 
2.3.14 History of severe hypersensitivity or contraindication to CT or PET contrast material uncontrolled 

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Protocol # 2018-0381 
Ipilumumab and Nivolumab 
 
 
 
with pre-medications (steroids, antihistamines). 
 
 
3. REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP 
 
3.1 Assessments pre-treatment: 
Assessments 
Days prior to C1D1 (unless specified)** 
Informed Consent 
28 
Patient’s smoking history 
28 
History and physical examination included 
height & weightA 
28 
Fiberoptic exam with 
laryngopharyngoscopy 
28 
CT/MRI of neck 
28 
Chest imaging (CT or FDG-PET/CT/) 
28 
FDG-PET/CT of neck* 
28 
Zubrod Performance Status 
14 
Cell blood count/differential 
14 
Bilirubin, AST or ALT 
14 
Serum creatinine or creatinine clearance 
14 
HIV testing 
14 
Hepatitis B and C testing 
14 
T3 (total or free), T4 and TSH 
14 
Serum pregnancy test, if applicable 
14 days prior to ipi/nivo 
Na, K, Cl, glucose, Ca, Mg, and albumin 
14 
Hepatic function panel, lipase, amylase 
14 
EKG 
28 
Modified Barium Swallow 
any time before treatment start 
MDASI/MDADI*** 
any time before treatment start 
Tumor Specimen 
28 
Oral rinse sample 
14 
Blood biospecimens**** 
day 1 prior to ipi/nivo 
*NOTE: Use of the same PET/CT scanner is strongly recommended for each on-protocol 
assessment. 
 
**4 day window allowed for the cut-point for the 28 day window assessments 
 
*** See Appendix II 
 
****Collection of blood biospecimens will be obtained 1 day prior to ipi/nivo and as follows: 
• 
2 x 10 cc red top tubes for serum, WBC 

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Protocol # 2018-0381 
Ipilumumab and Nivolumab 
 
 
 
• 
2 x 10 cc Streck tubes for plasma 
 
           A Concomitant medications will be captured in the participants’ medical record.  
 
3.2 Assessments during treatment: 
 
Assessments 
Prior to each dose of IOB 
Physical examination 
including height & weightA,C 
X (height only at baseline) 
Fiberoptic exam with 
laryngopharyngoscopy 
Within 7 days of start of radiation therapy 
Adverse events evaluationC 
X 
Zubrod Performance StatusC 
X 
Cell blood count/differentialC 
X 
Bilirubin, AST or ALT** 
X 
Serum creatinine or creatinine 
clearance** 
X 
T3 (total or free), T4 and 
TSH** 
Prior to start of every cycle 
Na, K, Cl, glucose, Ca, Mg, 
and albumin** 
X 
Lipase, amylase, hepatic 
function panel** 
X 
Serum pregnancy test, if 
applicable 
Within 24 hours of first ipi/nivo and every 4 weeks until end of 
therapy 
Tumor biopsy 
Cycle 1 Days 15-22 for first 15 patients that have started on 
therapy OR Cycle 1 Days 36-43 for the remainder of eligible 
participants that have started therapy  
Oral rinse collectionC 
X 
Blood biospecimen 
collection***, C 
X*** 
MDASI/MDADI 
Within 7 days after last day of radiotherapy 
CT/MRI of Neck* 
Within 7 days before first dose of radiotherapy 
 
*Chosen imaging modality should be same as baseline 
 
**Blood work window may be within 48 hours of each dose of immunotherapy 
 
***Collection of blood biospecimens will be as follows: 
• 
2 x 10 cc red top tubes for serum, WBC 
• 
2 x 10 cc Streck tubes for plasma 
 
         A Concomitant medications will be captured in the participants’ medical record.  
      B Subjects may be dosed with nivolumab no less than 12 days from the previous dose. 
Ipilimumab dosing should occur within a +/- 3 day window.  
C These assessments should be performed relative to IO dosing within 48 hours prior to IO dose, 
including collection of oral rinses and blood correlative samples.  

24 
Protocol # 2018-0381 
Ipilumumab and Nivolumab 
 
 
 
 
3.3 Assessments post treatment, follow-up: 
 
Assessments 
Timing post treatment 
 
4 weeks after 
the last dose 
of Nivolumab 
3 months 
from the end 
of IMRT  
(12-14 weeks) 
Every 3 months from the end 
of IMRT during first 2 years; 
every 6 month for 3 years, 
after annually 
Physical examination 
included height & weightA 
X 
X 
X 
CT/MRI of neck* 
8-10 weeks 
after RT 
X 
At 6, 9, and 12 mon after RT 
then every 6 mon X 1 year. 
FDG-PET/CT of neck and 
chest +/- contrast** 
 
X 
At 6 mon after RT in patients 
with an equivocal FDG-PET/CT 
at 12- 14 weeks, then only in the 
event of suspicion of disease 
i
Chest CT 
 
 
12 and 24 months from end of 
RT 
Modified Barium Swallow 
 
 
3- 6 months from end of RT  
(+/- 6 week window) 
MDADI/MDASI 
 
 
18-24 months from end of RT 
(+/- 2 month window) 
Adverse events evaluation 
X 
X 
 
Treatment related late 
toxicity 
 
 
X 
Zubrod Performance 
Status 
X 
X 
X 
Cell blood 
count/differential 
X 
X 
 
Bilirubin, AST or ALT 
X 
X 
 
Serum creatinine or 
creatinine clearance 
X 
X 
 
T3 (total or free), T4 and 
TSH 
X 
X 
 
Na, K, Cl, glucose, Ca, 
Mg, and albumin 
X 
X 
 
Serum pregnancy test, if 
applicable 
X 
X 
 
Oral rinse collection 
X 
X 
X 

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Protocol # 2018-0381 
Ipilumumab and Nivolumab 
 
 
 
Blood biospecimen 
collection 
X*** 
X 
 
Biopsy 
If suspicious of tumor recurrence 
 
*Chosen imaging modality should be same as baseline 
 
**NOTE: Use of the same PET/CT scanner is strongly recommended for each on-protocol 
assessment. 
 
***Collection of blood biospecimens will be performed 4 weeks after the last dose of Nivolumab 
and as follows: 
• 
2 x 10 cc red top tubes for serum, WBC 
• 
2 x 10 cc Streck tubes for plasma 
 
           A Concomitant medications will be captured in the participants’ medical record.  
        
       B For patients requiring FDG-PET/CT at 6 months (due to an equivocal FDG-PET/CT at 12-14 
weeks), a CT/MRI of neck is not required at 6 months after RT. 
 
 
4. DRUG INFORMATION 
Investigational Study Agent 
 
Study drug includes Investigational [Medicinal] Product (IP/IMP) and can consist of the following: 
 
Product Description / 
Class and Dosage 
Form 
Potency 
Blinded or 
Open Label 
Packaging / 
Appearance 
Storage 
Conditions 
(per label) 
Nivolumab Injectiona 
100 mg/vial 
(10 mg/mL) 
Open Label 
10mL vial containing 
a clear to opalescent, 
colorless to pale 
yellow liquid; may 
contain particulates  
Store 2 to 8°C. 
Store in 
original 
package. Do 
not freeze. 
Protect from 
light. 
Ipilimumab Injection 
200 mg/vial 
(5 mg/mL) 
Open Label 
40mL vial containing 
a clear, colorless 
liquid; may contain 
particulates 
 
Store 2 to 8°C. 
Store in 
original 
package. Do 
not freeze. 
Protect from 
light. 
a May be labeled as either “BMS-936558-01” or “Nivolumab”. 
 
 
4.1 Treatment plan/regimen description 
 
4.1.1 
Nivolumab and Ipilimumab dosing 
Subjects will receive a total of two, six-week cycles starting 6 weeks prior to start of RT. 
 

26 
Protocol # 2018-0381 
Ipilumumab and Nivolumab 
 
 
 
Intravenous nivolumab 3 mg/kg will be administered over 30 minutes on day 1, 15, and 29 and 
ipilimumab 1 mg/kg over 30 minute on day 1 of a six week cycle. 
 
When nivolumab and ipilimumab are administered on the same day, separate infusion bags and 
filters must be used for each infusion. Nivolumab is to be administered first. The second infusion 
will always be ipilimumab and will start no sooner than 30 minutes after completion of the nivolumab 
infusion. Subjects who require small volumes may infuse over < 30 minutes but no less than 20 
minutes. 
 
Nivolumab and ipilimumab may be diluted in 0.9% Sodium Chloride Solution or 5% Dextrose 
solution. 
 
Dosing calculations should be based on the actual body weight. If the subject’s weight on the day 
of dosing differs by >10% from the weight used to calculate the prior dose, the dose must be 
recalculated. All doses should be rounded to the nearest milligram. There will be no dose reductions 
allowed for toxicity both nivolumab and ipilimumab. 
 
Subjects may be dosed with nivolumab no less than 12 days from the previous dose. Ipilimumab 
dosing should occur within a +/- 3 day window. There are no premedications recommended. 
 
Doses of nivolumab and/or ipilimumab may be interrupted, delayed, or discontinued depending on 
how well the subject tolerates the treatment. No dose de-escalations will occur. 
 
Dosing Schedule 
 
 
Week 1 
(C1D1) 
Week 3 
(C1D15) 
Week 5 
(C1D29) 
Week 7 
(C2D1) 
(Start IMRT) 
Week 9 
(C2D15) 
Week 11 
(C2D29) 
Nivolumab 3 mg/kg 
X 
X 
X 
X 
X 
X 
Ipilimumab 1 mg/kg 
X 
 
 
X 
 
 
Ipilimumab 1 mg/kg 
(Alternate schedule 
if DLT observed) 
X 
 
 
 
 
X 
 
 
Definition of dose limiting toxicity 
The period of observation for a DLT is from the first dose of nivolumab/ipilimumab through to 28 
days after the completion of RT. 
 
A nivolumab or ipilimumab attributable, dose-limiting toxicity (DLT) will be defined as follows: 
 
• 
Any ≥ grade 3 adverse event (CTCAE, v. 4) that is related to nivolumab/ipilimumab that does 
not resolve to grade 1 or less within 28 days; 
 
• 
A delay in RT of >1 week due to toxicity related to nivolumab/ipilimumab; Inability to complete 
RT due to toxicity related to nivolumab/ipilimumab; 

27 
Protocol # 2018-0381 
Ipilumumab and Nivolumab 
 
 
 
 
• 
Grade 3 or greater radiation mucositis that does not resolve to <3 within 28 days from end of 
RT.  
 
Note: Toxicity related to nivolumab/ipilimumab that does not affect delivery of RT is not a dose 
limiting toxicity unless it satisfies criteria 1 noted above. In the event of 0-2 nivolumab/ipilimumab 
attributable DLT events, the study will proceed to phase 2. In the event of >2 of 8 
nivolumab/ipilimumab attributable DLT, a second cohort of 8 patients will be enrolled at an alternate 
schedule in which ipilimumab will be administered on cycle 2 day 29, equivalent to an every 12 
week schedule of ipilimumab. This alternate schedule is chosen due to the possibility of increased 
inflammation within the RT field, as indicated by the two grade 4 radiation dermatitis events in the 
completed trial of the addition of ipilimumab to cetuximab-RT at the University of Pittsburgh. We 
note, however, that this occurred with concomitant cetuximab and a total RT dose to 68-70 Gy. 
 
5. TREATMENT MODIFICATIONS/MANAGEMENT 
Nivolumab  and  ipilimumab  should  be  administered  only  if  all  hematological  and  non- 
hematological toxicity criteria are met. 
 
There will be no dose modifications for nivolumab or ipilimumab. Instead, the dose will be delayed 
or discontinued as specified below. 
 
Nivolumab may be continued in the event of a toxicity that in the opinion of the investigator is 
attributable to ipilimumab after review with the principal investigator. 
 
Radiation therapy may continue at the discretion of the treating physician if nivolumab and/or 
ipilimumab are held unless specific criteria to hold RT are met. 
 
If RT is delayed due to technical or scheduling constraints, the schedule of nivolumab and/or 
ipilimumab administration should not be altered. 
 
Tumor assessments for all subjects should continue as per protocol even if nivolumab and/or 
ipilimumab dosing is delayed (FDG-PET/CT will be performed 12 to 14 weeks from the end of 
IMRT). 
 
 
5.1 IO Dose Modifications 
 
5.1.1 
Dose Delay criteria for Nivolumab and Ipilimumab 
Dose delay criteria apply for all TRAEs. Treatment delay may be up to 6 weeks for nivolumab and 
up to 12 weeks for ipilimumab from the last dose. 
 
Nivolumab/Ipilimumab administration should be delayed for CTCAE, version 4, toxicities as 
indicated in the tables below that in the opinion of the treating physician are related to the study 
drug. Please note nivolumab and or ipilimumab therapy will not be delayed for the following: 
 
• 
Grade 2 weight loss; 
• 
Grade 2 nausea that in the opinion of the investigator is related to radiation; 
• 
Grade 3 radiation dermatitis; 
• 
Any Grade 2-3 mucositis, dysphasia, or pharyngolaryngeal pain that in the opinion of the 
treating physician is related to radiation therapy for head and neck cancer; 
• 
Grade 3 or 4 isolated lymphopenia; 
• 
Grade 3 asymptomatic elevation of lipase or amylase 

28 
Protocol # 2018-0381 
Ipilumumab and Nivolumab 
 
 
 
• 
Grade 3 isolated anemia if, in the opinion of the treating physician, the anemia is not related 
to the study drug (e.g. related to chronic disease, iron deficiency, RT) 
 
Bleeding from the tumor site may occur at any time in head and neck cancer patients receiving 
therapy. Appropriate clinical management of bleeding per standard of care is up to the patient’s 
treating physician. There is no evidence that immunotherapy increases rates or severity of bleeding 
(in the absence of drug induced thrombocytopenia), and therefore therapy should be continued 
after the patient has been stabilized and bleeding controlled.  
 
