Clinical trial NCT03944915
Conditions: Human Papilloma Virus Squamous Cell Carcinoma Squamous Cell Carcinoma of the Head and Neck HPV-Related Squamous Cell Carcinoma HNSCC
Sponsor: University of Chicago
Start date: 2019-08-26; Completion date: 2023-11-01
Enrollment: 35 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This study is looking to see if nivolumab, an immunotherapy drug, given with carboplatin and paclitaxel (2 chemotherapy agents) during induction therapy in advanced stage HPV negative patients can significantly shrink the subject's cancer.

Detailed description:

Arms: arm 1: Induction Therapy arm 2: Radiation therapy with chemotherapy
Interventions: intervention 1: Carboplatin intervention 2: Paclitaxel intervention 3: Nivolumab intervention 4: Radiation intervention 5: Hydroxyurea Pill intervention 6: 5-fluorouracil intervention 7: Filgrastim Injection intervention 8: Cisplatin
Intervention descriptions: intervention 1: Carboplatin will be given through IV infusions for 30-60 minutes on day 1 of each cycle. Each cycle will last 21 days. There will be 3 cycles. intervention 2: During Induction Therapy Paclitaxel (100 mg) will be given through IV infusions on days 1, 8 and 15 of each 21 day cycle. There will be 3 cycles.

During Radiotherapy, paclitaxel will be given after a dose of radiation by IV infusion for 60 minutes after day 1 of radiotherapy. intervention 3: Nivolumab will be given through IV infusions at 360 mg on day 1 every 21 days for 3 cycles. intervention 4: Patients will receive 4.5-5 cycles of radiation depending on response. Those with a positive response will receive radiation for 4.5 cycles with a total radiation dose of 66 Gy. Patients with a moderate or no response will receive 5 cycles with a total radiation dose of 70-75 Gy. 2 times a day for days 1-5 followed by a rest period for days 6-13 intervention 5: One dose of hydroxyurea pill by mouth at start of 5-FU infusion during radiotherapy cycle intervention 6: 5-FU will be given by IV infusion continuously for 5 days during radiotherapy cycles intervention 7: Filgrastim shot will be given if patient has certain side effects during radiotherapy cycle on days 6-12. intervention 8: Radiotherapy may also be given with a different chemotherapy agent called cisplatin. This is the traditional standard of care chemotherapy regimen. In this case, the radiotherapy will be given once daily for 5 days per week. Cisplatin will be administered via IV once every 21 days for 2 or 3 cycles.

Protocol documents:
Prot_SAP_000.pdf: 
Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
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A phase II trial of carboplatin, paclitaxel, and nivolumab induction therapy followed 
by response-stratified locoregional therapy for patients with locally advanced, HPV-
negative head and neck cancer. The DEPEND Trial.  
 
DEPEND – De-Escalation Therapy for Human Papillomavirus Negative Disease 
 
UCCCC IRB Number: 
19-0162 
 
BMS Protocol Number:  
CA209-8PH 
 
Coordinating Center:   
University of Chicago Medical Center 
 
Lead Principal Investigator: Everett Vokes, MD 
 
Sub-Investigators: 
 
Daniel Haraf, MD 
 
 
 
 
Nishant Agrawal, MD 
 
 
 
 
Alexander Pearson, MD, PhD 
 
 
 
 
Ari Rosenberg, MD 
 
 
 
 
Elizabeth Blair, MD 
 
 
 
 
Zhen Gooi, MD 
 
 
 
 
Louis Portugal, MD 
 
 
 
 
Corey Foster, MD 
 
Statistician: 
 
 
John Cursio, PhD  
Research Nurse: 
 
Courtney Mccampbell  
 
 
 
 
Margaret Klein 
 
 
 
 
Patricia Heinlen 
 
 
 
 
Kathryn Cialkowski 
 
Study Coordinator: 
 
Jeffrey Chin 
Katherine Rouse 
 
Data Manager: 
 
Melody Jones 
 
This study is being conducted by institutional members of the Personalized Cancer Care 
Consortium (PCCC), as well as additional sites.  
 


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Table of Contents 
1 
PROTOCOL SCHEMA ....................................................................................................................... 5 
1.1 
TRIAL SCHEMA .............................................................................................................................. 5 
2 
OBJECTIVES ....................................................................................................................................... 5 
2.1  
PRIMARY OBJECTIVE ..................................................................................................................... 5 
2.2  
SECONDARY OBJECTIVES ............................................................................................................... 5 
2.3  
EXPLORATORY OBJECTIVES ........................................................................................................... 6 
3 
BACKGROUND AND RATIONALE ................................................................................................ 6 
3.1 
LOCALLY ADVANCED HEAD AND NECK CANCER .......................................................................... 6 
3.2 
CHEMORADIOTHERAPY .................................................................................................................. 7 
3.3 
CRT PLATFORMS: CONCURRENT CISPLATIN-RADIATION OR TFHX ............................................. 7 
3.4 
INDUCTION CHEMOTHERAPY ......................................................................................................... 8 
3.5 
RESPONSE-ADAPTED VOLUME DE-ESCALATION (RAVD) ............................................................ 9 
3.6 
NIVOLUMAB/ANTI-PD-1 ................................................................................................................ 9 
3.7 
STUDY RATIONALE .......................................................................................................................10 
4   
PATIENT SELECTION .....................................................................................................................11 
4.1  
ELIGIBILITY CRITERIA ..................................................................................................................11 
4.2  
EXCLUSION CRITERIA ...................................................................................................................12 
4.3 
PREGNANCY PREVENTION.............................................................................................................13 
5 
REGISTRATION PROCEDURES ....................................................................................................14 
5.1 
GENERAL GUIDELINES ..................................................................................................................14 
5.2 
REGISTRATION PROCESS ...............................................................................................................15 
6 
TREATMENT PLAN ..........................................................................................................................16 
6.1 
GENERAL CONSIDERATIONS .........................................................................................................16 
6.2 
PRE-TREATMENT EVALUATION .....................................................................................................17 
6.3 
STUDY EVALUATIONS ...................................................................................................................17 
6.4 
INDUCTION CHEMOTHERAPY DETAILS AND GUIDELINES ..............................................................18 
6.5 
DEFINITIVE CHEMORADIATION DETAILS AND GUIDELINES ..........................................................18 
6.5.1 
Response Stratified Grouping ..................................................................................................18 
6.5.2 
Concurrent Cisplatin-Radiation ...............................................................................................19 
6.5.3 
TFHX Regimen .......................................................................................................................19 
6.5.4 
Radiation Therapy Guidelines .................................................................................................20 
6.5.5 
Nodal Planning Target Volume Delineation for Standard CRT Patients ................................23 
6.6 
CONSOLIDATIVE IMMUNOTHERAPY DETAILS AND GUIDELINES ....................................................29 
6.7  
SUPPORTIVE GUIDELINES DURING CHEMORADIATION ..................................................................29 
6.8 
POST-THERAPY FOLLOW-UP ........................................................................................................30 
6.9 
DURATION OF THERAPY ................................................................................................................31 
6.10 
CRITERIA FOR DISCONTINUATION/WITHDRAWAL OF INFORMED CONSENT ..................................31 
6.11  
LATE TOXICITY ASSESSMENT .......................................................................................................31 
6.11.1 
Late Toxicity Assessment Schedule ...................................................................................31 
6.11.2  
Assessment of Late Toxicity ..............................................................................................31 
6.11.3  
Quality of Life Assessments ...............................................................................................32 
7  
EXPECTED ADVERSE EVENTS, RISKS AND DOSE MODIFICATIONS ...............................32 


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7.1 
EXPECTED ADVERSE EVENTS .......................................................................................................33 
7.1.1  
Nivolumab ...............................................................................................................................33 
7.1.2 
Carboplatin ..............................................................................................................................33 
7.1.3 
Paclitaxel .................................................................................................................................33 
7.1.4 
5-Fluorouracil ..........................................................................................................................34 
7.1.5 
Hydroxyurea ............................................................................................................................34 
7.1.6 
Cisplatin ..................................................................................................................................34 
7.1.7 
Filgrastim ................................................................................................................................34 
7.1.8 
Radiation .................................................................................................................................35 
7.2 
DOSE MODIFICATIONS ..................................................................................................................35 
7.2.1 
Induction Chemotherapy Dose Modifications .........................................................................35 
7.2.2 
Nivolumab Dose Modifications during Induction Phase and Consolidative Phase .................37 
7.2.3 
Nivolumab Adverse Event Management Algorithms ..............................................................38 
7.2.4 
Dose Modifications During Concurrent Chemotherapy ..........................................................45 
8 
PHARMACEUTICAL INFORMATION ..........................................................................................47 
8.1  
CARBOPLATIN ...............................................................................................................................47 
8.2 
FLUOROURACIL .............................................................................................................................48 
8.3  
HYDROXYUREA ............................................................................................................................48 
8.4  
PACLITAXEL..................................................................................................................................48 
8.5 
CISPLATIN .....................................................................................................................................49 
8.6 
FILGRASTIM ..................................................................................................................................50 
8.7  
NIVOLUMAB ..................................................................................................................................52 
9 
CORRELATIVE STUDIES................................................................................................................54 
9.1 
OBJECTIVES ..................................................................................................................................54 
9.2 
CORRELATIVE ANALYSIS ..............................................................................................................54 
9.2.1 
Tissue ......................................................................................................................................54 
9.2.2  
Blood .......................................................................................................................................55 
9.3 
SAMPLE AND TISSUE PROCUREMENT ............................................................................................56 
9.3.1 
Archival Tumor Collection ......................................................................................................56 
9.3.2 
Tissue Biopsy ..........................................................................................................................56 
9.3.3 
Blood Isolation ........................................................................................................................56 
10 
STUDY CALENDAR ..........................................................................................................................58 
11 
CRITERIA FOR OUTCOME ASSESSMENT/THERAPEUTIC RESPONSE ............................60 
11.1 
OUTCOME RESPONSE ....................................................................................................................60 
11.2  
THERAPEUTIC RESPONSE ..............................................................................................................60 
11.2.1 Response Evaluation Criteria in Solid Tumors (RECIST)..........................................................60 
12 
REGULATORY AND REPORTING REQUIREMENTS ..............................................................62 
12.1 
REGULATORY GUIDELINES ...........................................................................................................62 
12.2 
ADVERSE EVENT CHARACTERISTICS ............................................................................................64 
12.3  
ADVERSE EVENT DEFINITIONS......................................................................................................64 
12.3.1  
Adverse Event.....................................................................................................................64 
12.3.2  
Serious Adverse Events (SAE) ...........................................................................................65 
12.3.3 
Relatedness .........................................................................................................................65 
12.3.4  
Adverse Reactions ..............................................................................................................65 
12.4  
ADVERSE EVENT REPORTING REQUIREMENTS ..............................................................................66 


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12.4.1 
Routine Adverse Event Reporting ......................................................................................66 
12.4.2  
Serious Adverse Event Reporting to Coordinating Center .................................................66 
12.4.3 
Serious and Unexpected Adverse Event Reporting by the Coordinating Center ................67 
12.4.4 
Serious Adverse Event Reporting to BMS .........................................................................67 
12.5 
DATA SUBMISSION ........................................................................................................................68 
12.6  
DATA AND SAFETY MONITORING .................................................................................................68 
12.7 
AUDITING .....................................................................................................................................69 
13 
STATISTICAL PLAN .........................................................................................................................70 
13.1 
ANALYSIS POPULATIONS ..............................................................................................................70 
13.2 
ENDPOINTS ...................................................................................................................................70 
13.2.1 
Primary Endpoint ................................................................................................................70 
13.2.2 
Secondary Endpoints ..........................................................................................................71 
13.2.3 
Exploratory Endpoints ........................................................................................................72 
13.3  
ACCRUAL RATE AND STUDY DURATION .......................................................................................73 
13.4 
SAFETY ANALYSIS PLAN ..............................................................................................................74 
13.5 
HANDLING OF MISSING DATA .......................................................................................................74 
14 
STUDY MANAGEMENT AND REGULATORY AFFAIRS .........................................................74 
14.1 
MULTICENTER GUIDELINES ..........................................................................................................74 
14.2 
INSTITUTIONAL REVIEW BOARD (IRB) APPROVAL AND CONSENT ...............................................74 
14.3  
FOOD AND DRUG ADMINISTRATION (FDA) APPROVAL ................................................................75 
14.4  
AMENDMENTS TO THE PROTOCOL .................................................................................................75 
14.6 
RECORD RETENTION .....................................................................................................................76 
14.7  
OBLIGATIONS OF STUDY SITE INVESTIGATORS .............................................................................76 
15  
REFERENCES ................................................................................................................................77 
16 
APPENDIX...........................................................................................................................................82 
16.1  
PSS-HN ........................................................................................................................................82 
16.2 
FACT H&N ..................................................................................................................................84 
16.3  
MULTICENTER GUIDELINES ..........................................................................................................87 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
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1 
PROTOCOL SCHEMA 
 
1.1 
Trial Schema  
 
2 
OBJECTIVES 
 
2.1  
Primary Objective 
 To intensify induction chemotherapy with the addition of an immune checkpoint 
inhibitor aimed at increasing the proportion of patients achieving a deep tumor 
response in order to subsequently allow risk-adapted definitive chemoradiotherapy 
in advanced stage HPV negative head and neck squamous cell cancer patients.  
o Endpoint: The proportion of patients who achieve a deep response rate 
(50% or greater response per RECIST v1.1 criteria) after induction 
chemoimmunotherapy 
 
2.2  
Secondary Objectives 
 Assess survival outcomes in all patients receiving induction chemoimmunotherapy 
and compare survival between radiation arms.  
o Endpoints 
 Progression free survival at 24 months after completing 
chemoradiation  
 Overall survival at 24 months after completing chemoradiation  
 Assess disease control in all patients receiving induction chemoimmunotherapy 
and compare disease control between radiation arms.  
o Endpoints 


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 Locoregional control at 24 months after completing chemoradiation 
 Distant control at 24 months after completing chemoradiation  
2.3  
Exploratory Objectives  
 Assess long-term/late toxicities including enteral tube dependence in all patients 
receiving induction chemoimmunotherapy.  
o Endpoints 
 Acute and late toxicity as assessed by CTCAE v5.0 measured 
during treatment and at 1 month, 3 months, and 1-year post-
chemoradiation 
 Enteral tube dependency at 3 months and 1-year post-
chemoradiation 
 Assess acute and long-term toxicity in patients who received risk-adapted 
chemoradiotherapy after deep response to induction chemoimmunotherapy. 
o Endpoints 
 Acute and late toxicity as assessed by CTCAE v5.0 measured 
during treatment and at 1 month, 3 months, and 1-year post-
chemoradiation  
 Enteral tube dependency at 3 months and 1-year post-
chemoradiation 
 Evaluate quality of life in patients who receive dose-reduced chemoradiotherapy 
after a deep response to induction therapy. 
 Interrogate and understand the immune micro-environment at baseline and 2-3 
weeks into induction therapy with extensive immunohistological and serum 
biomarkers. 
3 
BACKGROUND AND RATIONALE   
 
3.1 
Locally Advanced Head and Neck Cancer 
Approximately 50,000 new cases of head and neck cancer are diagnosed annually in the 
United States.1 The majority (90-95%) of these cases are squamous cell carcinomas of the 
head and neck and approximately two-thirds are locoregionally advanced cancers (AJCC 
stage III-IV). Despite advances over the past two decades, these patients still experience 
significant morbidity and mortality.  
 
Historically, locoregionally advanced tumors were treated with surgery, radiation therapy, 
or both. Locoregional failure rates were approximately 30% at 2 years and locoregional 
failures accounted for nearly 60% of failures. Survival at 5 years was reported to be only 
40%. Approximately 20% of patients developed metastatic disease and nearly one-fifth of 
these patients died of distant metastases without evidence of locoregional recurrence.2-4 
 


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3.2 
Chemoradiotherapy 
Given the discouraging outcomes with surgery and radiation, investigators became 
increasingly interested in the incorporation of chemotherapy for the treatment of locally 
advanced HNSCC. The feasibility of a non-surgical, organ preservation approach with 
concomitant chemoradiation was first established by the landmark Veterans Affairs 
Laryngeal Cancer Study.5 Since then, several randomized trials and meta-analyses have 
demonstrated improved disease-free and/or overall survival with concomitant 
chemoradiotherapy and confirmed its role as standard therapy for patients with 
locoregionally advanced unresectable disease.6-11 The positive effects of disease-free and 
overall survival seem to be predominantly mediated through improved locoregional 
control, thus affecting the traditionally predominant pattern of failure for this disease.  
 
Concurrent chemoradiotherapy attempts to capitalize on both the radiosensitizing 
properties of chemotherapy at sites of known disease targeted by radiation in addition to 
delivering agents that function systemically to treat occult metastatic disease. However, 
sensitizing effects are not tumor specific and exert both locoregional effects on adjacent 
normal tissues within the radiation field as well as systemic effects, particularly on the 
bone marrow and peripheral nervous system. Concurrent chemoradiotherapy trials have 
consistently reported an increased incidence of acute grade 3 and 4 toxic effects, with 
mucositis, dermatitis, and cytopenias being the most prominent.12 The rise creates concern 
about chronic toxic effects, including consequential late effects, which evolve from 
persistent severe acute toxic effects.  
 
Optimizing the therapeutic ratio of treatment benefit to toxicity has thus become a focus of 
recent investigation. Advances in the delivery of conformal radiation, including the 
development of intensity modulated radiation therapy (IMRT), have allowed significant 
improvements in sparing normal tissue structures. This is best exemplified by the 
reduction in rates of xerostomia with sparing of the parotid glands.13 However, other 
treatment-related morbidities such as dysphagia are still problematic. Rates of feeding 
tube dependence at 1 year in the 3D-confromal era have been reported to be approximately 
25%.14 This is particularly significant given recent data that quality of life among patients 
with HNSCC treated with radiotherapy is substantially affected by swallowing 
dysfunction and the need for enteral nutrition support.15 In the IMRT-era, efforts have 
been focused on decreasing the dose of radiation to dysphagia-related structures, 
particularly the pharyngeal constrictors, which are prone to structure formation with doses 
≥ 50 Gy.16 Single-institution reports of treatment of oropharyngeal cancer in the IMRT-era 
demonstrated long-term feeding tube dependence rates of approximately 5-10%.17   
 
3.3 
CRT Platforms: Concurrent Cisplatin-Radiation or TFHX 
Chemoradiotherapy with concurrent bolus cisplatin (100 mg/m2 delivered q3 weeks) and 
conventionally fractionated radiotherapy remains the commonly accepted standard of care 
for the treatment of locally advanced HNSCC. The randomized Head and Neck Intergroup 


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trial and RTOG 91-11 demonstrated improved locoregional control and prolonged 
survival with concomitant chemoradiotherapy with every-3-weeks cisplatin in 
unresectable locally advance HNSCC.18,19 
 
At the University of Chicago, we have investigated multiple intensive concomitant 
chemoradiotherapy regimens. We initially studied the interaction of 5-FU, hydroxyurea, 
and radiotherapy (FHX).20,21 Both chemotherapy agents have shown systemic activity and 
have been shown to act as radiation enhancers in vitro and in vivo.22,23 Cytotoxic activity 
is synergistic as hydroxyurea modulates the activity of 5-FU by depleting cellular pools of 
deoxyuridine monophosphate (dUMP) and facilitating the binding of the 5-FU metabolite, 
5-FdUMP, to its target enzyme thymidylate synthase.24 Paclitaxel was subsequently added 
to the FHX regimen (TFHX) and the radiation scheme changed to twice daily to further 
intensify the treatment.25-28 
 
The TFHX regimen was demonstrated to be a highly active and tolerable concomitant 
chemotherapy and hyperfractionated radiation regimen: overall survival and locoregional 
control rates at 3 years were 60% and 86%, respectively.27,29 Since surgery was used 
primarily as a salvage procedure, excellent organ preservation was also achieved. Acute 
toxicities were severe in a majority of patients but were considered tolerable overall. 
Mucositis (84% grade 3+), “in-field” dermatitis (38% grade 3+), leukopenia (34% grade 
3+), and anemia (22% required transfusion) were the most common side effects. At 1-year 
post-treatment, 61% of patients had severe xerostomia and 47% had compromised 
swallowing; the rate of feeding tube dependence was 20%.  
 
In an attempt to decrease the toxicity of concomitant chemoradiation, we conducted 
prospective investigations into reducing the radiation dose in sequential cohorts to areas at 
risk for microscopic disease.30,31 The cohort receiving 75 Gy to gross disease (high risk), 
54 Gy to intermediate-risk volumes, and 39 Gy to low-risk volumes experienced the best 
therapeutic ratio. Again, high locoregional and distant control rates were seen, though the 
rate of dermatitis (45%) was significantly lower. 
 
With improved locoregional control, the systemic control of micrometastatic disease 
emerged as an important goal that was not achieved optimally with the chemotherapy 
doses applied during concomitant chemoradiotherapy. Indeed, approximately 20% of 
patients were noted to recur distantly, despite the addition of cytotoxic chemotherapy to 
radiation therapy as part of the TFHX regimen.  
 
 
3.4 
Induction Chemotherapy 
On the basis of the aforementioned studies, induction chemotherapy was investigated as a 
method of successfully eradicating micrometastatic disease. At the University of Chicago, 
carboplatin and paclitaxel were initially chosen as an induction chemotherapy regimen 
because they are typically well-tolerated with low rates of mucositis. The first report of 


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this regimen demonstrated both high locoregional control and improved distant control.32 
Systemic disease progression was noted in 7% of patients; this translated into improved 3-
year progression-free and overall survival rates of 80% and 77%, respectively.  
 