For immunotherapy-induced lymphedema or edema of the head and neck of grade 1, continue 
without change, for grade 2 without airway or swallowing compromise, hold until resolved to ≤ 
grade 1. Oral steroids may be used if clinically appropriate. For grade 3 or with any airway 
compromise, stabilize the airway per the standard of care and initiate oral or IV steroids (per 
Appendix 1) and taper as clinically appropriate.    
 
 
Skin Rash and Oral 
Lesions 
Management/Next Dose for Ipilimumab/Nivolumab 
≤ Grade 1 
No change. Resume treatment. See guidelines for management in 
Appendix I. 
Grade 2 
No change*. Resume treatment. See guidelines for management in 
Appendix I. 
Grade 3 
Hold* until ≤ Grade 1; see guidelines for management in Appendix 
I. 
Resume at same level at investigator discretion 
Grade 4 
Off protocol therapy 
*Patients with grade 2 or greater purpuric or bullous lesions must be evaluated for vasculitis, 
Steven-Johnson syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), 
toxic epidemal necrolysis (TEN), and autoimmune bullous disease including oral lesions of 
bullous pemphigus/pemphigoid by a specialist. Pruritus may occur with or without skin rash 
and should be treated symptomatically if there is no associated liver or GI toxicity. Note skin 
rash typically occurs early and may be followed by additional events particularly during steroids 
tapering. Note this does not apply to oral mucositis due to radiation. 
 
Recommended management: TRAEs management guidelines (in Appendix I) 
 
 
Liver Function 
AST/ALT/T. Bili * 
 
Management/Next Dose for Ipilimumab/Nivolumab 
≤ Grade 1 
No change. Resume treatment. 
Grade 2 
Hold until UNL or baseline. See guidelines for management in Appendix I. 
Grade 3 
Off protocol therapy. See guidelines for management in Appendix I. 

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Protocol # 2018-0381 
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Grade 4 
Off protocol therapy. See guidelines for management in Appendix I. 
Continued treatment of active immune mediated hepatitis may exacerbate ongoing inflammation. 
Holding drug to evaluate liver function test (LFT) changes and early treatment are recommended. 
LFT changes may occur during steroid tapers from other events and may occur together with other 
GI events including cholecystitis/pancreatitis. 
 
Subjects with baseline Grade 1 AST/ALT or total bilirubin who require dose delays for reasons 
other than a 2-grade shift in AST/ALT or total bilirubin may resume treatment in the presence of 
Grade 2 AST/ALT or total bilirubin. 
Subjects with combined Grade 2 AST/ALT and total bilirubin values meeting discontinuation 
parameters should have treatment permanently discontinued. 
 
 
Renal Function 
Serum Creatinine 
Management/Next Dose for Ipilimumab/Nivolumab 
≤ Grade 1 
Resume treatment. 
Grade 2 
Hold until UNL or baseline. See guidelines for management in 
Appendix I. 
Grade 3 
Hold until UNL or baseline. See guidelines for management in 
Appendix I. 
Grade 4 
Off protocol therapy 
For Grade 2 or greater, consider renal biopsy. 
 
 
Diarrhea/ Colitis 
Management/Next Dose for Ipilimumab/Nivolumab 
≤ Grade 1 
No change. See guidelines for management in Appendix I. 
Grade 2 
Hold until Grade 0 or baseline. See guidelines for management in 
Appendix I. 
Grade 3 
Permanently discontinue Ipilimumab; may continue Nivolumab if 
diarrhea/colitis resolves to grade 1 or less at the discretion of the study 
PI.  
Grade 4 
Off protocol therapy. See guidelines for management in Appendix I. 

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Protocol # 2018-0381 
Ipilumumab and Nivolumab 
 
 
 
See GI TRAE Algorithm for management of symptomatic colitis (in IB). 
Patients with grade 2 symptoms but normal colonoscopy and biopsies may be retreated after 
resolution. Patients with persistent symptoms greater than 14 days who require steroids should 
be taken off study treatment. Please evaluate pituitary function prior to starting steroids if 
possible without compromising acute care. 
Evaluation for all patients for additional causes includes C. diff, acute and self-limited infectious 
and foodborne illness, ischemic bowel, diverticulitis, and IBD. 
 
 
Pancreatitis 
Amylase/Lipase 
Management/Next Dose for Ipilimumab/Nivolumab 
(See Note) 
≤ Grade 1 
If symptomatic, hold dose until Grade 0. Resume if asymptomatic.  
Grade 2 
If symptomatic, hold until Grade 0. Resume if asymptomatic. 
Grade 3* 
If symptomatic, hold until Grade 0. Resume if asymptomatic. Patients 
who develop symptomatic pancreatitis or DM should be taken off 
treatment. 
Grade 4** 
Off protocol therapy 
Patients may develop symptomatic and radiologic evidence of pancreatitis as well as DM and 
DKA. Lipase elevation may occur during the period of steroid withdrawal and with other immune 
mediated events or associated with colitis, hepatitis, and patients who have asymptomatic lipase 
elevation typically have self-limited course and may be retreated. For treatment management of 
symptomatic pancreatitis please follow the Hepatic Adverse Event Management Algorithm (in 
Appendix I). 
 
* Patients with Grade 3 asymptomatic lipase or amylase elevation (2-5 X ULN) may receive ipi or 
nivo treatment at the discretion of the treating physician.  
 
**Excluding asymptomatic amylase and lipase increases 
 
NOTE: RT to the head and neck is associated with transient elevations in salivary amylase that 
can be of any grade. In the event of asymptomatic solitary amylase elevation, the investigator 
should consider fractionation of salivary vs. pancreatic amylase. The investigator may attribute 
 
 
Pneumonitis 
Management/Next Dose for Ipilimumab/Nivolumab 
≤ Grade 1 
Hold dose pending evaluation and resolution to ≤ Grade 0 or baseline 
including baseline pO2. Resume after pulmonary and/or ID consultation. 
Grade 2 
Hold dose pending evaluation. Resume after pulmonary and/or ID 
consultation if lymphocytic pneumonitis is excluded. Off study if grade 2 
symptoms do not improve or worsen after 2 weeks of steroids and dose 
delay; see guidelines for management in Appendix I. 

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Protocol # 2018-0381 
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Grade 3 
Hold dose pending evaluation. Resume after pulmonary and/or ID 
consultation only if lymphocytic pneumonitis is excluded. Off protocol 
therapy if attributed to nivolumab/ipilimumab; see guidelines for 
management in Appendix I. 
Grade 4 
Off protocol therapy. See guidelines for management in Appendix I. 
Distinguishing inflammatory pneumonitis is often a diagnosis of exclusion for patients who do 
not respond to antibiotics and have no causal organism identified including influenza. Most 
patients with respiratory failure or hypoxia will be treated with steroids. Bronchoscopy may be 
required and analysis of lavage fluid for lymphocytic predominance may be helpful. Patients with 
new lung nodules should be evaluated for sarcoid like granuloma. Please consider 
recommending seasonal influenza killed vaccine for all patients. 
 
 
 
Other GI N-V 
Management/Next Dose for Ipilimumab/Nivolumab 
≤ Grade 1 
No change. Resume treatment. 
Grade 2 
Hold pending evaluation for gastritis duodenitis and other immune adverse 
events or other causes. Resume after resolution to ≤ Grade 1. 
Grade 3 
Hold pending evaluation. Resume after resolution to ≤ Grade 1. If 
symptoms do not resolve within 7 days with symptomatic treatment 
patients should go off protocol therapy. 
Grade 4 
Off protocol therapy. 
Patients with grade 2 or 3 N-V should be evaluated for upper GI inflammation and other 
immune related events. 
 
 
Fatigue 
Management/Next Dose for Ipilimumab/Nivolumab 
≤ Grade 1 
No change. Resume treatment. 
Grade 2 
No change. Resume treatment. 
Grade 3 
Hold until ≤ Grade 2. 
Fatigue is the most common adverse event associated with immune checkpoint therapy. 
Grade 2 or greater fatigue should be evaluated for associated or underlying organ involvement 
including pituitary, thyroid, and hepatic, or muscle (CPK) inflammation. G2 
 
 
Neurologic events 
Management/Next Dose for Ipilimumab/Nivolumab 
≤ Grade 1 
No change in dose. 

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Protocol # 2018-0381 
Ipilumumab and Nivolumab 
 
 
 
Grade 2 
Hold dose pending evaluation and observation. Hold until ≤ Grade 1; 
see guidelines for management in Appendix I. Resume for peripheral 
isolated n. VII (Bell’s palsy); see guidelines for management in Appendix I. 
Grade 3 
Off protocol therapy. See guidelines for management in Appendix I. 
Grade 4 
Off protocol therapy. See guidelines for management in Appendix I. 
*Patients with any CNS events including aseptic meningitis, encephalitis, or myopathy, 
peripheral demyelinating neuropathy, cranial neuropathy (other than peripheral n. VII), GB 
syndrome, myasthenia gravis should be off study. 
 
 
Endocrine 
Hypophysitis 
Adrenal 
Insufficiency 
Management/Next Dose for Ipilimumab/Nivolumab 
Note that protocol-specific actions and management are not strictly by CTCAE grade; see 
guidelines for management in Appendix I for recommendations on IO and management of 
TRAEs. 
 
 
Fever 
Management/Next Dose for Ipilimumab/Nivolumab 
≤ Grade 1 
Hold until ≤ Grade 1. Resume treatment. 
Grade 2 
Hold until ≤ Grade 1. Resume after. 
Grade 3 
Hold until ≤ Grade 1. Resume after. 
Grade 4 
Off treatment 
Patients with fever should be evaluated as clinically appropriate. Patients may experience 
isolated fever during infusion reactions or up to several days after infusion. Evaluation over the 
course of 1-2 weeks should be done for other autoimmune events that may present as fever 
 
 
ALL OTHER EVENTS 
Management/Next Dose for Ipilimumab/Nivolumab 
≤ Grade 1 
No change . 
Grade 2 
Hold until ≤ Grade 1 OR baseline.** When resolved or following 
steroids, resume. 

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Protocol # 2018-0381 
Ipilumumab and Nivolumab 
 
 
 
Grade 3 
Any grade 2 or 3 drug-related uveitis or eye pain or blurred vision 
that does not respond to topical therapy and does not improve to 
Grade 1 severity within the re-treatment period OR requires 
systemic treatment requires treatment discontinuation. 
Any other immune-related grade 3 toxicity not covered in the 
tables above would require that the patient go off protocol 
therapy with the following exceptions: 
Any grade 3 or 4 drug-related laboratory abnormality or 
electrolyte abnormality, not associated with underlying organ 
pathology, that does not require treatment except for electrolyte 
replacement OR hormone/steroid replacement does not require 
treatment discontinuation. 
Grade 4 
Off protocol therapy (except for drug-related laboratory 
abnormality or electrolyte abnormality, not associated with 
underlying organ pathology, that does not require treatment 
except for electrolyte replacement OR hormone/steroid 
replacement does not require treatment discontinuation). 
** Immunologically mediated 
Recommended management: As clinically indicated 
 
 
5.1.2 
Dose reductions for Nivolumab and Ipilimumab 
There will be no dose reductions for nivolumab or ipilimumab. 
 
5.1.3 
Criteria to Resume Nivolumab and Ipilimumab Dosing 
Subjects may resume treatment with nivolumab or ipilimumab when the TRAE(s) resolve(s) to 
Grade ≤ 1 or baseline, with the following exceptions: 
 
Subjects may resume treatment in the presence of Grade 2 fatigue. 
 
Subjects who have not experienced a Grade 3 drug-related skin TRAEs may resume treatment in 
the presence of Grade 2 skin toxicity. 
 
Subjects with baseline Grade 1 AST/ALT or total bilirubin who require dose delays for reasons other 
than a 2-grade shift in AST/ALT or total bilirubin may resume treatment in the presence of Grade 2 
AST/ALT or total bilirubin. 
 
Subjects with combined Grade 2 AST/ALT and total bilirubin values meeting discontinuation 
parameters should have treatment permanently discontinued. 
 
Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before treatment 
is resumed. Subjects with persistent Grade 1 pneumonitis after completion of a steroid taper over 
at least 1 month may be eligible for retreatment. 
 
Subjects who received systemic corticosteroids for management of any drug-related toxicity must 
be off corticosteroids or have tapered down to an equivalent dose of prednisone ≤10 mg/day. 
 
Drug-related endocrinopathies adequately controlled with only physiologic hormone replacement 
may resume treatment. 
 
Dose delay of ipilimumab which results in no ipilimumab dosing for > 12 weeks requires ipilimumab 
discontinuation. 

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Protocol # 2018-0381 
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Ipilimumab may not be resumed sooner than 6 weeks (± 5days) after the prior ipilimumab dose.  
 
Nivolumab may be delayed until the next planned nivolumab (every two weeks) to be synchronized 
with nivolumab and ipilimumab dosing. If one nivolumab dose is missing due to toxicity during IMRT 
period, it will be administrated after finishing IMRT, until a maximum of 6 doses of nivolumab are 
administrated. 
 