Currently, the triplet combination of a taxane (docetaxel or paclitaxel), cisplatin, and 5-FU 
(TPF) is considered one standard induction regimen (if induction therapy is considered). 
This is largely based on the results of a meta-analysis demonstrating a 5% increase in 
survival for cohorts using a cisplatin/5-FU combination and published phase III trials 
demonstrating the superiority of induction docetaxel, cisplatin, and 5-FU over cisplatin 
and 5-FU when followed by radiotherapy or chemoradiotherapy.10,33-35 
 
Controversy still exists regarding the overall survival benefit of adding induction TPF to 
chemoradiotherapy. Recent studies demonstrating no additional survival benefit are 
limited by methodological deficiencies.36-38 Additionally, recent data demonstrate that 
TPF and carboplatin/paclitaxel seem to have equivalent activity while the latter platform is 
associated with decreased toxicity.39 Two studies evaluating carboplatin/paclitaxel 
induction demonstrated 82% and 87% response rates compared to our DeCIDE trial 64% 
response to TPF.31,32,36 
 
3.5 
Response-Adapted Volume De-Escalation (RAVD) 
It has been shown that patients with favorable response to induction therapy have superior 
prognosis and are less likely to experience locoregional failure after definitive 
chemoradiation.30 Strategies to decrease the late toxicity associated with chemoradiation 
have focused on radiotherapy dose reduction and constraints for organs at risk. It has also 
been shown that the majority of locoregional failures after CRT are “in-field” and occur 
within the highest-risk radiation treatment volume.40 
 
 
Conventional head and neck radiation elective nodal volumes are based on historic 
surgical data regarding the risk of occult lymph node involvement. Several series have 
investigated decreasing elective nodal radiation coverage. For patients with limited 
tonsillar cancer, elimination of contralateral elective neck radiation has shown to be 
feasible.41 Additionally, it has recently been shown that elimination of elective radiation to 
the retropharyngeal and high level II lymph nodes in the contralateral uninvolved neck is 
feasible and results in decreased toxicity.42 In our RAVD trial, we utilized radically 
reduced radiation volumes entirely omitting elective nodal coverage in good responders to 
induction and significantly decreasing coverage in non-responders.43 
  
3.6 
Nivolumab/Anti-PD-1 
Nivolumab is a fully humanized, IgG4 (kappa) isotype monoclonal antibody that binds the 
programmed death receptor-1 (PD-1). PD-1 is a transmembrane protein primarily found 
expressed on activated immune cells. In its usual function, the binding of PD-1 to its 


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ligand PD-L1 and PD-L2 inhibits T-cell proliferation and activation. Upregulation of PD-
1 ligands can occur in tumors and is thought to serve as a means of immune evasion by the 
tumor.44 Nivolumab blocks the interaction of the PD-1 T-cell receptor with its ligands, 
potentially enabling the reactivation of immunosurveillance and cancer eradication.  
 
Nivolumab is currently approved for head and neck cancer based on the results of the 
CheckMate 141 study.45 In this phase III randomized trial, eligibility criteria included 
recurrent/metastatic HNSCC of the oral cavity, pharynx, or larynx with progression on or 
within 6 months of the last dose of platinum-based therapy (irrespective of number of 
prior lines of therapy or PD-L1 status). Patients were randomized to receive nivolumab (3 
mg/kg IV q 2 weeks) versus investigator’s choice of therapy. Median overall survival was 
7.5 months for nivolumab versus 5.1 months for investigator’s choice therapy (HR 0.70, p 
= 0.01). The 1-year overall survival rate was 36.0% for nivolumab versus 16.6% for 
investigator’s choice. The objective response rate with nivolumab was 13.3% (2.5% 
complete, 10.8% partial). Overall, nivolumab was well-tolerated with 3.8% of patients not 
continuing treatment due to study drug toxicity and 13.1% of patients experiencing any 
treatment-related grade 3-4 adverse event. The most common grade 3-4 treatment related 
adverse events were fatigue (2.1%), anemia (1.3%), and asthenia (0.4%).  
 
3.7 
Study Rationale 
 
At the University of Chicago, we have demonstrated the ability to de-escalate therapy for 
patients with HPV-positive oropharyngeal HNSCC. Patients with response to induction 
chemotherapy received modified radiation doses based off the depth of response. In doing 
so, we demonstrated reduced toxicities and excellent outcomes while delivering nearly 
one-third lower total dose of radiation therapy.46 To build on this promising data, our 
follow up trial added nivolumab to the induction regimen with the intention of improving 
deep response rates allowing more patients to receive de-escalated therapy. 
 
While a majority of oropharyngeal cancers are HPV-related, the remainder of head and 
neck cancers are typically not. Much of the historical data in HPV negative disease has 
investigated how to safely perform treatment intensification since about 30% of these 
patients will have recurrence. In order to accomplish this goal, many trials have tested the 
role of altered fractionation including hyperfractionation and accelerated fractionation.47,48 
While these trials have formed a strong foundation for the current standard of care for 
HPV negative HNSCC, treatment-related toxicity is a potential drawback to such 
aggressive management. As discussed earlier, we have studied the use of induction 
therapy to stratify patients who may be better or worse candidates for smaller radiation 
fields as one approach to de-escalated therapy. Patients with a response to induction did 
not require elective nodal coverage which was associated with similar oncologic outcomes 
and an improved toxicity profile.43 
 


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Increasing the response rate to induction therapy is an important endpoint in order to 
increase the proportion of patients who qualify for de-intensified locoregional therapy and 
extend this concept from HPV+ disease to carcinogen-induced head and neck cancer. With 
the addition of nivolumab to the induction chemotherapy regimen, we hope to increase 
this response rate as demonstrated in squamous cell lung cancer.49 Chemotherapy leads to 
tumor lysis and release of tumor antigens, which may prime the immune system for 
checkpoint inhibitors.  
 
Given the above, we hypothesize that the addition of a checkpoint inhibitor to induction 
chemotherapy will increase the response rate to induction therapy, and therefore increase 
the proportion of patients who may qualify for de-escalated locoregional therapy. 
 
In this study, we propose adding nivolumab to induction carboplatin and paclitaxel to 
increase deep response rate and hence, de-intensify definitive chemoradiation for patients 
with non-metastatic, locally advanced HPV negative HNSCC. The ability to obtain deep 
responses with induction chemotherapy may be particularly meaningful for such patients 
and holds immediate potential to translate into more effective and less toxic definitive 
locoregional therapy. In particular, de-escalation of locoregional radiation therapy may be 
associated with improved quality of life, decreased enteral tube dependence, and improved 
swallowing function.  
 
As an institution, we have had great success treating HPV negative head and neck cancer, 
but despite a high cure rate, many patients suffer from debilitating long-term side effects 
5-10 years after completing therapy. The therapy approach proposed in this trial has 
already generated encouraging results in HPV positive disease, extending this treatment 
paradigm to HPV negative disease represents a natural progression for advancement of 
oncological care. 
4   
PATIENT SELECTION 
 
4.1  
Eligibility Criteria  
1) Patients must have pathologically confirmed locally advanced, non-metastatic, 
HPV-negative head and neck squamous cell carcinoma of the oral cavity, 
oropharynx, hypopharynx, nasopharynx, larynx, or sinuses.  
2) Stage IV disease with the exception of nasopharyngeal T3N2 (stage III) based of 
AJCC staging 8th edition.  
3) If a primary oropharyngeal squamous cell carcinoma is diagnosed, HPV must be 
ruled out by immunohistochemistry. 
4) Availability of ≥10 unstained 5 micron slides (to be provided to HTRC at the 
University of Chicago). Patients who cannot fulfill this requirement will need to 
undergo a new biopsy prior to enrollment on study. 


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5) Patients must be at least 18 years of age. 
6) Measurable disease (either primary site and/or nodal disease) by RECIST 1.1 
criteria. 
7) No previous radiation or chemotherapy for a head and neck cancer. 
8) No complete surgical resection for a head and neck cancer within 8 weeks of 
enrollment (although lymph node biopsy including excision of an individual node 
with presence of residual nodal disease, or surgical biopsy/excision of the tumor 
with residual measurable disease is acceptable.) No surgical procedures or biopsies 
will occur after baseline scans are performed and measurable lesions are identified.   
9) ECOG performance status 0-1 
10) Normal Organ Function 
a. Leukocytes ≥ 3000/mm3 
b. Platelets ≥ 100,000/mm3 
c. Absolute neutrophil count ≥ 1,500 
d. Hemoglobin ≥ 9.0 gm/dL 
e. AST and ALT ≤ 2.5x upper limit of normal 
f. Alkaline phosphatase ≤ 2.5x upper limit of normal  
g. Albumin > 2.9 gm/dL 
h. Total bilirubin ≤ 1.5 mg/dL 
i. Creatinine clearance > 45 mL/min, normal within 2 weeks prior to start of 
treatment (Of note, the standard Cockcroft and Gault formula must be used 
to calculate CrCl for enrollment or dosing) 
11) Patients must sign a study-specific informed consent form prior to study entry. 
Patients should have the ability to understand and the willingness to sign a written 
informed consent document. 
12) Women of childbearing potential must have a negative serum or urine pregnancy 
test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours 
prior to the start of study drug 
13) Women must not be breastfeeding  
14) Women of childbearing potential must agree to follow instructions for method(s) 
of contraception for the duration of treatment with study drug(s) plus 5 months 
after completing chemoradiation or receiving the last dose of consolidative 
nivolumab, whichever occurs latest.   
15) Men who are sexually active with women of childbearing potential must agree to 
follow instructions for method(s) of contraception for the duration of treatment 
with study drug(s) plus 7 months after completing chemoradiation or receiving the 
last dose of consolidative nivolumab, whichever occurs latest.   
 
4.2  
Exclusion Criteria  
1) Unequivocal demonstration of distant metastatic disease (M1 disease). 
2) Unidentifiable primary site. 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
13
3) Intercurrent medical illnesses which would impair patient tolerance to therapy or 
limit survival. This includes but is not limited to ongoing or active infection, 
immunodeficiency, symptomatic congestive heart failure, pulmonary dysfunction, 
cardiomyopathy, unstable angina pectoris, cardiac arrhythmia, or psychiatric 
illness/social situations that would limit compliance. Patients with clinically stable 
and/or chronically managed medical illnesses that are not symptomatic and/or are 
not expected to impact treatment on protocol are still eligible (conditions to be 
reviewed by the PI to confirm eligibility). 
4) Prior surgical therapy other than incisional/excisional biopsy or organ-sparing 
procedures such as debulking of airway-compromising tumors. Residual 
measurable tumor is required for enrollment as discussed above. 
5) Patients receiving other investigational agents. 
6) Diagnosis of immunodeficiency or is receiving systemic steroid therapy in excess 
of physiologic dose or any other form of immunosuppressive therapy within 7 days 
prior to the first dose of trial treatment. 
7) Known history of active tuberculosis (Bacillus Tuberculosis infection). 
8) Hypersensitivity to nivolumab or any other drug used in this protocol. 
9) Prior systemic anti-cancer treatment within the last 8 weeks.  
10) Has a known additional malignancy that is progressing or requires active 
treatment. Exceptions include basal cell carcinoma of the skin or squamous cell 
carcinoma of the skin that has undergone potentially curative therapy or in situ 
cervical cancer or any tumors that are not likely to influence life expectancy in the 
subsequent 3 years without active treatment. 
11) Has active autoimmune disease that has required systemic therapy in the past year 
(i.e. with steroids or immunosuppressive drugs). Replacement therapy e.g. 
levothyroxine, insulin, or physiologic corticosteroid doses for adrenal or pituitary 
insufficiency, etc. are not considered a form of systemic treatment.  
12) Has known history of, or any evidence of active, non-infectious pneumonitis. 
13) Has a history of HIV. 
14) Has known active Hepatitis B or hepatitis C.  If eradicated, patient is eligible. 
15) Has received a live vaccine within 28 days of planned start of study therapy. 
 
4.3 
Pregnancy Prevention 
Investigators shall counsel women of child-bearing potential (WOCBP) and male patients 
who are sexually active with WOCBP on the importance of pregnancy prevention and the 
implications of an unexpected pregnancy. Investigators shall advise WOCBP and male 
patients who are sexually active with WOCBP on the use of highly effective methods of 
contraception. Highly effective methods of contraception have a failure rate of <1% when 
used consistently and correctly.  
 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
14
At a minimum, patients must agree to the use of one method of highly effective 
contraception as listed below. In addition, male patients are expected to use a condom as 
noted in the list below. 
 
Highly effective methods of contraception include:  
 Hormonal methods of contraception including combined oral contraceptive pills, 
vaginal ring, injectables, implants and intrauterine devices (IUDs) 
 Non-hormonal IUDs 
 Bilateral tubal ligation 
 Vasectomized partner  
 Complete abstinence which is defined as complete avoidance of heterosexual 
intercourse and is an acceptable form of contraception for all study drugs.  
 
WOCBP must continue to have pregnancy tests. Acceptable alternate methods of highly 
effective contraception must be discussed in the event that the patient chooses to forego 
complete abstinence. Patients are encouraged to use two methods of contraception, with 
one method being highly effective and the other being either highly effective or less 
effective as listed below. 
 
Less effective methods of contraception include: 
 Diaphragm with spermicide  
 Male condoms and spermicide  
 Male condom without spermicide 
 Female condom – A male and female condom must not be used together 
 
Unacceptable methods of contraception include:  
 Vaginal sponge 
 Progestin only pills 
 Cervical cap with spermicide 
 Periodic abstinence (calendar, sympthothermal, post-ovulation methods) 
 Withdrawal (coitus interruptus) 
 Spermicide only 
 Lactation amenorrhea method 
 
5 
REGISTRATION PROCEDURES 
 
5.1 
General Guidelines 
Prior to registration and any study-specific evaluations being performed, all patients must 
have given written informed consent for the study and must have completed the pre-


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
15
treatment evaluations. Patients must meet all of the eligibility requirements listed in 
Section 4. Eligible patients will be entered on study centrally by the University of Chicago 
study coordinator. All sites should email PhaseIICRA@medicine.bsd.uchicago.edu to 
verify availability of a slot. 
 
5.2 
Registration Process  
When a potential patient has been identified, notify the CRC via email at 
phaseIIcra@medicine.bsd.uchicago.edu to ensure a reservation on the study. Reservations 
for potential subjects will only be held for subjects who have signed consent for that 
particular study.  
 
When registering a subject, the following must occur:  
 Confirm that the institution has a current IRB approval letter for the correct 
version of protocol/consent and has an annual update on file, if appropriate.  
 Submit all required materials (Eligibility Checklist, Source documentation, & 
signed consent form) to confirm eligibility and required pre-study procedures 
to the CRC a minimum of 48 hours prior to the subject’s scheduled therapy 
start date.  
 Source documentation includes copies of all original documents that support 
each inclusion/exclusion criteria.  The eligibility checklist does not serve as 
source documentation but rather as a checklist that original source 
documentation exists for each criterion. 
 Communicate with the CRC to ensure all necessary supporting source 
documents are received and the potential subject is eligible to start treatment 
on schedule. If there are questions about eligibility, the CRA will discuss it 
with the PI. PI may clarify, but not overturn, eligibility criteria.  
 Affiliate sites must confirm registration of subjects by obtaining a subject study 
ID number from the CRC via phone, fax or email.  
 If a subject does not start on the scheduled day 1 treatment date, promptly 
inform the CRC as the delay in start may deem the subject ineligible and/or 
require further or repeat testing to ensure eligibility.  
 The date the patient is randomized if randomization is involved or receives 
treatment for the first time will be considered the patient’s “OnStudy Date.” 
The patient’s subject ID will be assigned and a confirmation of registration will 
be issued by the CRC on this date. Subjects that sign consent and do not go 
“OnStudy” will be recorded in the database with the date they signed consent 
and the reason for not going “OnStudy” (e.g., Ineligible, Screen Failure or 
Withdrawn Consent). 
 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
16
6 
TREATMENT PLAN 
 
6.1 
General Considerations 
Induction chemoimmunotherapy will be administered on an outpatient basis. 
Chemoradiotherapy may be administered on an inpatient basis (using the TFHX regimen) 
or outpatient basis (with cisplatin). Patients receiving consolidative nivolumab will receive 
this on an outpatient basis. All patients will be evaluated by surgical, medical, and 
radiation oncologists prior to trial entry to determine optimal local treatment. Patients will 
start induction chemoimmunotherapy within 2 weeks of signing consent. Three cycles of 
carboplatin, paclitaxel, and nivolumab induction chemoimmunotherapy will be followed 
by response-adjusted locoregional control. In no case should the three cycles of induction 
chemotherapy be given over a period exceeding 12 weeks. As we have had extensive 
experience with this regimen in our HPV-positive de-escalation trials, we do not anticipate 
significant delays in chemoradiation. 
 
Patients in the de-escalated cohort will undergo de-escalated chemoradiation with a total 
of 66 Gy to the gross tumor volume, nodal disease, and margins. Patients in the standard 
arm will receive chemoradiation to a total of 70-75 Gy to the gross tumor volume, nodal 
disease, and margin in addition to 45-50 Gy to elective nodal basins. Patients will have a 
pre-induction chemotherapy CT simulation performed. Chemoradiation should be initiated 
within 10 days of the last dose of paclitaxel during the induction regimen, and no later 
than 14 days. Chemoradiation should be initiated no later than 13 weeks after the first 
dose of induction therapy (12 weeks, as above, plus 1 week to recover from any potential 
toxicity). Discontinuation of this trial will occur if excessive toxicity leads to delays in 
definitive chemoradiation. Delays will be defined as starting chemoradiation >13 weeks 
after receiving the first dose of induction therapy or >14 days after completing the last 
dose of induction therapy. Excessive toxicity leading to delays to definitive treatment with 
concurrent chemoradiation will be based on continuous assessment after the fifth patient 
has been enrolled. If >30% of patients experience a delay in definitive chemoradiation, the 
trial will be halted (as an example, a table has been provided for the first 10 patients 
below).  Consolidative nivolumab will be offered to all patients for 9 months on an 
outpatient basis.   
 
Number of Patients 
Starting Induction 
Therapy 
Number of Patients 
Experiencing Delay to 
Definitive CRT 
Further Enrollment 
5 
2 
Halt 
6 
2 
Halt 
7 
3 
Halt 
8 
3 
Halt 
9 
4 
Halt 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
17
10 
4 
Halt 
  
6.2 
Pre-treatment evaluation 
Patient must have completed the following within 4 weeks of starting therapy unless noted 
(also see study calendar in section 10 for additional details): 
 Inclusion and exclusion criteria reviewed. 
 Physical examination including examination by a head and neck surgeon 
 Pan-endoscopy with biopsy, tumor mapping, and documentation (if clinically 
indicated per assessment at the multidisciplinary tumor board) 
 Biopsy proven squamous cell carcinoma.  
 Baseline diagnostic CT or MRI scan of the head and neck. 
 CT chest that includes entire disease extent within 1 month before initiating 
therapy. CT chest only required if PET/CT not performed. 
 Multidisciplinary team recommendation to proceed with induction therapy.  
 PET/CT is recommended but not required prior to start of induction 
chemoimmunotherapy. 
 One week prior to chemoimmunotherapy - CBC with differential and platelet 
count, and complete metabolic profile. 
 Ultrasound or CT imaging of the liver if chemistries (SGOT, SGPT, and bilirubin) 
are above upper limit of normal. 
 Additional studies (bone scan, barium swallow, etc.) to exclude distant metastases 
or second primaries as clinically indicated.  
 Complete dental evaluation before or during induction therapy, unless not 
clinically indicated and waiver approved by PI.  If indicated, this must be 
completed prior to starting chemoradiation.  
 Speech and swallowing consultation before or during induction therapy.  This must 
be completed prior to starting chemoradiation.   
 Blood draws for basic labs and study labs including cell free DNA 
 Refer to section 10 for a complete list of required baseline evaluations. 
 
6.3 
Study Evaluations 
Patients will have the following exams and tests throughout the study as specified time 
points (please see study chart in section 10): 
 Physical examination 
 Performance status evaluation 
 CBC with differential and platelet count 
 Complete metabolic panel 
 Study blood draws including cell free DNA 
 Toxicity and quality of life evaluations 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
18
 Optional second biopsy of original biopsy site around cycle 2, day 8 of induction 
therapy 
 Repeat imaging of the head and neck (CT or MRI; generally the same modality as 
pre-treatment imaging) on or within 10 days of cycle 3 day 15 for stratification of 
locoregional therapy.   
 Recommended PET/CT between the completion of induction therapy and the 
beginning of definitive chemoradiation.  
 Follow up imaging of head and neck (CT or MRI) with re-staging PET/CT at 12 
weeks post-chemoradiation. 
 Option for neck dissection and organ-preserving surgery at the primary site after 3 
cycles of induction chemoimmunotherapy will be allowed if it allows for a 
reduction in radiotherapy field size. 
 
6.4 
Induction Chemotherapy Details and Guidelines 
Induction chemotherapy will be administered on an outpatient basis. Expected adverse 
events (AEs) and appropriate dose modifications for these agents are described in section 
7. No other investigational agents or therapies other than those described below may be 
administered with the intent to treat the patient’s malignancy.  
 
Carboplatin, paclitaxel, and nivolumab combination will be administered for three cycles 
of three weeks duration each. Dose delays and dose modifications should take place as 
outlined in section 7. In no case should the three cycles of induction chemotherapy be 
given over a period exceeding twelve weeks.  
 Nivolumab: 360 mg flat dose on day 1; every 21 days (3 doses) 
 Paclitaxel: 100 mg/m2 on days 1, 8, and 15 (9 doses total) 
 Carboplatin: AUC 5 on day 1 (3 doses total). A baseline creatinine level should be 
drawn within 1 week prior to starting chemotherapy.  
 Anti-emetics: Pre-treatment with a 5 HT-3 antagonist prior to chemotherapy on 
day 1 is recommended. The use of additional anti-emetics and the prevention of 
delayed emesis are left to the discretion of the treating investigator. 
Dexamethasone/steroids as anti-emetic therapy should be avoided, and only should 
be given after discussion with the study PI.  
 Hydration: Hydration is left to the discretion of the treating physician. 
 For each cycle: Filgrastim can be given on days 16, 17, and 18 if clinically 
indicated.  This can also be increased or decreased as clinically indicated.  
 
6.5 
Definitive Chemoradiation Details and Guidelines 
 
6.5.1 Response Stratified Grouping 
Response and extent of response will be assessed during treatment week 9 (during cycle 
3), and depending on extent of response:  


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
19
 If <50% reduction decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum diameters according to RECIST v1.1: 
o Standard chemoradiotherapy with paclitaxel, 5-FU, hydroxyurea and 
hyperfractionated, accelerated radiotherapy to 75 Gy encompassing GTV 
of primary and nodal disease as well as elective prophylactic nodal 
irradiation. OR 
o Standard chemoradiotherapy with cisplatin and radiotherapy to 70 Gy 
encompassing GTV of primary and nodal disease as well as elective 
prophylactic nodal irradiation 
 If  50% reduction decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum diameters according to RECIST v1.1: 
o De-escalated chemoradiotherapy with paclitaxel, 5-FU, hydroxyurea and 
hyperfractionated, accelerated radiotherapy to 66 Gy encompassing GTV 
of primary and nodal disease without elective prophylactic nodal 
irradiation. OR 
o De-escalated chemoradiotherapy with cisplatin and radiotherapy to 66 Gy 
encompassing GTV of primary and nodal disease without elective 
prophylactic nodal irradiation.  
 Any patient who has progressive disease will receive CRT to 75 Gy on the TFHX 
platform (5 cycles). 
 
Expected adverse events and appropriate dose modifications for carboplatin, paclitaxel, 
nivolumab, and radiation are described in section 7.1 and 7.2.  
 
6.5.2 Concurrent Cisplatin-Radiation 
Cisplatin will be given on an every-3-weeks basis at a dose of 100 mg/m2 IV over 3-4 
hours day 1 (or 2), 22 (or 23), and day 43 (or 44). Mannitol should be given to decrease 
risk of toxicity if clinically appropriate. Radiation therapy is administered once daily at 2 
Gy per fraction. 
 