In general, subjects who meet criteria to resume ipilimumab will also have met criteria to resume 
nivolumab, so it should be feasible to synchronize dosing of both drugs when resuming ipilimumab. 
In order to facilitate this, the dosing days of nivolumab and ipilimumab may be adjusted within the 
permitted ± 5 day window, as long as consecutive nivolumab doses are given at least 12 days apart.  
 
Investigator attribution of this toxicity to the ipilimumab dosing must be clearly noted in the subject’s 
medical chart. 
 
5.2 IO treatment Discontinuation Criteria 
NOTE: In the event of clinical disease progression during the first six week cycle of IO, the 
patient may be withdrawn from therapy at the discretion of the treating physician to receive 
standard of care therapy off protocol. The patient will continue to be followed per protocol 
and will remain evaluable for DLT.  
 
The assessment for discontinuation of ipilimumab should be made separately from the assessment 
made for discontinuation of nivolumab. Although there is overlap among the discontinuation criteria, 
if discontinuation criteria are met for ipilimumab but not for nivolumab, treatment with nivolumab 
may continue if ipilimumab is discontinued at the study PI’s discretion. If a subject meets criteria for 
discontinuation and investigator is unable to determine whether the event is related to both or one 
study drug, the subject should discontinue both nivolumab and ipilimumab and be taken off the 
treatment phase of the study. 
 
Collection of data and biospecimens for correlative studies from patients that are 
withdrawn from therapy due to progression or toxicities will continue as per protocol (see 
Oral Rinse collection, Blood biospecimen collection, and biopsy under Section 3.3 
Assessments post-treatment, follow-up) 
 
5.2.1 
Nivolumab and Ipilimumab Discontinuation 
Treatment should be permanently discontinued for any of the following: 
 
Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment, unless attributed to (an) alternative diagnosis(es) by a referring 
ophthalmologist; 
 
Any Grade ≥ 2 drug-related pneumonitis or interstitial lung disease that does not resolve with dose 
delay and systemic steroids; 
 
Any Grade 3 drug-related bronchospasm, hypersensitivity reaction, or infusion reaction, regardless 
of duration; 
 
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following exceptions 
for uveitis, pneumonitis, bronchospasm, diarrhea, colitis, neurologic toxicity, hypersensitivity 
reactions, infusion reactions, endocrinopathies, and laboratory abnormalities; 

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Protocol # 2018-0381 
Ipilumumab and Nivolumab 
 
 
 
 
Any Grade 3 drug-related uveitis, pneumonitis, bronchospasm, neurologic toxicity, hypersensitivity 
reaction, or infusion reaction of any duration requires discontinuation; 
 
For patients with Grade 3 or higher diarrhea/colitis, the investigator can discontinue ipilimumab and 
continue nivolumab on study after discussion with the study PI once the symptoms have resolved 
to ≤grade 1 if patient is still in treatment window; 
 
Any Grade 3 drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement do not require discontinuation; 
 
Any Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation except: 
Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation. 
Any drug-related LFT abnormality that meets the following criteria require discontinuation (also 
see Hepatic Adverse Event Management Algorithm): 
• 
AST or ALT > 5-10x ULN for > 2 weeks 
• 
AST or ALT > 10x ULN 
• 
Total bilirubin > 5 x ULN 
• 
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN 
 
Any Grade 4 drug-related adverse event or laboratory abnormality, except for the following events, 
which do not require discontinuation: 
• 
Grade 4 neutropenia ≤ 7 days 
• 
Grade 4 lymphopenia or leukopenia 
• 
Isolated Grade 4 amylase or lipase abnormalities that are not associated with 
symptoms or clinical manifestations of pancreatitis and decrease to < Grade 4 within 1 
week of onset. 
The Monitor should be consulted for Grade 4 amylase or lipase abnormalities 
• 
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with 
clinical sequelae and are corrected with supplementation/appropriate management 
within 72 hours of their onset 
• 
Grade 4 drug-related endocrinopathy adverse events such as adrenal insufficiency, 
ACTH deficiency, hyper- or hypothyroidism, or glucose intolerance, which resolve or 
are adequately controlled with physiologic hormone replacement (corticosteroids, 
thyroid hormones) or glucose controlling agents, respectively, may not require 
discontinuation after discussion with and approval from the Monitor. 
 
Periodic study visits to assess safety and laboratory studies should also continue every 6 weeks 
or more frequently if clinically indicated during such dosing delays. 
 
 
 
 
5.3 Treatment of Infusion Reactions 
 
5.3.1 
Nivolumab or Ipilimumab Infusion Reactions 
Since nivolumab and ipilimumab contain only human immunoglobulin protein sequences, they are 
unlikely to be immunogenic and induce infusion or hypersensitivity reactions. However, if such a 
reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, 
arthralgias, hypo- or hypertension, bronchospasm, or other symptoms. All Grade 3 or 4 infusion 
reactions should be reported within 24 hours to the Medical Monitor and reported as an SAE if 

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Protocol # 2018-0381 
Ipilumumab and Nivolumab 
 
 
 
criteria are met. Infusion reactions should be graded according to NCI CTCAE (Version 4.0) 
guidelines. 
 
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines, as appropriate: 
 
For Grade 1 symptoms: (mild reaction; infusion interruption not indicated; intervention not 
indicated) 
Remain at bedside and monitor subject until recovery from symptoms. The following prophylactic 
premedications are recommended for future infusions: diphenhydramine 50 mg (or equivalent) 
and/or acetaminophen/paracetamol 325 to 1000 mg at least 30 minutes before additional nivolumab 
or ipilimumab administrations. 
 
For Grade 2 symptoms: (moderate reaction requires therapy or infusion interruption but 
responds promptly to symptomatic treatment [eg, antihistamines, non-steroidal anti- 
inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic 
medications indicated for ≤ 24 hours) 
-Stop the nivolumab or ipilimumab infusion, begin an IV infusion of normal saline, and treat the 
subject with diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen/paracetamol 325 to 
1000 mg; remain at bedside and monitor subject until resolution of symptoms. Corticosteroid and/or 
bronchodilator therapy may also be administered as appropriate. If the infusion is interrupted, then 
restart the infusion at 50% of the original infusion rate when symptoms resolve; if no further 
complications ensue after 30 minutes, the rate may be increased to 100% of the original infusion 
rate. Monitor subject closely. If symptoms recur, then no further nivolumab or ipilimumab will be 
administered at that visit. Administer diphenhydramine 50 mg IV, and remain at bedside and monitor 
the subject until resolution of symptoms. 
 
-For 
future 
infusions, 
the 
following 
prophylactic 
premedications 
are 
recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg should 
be administered at least 30 minutes before nivolumab or ipilimumab infusions. If necessary, 
corticosteroids (up to 25 mg of SoluCortef or equivalent) may be used. 
 
For Grade 3 or 4 symptoms: (severe reaction, Grade 3: prolonged [ie, not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical 
sequelae [eg, renal impairment, pulmonary infiltrates]. Grade 4: Life threatening; pressor 
or ventilatory support indicated) 
- Immediately discontinue infusion of nivolumab or ipilimumab. Begin an IV infusion of normal saline 
and treat the subject as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 1:1000 
solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution injected slowly for 
IV administration, and/or diphenhydramine 50 mg IV with methylprednisolone 100 mg IV (or 
equivalent), as needed. Subject should be monitored until the investigator is comfortable that the 
symptoms will not recur. Nivolumab or ipilimumab will be permanently discontinued. Investigators 
should follow their institutional guidelines for the treatment of anaphylaxis. Remain at bedside and 
monitor subject until recovery of the symptoms. 
 
In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral antihistamine 
or corticosteroids). 
 
Preparation/Handling/Storage/Accountability  
 

37 
Protocol # 2018-0381 
Ipilumumab and Nivolumab 
 
 
 
Please refer to the current version of the Investigator Brochure (IB) and/or pharmacy manual for 
complete storage, handling, dispensing, and infusion information for nivolumab and ipilimumab. Any 
unused portion of the infusion solution cannot be stored for reuse, and any unused medicine or 
waste should be disposed of in accordance with local requirements. 
 
 
6. RADIATION THERAPY 
 
6.1 Radiation Therapy 
All patients will receive an initial plan of 20 fractions (4 weeks) followed by a boost plan of either 5 
or 10 fractions. Volume will be assessed independently for the primary and nodal disease. 
 
Note that overall interpretation of response to induction will be based upon RECIST 1.1 on week 
5-6 imaging. However, radiation treatment planning will be stratified by primary site and nodal 
disease.  
 
Primary disease volume ≥3cm and/or nodal disease volume ≥2cm (intermediate volume) will 
receive a final dose of 63-66 Gy in 30 fractions (intermediate volume).  
 
Primary disease volume <3cm and/or nodal disease volume <2cm will receive a final dose of 60 
Gy in 30 fractions (low volume).  
 
Primary and/or nodal disease with CR (<10 mm in short axis) after induction IO will receive a final 
dose of 50 Gy in 25 fractions (CR).  
 
 
Full details of radiation dose prescriptions are provided in Section 6.1.6 - 6.1.7. 
 
• 
Intermediate volume defined as: primary ≥3cm; node ≥2cm 
• 
Low volume primary defined as: primary <3cm; node <2cm 
• 
CR determined via RECIST 1.1 on restaging imaging. 
 
Initial plan: All patients will receive an initial plan of 20 fractions (4 weeks). Intermediate volume 
primary/nodal disease will receive 42-44 Gy at 2.1-2.2 Gy per fraction. Small volume gross 
primary/nodal disease and/or primary/nodal disease with CR after induction IO will receive 40 Gy 
at 2.0 Gy per fraction.  High risk subclinical sites will receive 36 Gy at 1.8 Gy per fraction. 
 
Boost plan: Intermediate volume primary/nodal disease will receive a boost of 21-22 Gy at 2.2 Gy 
per fraction (total dose of 63-66 Gy in 30 fractions).  Small volume gross primary/nodal disease 
will receive a boost of 20 Gy at 2.0 Gy per fraction (total dose of 60 Gy in 30 fractions).  Primary 
and/or nodal disease with CR after induction IO will receive a boost of 10 Gy in 5 fractions (total 
dose of 50 Gy in 25 fractions).  No boost will be given to high risk subclinical sites. 
 
Baseline imaging will be utilized to guide radiotherapy volume for high-risk subclinical sites. In 
instances of partial or complete response, radiation planning will be based upon determination of 
volume on post-induction CT imaging at 5-6 weeks.  
 
Unilateral radiation will be permitted in selected patients; see Section on target volume below 
 
6.1.1 
Treatment Technology 
 
All patients will be managed with radiation therapy using IMRT (static-beam IMRT and volumetric 

38 
Protocol # 2018-0381 
Ipilumumab and Nivolumab 
 
 
 
arc therapy technique allowed) delivered with megavoltage photons. 
 
6.1.2 
Immobilization and Simulation 
 
Patients will be treated supine and must have a secure head and neck immobilization (e.g. 
aquaplast mask) made prior to the treatment planning CT scan. It is strongly encouraged to also 
include an oral stent with bite-block attachment to further ensure accurate patient set-up on a 
daily basis. 
 
The treatment planning CT scan should be obtained in the immobilization device and in the 
treatment position with a slice thickness of 3 mm or less. The use of IV contrast with planning CT 
is recommended unless contraindicated but not required. 
 
Imaging for Structure Definition, Image Registration/Fusion and Follow-up 
A diagnostic CT or MRI for structure delineation is recommended. These may be fused to the 
planning CT scans to facilitate target and structure definition. When available FDG PET/CT, IV 
contrast CT and/or MRI images may also be fused to the planning CT data set. 
 
6.1.3 
Definition of Target Volumes and Margins 
 
All specified target volumes and organs-at-risk (OAR) will be contoured on the planning CT scan 
data sets and named according to the nomenclature described below. For the purposes of 
contouring, MRI and PET images, if available and clinically indicated, may be fused with the 
planning CT data set. Target volumes and OARs will be labeled according to published guidelines 
(Santanam 2012). 
 
Gross Tumor Volume (GTV) 
 
The GTV represents clinically or radiographic grossly involved regions of primary tumor 
designated GTVp_66 for intermediate volume disease, GTVp_60 for low volume disease, or 
GTVp_50 for CR disease, or involved nodes designated GTVn_66 for intermediate volume 
disease, GTVn_60 for low volume disease, or GTVn_50 for disease with CR. These volumes are 
defined based on physical exam and review of available imaging. FDG-PET and/or MRI may 
assist in GTV identification but GTV border delineation should not rely exclusively on PET signal 
given the known variable association between gross tumor extent and PET signal cutoff. CR will 
be determined per RECIST 1.1. 
 