6.5.3 TFHX Regimen 
Patients received de-escalated or standard CRT will receive chemoradiation for 4.5-5 
cycles (8.5-9 weeks) and chemotherapy should be administered during all weeks of 
radiotherapy except during the last week of radiation for patients receiving de-escalated 
CRT.  
 
Day 0 
PM: Start hydroxyurea at 500 mg PO q12 hours x 6 days (11 doses). The first daily dose 
of hydroxyurea on days 1-5 is given 2 hours prior to the first fraction of daily 
radiotherapy.  
6:00 PM: Start continuous infusion of 5-FU at 600 mg/m2/day x 5 days (120 hours). 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
20
 
Days 1-5 
Dexamethasone 20 mg PO (IV) in morning day 1, 1 hour prior to paclitaxel 
Famotidine 20 mg PO (IV) in morning day 1, 1 hour prior to paclitaxel 
Diphenhydramine 50 mg PO (IV) in morning day 1, 30 minutes prior to paclitaxel  
 
Start paclitaxel 100 mg/m2 after first RT fraction on day 1 of each cycle with exception for 
the last half cycle for patients receiving de-escalated CRT. Paclitaxel should be 
administered in 250 mL 0.95 NaCl over 60 minutes.  
 
Radiation therapy is administered twice daily at 1.5 Gy per fraction.  
 
Days 6-13 
No chemoradiotherapy. Patients should be seen once on an outpatient basis during these 
non-treatment days to monitor for toxicity.  
 
For each cycle 
Administer 5 micrograms/kg subcutaneously (SQ) of G-CSF (filgrastim) daily, beginning 
on day 6 through 12 at a minimum of 24 hours after completion of 5-FU in patients who 
develop grade 3 neutropenia or who have grade 2+ neutropenia on Day 0 of any cycle. In 
these patients, G-CSF should be utilized in all subsequent cycles. G-CSF can be utilized 
prophylactically from the start of chemoradiotherapy in all cycles at the discretion of the 
treating physician.  
 
Chemoradiotherapy cycles are repeated every 14 days until the completion of 
radiotherapy.  If patients are on the de-escalated cohort, the final half cycle of TFHX will 
be completed without chemotherapy.  
 
6.5.4 Radiation Therapy Guidelines 
1. When indicated, all patients will have a complete dental evaluation prior to the start of 
radiation therapy, ideally prior to the start of chemotherapy. 
 
2. Treatment approaches will use intensity-modulated radiotherapy (IMRT) or volumetric-
modulated arc therapy (VMAT) and, in selected cases, 3D conformal radiotherapy will be 
used alone or in combination with IMRT/VMAT. In both instances, the physician will 
attempt to deliver an even dose to the target tissue and minimize doses to surrounding 
normal structures. The use of customized blocks or multileaf collimation for field shaping 
is strongly recommended.  
 
3. Localization requirements: All patients will be immobilized and simulated in the 
treatment position prior to the start of induction chemotherapy and after induction 
chemotherapy within 1-2 weeks after the last cycle of chemotherapy. A contrast-enhanced 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
21
CT simulation scan (or PET-CT simulation scan) with immobilization is required for 
planning. Slice thickness should be optimally 3 mm and no greater than 5 mm. The pre- 
and post-chemotherapy diagnostic scans will be fused to define the targets below. Patients 
must be reproducibly immobilized. Radio-opaque markers may be used whenever possible 
to delineate the surgical scars, extent of nodal disease, skin involvement, and any gross 
disease.  
 
4. Target volumes: Appropriate volumes will be delineated at the time of simulation to 
treat the pre-chemotherapy extent of gross disease and areas of potential microscopic 
disease. 
 GTV will be all gross tumor and involved lymph nodes identified by physical 
exam, additional clinical information, and radiographic studies prior to induction 
chemotherapy.  
 CTV1 will be an isotropic expansion of GTV by 1.0 cm and may be modified at 
the discretion of the treating physician to respect anatomic boundaries to spread of 
tumor (e.g., bone or air). 
 PTV1 will be an isotropic expansion of the CT1 by 0.5 cm. 
 CTV2 will be delineated only for standard CRT patients. This will include CTV1 
plus the next echelon of uninvolved but at risk lymph nodes that include the nodal 
stations at risk for microscopic spread as described in the tables in section 6.5.5. 
Inclusions of the retropharyngeal nodes will be at the discretion of the treating 
radiation oncologist. CTV2 may be modified at the discretion of the treating 
physician to respect anatomic boundaries to spread of tumor (e.g., bone or air).  
 PTV2 will be an isotropic expansion of the CTV by 0.5 cm.  
 
5. Dose and fractionation 
For patients treated with CRT on the TFHX platform  
 De-escalated CRT: PTV1 will be treated to 66 Gy (1.5 Gy BID) over the course of 
4.5 cycles. There will be no PTV2 volume for these patients with ≥ 50% response 
to induction chemoimmunotherapy. Chemoradiation will be given on an 
alternating week basis during the first 4 cycles, and no concurrent chemotherapy 
will be given during the final 4 fractions of radiation. There should be a minimum 
of 6 hours between fractions. All fields will be treated each day. In the case of a 
mechanical failure or a holiday, one day of BID radiotherapy can be replaced with 
a single daily fraction of 2 Gy. Accordingly, the final cumulative dose will be 
slightly less. 
 Standard CRT: PTV1 will be treated to 75 Gy (1.5 Gy BID) over the course of 5 
cycles and PTV2 will be treated to 45 Gy (1.5 Gy BID) over the first 3 cycles of 
CRT. Chemoradiation will be given on an alternating week basis. There should be 
a minimum of 6 hours between fractions. All fields will be treated each day. In the 
case of mechanical failure or a holiday, one day of BID radiotherapy can be 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
22
replaced with a single daily fraction of 2 Gy. Accordingly, the final cumulative 
dose will be slightly less.  
 
6. Field size: Appropriate volumes will be determined at the time of simulation to treat 
gross disease and areas of potential microscopic disease as indicated. The optimal field 
arrangements will be determined on the treatment planning techniques employed. All 
fields must be treated during each treatment session. 
 
7. Treatment technique: Blocking will be individualized for each patient. Either custom 
Cerrobend blocks or multileaf collimator will be acceptable.  
 Intensity Modulation Radiotherapy: Optimal IMRT planning will depend on the 
planning system employed.  We anticipate the optimal plan will use 7-11 gantry 
positions.  Acceptable plans will encompass the PTV with the 95% prescribed 
dose.  No more than 1% of the PTV should receive less than 95% of the prescribed 
dose.  Plans should be reviewed to ensure that any part of the PTV getting less than 
95% of the prescribed dose is at the edge of the volume.  In no case should a 
central area of the PTV receive less than 95% of the prescribed dose.  No more 
than 1% of the PTV should receive more than 110% of the prescribed dose. 
 3D Conformal Radiotherapy: The neck should be treated with opposed lateral 
fields using a half-field technique.  The lower neck should be treated with an 
anterior field prescribed to a depth of 3 cm.  Opposed fields for the lower neck are 
permitted in order to improve PTV coverage and increase homogeneity.  Wedges, 
tissue compensators, or segmented fields should be used to ensure uniformity of 
PTV coverage.  Electron boosts of the posterior neck are permitted to limit the 
dose to the spinal cord.  Electron fields shall be prescribed to the depth of 
maximum dose with the energy and field size chosen so that the target volume is 
encompassed within 90% of the prescribed isodose line.  A cord block is permitted 
on the anterior or lateral fields provided it does not block tumor.  Feathering the 
match line is permitted in cases where a cord block would block the tumor.  For 
3D techniques, acceptable plans will encompass the PTV within the 95% isodose 
line.  The dose variation in the PTV will be +7% and -5% of the prescription point 
dose. 
 
8.  Normal Tissue Constraints/Dose Volume Histogram:  Isodose calculations in the axial, 
sagittal, or coronal planes are required.  In addition, dose volume histograms for the 
planning treatment volumes and the spinal cord are required.  The dose limit to the spinal 
cord will vary depending upon the technique used.  Attempts should be made to limit the 
spinal cord dose to < 45 Gy in all cases. 
 
9.  Adaptive Re-planning:  Patients on the standard CRT arm treated on the TFHX 
platform will undergo repeat CT simulation during cycle 3 for adaptive replanning of 
treatment volumes. 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
23
 
10.  Surrounding critical normal structures should be outlined for study purposes.  
Including the brainstem, spinal cord, superior/inferior constrictor muscles, optic 
nerves/chiasm, parotid and submandibular glands, temporo-mandibular joints and cochlea, 
oral cavity, mandible, eyes, lens, brachial plexus, esophagus (including postcricoid 
pharynx) and glottic larynx.  The normal tissues will be contoured and considered as solid 
organs.  DVH plots must be generated for relevant critical normal structures, any 
corresponding PRVs, and the unspecified tissues.  Institutions that use PRVs must clearly 
define them as such.  Ultimate inclusion of the normal structures and exceptions from the 
above guidelines will be made at the discretion of the treating radiation oncologist. 
 
11.  Special situations:  3D conformal treatment techniques may be preferable to IMRT in 
certain situations.  Some large primary tumors and some large neck nodes may extend up 
to the skin.  In these situations, it may not be possible to add a sufficient margin to the 
GTV to account for variability in the patient set up.  In such a situation, 3D conformal 
treatment techniques may be preferable to IMRT. 
 
6.5.5 Nodal Planning Target Volume Delineation for Standard CRT Patients  
 
Lateralized Base of Tongue 
 
Adenopathy Level 
 
Ipsilateral  
Contralateral  
Involved 
Nodes 
IA 
IB 
II 
III 
IV 
V 
IA 
IB 
II 
III 
IV 
V 
CTV2 
 
 
 
 
 
 
 
 
 
 
 
 
Ipsilateral 
IB, 
II 
IA, 
II 
IB, 
III 
II, 
IV 
II, 
III, 
SCV 
II, 
III 
IA, 
IB, 
II 
II 
II 
II 
II 
II 
Contralateral
IA 
II 
II 
II 
II 
II 
IB 
II 
IB 
II, 
IV 
II, 
III, 
SCV
II, 
III 
 
Base of Tongue Crossing Midline 
 
Adenopathy Level 
 
Ipsilateral  
Contralateral  
Involved 
Nodes 
IA 
IB 
II 
III 
IV 
V 
IA 
IB 
II 
III 
IV 
V 
CTV2 
 
 
 
 
 
 
 
 
 
 
 
 
Ipsilateral 
IB, 
II 
IA, 
II 
IB, 
III 
II, 
IV 
II, 
III, 
SCV 
II, 
III 
IA, 
IB, 
II 
II 
II 
II 
II 
II 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
24
Contralateral
IA 
II 
II 
II 
II 
II 
IB 
IA, 
II 
IB, 
III 
II, 
IV 
II, 
III, 
SCV
II, 
III 
 
Soft Palate 
 
Adenopathy Level 
 
Ipsilateral  
Contralateral  
Involved 
Nodes 
IA 
IB 
II 
III 
IV 
V 
IA 
IB 
II 
III 
IV 
V 
CTV2 
 
 
 
 
 
 
 
 
 
 
 
 
Ipsilateral 
IB, 
II 
IA, 
II 
IB, 
III 
II, 
IV 
II, 
III, 
SCV 
II, 
III 
IA, 
IB, 
II 
II 
II 
II 
II 
II 
Contralateral
IA 
II 
II 
II 
II 
II 
IB 
IA, 
II 
IB, 
III 
II, 
IV 
II, 
III, 
SCV
II, 
III 
 
Lateralized Tonsil: No Base of Tongue Invasion 
 
Adenopathy Level 
 
Ipsilateral  
Contralateral  
Involved 
Nodes 
IA 
IB 
II 
III 
IV 
V 
IA 
IB 
II 
III 
IV 
V 
CTV2 
 
 
 
 
 
 
 
 
 
 
 
 
Ipsilateral 
IB, 
II 
IA, 
II 
IB, 
III 
II, 
IV 
II, 
III, 
SCV 
II, 
III 
IA, 
IB, 
II 
II 
II 
II 
II 
II 
Contralateral
IA 
--- 
--- 
--- 
--- 
--- IB 
IA, 
II 
IB, 
III 
II, 
IV 
II, 
III, 
SCV
II, 
III 
 
Tonsil with Base of Tongue Invasion 
 
Adenopathy Level 
 
Ipsilateral  
Contralateral  
Involved 
Nodes 
IA 
IB 
II 
III 
IV 
V 
IA 
IB 
II 
III 
IV 
V 
CTV2 
 
 
 
 
 
 
 
 
 
 
 
 
Ipsilateral 
IB, 
II 
IA, 
II 
IB, 
III 
II, 
IV 
II, 
III, 
SCV 
II, 
III 
IA, 
IB, 
II 
II 
II 
II 
II 
II 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
25
Contralateral
IA 
II 
II 
II 
II 
II 
IB 
II 
IB, 
III 
II, 
IV 
II, 
III, 
SCV
II, 
III 
 
Oropharynx involving Larynx 
 
Adenopathy Level 
 
Ipsilateral  
Contralateral  
Involved 
Nodes 
IA 
IB 
II 
III 
IV 
V 
IA 
IB 
II 
III 
IV 
V 
CTV2 
 
 
 
 
 
 
 
 
 
 
 
 
Ipsilateral 
IB, 
II 
IA, 
II 
III 
II, 
IV 
II, 
III, 
SCV 
II, 
III 
IA, 
IB, 
II 
II 
II 
III 
III 
II 
Contralateral
IA 
II 
II 
II 
II 
II 
IB 
IA, 
II 
IB, 
III 
II, 
IV 
II, 
III, 
SCV
II, 
III 
 
Oropharynx involving Oral Cavity (Lateralized) 
 
Adenopathy Level 
 
Ipsilateral  
Contralateral  
Involved 
Nodes 
IA 
IB 
II 
III 
IV 
V 
IA 
IB 
II 
III 
IV 
V 
CTV2 
 
 
 
 
 
 
 
 
 
 
 
 
Ipsilateral 
IB, 
II 
IA, 
II 
IA, 
IB, 
III 
IA, 
IB, 
II, 
IV 
IA, 
IB, 
II, 
III, 
IV, 
SCV
IA, 
IB, 
II, 
III 
IA, 
IB, 
II 
IA, 
IB, 
II 
IA, 
IB, 
II 
IA, 
IB, 
II 
IA, 
IB, 
II 
IA, 
IB, 
II 
Contralateral
IA, 
IB 
--- 
--- 
--- 
--- 
--- 
IB, 
II 
IA, 
II 
IA, 
IB, 
III 
IA, 
IB, 
II, 
IV 
IA, 
IB, 
II, 
III, 
SCV
II, 
III 
 
Oropharynx involving Oral Cavity (Crosses Midline) 
 
Adenopathy Level 
 
Ipsilateral  
Contralateral  
Involved 
Nodes 
IA 
IB 
II 
III 
IV 
V 
IA 
IB 
II 
III 
IV 
V 
CTV2 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
26
Ipsilateral 
IB, 
II 
IA, 
II 
IA, 
IB, 
III 
IA, 
IB, 
II, 
IV 
IA, 
IB, 
II, 
III, 
IV, 
SCV 
IA
, 
IB
, 
II, 
III 
IA, 
IB, 
II 
IA, 
IB, 
II 
IA, 
IB, 
II 
IA, 
IB, 
II 
IA, 
IB, 
II 
IA, 
IB, 
II 
Contralateral
IB, 
II 
IB, 
II 
IB, 
II 
IB, 
II 
IB, II 
IB
, 
II 
IB, 
II 
IA, 
II 
IA, 
IB, 
III 
IA, 
IB, 
II, 
IV 
IA, 
IB, 
II, 
III, 
SCV
II, 
III 
 
Oropharynx involving Nasopharynx  
 
Adenopathy Level 
 
Ipsilateral  
Contralateral  
Involved 
Nodes 
IA 
IB 
II 
III 
IV 
V 
IA 
IB 
II 
III 
IV 
V 
CTV2 
 
 
 
 
 
 
 
 
 
 
 
 
Ipsilateral 
IB, 
II 
VA 
IA, 
II, 
VA 
IB, 
III, 
VA 
II, 
IV, 
VA 
II, 
III, 
VA, 
SCV 
II, 
III 
IA, 
IB, 
II, 
VA 
II, 
VA 
II, 
VA 
II, 
VA 
II, 
VA 
II, 
VA 
Contralateral
IA 
II 
II 
II 
II 
II 
IB, 
VA 
IA, 
II, 
VA 
IB, 
III, 
VA 
II, 
IV, 
VA 
II, 
III, 
SCV
, VA
II, 
III, 
VA 
 
Larynx: T1-T2 
 
Adenopathy Level 
 
Ipsilateral  
Contralateral  
Involved 
Nodes 
IA 
IB 
II 
III 
IV 
V 
IA 
IB 
II 
III 
IV 
V 
CTV2 
 
 
 
 
 
 
 
 
 
 
 
 
Ipsilateral 
IB, 
II 
IA, 
II 
III 
II, 
IV 
II, III 
II, 
III 
IA, 
IB, 
II 
II 
II 
III 
III 
II 
Contralateral
IA 
--- 
II 
II 
II 
II 
IB 
II 
III 
II, 
IV 
II, 
III 
II, 
III 
 
Larynx: T3-T4 
 
Adenopathy Level 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
27
 
Ipsilateral  
Contralateral  
Involved 
Nodes 
IA 
IB 
II 
III 
IV 
V 
IA 
IB 
II 
III 
IV 
V 
CTV2 
 
 
 
 
 
 
 
 
 
 
 
 
Ipsilateral 
IB, 
II  
IA, 
II 
III 
II, 
IV 
II, III 
II, 
III 
IA, 
IB, 
II 
II 
II 
III 
III 
II 
Contralateral
IA 
--- 
II 
II 
II 
II 
IB 
II 
III 
II, 
IV 
II, 
III 
II, 
III 
 
Hypopharynx  
 
Adenopathy Level 
 
Ipsilateral  
Contralateral  
Involved 
Nodes 
IA 
IB 
II 
III 
IV 
V 
IA 
IB 
II 
III 
IV 
V 
CTV2 
 
 
 
 
 
 
 
 
 
 
 
 
Ipsilateral 
IB, 
II 
II, 
III 
III, 
IV 
II, 
IV 
II, III 
II, 
III
, 
IV 
IA, 
IB, 
II 
II 
II 
III 
III 
II 
Contralateral
IA 
--- 
II, 
III 
II, 
III 
II, III 
II, 
III 
IB 
II 
III 
II, 
IV 
II, 
III 
II, 
III 
 
Lower Gingiva 
 
Adenopathy Level 
 
Ipsilateral  
Contralateral  
Involved 
Nodes 
IA 
IB 
II 
III 
IV 
V 
IA 
IB 
II 
III 
IV 
V 
CTV2 
 
 
 
 
 
 
 
 
 
 
 
 
Ipsilateral 
IB, 
II 
IA, 
II 
IA, 
IB, 
III 
IA, 
IB, 
II, 
IV 
IA, 
IB, 
II, III 
IA
IB
II 
III 
IA, 
IB 
IA, 
II 
IA, 
IB, 
II 
IA, 
IB, 
II 
IA, 
IB, 
II 
IA, 
IB, 
II 
Contralateral
IA, 
IB 
--- 
--- 
--- 
--- 
--- IB, 
II 
IA, 
II 
IA, 
IB, 
III 
IB, 
IA, 
II, 
IV 
IA, 
IB, 
II, 
III 
II, 
III 
 
Retromolar Trigone 
 
Adenopathy Level 
 
Ipsilateral  
Contralateral  


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
28
Involved 
Nodes 
IA 
IB 
II 
III 
IV 
V 
IA 
IB 
II 
III 
IV 
V 
CTV2 
 
 
 
 
 
 
 
 
 
 
 
 
Ipsilateral 
IB, 
II 
IA, 
II 
IB, 
III 
IB, 
II, 
IV 
IB, 
II, III 
IB
II 
III 
IA, 
IB 
IA, 
II 
IB, 
II 
IB, 
II 
IB, 
II 
IB, 
II 
Contralateral
IA, 
IB 
--- 
--- 
--- 
--- 
--- IB, 
II 
IA, 
II 
IB, 
III 
IB, 
II, 
IV 
IB, 
II, 
III 
II, 
III 
 
Lateralized Oral Tongue  
 
Adenopathy Level 
 
Ipsilateral  
Contralateral  
Involved 
Nodes 
IA 
IB 
II 
III 
IV 
V 
IA 
IB 
II 
III 
IV 
V 
CTV2 
 
 
 
 
 
 
 
 
 
 
 
 
Ipsilateral 
IB, 
II 
IA, 
II 
IA, 
IB, 
III 
IA, 
IB, 
II, 
IV 
IB, 
IA, 
II, III 
IA
IB 
II 
III 
IA, 
IB, 
II 
IA, 
II 
IA, 
IB, 
II 
IA, 
IB, 
II 
IA, 
IB, 
II 
IA, 
IB, 
II 
Contralateral
IA, 
IB 
--- 
--- 
--- 
--- 
--- IB, 
II 
IA, 
II 
IA, 
IB, 
III 
IB, 
IA, 
II, 
IV 
IA, 
IB, 
II, 
III 
II, 
III 
 
Oral Tongue Crossing Midline  
 
Adenopathy Level 
 
Ipsilateral  
Contralateral  
Involved 
Nodes 
IA 
IB 
II 
III 
IV 
V 
IA 
IB 
II 
III 
IV 
V 
CTV2 
 
 
 
 
 
 
 
 
 
 
 
 
Ipsilateral 
IB, 
II 
IA, 
II 
IA, 
IB, 
III 
IA, 
IB, 
II, 
IV 
IB, 
IA, 
II, III 
IA 
IB 
II 
III 
IA, 
IB, 
II 
IA, 
II 
IA, 
IB, 
II 
IA, 
IB, 
II 
IA, 
IB, 
II 
IA, 
IB, 
II 
Contralateral
IA, 
IB 
IA, 
IB 
IA, 
IB 
IA, 
IB 
IA, 
IB 
--- IB, 
II 
IA, 
II 
IA, 
IB, 
III 
IA, 
IB, 
II, 
IV 
IA, 
IB, 
II, 
III 
II, 
III 
 
Floor of Mouth 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
29
 
Adenopathy Level 
 
Ipsilateral  
Contralateral  
Involved 
Nodes 
IA 
IB 
II 
III 
IV 
V 
IA 
IB 
II 
III 
IV 
V 
CTV2 
 
 
 
 
 
 
 
 
 
 
 
 
Ipsilateral 
IB, 
II 
IA, 
II 
IA, 
IB, 
III 
IA, 
IB, 
II, 
IV 
IA, 
IB, 
II, III 
IA
IB 
II 
III 
IA, 
IB, 
II 
IA, 
II 
IA, 
IB, 
II 
IA, 
IB, 
II 
IA, 
IB, 
II 
IA, 
IB, 
II 
Contralateral
IA, 
IB 
IA, 
IB 
IA, 
IB 
IA, 
IB 
IA, 
IB 
-- 
IB, 
II 
IA, 
II 
IA, 
IB, 
III 
IA, 
IB, 
II, 
IV 
IA, 
IB, 
II, 
III 
II, 
III 
 
6.6 
Consolidative Immunotherapy Details and Guidelines 
Nivolumab will be given at 480 mg flat dose every 28 days (9 doses total, 9 months of 
consolidation treatment). The goal of consolidative nivolumab is to re-activate a potential 
anti-tumor response triggered during the induction phase after chemoradiation and to 
eradicate micro-metastatic residual disease.  
 