Post-Biopsy GTV 
 
Patients undergoing gross total excision of both primary and gross nodal disease with curative 
intent are not eligible for this study. Patients undergoing diagnostic procedures at the primary site, 
such as simple/diagnostic tonsillectomy or excisional biopsy, are eligible but are not considered to 
have had an oncologically therapeutic surgical procedure even in the absence of clinically or 
radiologically appreciable gross residual disease at the primary site. As such, these patients 
require full radiation dose (60 Gy) to be delivered to a volume immediately adjacent to the tissues 
removed at the time of the biopsy. For purposes of planning, this volume will be labeled GTVp_60 
and it should be defined relative to the extent of disease prior to removal. This GTVp_60 may be 
defined by fusion of pre-biopsy imaging studies (CT, MRI) with the planning CT data set. The 
gross primary tumor on the pre-biopsy imaging may be projected on the planning CT and defined 
as the intersection with the residual tissues. If there is not such an intersection or the residual 
tissues lie in a different anatomic orientation post-biopsy, the GTVp_60 may be defined as a 5 
mm expansion into the residual tissues circumferential to the area of the biopsy. In the event that 

39 
Protocol # 2018-0381 
Ipilumumab and Nivolumab 
 
 
 
pre-biopsy imaging is not available the GTVp_60 must be defined relative to the clinical exam of 
the biopsy site and normal anatomic landmarks. For instance, in the specific case of tonsillectomy 
the GTVp_60 will include, at a minimum, the tonsillar bed to include anterior and posterior tonsillar 
pillars up to the level of the soft palate and inferiorly to the pharyngoepiglottic fold; the GTVp 
should be expanded superiorly or inferiorly if the pre-biopsy tumor extended past these 
landmarks. A CTV_60 is then defined for this GTVp_60 according to methods defined below. 
 
Nodal Definitions 
 
● 
Grossly Positive Nodes (GTVn_60) are defined as those greater than 1.5 cm in long axis 
and/or > 1 cm in short axis, a cluster of 3 or more borderline size nodes, 
radiographicevidence of extracapsular extension (ECE), or a node of any size with 
evidence of necrosis. Smaller nodes may be determined to be gross disease objects 
depending on clinical suspicion (based on proximity to the primary site or other involved 
nodes) or demonstration of significant uptake of FDG on PET scanning. Intermediate 
volume nodes (GTVn_66) are defined as an individual or cluster of matted node(s) ≥4cm 
• 
Extracapsular extension (ECE): is defined as radiographic evidence of irregular borders 
and/or perinodal fat stranding, invasion of adjacent structures, or both. Any areas of 
potential involvement should be included within the GTV. Clinicians are highly encouraged 
to request radiologist review if the determination is unclear. 
 
 
Clinical Target Volume (CTV) 
 
• 
CTVs are defined and contoured in relation to the targets they are intended to encompass and 
the dose they are intended to receive. For gross targets (GTVs), the CTVs are defined by 3D 
isotropic expansions that should then be limited by potential barriers to tumor spread such as 
air cavities, external contours and bony or fascial planes through which tumor spread is not 
possible or apparent. CTV must be determined by the treating physician with quality 
assurance from the head and neck radiation oncology team. This margin can be reduced as 
needed for tumors in close proximity to critical structures in order to meet their dose constraint 
at discretion of treating radiation oncologist. Similarly, CTVs may be expanded beyond the 
limits defined in this protocol in order to cover areas deemed at risk of tumor extension (e.g. 
neck musculature invaded by nodal disease, or pterygoid regions of infratemporal fossa in 
superiorly extending tonsillar cancers). For nodal regions of potential microscopic involvement 
CTVs are defined according to normal anatomic landmarks (Gregoire 2014). 
• 
CTV_66: Intermediate Volume Primary Tumor and Involved Nodes 
A CTV_66 will be defined for primary tumor and involved nodes as up to 0.5 cm expansion of 
the GTVs defined for these structures. When defined for nodes, the CTV_66 should be 
suffixed as CTVn_66 to distinguish this from the primary, CTVp_66, for the purposes of plan 
evaluation. CTV_66 is the sum of CTVp_66 and CTVn_66. 
• 
CTV_60: Small Volume Primary Tumor and Involved Nodes 
A CTV_60 will be defined for primary tumor and involved nodes as up to 0.5 cm expansion of 
the GTVs defined for these structures. When defined for nodes, the CTV_60 should be 
suffixed as CTVn_60 to distinguish this from the primary, CTVp_60, for the purposes of plan 
evaluation. CTV_60 is the sum of CTVp_60 and CTVn_60. 
• 
CTV_50: Primary Tumor and Involved Nodes with CR 
A CTV_50 will be defined for primary tumor and involved nodes as up to 0.5 cm expansion of 
the GTVs defined for these structures. When defined for nodes, the CTV_50 should be 
suffixed as CTVn_50 to distinguish this from the primary, CTVp_50, for the purposes of plan 
evaluation. CTV_50 is the sum of CTVp_50 and CTVn_50. 
• 
CTV_36: High-Risk Subclinical Sites 

40 
Protocol # 2018-0381 
Ipilumumab and Nivolumab 
 
 
 
High-risk subclinical sites are defined as areas of potential subclinical tumor infiltration beyond 
the primary site CTVp. In the event of a node excision that occurred at time of diagnosis, the 
node levels that contained grossly involved adenopathy should be included in CTV_36, even if 
there is no residual post excision adenopathy. In patients with a CR to induction, the first 
echelon node levels to the primary site may be omitted from CTV_36. 
 
A CTV_36 will be defined for these sites and include the following: 
i) 
An up to 0.5 cm expansion on the CTVp_60 and/or CTVp_66 
ii) All node levels containing a CTVn_60 and/or CTVn_66 that has been assigned to 
involved nodes (all grossly involved nodal levels). Coverage of these sites are required. 
iii) Other high-risk subclinical sites may include nodes < 1cm not thought to harbor gross 
disease yet thought to be at risk of containing more than subclinical disease based on 
their location relative to the primary site. In such cases of clinical concern that do not 
meet the above criteria, an expansion up to 0.5 cm on these nodes can be added to the 
CTV_36 at the discretion of the treating clinician. 
iv) 1st echelon node levels based on standard anatomic definitions. In most cases 1st 
echelon would be ipsilateral level II, but in cases of midline primary site involvement 
thiscan include bilateral level II. In cases with soft palate or posterior pharyngeal wall 
involvement this should include the lateral retropharyngeal lymph nodes. Coverage of 
these sites will be determined by the treating physician with quality assurance from the 
head and neck radiation oncology team. 
v) CTV_36 may be omitted in patients with CR of primary and nodal sites 
 
 
Contralateral Neck. 
 
Groups of Patients with Regard to Unilateral or Bilateral Neck Irradiation 
 
Group 1: Unilateral treatment is recommended. 
 
T1 to T2 tonsil primaries with < 0.3cm clinical or radiographic extension into tongue base and/or 
<1cm clinical or radiographic extension into palate, no posterior pharyngeal wall extension, N0- 
N2a. 
 
Group 2: Unilateral treatment is optional. 
 
T1 to T3 tonsil primaries with < 1cm clinical or radiographic extension into tongue base and/or 
palate, no posterior pharyngeal wall extension, N2b with involved adenopathy confined to 
ipsilateral level 2 of the neck 
 
Group 3: Bilateral treatment is mandatory. 
 
Tongue base, soft palate or posterior pharyngeal wall primaries or tonsil primaries with > 1cm soft 
palate and/or tongue base extension or any posterior pharyngeal wall extension. 
 
Prior to enrollment, oncologists will declare their intention to treat unilaterally or bilaterally. 
Exploratory analyses adjusted for unilateral vs. bilateral radiotherapy will be conducted when the 
results are available. 
 
Management of the Low Neck (levels III, IV, V) 
The low and posterior neck will only be treated if there is evidence of nodal involvement in these 
level or suspicious nodes < 1cm, not thought to harbor gross disease, yet thought to be at risk  of 

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Protocol # 2018-0381 
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containing more than subclinical disease based on their location relative to the primary site or the 
involved nodes. For example, if there is involved node in the level II and small < 1cm suspicious 
nodes in level III, then the level III nodes will be treated to 36 Gy. 
 
Table 6.1.4: Clinical Target Volume Nomenclature and Description. 
 
Note: All structures marked as Required in the table below must be contoured, and labeled as 
listed under “Standard Name” for digital RT data submission. All structures marked as Required if 
applicable must be contoured and labeled as listed under “Standard Name” for digital data 
submission IF they are applicable to the patient’s plan. Resubmission of data is necessary when 
labeling of structures does not conform to the DICOM Standard Name listed. 
 
Standard Name 
Description 
Detailed Specification 
GTVp_66 
GTV to receive 63-66 Gy at the 
primary site 
 
Required if applicable 
Equivalent to GTVp as defined above 
GTVn_66 
GTV to receive 63-66 Gy at involved 
nodes 
 
Required if applicable 
Equivalent to GTVn as defined above 
CTVp_66 
CTV to receive 63-66 Gy at the 
primary site 
 
Required if applicable 
Up to 0.5 cm isotropic expansion of 
GTVp_66 limited by potential anatomic 
barriers to tumor spread 
CTVn_66 
CTV to receive 63-66 Gy at involved 
nodes 
 
Required if applicable 
Up to 0.5 cm isotropic expansion of 
GTVn_ 66 limited by potential anatomic 
barriers to tumor spread 
CTV_66 
CTV to receive 63-66 Gy 
 
Required if applicable 
Sum of CTVp_66 and CTVn_66 
GTVp_60 
GTV to receive 60 Gy at the primary 
site 
 
Required if applicable 
Equivalent to GTVp as defined above 
GTVn_60 
GTV to receive 60 Gy at involved 
nodes 
 
Required if applicable 
Equivalent to GTVn as defined above 
CTVp_60 
CTV to receive 60 Gy at the primary 
site 
 
Required if applicable 
Up to 0.5 cm isotropic expansion of 
GTVp_60 limited by potential anatomic 
barriers to tumor spread 

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CTVn_60 
 CTV to receive 60 Gy at involved 
nodes 
 
Required if applicable 
Up to 0.5 cm isotropic expansion of 
GTVn_ 60 limited by potential anatomic 
barriers to tumor spread 
CTV_60 
CTV to receive 60 Gy  
 
Required if applicable 
Sum of CTVp_60 and CTVn_60 
GTVp_50 
GTV to receive 50 Gy at the primary 
site 
 
Required if applicable 
Equivalent to pre-induction GTVp as 
defined above 
GTVn_50 
GTV to receive 50 Gy at involved 
nodes 
 
Required if applicable 
Equivalent to pre-induction GTVn as 
defined above 
CTVp_50 
CTV to receive 50 Gy at the primary 
site 
 
Required if applicable 
Up to 0.5 cm isotropic expansion of pre-
induction GTVp_50 limited by potential 
anatomic barriers to tumor spread 
CTVn_50 
CTV to receive 50 Gy at involved 
nodes 
 
Required if applicable 
Up to 0.5 cm isotropic expansion of pre-
induction GTVn_50 limited by potential 
anatomic barriers to tumor spread 
CTV_50 
CTV to receive 50 Gy 
 
Required if applicable 
Sum of CTVp_50 and CTVn_50 
 
CTV_36 
CTV to receive 36 Gy at high risk 
volume at the primary site and 
applicable node levels 
 
Required if applicable 
i) Up to 0.5 cm expansion on the 
CTVp_60 or CTVp_66 
 
ii) node levels containing involved 
nodes 
 
Recommended but not required: 
 
iii) First echelon nodes (unilateral or 
bilateral) 
 
iv) Up to 0.5 cm expansion on nodes < 
1 cm thought to be at risk of 
containing more than subclinical 
disease. 
 
v) Nodal level outside of level II (level 
III, IV or V) only if they contain < 1 
cm nodes thought to be at risk of 
containing more than subclinical 
disease 
 

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6.1.4 
Definition of Organs at Risk 
 
Note: All structures marked as Required in the table below must be labeled as listed under 
“Standard Name” for digital RT data submission. Resubmission of data is necessary when labeling 
of structures does not conform to the DICOM Standard Name listed. 
 
Table 6.1.5: Organ at Risk Nomenclature 
 
For detailed descriptions see below. 
 
OAR Standard Name 
Description 
SpinalCord 
Spinal cord 
 
Required 
SpinalCord_05 
PRV = 5 mm expansion on spinal cord 
 
Required 
BrainStem 
Brain stem 
 
Required 
BrainStem_03 
PRV= 3 mm expansion on brainstem 
 
Required 
Lips 
Lips 
 
Required 
OralCavity 
Oral cavity 
 
Required 
Parotid_R 
Right parotid gland 
 
Required 
Parotid_L 
Left parotid gland 
 
Required 
Submandibular_R 
Right submandibular gland 
 
Required, if applicable 
Submandibular_L 
Left submandibular gland 
 
Required, if applicable 
Pharynx 
Non-treated pharynx 
 
Required 

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Esophagus_Up 
Cervical esophagus 
 
Required 
Larynx 
Larynx 
 
Required 
Mandible 
Mandible 
 
Required 
Thyroid 
Thyroid gland 
 
Required 
NonPTV 
Unspecified tissue, External minus all 
PTVs 
 
Required 
External 
External border of the patient 
 
Required 
 
• 
Spinal Cord: The cord begins at the cranial-cervical junction (ie, the top of the C1 vertebral 
body). Superior to this is brainstem and inferior to this is cord. The spinal cord must be 
contoured at least 1 cm below the lowest extent of the neck PTVs. The spinal cord shall be 
defined based on the treatment planning CT scan. In addition, however, a Planning Risk 
Volume (PRV) spinal cord shall be defined as: SpinalCord_05 = cord + 5 mm in each 
dimension. 
• 
Brain Stem: The inferior most portion of the brainstem is at the cranial-cervical junction where 
it meets the spinal cord. For the purposes of this study, the superior most portion of the 
brainstem is approximately at the level of the top of the posterior clinoid. The brainstem shall 
be defined based on the treatment planning CT scan. In addition, however, a Planning Risk 
Volume (PRV) brainstem shall be defined as: BrainStem_03 = brainstem + 3 mm in each 
dimension. 
• 
Lips: The definition of lips is self-explanatory. 
• 
Oral Cavity: The oral cavity will be defined as a composite structure posterior to lips 
consisting of the anterior ½ to 2/3 of the oral tongue/floor of mouth, buccal mucosa, and 
superiorly the palate, and inferiorly to the plane containing the tip of the mandible. 
• 
Parotid Glands: Parotid glands will be defined in their entirety (superficial and deep lobes) 
based on the treatment planning CT scan. 
• 
Submandibular Glands: Submandibular glands will be defined in their entirety based on 
treatment planning CT scans. 
• 
Pharynx: This will be defined as the pharyngeal wall plus adjacent constrictor muscles 
deemed not to require treatment (external to PTVs). This extends from the superior constrictor 
region (level of the inferior pterygoid plates) to the cricopharyngeal inlet (level of the posterior 
cricoid cartilage). 
• 
Esophagus: This will be defined as the cervical (upper) esophagus, a tubular structure that 
starts at the bottom of pharynx (cricopharyngeal inlet) and extends to the thoracic inlet. 
• 
Larynx: This will be defined as the glottic and supraglottic larynx, the aryepiglottic folds, 
arytenoids, false cords, and true cords, bounded by the thyroid cartilage laterally, anteriorly 
including the anterior edge of the pre-epiglottic fat, and posteriorly bounded by the anterior 

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edge of the pharyngeal wall or the posterior edge of the arytenoid and/or cricoid cartilage. 
Inferiorly, bottom of cricoid cartilage. 
• 
Mandible: This includes the entire bony structure of the mandible from TMJ through the 
symphysis. It is recognized that for oral cavity cancers, this may overlap with CTVs and PTVs. 
• 
Thyroid: This includes both lobes (left and right) of the thyroid gland 
• 
Unspecified Tissue Outside the Targets (NonPTV): This will be defined as tissue located 
between the skull base and thoracic inlet external to all PTVs and defined normal stuctures 
within the external contour of the patient. 
 
6.1.5 
Planning Target Volumes 
 
All CTVs will have associated PTVs which represent the volumes to which radiation dose will be 
prescribed, delivered and evaluated. The PTVs are isotropic expansions of the CTVs to account 
for internal motion and residual set-up error. 
 
PTVs are defined as 2-5 mm expansion of the CTV in all planes, depending on the 
frequency of IGRT (see IRGT Section below), except when the isotropic expansion results 
in the following dosimetric challenges: 
 
i. 
when the CTV expansion results in a PTV that overlaps a critical OAR or its PRV, hence 
dose delivered to this PTV will exceed the acceptable dose limits for the OAR; 
ii. 
and when the CTV expansion results in PTVs extending beyond the patient external 
contour, making PTV dose calculation and evaluation unreliable. 
iii. 
In such instances, the PTVs may be modified in the following manner: 
 
1) When a PTV overlaps a critical OAR (e.g. spinal cord, brainstem and/or larynx) and 
its associated PRV, the PTV should be modified to exclude the PRV. 
2) The PTVs should be constrained to be within the external contour. For situations 
where gross disease is external to the external contour (disease at or through the skin 
surface), the use of 3-5 mm tissue equivalent material (bolus) is recommended, and 
no PTV constraint should be used underneath the bolus. 
 
Table 6.1.6: Planning Target Volume Nomenclature and Description 
 
Note: All structures marked as Required in the table below must be contoured and labeled as 
listed under “Standard Name” for digital RT data submission. All structures marked as Required if 
applicable must be contoured and labeled as listed under “Standard Name” for digital data 
submission IF they are applicable to the patient’s plan. Resubmission of data is necessary when 
labeling of structures does not conform to the DICOM Standard Name listed. 
 
Standard Name 
Description 
Detailed Description 
PTVp_66 
PTV to receive 63-66 Gy at the 
primary site 
 
Required if applicable 
2-5mm expansion of CTVp_66 
PTVn_66 
PTV to receive 63-66 Gy at 
involved nodes 
 
Required 
2-5mm expansion of CTVn_66 

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PTV_66 
PTV to receive 63-66 Gy  
 
Required if applicable 
Sum of PTVp_66 and PTVn_66 
PTVp_60 
PTV to receive 60 Gy at the 
primary site 
 
Required if applicable 
2-5mm expansion of CTVp_60 
PTVn_60 
PTV to receive 60 Gy at involved 
nodes 
 
Required if applicable 
2-5mm expansion of CTVn_60 
PTV_60 
PTV to receive 60 Gy  
 
Required if applicable 
Sum of PTVp_60 and PTVn_60 
PTVp_50 
PTV to receive 50 Gy at the 
primary site 
 
Required if applicable 
2-5mm expansion of CTVp_50 
PTVn_50 
PTV to receive 50 Gy at involved 
nodes 
 
Required if applicable 
2-5mm expansion of CTVn_50 
PTV_50 
PTV to receive 50 Gy  
 
Required if applicable 
Sum of PTVp_50 and PTVn_50 
PTV_36 
PTV to receive 36 Gy at the 
primary site and applicable node 
levels 
 
Required if applicable 
2-5mm expansion of CTV_36 
 
 
6.1.6 
Dose Prescription 
 
All PTVs are to be treated at 1.8-2.2 Gy/Fx . In the initial plan, prescribed dose to both PTV_30 
and PTV_60 will be 30 Gy in 15 fractions at 2 Gy/fraction. After that PTV_60 will be boosted with 
an addition 30 Gy in 15 fractions at 2 Gy/fraction. The total number of fractions to PTV_30 will 
therefore be 30 fractions over 6 weeks. Unilateral radiation will be permitted in selected patients; 
see Section 6.1.3. Doses prescribed are indicated in Table 6.1.7 below. 
 
Table 6.1.7: Doses Prescribed to PTVs 
 
Target 
Standard Name 
Dose (Gy) Fraction 
Size (Gy) 
# of 
fractions 
Dose specification 
technique 
PTV_66 
63-66 
2.1-2.2 
30 
Covering ≥ 95% of PTV_66 
PTV_60 
60 
2.0 
30 
Covering ≥ 95% of PTV_60 

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PTV_50 
50 
2.0 
25 
Covering ≥ 95% of PTV_50 
PTV_36 
36 
1.8 
20 
Covering ≥ 95% of PTV_36 
 
 
6.1.7 
Treatment Planning Priorities and Instructions 
 
IMRT Dose Prescription to PTVs 
 
Doses are prescribed to PTVs as outlined in Table 6.1.7. The treatment goal is that 95% of the 
volume of all PTVs must receive the prescribed dose with a minimum dose (defined as dose to 
99% of PTVs) greater than 93% of the prescription dose and a maximum dose (defined as dose 
encompassing 0.03 cc of the PTV) less than 110-115% of the highest prescription dose. 
 
It is recognized that portions of PTVs close to the skin or critical PRVs (spinal cord and 
brainstem) may receive significantly less than the prescription doses. This is acceptable in these 
regions as long as cold spots within these PTVs do not exist within the GTV. In cases of PTVs 
close to skin, tissue equivalent bolus must be utilized to ensure adequate dose. 
 
It is also recognized that PTVs abutting or enclosing higher dose PTVs will have regions of 
maximum dose that may exceed their prescribed dose in order to achieve acceptable minimal 
doses to the higher dose PTVs which are considered a higher priority target. 
 
Prioritization for IMRT Planning 
 
1) Spinal Cord 
 
2) Brainstem 
 
3) PTV_66 and/or PTV_60 and/or PTV_50 
 
4) PTV_36 
 
5) a.   Parotid gland contralateral to primary tumor site 
 
b. Larynx 
 
6) a.   Pharynx 
 
b. Contralateral submandibular 
 
7) a.   Oral Cavity 
 
b.   Lips 
 
c. Esophagus 
 
d. Thyroid 
 
8) a.   Parotid gland ipsilateral to primary tumor site 
 
b. Mandible 

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9) Unspecified tissue outside the targets 
 
6.1.8 
Doses to Normal Structure 
Dose limitations to normal structures are described below. For the critical structures of spinal cord 
and brainstem these are mandatory. For other structures recommended limits are provided, but 
the doses delivered should always be as low as reasonably achievable without compromising 
doses to PTVs. 
 
• 
Spinal Cord: The PRV for spinal cord (SpinalCord_05) should not exceed 48 Gy to any 
volume in excess of 0.03 cc (approximately 3 mm x 3 mm x 3 mm). In treatment planning, the 
spinal cord PRV should be given the highest priority. 
• 
Brainstem: The PRV for brainstem (BrainStem_03) should not exceed 50 Gy to any volume 
in excess of 0.03 cc (approximately 3 mm x 3 mm x 3 mm). In treatment planning, the 
BrainStem_03 should be given less priority than the SpinalCord_05, but more than the critical 
structures listed below. 
• 
Lips: Reduce the dose as much as possible. The mean dose should be < 20 Gy. 
• 
Oral Cavity: Reduce the dose as much as possible. The mean dose should be < 30 Gy for 
the oral cavity. Efforts should also be made to avoid hot spots (> 50 Gy) within the non-
involved oral cavity. 
• 
Parotid Glands: In most cases, it will be easier to spare one parotid than the other. The 
treatment planning goal will be for this individual parotid gland to receive a mean dose of < 
26 Gy but efforts should be made to reduce this further if possible without compromising 
dose to PTVs. 
• 
Contralateral submandibular gland: If contralateral level Ib is not a target, aim to reduce 
mean contralateral submandibular gland to < 39 Gy. 
• 
Pharynx: Reduce the dose as much as possible. Some recommended (but not mandatory) 
treatment goals include:  
1) No more than 33% of the Pharynx exceeds 45 Gy;  
2) Mean dose < 35-40 Gy;  
3) No more than 15% of the Pharynx exceeds 50 Gy. 
• 
Esophagus: Reduce the dose as much as possible; recommended (but not mandatory) 
treatment goal: mean dose < 30 Gy. 
• 
Larynx: Reduce the dose as much as possible. The larynx mean dose is recommended to 
be ≤ 30-35 Gy if whole-neck IMRT is used. 
• 
Thyroid: Mean dose should be < 30 Gy. 
• 
Mandible: Reduce the dose as much as possible. Hot spots within the mandible should be 
avoided. It is recommended that maximum dose within the mandible be < 50 Gy. 
• 
Unspecified Tissue Outside the Targets (NonPTV): No more than 1cc of unspecified 
tissue outside the targets can receive ≥ 50 Gy. 
 
 
6.1.9 
Dose Compliance Criteria 
 
The compliance criteria listed in Table 6.1.10 will be used to evaluate each case. The Per 
Protocol and Variation Acceptable categories are both considered to be acceptable. The Per 
Protocol cases can be viewed as ideal plans, and the Variation Acceptable category can include 
more challenging plans that do not fall at or near the ideal results. A final category, called 
Deviation Unacceptable, results when cases do not meet the requirements for either Per Protocol 
or Variation Acceptable. Plans falling in this category are considered to be suboptimal and 
additional treatment planning optimization is recommended to avoid protocol deviation. 

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Table 6.1.10: Planning Target Volume and Critical OAR Constraints and Compliance 
Criteria 
Name of Structure 
Dosimetric 
parameter* 
Per Protocol 
Dose (Gy) 
Variation Acceptable 
PTV_66 
D95%*(Gy) 
 
D99%(Gy) 
 
Dmax**(Gy) 
63-66 
≥ 63 and < 70 
CTV_66 
V63-66 Gy (%) 
≥ 99 % 
95 to 99 % 
PTV_60 
D95%*(Gy) 
 
D99%(Gy) 
 
Dmax**(Gy) 
60 
> 60 and ≤ 63 
CTV_60 
V60 Gy (%) 
≥ 99 % 
95 to 99 % 
PTV_50 
D95%*(Gy) 
 
D99%(Gy) 
 
Dmax**(Gy) 
50 
>50 and ≤ 53 
CTV_50 
V50 Gy (%) 
≥ 99 % 
95 to 99 % 
PTV_36 
D95%*(Gy) 
 
D99%(Gy) 
≥ 30 
 
≥ 28 
≥ 28.5 
 
≥ 27 
CTV_36 
V36 Gy (%) 
≥99 % 
95 to 99 % 
SpinalCord_05 
Dmax**(Gy) 
≤48 
≤50 
Spinal Cord 
Dmax**(Gy) 
≤45 
≤48 
BrainStem_03 
Dmax**(Gy) 
≤ 50 
≤52 
A Deviation Unacceptable will be scored when the Variation Acceptable limits are not met. 
 
*D95%(Gy) = dose to 95% of volume; **Dmax = maximum dose to 0.03 cc of the volume 
 
 
Recommended dose acceptance criteria for other normal tissue, but not to be used for 
plan score 
 
Structure 
Recommended dose acceptance criteria 
Parotid 
Mean dose to one parotid ≤ 26 Gy 
Larynx 
Mean dose ≤ 30 Gy 

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Pharynx 
Mean dose ≤ 35-40 Gy 
Submandibular_R or Submandibular_L 
(contralateral) 
Mean Dose ≤ 39 Gy 
Oral Cavity (excluding PTV’s) 
Mean dose ≤ 30 Gy 
Esophagus_Up 
Mean dose ≤ 30 Gy 
Thyroid 
Mean dose < 30 Gy 
NonPTV 
D1cc < 50 Gy 
Mandible 
D0.03cc < 50 Gy 
 
 
6.1.10 
Radiation Delivery Compliance Criteria 
 
Radiation should begin on day 1 of cycle 2 of immunotherapy. Treatment breaks must be clearly 
indicated in the treatment record along with the reason(s) for the treatment break(s). Treatment 
breaks, if necessary, should not exceed 3 treatment days at a time and 5 treatment days total. 
Treatment breaks should be allowed only for resolution of severe acute toxicity and/or for 
intercurrent illness and not for social or logistical reasons. Any treatment break(s) exceeding 2 
treatment days for reasons other than toxicity/illness will be considered a protocol deviation. 
 