6.7  
Supportive Guidelines during Chemoradiation  
 Anti-emetics will be ordered at the discretion of the attending physician. 
 Use of growth factor support (G-CSF) during induction as above. During the 
TFHX regimen G-CSF may be used during the off week at the treating physician’s 
discretion. 
 A double lumen venous access device is recommended prior to initiation of 
therapy, although peripheral IV access is acceptable. 
 Use of a feeding device is recommended for high-risk patients. Placement of a 
feeding device is left to the discretion of the treating physician/investigator. 
Commonly applied criteria for feeding device placement include:  
o Loss of > 10% of body weight from the start of therapy 
o Dehydration or inability to maintain adequate oral hydration 
o Inability to maintain intake of 25+ kcal/kg of ideal body weight 
 During chemoradiotherapy patients should receive instructions for oral hygiene 
and prescriptions to include standard of care treatment typical for the care of 
HNSCC patients undergoing chemoradiation: 
o Oral nystatin or fluconazole (100 mg daily) 
o Viscous lidocaine HCl and/or Grade I mouthwash 10 mL QID, swish and spit 
 Grade 1 Mouthwash contains 50 mL 2% viscous lidocaine, 50 mL 
diphenhydramine elixir (12.5 mg/5 mL), 100 mL sodium bicarbonate 
injection, and 500 mL normal saline irrigation for a total volume of 700 mL 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
30
o Normal saline mouthwash 10 mL QID swish and spit 
o Natural Care Gel (or similar product) BID during chemoradiotherapy and TID 
during rest week 
o Vigilon (or similar product) to be applied to open wounds during 
chemoradiotherapy 
o Silvadene cream to open wounds followed by zinc oxide cream and then Telfa 
dressings BID during rest week (discontinue Silvadene and zinc oxide creams 
1 day prior to radiotherapy)  
o Aquaphor (or similar brand) cream to lips PRN 
o Adequate analgesia is essential to maintain oral intake and patient comfort. 
Narcotic analgesics are usually necessary and should be used at the 
physician/investigator discretion. 
o Therabite for trismus if appropriate. 
o Replacement for electrolyte imbalances when applicable. 
 Prior to discharge of the patients after a cycle of chemoradiation, a CBC and 
platelet count, and determination of serum electrolytes, including creatinine will be 
performed. 
 A visit to the treating physician is strongly recommended between cycles of 
chemoradiation (i.e., days 6-14).  
 Use of IV home hydration is strongly recommended in patients with inadequate 
oral intake: normal saline 1000 mL IV daily during rest weeks (days 6-14). 
 If Hb < 10, patients should generally be transfused an amount sufficient to increase 
Hb to > 10. The Hb level should be maintained > 10 mg/dL for the duration of 
chemoradiotherapy in all patients.  
 The use of amifostine during chemoradiotherapy is not permitted.  
 
6.8 
Post-Therapy Follow-Up 
Every patient should be followed clinically until taken off study. Patients will be seen in 
clinic for evaluation by Medical Oncology, Radiation Oncology, and Otolaryngology 
approximately 4 weeks after completing locoregional therapy. Repeat imaging of the head 
and neck with a PET/CT at 12 weeks post-completion of locoregional therapy will be 
obtained. Neck dissection or repeat biopsy may be indicated by 12-week post-treatment 
imaging findings (upon review in multidisciplinary tumor board).  
 
Patients should undergo clinical and radiographic disease evaluation every 3 months in 
year 1, every 6 months in years 2 and 3, and annually in years 4 and 5 after completion of 
definitive chemoradiation. Radiographic assessment should include imaging of the head, 
neck, and optionally, the chest. Laboratory evaluation should consist of at least a CBC, 
serum electrolytes, serum creatinine, liver enzymes, serum calcium, and serum albumin. 
TSH should be measured at least annually. This schedule can be altered according to the 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
31
physician’s discretion. Suspicion of progressive disease should be evaluated by 
radiographic studies whenever possible.  
 
6.9 
Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue for the 
allotted treatment time period (as described above) or until one of the following criteria 
applies: 
 Disease progression. 
 Intercurrent illness that prevents further administration of treatment. 
 Unacceptable adverse event(s). 
 Patient decides to withdraw from the study. 
 General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator.  
 
6.10 
Criteria for Discontinuation/Withdrawal of Informed Consent 
Patients may be discontinued from trial treatment at any time, at the discretion of the 
investigator(s). Specific reasons for discontinuing a patient from study treatment include: 
 Objective progression of disease if deemed inappropriate for further study 
treatment 
 Unacceptable adverse events including abnormal laboratory values  
 Abnormal test procedure result(s) 
 Protocol non-compliance 
 Study closure 
 Patient decision to withdraw from the study 
 Patient lost to follow-up 
 In the judgment of the investigator, further treatment would not be in the best 
interest of the patient 
 Death 
 
 
6.11  Late Toxicity Assessment  
 
6.11.1 Late Toxicity Assessment Schedule 
Swallowing function and speech will be assessed pre-treatment, at first follow-up after 
completion of definitive locoregional therapy, and then at 3, 6, 12, and 24 months after 
completion of definitive chemoradiation.  
 
6.11.2  Assessment of Late Toxicity 
Performance measures will be assessed by determining swallowing function and speech. 
Voice will be assessed as a simple yes/no response from patients as to whether their voice 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
32
has returned to normal. Swallowing will be determined by a patient’s ability to swallow 
table food. A formal swallow evaluation will be done on patients experiencing dysphagia. 
Additionally, late toxicity will be determined by evaluating presence and degree of 
xerostomia, dental decay, osteoradionecrosis, as well as the presence of enteral or 
tracheostomy dependence. 
 
6.11.3  Quality of Life Assessments  
The proposed regimen aims to decrease treatment toxicity without compromising 
outcomes. Thus, quality of life and performance are important treatment endpoints. The 
objective is to describe these dimensions prospectively, pre-treatment, through treatment, 
to long-term follow-up. Specific aims are to document patient’s experience of treatment 
effects; evaluate changes in quality of life and performance as a function of treatment 
regimen; determine extensiveness and persistence of quality of life and function-related 
treatment effects; and describe the pattern, timing and extent of recovery of function and 
quality of life. 
 
Quality of life and performance measures to be used in this protocol include: 
 Performance Status Scale for Head and Neck Cancer Patients (PSS-HN) 
 Functional Assessment of Cancer Therapy – Head and Neck Version 4 (FACT – 
H&N) 
 
The PSS-HN is a clinical rated instrument consisting of three subscales: Normalcy of Diet, 
Eating in Public, and Understandability of Speech. It has been demonstrated to be reliable 
and valid in head and neck cancer patients. 
 
The FACT-H&N is a multidimensional, self-report quality of life instrument specifically 
designed for use with head and neck cancer patients. The core scale (FACT-G) consists of 
27 core items assessing patient well-being in four areas: Physical, Social/Family, 
Emotional, and Functional. The core scale is supplemented with site-specific modules of 
which the head and neck version (12 items) will be employed here. 
 
These surveys can be found in the appendix.  
 
These instruments will be administered on paper pre-treatment (pre-induction), post-
induction, at first follow-up (4 weeks) after completion of definitive locoregional therapy, 
and then at 3, 6, 12, and 24 months after completion of definitive chemoradiation.  
7  
EXPECTED ADVERSE EVENTS, RISKS AND DOSE 
MODIFICATIONS 
 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
33
7.1 
Expected Adverse Events 
 
7.1.1  Nivolumab (during induction and consolidative therapy) 
 Central nervous system: Fatigue, malaise  
 Dermatologic: Skin rash  
 Endocrine and metabolic: Hyperglycemia, hypothyroidism 
 Gastrointestinal: Diarrhea, nausea  
 Hematologic and oncologic: Lymphocytopenia, anemia  
 Hepatic: Increased serum AST, ALT, bilirubin, and alkaline phosphatase  
 Respiratory: Pneumonitis  
 Miscellaneous: Febrile reaction, infusion reaction  
 Please see investigational brochure for full list of side effects 
 
7.1.2 Carboplatin (during induction therapy) 
 
Dermatologic: Alopecia (includes other agents in combination with carboplatin)  
 
Endocrine & metabolic: Hypomagnesemia, hypokalemia, hyponatremia, 
hypocalcemia; less severe than those seen after cisplatin (usually asymptomatic)  
 
Gastrointestinal: Nausea, vomiting, stomatitis, diarrhea, anorexia  
 
Hematologic: Myelosuppression is dose related and is the dose-limiting toxicity; 
thrombocytopenia is the predominant manifestation, with a reported incidence of 37% 
in patients receiving 400 mg/m2 as a single agent and 80% in patients receiving 520 
mg/m2; leukopenia has been reported in 27% to 38% of patients receiving carboplatin 
as a single agent (nadir: ~21 days following a single dose)  
 
Hepatic: Alkaline phosphatase increased, AST increased (usually mild and reversible)  
 
Otic: Hearing loss at high tones (above speech ranges, up to 19%); clinically-
important ototoxicity is not usually seen  
 
Renal: Increases in creatinine and BUN have been reported; most of them are mild and 
they are commonly reversible; considerably less nephrotoxic than cisplatin  
 
Neuromuscular & skeletal: Peripheral neuropathy (4% to 6%; up to 10% in older 
and/or previously-treated patients)  
 
<1% (Limited to important or life-threatening): Neurotoxicity, urticaria, rash, 
nephrotoxicity, secondary malignancies, anaphylaxis, malaise, hypertension  
 
7.1.3 Paclitaxel (during induction and TFHX concurrent chemoradiation)  
 Cardiovascular: Flushing, edema, hypotension 
 Central nervous system: Peripheral neuropathy 
 Dermatologic: Alopecia, rash, nail changes  
 Gastrointestinal: Nausea, vomiting, diarrhea, mucositis 
 Hematologic and oncologic: Neutropenia, leukopenia, anemia, thrombocytopenia 
 Hepatic: Increased alkaline phosphatase, increased serum AST 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
34
 Hypersensitivity: Hypersensitivity reaction 
 Neuromuscular and skeletal: Arthralgia, myalgia  
 May cause a hypersensitivity reaction which often occur within the first 10 
minutes of an infusion  
 
7.1.4 5-Fluorouracil (during TFHX concurrent chemoradiation)  
 
Gastrointestinal: Diarrhea, mucositis, nausea, and vomiting  
 
Hematologic: Myelosuppression  
 
Dermatologic: Photosensitivity, skin dryness, hand-foot syndrome, increased 
pigmentation of skin, increased pigmentation of veins used for infusion, nail changes  
 
Cardiac: myocardial ischemia, arrhythmias 
 
Allergic reactions 
 
Neurologic: Acute cerebellar syndrome, disorientation, headache 
 
Eye: Lacrimal duct stenosis, lacrimation, photophobia, and visual changes 
 
May cause birth defects and should not be used in pregnant women.  
 