Given the importance of timeliness of treatment delivery in this study, it is strongly recommended 
that patients receive twice-daily treatments with a minimum 6-hour inter-fraction interval to 
compensate for missed days including holidays and those for toxicity or illness once sufficiently 
recovered with the goal of keeping the overall treatment time within the limits defined below. 
 
Table 6.1.11: Delivery Compliance Criteria 
 
 
Per 
Protocol 
Variation 
Acceptable 
Deviation Unacceptable 
Overall Treatment time 
<49 days 
50-54 days 
>55 days without a medically 
appropriate indication for 
delay 
Interruptions (without 
medical indication) 
0-2 days 
2-4 days 
>4 days 
 
 
6.1.11 
Dose Calculations 
 
The primary data set for dose calculation is CT. In the case in which contrast is present during the 
treatment planning CT, the density of the contrast should be overridden to a representative 
background electron density. The dose grid size should be ≤ 3 mm in all directions, which means 
that the CT slice thickness should be ≤ 3 mm. 
 
6.1.12 
Daily Treatment Localization/IGRT 
 

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Protocol # 2018-0381 
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Daily image guidance (IGRT) of IMRT is required if PTV margins of ≤0.3 cm are used. If using 
PTV margins of 0.4-0.5 cm, a minimum of weekly IGRT will be required, and the imaging 
alignment must be approved by the attending physician on the first day of treatment and weekly 
thereafter 
 
IGRT may be achieved using any one of more of the following techniques: 
 
• 
Orthogonal kilovoltage (KV) images, ExacTrac; 
• 
Linear-accelerator mounted kV and MV conebeam CT images; 
• 
Linear-accelerator mounted MV CT images; 
• 
Other mechanism, after discussion with the Radiation Oncology Co-Chair and/or 
Medical Physics Co-chair. 
 
The institution’s procedure to register the treatment day imaging dataset with the reference 
dataset is suggested to include the following recommendations: 
 
• 
Region-of-interest (ROI) or “clip box” for fusion should be set to encompass the high 
dose target volumes and adjacent critical structures such as spinal cord when 
applicable; 
• 
If the fusion software allows the user to create an irregular ROI (e.g. ExacTrac), 
treatment room objects seen on in-room X-rays should be excluded from the 
registration; 
• 
Both manual (e.g. based on bony anatomy) and automatic (e.g. based on mutual 
information) types of registration can be used; the result of the fusion must be visually 
checked for the alignment of the bony anatomy, such as vertebral bodies and 
applicable surgical clips and soft tissue structures (e.g. optic nerves and/or optic 
chiasm); 
• 
Following the registration, the translational and (if the appropriate technology is  
available) rotational corrections should be applied to the treatment couch. If all the 
variances are less than 2.5 mm (this typically corresponds to one half of the usual PRV 
margin), the treatment can proceed without correction (however, the physician/team 
may elect to perform adjustments even for a variance < 2.5 mm). If one or more 
corrections are 2.5-5 mm, adjustment is necessary prior to treatment; however, 
reimaging is not mandatory. If one or more of the corrections are larger than 5 mm, the 
imaging must be repeated in addition to performing table/positioning adjustments. 
 
6.1.13 
Replanning 
 
In cases of weight loss > 10% or substantial shrinkage of lymphadenopathy during therapy, it is 
recommended that the immobilization mask be adjusted or re-made in order to preserve adequate 
immobilization, and that a repeated simulation CT be performed to assess the dose distributions 
in the current anatomy. Whether or not a new IMRT plan will be generated is at the discretion of 
the treating physician. The new CT dataset should be used for IGRT image registration when the 
patient’s shape changes significantly. 
 
6.1.14 
Radiation Therapy Adverse Events 
 
Grade 3-4 (CTCAE, v. 4) therapy-induced mucositis and/or dysphagia are expected to develop in 
about two thirds of patients. Nutritional evaluation prior to the initiation of therapy to decide on the 
use of a prophylactic gastrostomy (PEG) tube placement is recommended, but in the absence of 
significant pretreatment dysphagia and associated weight loss of < 10% body weight, the insertion 
of a prophylactic PEG is not recommended. If done the placement of a feeding tube should be 

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Protocol # 2018-0381 
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recorded, as should proportion of use of a feeding tube during and after treatment (e.g. greater 
than or less than 50% of nutrition by tube). Other common radiation adverse events include: 
fatigue, weight loss, regional alopecia, xerostomia, hoarseness, transient ear discomfort, 
dysgeusia, and skin erythema and desquamation within the treatment fields. 
 
Less common long-term treatment adverse events include: hypothyroidism, loss of hearing, 
chronic swallowing dysfunction requiring permanent feeding tube, and cervical fibrosis. Much less 
common radiation adverse events include: mandibular osteoradionecrosis (< 5% incidence with 
attention to the dental recommendations provided in Appendix I, “Dental Assessment and 
Management Document), and cervical myelopathy (< 1% with restriction of spinal cord dose to ≤ 
45 Gy). 
 
 
6.1.15 
Radiation Discontinuation 
 
Radiation is the primary treatment for these patients and should not be discontinued for any 
reason. If radiation is discontinued due to toxicity concerns, this is considered to be a dose limiting 
toxicity of the study. 
 
7. SURGERY 
 
Surgery is expected to play only a limited role in the favorable risk HPV-associated cancers 
included in this study. Locoregional progression is expected in <10% of patients. The role of neck 
dissection has been declining in recent years, in part due to a high rate of negative specimens 
when planned neck dissections are performed in cancers of the oropharynx. 
 
8. POST-TREATMENT ASSESSMENT OF CLINICAL RESPONSE TO THERAPY 
 
Patient’s response will be followed with both clinical and radiographic assessment as indicated in 
the table of assessments. Clinical response at the primary site and nodal regions will be evaluated 
after six weeks of induction IO and 8-10 weeks after completion of RT by physical exam and 
CT/MRI of neck (modality should be the same as baseline). Treatment response will be evaluated 
by RECIST v1.1 and scored as indicated in the table 1 below. If unequivocal signs of persistent 
disease are demonstrated by clinical exam or imaging studies, histological or cytological 
pathological confirmation of persistent disease at the primary or nodal sites should be obtained. 
Patient should be evaluated for salvage surgery. Patients with persistently enlarged lymph nodes 
at 8-10 weeks post RT may be observed or undergo ultrasound with fine-needle aspiration at the 
discretion of the treating physician and evaluation by FDG-PET/CT 12-14 weeks from the end of 
RT (see table 2 for FDG-PET/TC criteria evaluation). An algorithm for clinical management of 
findings on the 12-14 week FDG-PET/CT scan is provided in Figure 1. If residual tumor is 
demonstrated by FDG-PET/CT, histological or cytological pathological confirmation of persistent 
disease at the primary or nodal sites should be obtained. Patient should be evaluated for salvage 
surgery. If response per FDG-PET/CT is indeterminate (PET/CT interpretation score of 3), FDG- 
PET/CT should be repeated at 3 months and evaluated for continued resolution versus evidence 
of persistent disease. A patient will be considered to have persistent disease after completion of 
RT only if histopathological or cytological confirmation of squamous cell carcinoma is confirmed 
by biopsy or is present within the resection specimen. Table 3 described failure response criteria. 
 
 
 
 
 

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Table 1: RECIST 1.1 response criteria. 
Complete 
Response (CR) 
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 
mm. 
Partial 
Response (PR) 
At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters. 
Progressive 
Disease (PD) 
At least a 20% increase in the sum of diameters of target lesions, taking 
as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study). In addition to the relative increase of 20%, 
the sum must also demonstrate an absolute increase of at least 5 mm. 
(Note: the appearance of one or more new lesions is also considered 
progression). 
Stable Disease 
(SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
 
Table 2: FDG-PET/CT Five-Point Qualitative Post therapy Assessment Scoring System 
 
Score 
FDG uptake pattern 
Response category 
1 
FDG uptake at the primary site and nodes less than 
IJV. 
Complete metabolic 
response 
2 
Focal F-FDG uptake at the primary site and nodes 
greater than IJV but less than liver. 
Likely complete metabolic 
response 
3 
Diffuse F-FDG uptake at the primary site or nodes is 
greater than IJV or liver. 
Likely postradiation 
inflammation 
4 
Focal F-FDG uptake at the primary site or nodes 
greater than liver. 
Likely residual tumor 
5 
Focal and intense F-FDG uptake at the primary site 
or nodes. 
Residual tumor 
IJV: Internal Jugular Vein. Scores 1, 2, and 3, which represent complete metabolic response, 
likely complete metabolic response, and likely postradiation inflammation, respectively, were 
considered negative for tumor. Score of 3 requires further investigation with either ultrasound and 
FNA and/or repeat PET in 12 weeks. Scores 4 and 5, which represent likely residual tumor and 
residual tumor, respectively, were considered positive for tumor. New lesion would be considered 
as progressive disease. 
 
Table 3: Failure response criteria 
 
For the purposes of this protocol, failure response criteria will be defined as follows: 
Clinical or image evidence of persistent disease pathologically confirmed 
Clinical or image evidence of progression disease pathologically confirmed. 
Pathological evidence of invasive squamous cell carcinoma after salvage surgery. 

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Appearance of one or more new lesions pathologically confirmed. 
Any other reason which may lead to abandoned the study treatment. 
 
 
Evaluation Response Schema 
 
 
 
8.1.1 
Post-Treatment Surgical Salvage of Residual Disease 
The standard of care for management of residual disease at the primary site or at the cervical 
nodal basin based upon an abnormal physical exam or imaging evaluation by FDG-PET/CT is 
surgical salvage if feasible. The extent of neck dissections performed for nodal persistence or 
recurrence or salvage of disease at the primary site ultimately will be determined by the treating 
surgeon. In the case of negative FDG-PET/CT in patients who did not achieve clinical nodal 
complete response, a minimum of careful clinical examination is required at 3 months. 
 
 
9. ADVERSE EVENT REPORTING FOR INTERVENTIONAL PROTOCOLS 
 
• 
All Serious Adverse Events (SAEs) that occur following the subject’s first protocol specific 
intervention through 100 days of discontinuation of dosing must be reported to BMS 
Worldwide Safety. If applicable, SAEs must be collected that relate to any later protocol-
specified procedure (eg, a follow-up skin biopsy). 
 
• 
The MD Anderson IRB SAE form for Unexpected and Related SAE should be used to report 
SAEs. The BMS protocol ID number must be included on the form submitted by the 
Sponsor/Investigator. 
 
• 
Following the subject’s first protocol specific intervention, all SAEs, whether related or not 
related to study drug, are collected, including those thought to be associated with protocol-
specified procedures. The investigator should report any SAE occurring after these time 
periods that is believed to be related to study drug or protocol-specified procedure. The 
duration of SAE collection should be extended to 100 days. 

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• 
The drug supporter company will reconcile the clinical database AE cases (case level only) 
transmitted to BMS Global Pharmacovigilance (Worldwide.Safety@bms.com). The 
Investigator will request from BMS GPV&E (aepbusinessprocess@bms.com) the SAE 
reconciliation report and include the BMS protocol number every 3 months and prior to data 
base lock or final data summary. GPV&E will send the investigator the report to verify and 
confirm all SAEs have been transmitted to BMS GPV&E. The data elements listed on the 
GPV&E reconciliation report will be used for case identification purposes. If the Investigator 
determines a case was not transmitted to BMS GPV&E, the case should be sent immediately 
to BMS (Worldwide.Safety@bms.com). 
 
 
• 
In accordance with local regulations, BMS will notify investigators of all reported SAEs that 
are suspected (related to the investigational product) and unexpected (ie, not previously 
described in the IB). In the European Union (EU), an event meeting these criteria is termed 
a Suspected, Unexpected Serious Adverse Reaction (SUSAR). Investigator notification of 
these events will be in the form of an expedited safety report (ESR). 
 
o Other important findings which may be reported by BMS as an ESR include: 
increased frequency of a clinically significant expected SAE, an SAE considered 
associated with study procedures that could modify the conduct of the study, lack of 
efficacy that poses significant hazard to study subjects, clinically significant safety 
finding from a nonclinical (eg, animal) study, , or sponsor decision to end  or 
temporarily halt a clinical study for safety reasons. 
 
o Upon receiving an ESR from BMS, the investigator must review and retain the ESR 
with the IB. Where required by local regulations or when there is a central IRB/IEC for 
the study, the sponsor will submit the ESR to the appropriate IRB/IEC. The 
investigator and IRB/IEC will determine if the informed consent requires revision. The 
investigator should also comply with the IRB/IEC procedures for reporting any other 
safety information. 
 
o In addition, suspected serious adverse reactions (whether expected or unexpected) 
shall be reported by BMS to the relevant competent health authorities in all concerned 
countries according to local regulations (either as expedited and/or in aggregate 
reports). 
 
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS 
within 24 hours. SAEs must be recorded on BMS or an approved form; pregnancies must be 
reported on a Pregnancy Surveillance Form. 
 
SAE Email Address: Worldwide.Safety@BMS.com 
 
SAE Facsimile Number: 609-818-3804 
 
If only limited information is initially available, follow-up reports are required. (Note: Follow-up SAE 
reports should include the same investigator term(s) initially reported.) 
 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to BMS (or designee) 
using the same procedure used for transmitting the initial SAE report. 
 

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All SAEs should be followed to resolution or stabilization. 
 
• 
An SAE report should be completed for any event where doubt exists regarding its 
seriousness. 
• 
If the investigator believes that an SAE is not related to study drug, but is potentially 
related to the conditions of the study (such as withdrawal of previous therapy or a 
complication of a study procedure), the relationship should be specified in the narrative 
section of the SAE Report Form. 
 
• 
If only limited information is initially available, follow-up reports are required. (Note: 
Follow-up SAE reports should include the same investigator term(s) initially reported.) 
 
• 
If an ongoing SAE changes in its intensity or relationship to study drug or if new 
information becomes available, a follow-up SAE report should be sent within 24 hours to 
BMS using the same procedure used for transmitting the initial SAE report. All SAEs 
should be followed to resolution or stabilization. All SAEs should be followed to resolution 
or stabilization. 
 
MD Anderson Serious Adverse Event (SAE) Reporting 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or the sponsor, it results in any of the following outcomes: 
 
• 
Death 
• 
A life-threatening adverse drug experience – any adverse experience that places the 
patient, in the view of the initial reporter, at immediate risk of death from the adverse 
experience as it occurred. It does not include an adverse experience that, had it occurred 
in a more severe form, might have caused death. 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• 
A congenital anomaly/birth defect. 
 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples 
of such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse (21 CFR 312.32). 
 
• 
Important medical events as defined above, may also be considered serious adverse 
events. Any important medical event can and should be reported as an SAE if deemed 
appropriate by the Principal Investigator or the IND Sponsor, IND Office. 
• 
All events occurring during the conduct of a protocol and meeting the definition of a SAE 
must be reported to the IRB in accordance with the timeframes and procedures outlined in 
“The University of Texas M. D. Anderson Cancer Center Institutional Review Board Policy 
for Investigators on Reporting Serious Unanticipated Adverse Events for Drugs and 
Devices”. Unless stated otherwise in the protocol, all SAEs, expected or unexpected, must 
be reported to the IND Office, regardless of attribution (within 5 working days of knowledge 
of the event). 

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• 
All life-threatening or fatal events, that are unexpected, and related to the study drug, 
must have a written report submitted within 24 hours (next working day) of knowledge of 
the event to the Safety Project Manager in the IND Office. 
• 
Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety 
reporting to the IND Office and MDACC IRB. 
 
• 
Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 100 days after the last dose of drug, unless the participant withdraws 
consent. Serious adverse events must be followed until clinical recovery is complete and 
laboratory tests have returned to baseline, progression of the event has stabilized, or there 
has been acceptable resolution of the event. 
• 
Additionally, any serious adverse events that occur after the 100 day time period that are 
related to the study treatment must be reported to the IND Office. This may include the 
development of a secondary malignancy. 
 
 
Reporting to FDA: 
 
• 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project 
Manager IND Office) according to 21 CFR 312.32. 
 
 
It is the responsibility of the PI and the research team to ensure serious adverse events are 
reported according to the Code of Federal Regulations, Good Clinical Practices, the 
protocol guidelines, the sponsor’s guidelines, and Institutional Review Board policy. 
 
The Case Report Form (CRF) for this study is DMI. The PI and designee will be responsible 
for assigning attribution to study drug, and record AEs in Adverse Event Logs. 
 
 
9.1 DEFINITIONS 
 
The protocol must include a definition for Serious Adverse Events (SAE). 
 
 
9.1.1 
SERIOUS ADVERSE EVENTS 
 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 
 
• 
results in death 
 
• 
is life-threatening (defined as an event in which the participant was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 
 
• 
requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
• 
NOTE below) 
 
• 
results in persistent or significant disability/incapacity 
 
• 
is a congenital anomaly/birth defect 
 

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• 
is an important medical event (defined as a medical event(s) that may not be  
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the subject or may require 
intervention [eg, medical, surgical] to prevent one of the other serious outcomes listed in 
the definition above.) Examples of such events include, but are not limited to, intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias 
or convulsions that do not result in hospitalization.) 
 
• 
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the 
study drug is an SAE. 
 
Although pregnancy, overdose, potential drug-induced liver injury (DILI) and cancer are not 
always serious by regulatory definition, these events must be handled as SAEs. 
 
Any component of a study endpoint that is considered related to study therapy should be reported 
as an SAE (eg, death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported). 
 
NOTE: (PI determines if this information regarding hospitalizations are considered SAEs and 
should be included in the protocol. This is supplemental information that is included in 
BMS-sponsored trials) 
 
The following hospitalizations are not considered SAEs in BMS clinical studies: 
 
• 
a visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered an important medical or life-threatening event) 
 
• 
elective surgery, planned prior to signing consent 
 
• 
admissions as per protocol for a planned medical/surgical procedure 
 
• 
routine health assessment requiring admission for baseline/trending of health status (eg, 
routine colonoscopy) 
 
• 
Medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases 
 
• 
Admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason). 
 
• 
Admission for administration of anticancer therapy in the absence of any other SAEs 
(applies to oncology protocols) 
 
9.1.2 
ADVERSE EVENTS 
 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation participant administered study drug and 
that does not necessarily have a causal relationship with this treatment. An AE can therefore be 
any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of investigational product, whether or not considered 
related to the investigational product. 

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The causal relationship to study drug is determined by a physician and should be used to assess 
all adverse events (AE). The casual relationship can be one of the following: 
 
Related: There is a reasonable causal relationship between study drug administration and the AE. 
 
Not related: There is not a reasonable causal relationship between study drug administration and 
the AE. 
 
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship. 
 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.) 
 
9.2 NONSERIOUS ADVERSE EVENT 
 
• 
Nonserious Adverse Events are to be provided to BMS in aggregate via interim or final study 
reports as specified in the agreement or, if a regulatory requirement [e.g. IND US trial] as part 
of an annual reporting requirement. 
 
• 
Nonserious AE information should also be collected from the start of a placebo lead-in period 
or other observational period intended to establish a baseline status for the subjects. 
 
A nonserious adverse event is an AE not classified as serious. 
 
9.2.1 
Nonserious Adverse Event Collection and Reporting 
 
The collection of nonserious AE information should begin at first protocol specific intervention. All 
nonserious adverse events (not only those deemed to be treatment-related) should be collected 
continuously during the treatment period and for a minimum of 100 days following the last dose of 
study treatment. 
 
The drug supporter company will reconcile the clinical database AE cases (case level only) 
transmitted to BMS Global Pharmacovigilance (Worldwide.Safety@bms). Frequency of 
reconciliation should be every 3 months and prior to the database lock or final data summary. 
BMS GPV&E will email, upon request from the Investigator, the GPV&E reconciliation report. 
Requests for reconciliation should be sent to aepbusinessprocess@bms.com. The data elements 
listed on the GPV&E reconciliation report will be used for case identification purposes. If the 
Investigator determines a case was not transmitted to BMS GPV&E, the case should be sent 
immediately to BMS. 
 
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious. Follow-up is also required for nonserious AEs that cause interruption or 
discontinuation of study drug and for those present at the end of study treatment as appropriate. 
 
Recommended Adverse Event Recording Guidelines 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
Phase I 
Phase I 
Phase I 
Phase I 
Phase I 
Phase II 
Phase II 
Phase II 
Phase III 
Phase III 

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Unlikely 
Phase I 
Phase I 
Phase I 
Phase I 
Phase I 
Phase II 
Phase II 
Phase II 
Phase III 
Phase III 
Possible 
Phase I 
Phase I 
Phase I 
Phase I 
Phase I 
Phase II 
Phase II 
Phase II 
Phase II 
Phase II 
Phase III 
Phase III 
Phase III 
Phase III 
Probable 
Phase I 
Phase I 
Phase I 
Phase I 
Phase I 
Phase II 
Phase II 
Phase II 
Phase II 
Phase II 
Phase III 
Phase III 
Phase III 
Phase III 
Definitive 
Phase I 
Phase I 
Phase I 
Phase I 
Phase I 
Phase II 
Phase II 
Phase II 
Phase II 
Phase II 
  
 
 
 
  Phase III 
    Phase III 
      Phase III         Phase III  
 
 
9.3 Laboratory Test Abnormalities 
 
All laboratory test results captured as part of the study should be recorded following institutional 
procedures. Test results that constitute SAEs should be documented and reported as such. 
 
The following laboratory abnormalities should be documented and reported appropriately: 
 
• 
any laboratory test result that is clinically significant or meets the definition of an SAE 
• 
any laboratory abnormality that required the participant to have study drug discontinued 
or interrupted 
• 
any laboratory abnormality that required the subject to receive specific corrective therapy. 
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value). 
 
9.3.1 
Potential Drug Induced Liver Injury (DILI) 
 
Specific criteria for identifying potential DILI have not been identified for this protocol. Standard 
medical practice in identifying and monitoring hepatic issues should be followed. 
 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should occur 
prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting the 
defined criteria, must be reported as SAEs. 
 
Potential drug induced liver injury is defined as: 
 
1) AT (ALT or AST) elevation > 3 times upper limit of normal (ULN)  
AND 
2) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase), 
      AND 
3) No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic. 
 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should occur 
prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting the 
defined criteria, must be reported as SAEs. 
 

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9.4 Pregnancy 
 
If, following initiation of the investigational product, it is subsequently discovered that a study 
participant is pregnant or may have been pregnant at the time of investigational product exposure, 
including during at least 5 half-lives after product administration, the investigational product will be 
permanently discontinued in an appropriate manner (eg, dose tapering if necessary for 
participant). 
 
The investigator must immediately notify Worldwide.Safety@bms.com of this event via the 
Pregnancy Surveillance Form in accordance with SAE reporting procedures. 
 
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
participant. 
 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form [provided upon request from BMS] 
 
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form. In 
order for Sponsor or designee to collect any pregnancy surveillance information from the female 
partner, the female partner must sign an informed consent form for disclosure of this information. 
 
9.5 Overdose 
 
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE. 
 
9.6 Other Safety Considerations 
 
Any significant worsening noted during interim or final physical examinations, 
electrocardiograms, x-rays, and any other potential safety assessments, whether or not these 
procedures are required by the protocol, should also be recorded as a nonserious or serious AE, 
as appropriate, and reported accordingly. 
 
9.7 Data management and monitoring plan 
 
We will build an integrated database for web-based clinical trial data collection, trial monitoring, 
reporting, and data quality assurance. Patient medical-demographic information, treatment 
course, toxicity, and efficacy outcomes will be entered into the database in a timely fashion. A 
monthly report of study enrollment will be generated automatically and distributed to the study 
team. Toxicity, response status, and PFS will also be monitored via an integrated statistical 
program to check against the stopping boundaries.At the time when the stopping boundary is 
crossed, the study statistician and the PI will be notified by an e-mail generated by the statistical 
program automatically. The study team will check the data quality to affirm the finding. 
 
STUDY MONITORING AND EARLY STOPPING RULES 
As a single-arm Phase II trial, he study will not be monitored by the MD Anderson Data Safety 
and Monitoring Board (DSMB). Toxicity monitoring will include grade ≥2 toxicities, attribution (e.g., 
possibly related, probably related or definitely related), whether the toxicity is expected vs. not 
expected, or whether the toxicity is an SAE vs. not an SAE. All grade immununotherapy- related 

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toxicities will be reported. SAE reporting will follow standard clinical trial guidelines. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10. STATISTICAL CONSIDERATIONS 
 
10.1 Study Design and Study Endpoints 
 
 
 
 
 
10.1.1 
Safety lead in: 
 
Primary Endpoint: 
 
Dose limiting toxicity for the addition of anti-CTLA4 (ipilimumab) and anti-PD-1 (nivolumab) to 
IMRT 60 Gy and reduced fields in patients with low-volume, HPV-positive OPSCC. 
 
Secondary Endpoints: 
 
• 
Number of patients who experience a ≥grade 3 treatment-related adverse event 
 
• 
Number of patients who tolerated protocol therapy, including completion of radiotherapy 
without a treatment break and who were administered IO per protocol 

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• 
Number of patients who achieve a clinical complete response  
 
Safety lead in design: 
 
The dose finding study will include the dose and schedule of the nivolumab/ ipilimumab 
combination that was observed to provide clinical efficacy and reduced toxicity in patients with 
NSCLC. Patients will be administered two cycles of ipilimumab 1 mg/kg on day 1 and nivolumab 3 
mgs/kg on day 1, 15 and 29 of a six week schedule, starting 6 weeks prior to day 1 of RT. A 
cohort of 8 patients will be enrolled. The period of observation for DLT is from the start of IO 
through 28 days post-completion of radiotherapy. In the event of 0-2 DLT events in the lead-in 
phase of the protocol, the study will proceed to phase 2. In the event of >2 treatment- attributable 
DLTs in a cohort of 8 patients, an alternative schedule may be considered in which the second 
dose of ipilimumab is administered on day 29 cycle 2 and if additional DLT are observed, only one 
dose of iplimumab may be administered to prime to T cell response. Observation of the last 
patient for the period of DLT (28 days post-completion of RT) is mandatory. A DLT will be defined 
as: (1) Any ≥ grade 3 adverse event (CTCAE, v. 4) that is related to IO that does not resolve to 
grade 1 or less within 28 days; (2) A delay in radiotherapy of >1week due to toxicity related to IO; 
(3) Inability to complete radiotherapy due to toxicity related to IO; (4) ≥Grade 3 radiation-induced 
mucositis that does not resolve to < grade 3 within 28 days after radiotherapy.  With a cohort of 8 
patients, the probability of the combination IO being judged to be too toxic when the true toxicity 
rate is 45% or higher is at least 78%. If the true toxicity rate is 20% or lower, the probability that 
the therapy will be safe is 80%. Should schedule adjustment be necessary, given a signal of 
safety concern, the second cohort of patients will include 8 patients. The phase 2 trial will proceed 
based upon the DLT data from the first 8 (schedule 1) and first 8 (schedule 2, if necessary) 
patients. However, data from all patients will be evaluated when available. The principal 
investigators and BMS will review this data to determine if the study design will need to be 
adjusted. 
 
10.1.2 
Phase II: 
 
Primary endpoint: Two co-primary endpoints are specified: (1) the complete response (CR) rate 
at 6 months and (2) the two-year progression-free survival (PFS) rate. 
 
Secondary endpoints: 
 
• 
acute and chronic toxicities per CTCAE v4; 
• 
acute toxicity profiles per CTCAE v4 at the end of radiation therapy, end of IO and 6 
months; 
• 
≥grade 3 treatment-related adverse events at end of radiotherapy, end of IO and 6 
months; 
• 
late toxicity profiles per CTCAE v 4 at 1 and 2 years; 
• 
patient-reported, swallowing outcomes at 1 and 2 years; 
• 
patterns of failure (local-regional relapse vs. distant) at 1 and 2 years; 
• 
overall survival (OS) at 1 and 2 years. 
 
 
10.2 Exploratory Objectives: 
To measure changes in the tumor microenvironment in tumor biopsy specimens pre and post 
induction IO. 
 
To measure changes in serum cytokine profiles before and after induction IO; 

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To measure alterations in PD-L1 expression in tumor biopsy specimens pre and post induction 
IO and at progression; 
 
To perform T cell receptor repertoire analysis of TIL in tumor biopsy specimens pre and post 
induction IO; 
 
To evaluate changes in HPV viral load in plasma and oral rinses during primary therapy and 
follow-up; 
 
To determine the NPV and PPV of FDG-PET/CT12-14 weeks after end of RT for 6 month, 1 year 
and 2 year PFS and OS. 
 
10.3 Study Design: 
This is a phase II, open label, single arm study. The study is designed to evaluate the safety, 
feasibility and clinical efficacy of a treatment strategy of combination anti-CTLA4 (ipilimumab) and 
anti-PD-1 (nivolumab) IO with reduced dose and field IMRT to 60 Gy for patients with low volume, 
local-regionally advanced HPV-positive OPSCC (AJCC 7th edition T1N2a-N2c, T3N0, T2-T3N1-
N2C; AJCC 8th edition stage 1-2, excluding T1N0-1, T2N0). Treatment will include two, six- week 
cycles of ipilmumab 1 mg/kg day 1 and nivolumab 3 mg/kg on days 1, 15, and 29 starting 6 weeks 
before start of IMRT (60 Gy; 2 Gy/fx, 6 fx/week), equivalent to cycle 2 day 1 of the IO. 
 
The statistical considerations for the Phase II design are described as follows. The primary 
objective of this study is to establish the efficacy of the new immunotherapy regimen such that it is 
non-inferior to the current standard therapy. Two co-primary endpoints are specified: (1) the 
complete response (CR) rate at 6 months and (2) the two-year progression-free survival (PFS) 
rate. Time 0 is defined at start of treatment. Based on the available data (reference), the standard 
therapy yields a 6-month CR rate of 0.87 and a two-year PFS of 0.91. The non- inferiority margin 
is set at 0.05 for the 6-month CR rate and at 0.06 for the 2-year PFS. Thus, the new treatment is 
considered non-inferior to the standard therapy if the 6-month CR rate is at least 0.82 and the 
two-year PFS is at least 0.85. Otherwise, the new treatment is considered inferior to the standard 
therapy. 
 
The study comprises a three-year accrual period with 5 patient enrolled per month and additional 
two years of follow up. Futility early stopping rule will be implemented monthly starting month 7 to 
protect patients from receiving inferior therapy. In order to assure that the new regimen is safe 
and efficacious, patient accrual will be paused after 35 patients are enrolled. After the toxicity data 
and the 6-month CR status are available, study statistician will perform the first interim analysis. 
The study PI will discuss with sponsor and make a decision to either resume accrual and expand 
the study size beyond 35 patients if the new regimen is deemed to be safe and efficacious or 
close the study otherwise. If the trial is not stopped early after the first interim analysis, patient 
accrual will resume and additional interim monitoring will be performed monthly. If the trial is not 
stopped early, the non-inferiority boundary is evaluated at the end of study. Patients in the safety 
evaluation will be included in the phase 2 trial. The maximum total sample size is 180 and the 
total study duration is up to 5 years. 
 
Assume that the 6-month response rate follows a binomial distribution and the PFS follows a 
Weibull distribution, given the parameters specified above, the study will have 82% power of 
establishing the non-inferiority if the efficacy of the new treatment is as good as the standard 
treatment. In this case, the early futility stopping probability is 0.12 with an average sample size of 
170.2. On the other hand, if the new treatment yields a 6-month response rate of 0.75 and a two-

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year PFS of 0.85, the early stopping probability is 0.93 with an average sample size of 127.6. The 
probability of claiming non-inferiority is 0.06 (type I error). If the new treatment is apparently worse 
than the standard treatment with a 6-month response rate of 0.70 and a two- year PFS of 0.79, 
the early stopping probability is 1 with an average sample size of 57.0, and a probability of 0 
claiming non-inferiority. Detailed model specification, hypothesis testing framework, derivation of 
test statistics and stopping boundaries can be found in the Appendix. The results were based on 
simulation studies with 1,000 runs. 
 
The Investigator is responsible for completing safety/efficacy summary reports and submitting 
them to the IND office Medical Affairs and Safety Group for review. These should be submitted 
as follows: 
 
• 
Lead-In Phase: 
A toxicity summary will be submitted after the first 8 evaluable subjects enrolled in 
Schedule 1, complete 28 days post radiotherapy, and if required, after the first group of 8 
evaluable patients enrolled in Schedule 2, complete the same toxicity monitoring timeline. 
IND Office approval must be obtained prior to advancing/changing dose levels. 
 
• 
Phase II: 
An efficacy/toxicity summary will be submitted after the first 5 evaluable subjects 
complete 6 months of study treatment, and every 5 patients thereafter. The study 
enrollment must be paused after 35 patients are enrolled, when study statistician will 
perform the first interim analysis. Subsequently, summaries submission to IND Office will 
continue every 5 evaluable subjects until the study is complete. Best response 
information must be assess after 6 months of initiation of study treatment, and toxicity 
information after 28 days post radiotherapy. 
 
A copy of the cohort summary should be placed in the Investigator’s Regulatory Binder under 
“sponsor correspondence”. 
 
 
11. CORRELATIVE STUDIES 
 
11.1 Rationale for PD-L1 detection 
In CheckMate 141, response rate to single agent nivolumab increased with PD-L1 expression 
cut-point, but OS did not. As noted in the table below, PD-L1 expression has been associated 
with efficacy of PD-1/PD-L1 checkpoint blockade (Table 1). 
 
Table 1: Association of PD-L1 expression on tumor cells with immune response of anti-PD-1 
antibody Nivolumab. (Modified from X. Meng et al. (Meng et al. 2015) 
 
Tumor 
Cut off 
values 
PD-L1 
+ (%) 
Anti- 
body 
ORR 
PD-L1+ 
ORR 
PD- 
L1- 
p-val 
Conclusion 
Melanoma1 
5% 
35.4 
Dako 
52.7% 
33.1% 
NR 
No sig. association 
NSCLC 
1% 
83 
Dako 
18% 
17% 
0.94 
No association 
squamous2 
5% 
21% 
15% 
0.29 
10% 
19% 
16% 
0.64 
RCC3 
5% 
27 
28-8 
31% 
18% 
NR 
No sig. association 
NSCLC 
non- 
squamous4 
1% 
78 
Dako 
31% 
9% 
0.0019 
PD-L1 expression sig. 
5% 
 
 
36% 
10% 
0.0020 
associated with ORR 
10% 
 
 
37% 
11% 
0.0021 
 

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Melanoma5 
5% 
46 
Dako 
43.6% 
20.3% 
NR 
No sig. association 
Melanoma, 
NSCLC 
RCC 
CRC6 
5% 
53 
53 
89 
13 
5H1 
39% 
6% 
0.0025 
PD-L1 expression sig. 
associated with ORR 
Melanoma, 
RCC,  
NSCL C, 
CRC, 
Prostate7 
5% 
60 
5H1 
36% 
0% 
0.006 
PD-L1 expression sig. 
associated with ORR 
Melanoma8 
1% 
52 
28-8 
39% 
23% 
0.004 
PD-L1 expression sig. 
associated with ORR 
5% 
27 
 
67% 
19% 
 
Abbreviations: PD-1, programmed death-1; PD-L1, programmed death-ligand 1; RCC, renal cell 
cancer; NSCLC, non-small cell lung cancer; CRC, colonrectal cancer; NR, not reported; TC, 
tumor cells. 
1. Robert C, et al. N Engl J Med 2015; 2. Brahmer J, et al. N Engl J Med 2015; 3. Motzer RJ, et 
al. JCO 2015; 4. Borghaei H, et al. N Engl J Med 2015; 5. Weber JS, et al. Lancet Oncol 2015; 
6. Taube JM, Clin Cancer Res 2014; 7. Topalian SL, et al. N Engl J Med 2012; 8. Weber JS, et 
al. JCO 2013. 
 
PD-L1 expression appears associated with ORR (Taube et al. 2014). Nevertheless, patients with 
PD-L1 negative HNSCC still derive clinical benefit with regard to ORR. This clinical trial design 
will allow for the evaluation of changes in PD-L1 expression before and after IO among 
previously untreated patients as well as associations with clinical outcomes. 
 
11.2 HPV-positive head and neck cancer and response to IO: neoantigens and T cell 
repertoire 
Studies first carried out in the 1980s demonstrated murine T cells recognize mutated gene 
products, known as neoantigens, and that these T cells are capable of mediating tumor rejection 
(Lu and Robbins 2016). Thus, mutational burden may be related to response to immune 
checkpoint blockade. For example, neoantigen burden was positively correlated with the clinical 
benefit and progression-free survival in patients with NSCLC receiving the anti-PD-1 antibody 
pembrolizumab (Rizvi et al. 2015). 
 
Tumors with an immune-active microenvironment (so called “hot tumors”) are more likely to 
respond to IO agents targeting key immunosuppressive pathways (Denkert et al. 2010).Tumor 
regression in response to IO may be mediated in part by CTLs and NK cells that recognize 
neoepitopes expressed by tumors. HPV E6 and E7 proteins are tumor-specific, foreign 
neoantigens that can be recognized by T cells, thus inducing tumor rejection. Moreover, high 
levels of TILs in a diagnostic specimen among HPV-positive patients treated primarily with RT 
was associated with a high 3-year OS of 96% (Ward et al. 2014). Moreover, as a response to viral 
infection, HPV associated tumors display evidence of induction of a component of innate immunity 
known as the apoliprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) family of 
proteins, leading to high potential for generation of neoantigens (Cleary et al. 2016). As an 
example, two specific codons (E542K and E545K) within the helicase domain of PIK3CA are 
frequently mutated in HPV-positive SCCHN due to C>T transitions in a T*pC context (Hayes, Van 
Waes, and Seiwert 2015). We note that smoking is a negative prognostic factor for HPV-positive 
HNSCC. However, higher tobacco-signature mutations may result in neoantigen generation. We 
will perform WES and RNAseq on tumor biospies at baseline to determine mutational burden and 
resulting expressed neoantigen generation and frequency distribution. Somatic mutations in DNA 
repair proteins (eg. FA, POLE) and their association with mutational burden will also be of 

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interest.  
 
 
 
11.3 Changes in the microenvironment among HPV-positive OPSCC treated with IO:  
The study design provides an opportunity to evaluate the effect of dual IO checkpoint blockade 
with ipilimumab and nivolumab on the tumor microenvironment among previously untreated 
patients. We will explore T cell receptor diversity and expansion in the peripheral blood and tumor 
microenvironment before and after neoadjuvant ipi/nivo, if feasible, by means of targeted T cell 
sequencing and presence and phenotype distribution of the inflammatory infiltrate by multi- 
spectral immunofluorescence and possibly single cell RNAseq in before and after biopsies. We 
will explore associations between biomarkers of interest and 6-months CR and 2-year PFS 
outcomes. For example, alterations that will be evaluated include the frequency and phenotype 
distribution of TIL in the tumor microenvironment (e.g. CTLA-4, PD-L1 expressing CD8+ and 
CD4+FoxP3+Treg and associated ratios; NKp46 CD56dim NK cells). 
 
 
 
  
12. Appendices 
 
APPENDIX I: Nivolumab and Ipilimumab TOXICITY MANAGEMENT ALGORITHMS 
 
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with Prof. Dr. Ferrarotto. The guidance applies to all immune-oncology agents and 
regimens. 
 
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated. 
 
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The 
oral equivalent of the recommended IV doses may be considered for ambulatory patients with 
low-grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids. 
 
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended. 
 
The frequency and severity of the related adverse events covered by these algorithms will 
depend on the immuno-oncology agent or regimen being used. 
 

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APPENDIX II: MADSI/MDAMI
 
 

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