A known radiation sensitizer and may potentiate side effects of radiation  
 
7.1.5 Hydroxyurea (during TFHX concurrent chemoradiation) 
 Cardiovascular: Edema 
 Gastrointestinal: Nausea, vomiting, diarrhea, constipation 
 Hematologic and oncologic: Leukopenia, bone marrow depression  
 Renal: Increased blood urea nitrogen, increased serum creatinine  
 It may aggravate the inflammation of mucous membranes secondary to irradiation. 
 Less common side effects include: dysuria or impairment of renal tubular function, 
rare neurological disturbances (headaches, dizziness, disorientation, hallucination, 
and convulsion.  
 
7.1.6 Cisplatin (during cisplatin concurrent chemoradiation) 
 Central nervous system: Peripheral neuropathy 
 Gastrointestinal: Nausea, vomiting 
 Hematologic and oncologic: Anemia, leukopenia, thrombocytopenia 
 Hepatic: Increased liver enzymes 
 Otic: Ototoxicity  
 Renal: Nephrotoxicity  
 
7.1.7 Filgrastim 
 Cardiovascular: Chest pain 
 Central nervous system: Fatigue 
 Gastrointestinal: Nausea 
 Hematologic and oncologic: Thrombocytopenia 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
35
 Hepatic: Increased serum alkaline phosphatase  
 Neuromuscular and skeletal: Ostealgia, back pain  
 Miscellaneous: Fever 
 
7.1.8 Radiation 
 Radiation to the head and neck will cause skin irritation, dry mucous membranes 
due to salivary gland dysfunction, mucositis, and stomatitis. The concomitant 
administration of chemotherapy will aggravate these side effects. Long-term side 
effects include myelitis, osteoradionecrosis, hoarseness, hypothyroidism, trismus, 
swallowing dysfunction, fibrosis of soft tissues, and enteral tube dependency.  
 
7.2 
Dose Modifications 
 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse 
Events) Version 5 for toxicity and Adverse Event reporting. A copy of the CTCAE 
Version 5.0 can be downloaded from the CTEP home page. This section discussed the 
general dose modifications in the setting of the most commonly observed adverse events 
with systemic therapy and radiation therapy. These are general guidelines to be followed, 
but deviations from the listed dose modifications are allowed at the discretion of the 
treating physician.  
 
7.2.1 Induction Chemotherapy Dose Modifications  
 
7.2.1.1 Hematologic Toxicity  
 Patient should not begin a new cycle of induction therapy unless the ANC is ≥ 
1500 cells/mm3 and the platelet count is ≥ 100,000 cells/mm3. Repeat counts 
should be obtained weekly until resolved. In the setting of low blood counts as 
specified above, dose reductions on subsequent cycles are provided in the table 
below.  
 A delay in therapy of up to 2 weeks is permitted for count recovery 
 If ANC are < 1500 or platelets < 100,000 on day 8 or 15 of each cycle, reduce all 
subsequent doses of paclitaxel and carboplatin (if any) to one dose reduction of the 
previous dose. Withhold treatment until counts recover to an absolute neutrophil 
count of at least 500 cells/mm3 or platelets of at least 50,000 on days 8 or 15 of the 
cycle. Growth factor support should then be used with subsequent cycles.  
 Dose reduction per the table below: 
 
 
 
 
 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
36
Adverse Reaction 
Occurrence
Paclitaxel 
Dose (mg/m2)
Carboplatin Dose 
(AUC mg·min/mL) 
ANC < 1500/mm3 OR ANC < 500/mm3 for more than 
7 days 
First 
75 
4.5 
Second 
50 
3 
Third 
Discontinue Treatment 
Platelet count less than 100,000/mm3 
First 
75 
4.5 
Second 
Discontinue Treatment 
 
7.2.1.2 Neurotoxicity (Peripheral) 
 Patients with grade 1 peripheral neuropathy should be carefully watched for 
progression of symptoms. A dose reduction is not necessary in this setting  
 In the setting of grade 2 peripheral neuropathy – paclitaxel should be dose reduced 
according to the table below.  
 Withhold paclitaxel for grade 3-4 peripheral neuropathy.  Paclitaxel at reduced 
doses can be resumed when peripheral neuropathy improves to grade 1.  
 Dose reduction table below: 
Adverse Reaction 
Occurrence
Paclitaxel Dose (mg/m2) 
Severe sensory neuropathy 
First 
75 
Second 
50 
Third 
Discontinue Treatment 
 
7.2.1.3 Ototoxicity 
 If grade 2 hearing loss, subsequent doses of cisplatin may be replaced by 
carboplatin AUC 6. For grade 3 ototoxicity, discontinue carboplatin. 
 
7.2.1.4 Hypersensitivity  
 In case of paclitaxel hypersensitivity reactions, the investigator should institute 
treatment measures medically appropriate per institutional guidelines.  
 For grade 1 allergic reactions, supervise at the bedside without further treatment. 
Consider decreasing rate of infusion until recovery from symptoms. 
 For grade 2 reactions, interrupt the infusion of paclitaxel, and resume upon 
recovery of symptoms. The infusion should be resumed at a slower rate and if no 
further symptoms appear, complete the administration of the dose. If symptoms 
recur, discontinue infusion and follow guidelines below. 
 For grade 3-4 reactions, stop the infusion and administer additional doses of H1 
and H2 blockers intravenously. Administer IV steroids and consider epinephrine 
and bronchodilators as clinically indication.  
 For recurrent grade 2 or grade 3 reactions, prior to re-challenge and with all 
subsequent cycles, consider both an H1 and H2 blocker intravenously plus 
dexamethasone 20 mg x2 doses (orally or IV) 12 and 6 hours pre-paclitaxel.  


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
37
 Grade 4 reactions are considered severe hypersensitivity reactions, and rechallenge 
is contraindicated.  
 
7.2.1.5 Hepatic  
 Mild impairment (AST or ALT < 10 times ULN or bilirubin ≤ 1.25 times ULN): 
No adjustments  
 Moderate impairment (AST or ALT < 10 times ULN or bilirubin 1.26-2 times 
ULN): Reduce paclitaxel dose by 25%. 
 Severe impairments (AST or ALT < 10 times ULN or bilirubin 2.01-5 times 
ULN): Reduce paclitaxel dose to 50%. May increase up to a reduction of 25% in 
subsequent cycles if liver impairment improves to either moderate or mild 
impairment.  
 AST or ALT > 10 times ULN or bilirubin > 5 times ULN: Discontinue paclitaxel.  
 
7.2.1.6 Other Toxicities  
 For all other grade 3+ toxicities (except alopecia, nausea, vomiting, fatigue and 
anorexia), reduce carboplatin and paclitaxel by 25% for all subsequent doses 
during induction. 
 In the event of recurrent grade 3 or 4 toxicity attributed to chemotherapy 
(excluding transaminase elevation, nausea, vomiting, alopecia) reduce carboplatin 
and paclitaxel by a further 25% during induction.  
 
7.2.2 Nivolumab Dose Modifications during Induction Phase and Consolidative 
Phase 
There will be no dose adjustments for nivolumab, however treatment can be held or 
discontinued based on occurrence of immune related adverse events. Please refer to the 
below tables/guidelines for guidance as well as investigator brochure for most up to date 
detailed management guidelines.  
 
Guidelines for permanent discontinuation or withholding of doses are described below.  
 


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7.2.3 Nivolumab Adverse Event Management Algorithms  
 
 
 
 


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7.2.3.1 Nivolumab Dose Delay Criteria 
Because of the potential for clinically meaningful nivolumab-related adverse events 
requiring early recognition and prompt intervention, management algorithms have been 
developed for suspected adverse events of selected categories. These algorithms are 
specified above. Dose delays will occur when nivolumab-related AEs have not resolved 
upon the next cycle of treatment or the patient remains on an equivalent of 10 mg 
prednisone or higher. In the setting of an adverse event likely due to nivolumab, the 
treating physician has the option to continue induction therapy with carboplatin and 
paclitaxel while holding nivolumab.   
 
In the event there are adverse events related to carboplatin or paclitaxel that require 
holding treatment, nivolumab must also be held and delayed until chemotherapy can 
resume. 
 
Nivolumab should also be permanently discontinued for grade 2 or 3 immune-related 
adverse reactions that persist despites treatment modifications or for inability to reduce 
corticosteroid dose to 10 mg prednisone or equivalent per day.  


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
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7.2.3.2 Treatment of Nivolumab Infusion Reaction  
Since nivolumab contains only human IgG protein sequences, it is 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, pruritis, 
arthralgias, blood pressure shifts, bronchospasms, or other symptoms. All grade 3, 4, or 5 
infusion reactions should be reported within 24 hours to the primary investigator and 
reported as an SAE. Infusion reactions should be graded according to NCI CTCAE v 5.0 
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 patient until recovery 
from symptoms. The following prophylactic premedications are recommended for 
future infusions: diphenhydramine 50 mg (or equivalent) and/or paracetamol 325 
to 1000 mg (acetaminophen) at least 30 minutes before additional nivolumab 
administrations.  
 For Grade 2 symptoms: (Moderate reaction requires therapy or infusion 
interruption but responds promptly to symptomatic treatment (e.g., antihistamines, 
non-steroidal anti-inflammatory drugs, narcotics, corticosteroids, bronchodilators, 
IV fluids); prophylactic medications indicated for 24 hours).  
Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the 
patient with diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 to 
1000 mg (acetaminophen); remain at bedside and monitor patient until resolution 
of symptoms. Corticosteroid 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 patient closely. If symptoms recur, then no further nivolumab will be 
administered at that visit. Administer diphenhydramine 50 mg IV and remain at 
bedside and monitor the patient until resolution of symptoms. The amount of study 
drug infused must be recorded on the electronic case report form (eCRF). The 
following prophylactic premedications are recommended for future infusions: 
diphenhydramine 50 mg (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen) should be administered at least 30 minutes before additional 
nivolumab administrations. If necessary, corticosteroids (recommended dose: up to 
25 mg of IV hydrocortisone or equivalent) may be used.  
 For Grade 3 or Grade 4 symptoms: (Severe reaction, Grade 3: prolonged (i.e., 
not rapidly responsive to symptomatic medication and/or brief interruption of 
infusion); recurrence of symptoms following initial improvement; hospitalization 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
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indicated for other clinical sequelae (e.g., renal impairment, pulmonary 
infiltrates)). Grade 4: (life threatening; pressor or ventilatory support indicated).  
Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal 
saline, and treat the patient as follows. Recommend bronchodilators, epinephrine 
0.2 to 1 mg of a 1:1,000 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. Patient should be monitored until the investigator is comfortable that 
the symptoms will not recur. Nivolumab will be permanently discontinued. 
Investigators should follow their institutional guidelines for the treatment of 
anaphylaxis. Remain at bedside and monitor patient until recovery from 
symptoms. In the case of late-occurring hypersensitivity symptoms (e.g., 
appearance of a localized or generalized pruritis within 1 week after treatment), 
symptomatic treatment may be given (e.g., oral antihistamine, or corticosteroids). 
 
7.2.4 Dose Modifications During Concurrent Chemotherapy 
 
7.2.4.1 Hematologic Dose Modifications for Hydroxyurea  
 Neutropenia: If the absolute neutrophil count (ANC) is between 500 and 1000 on day 
0 – 5 of each cycle, decrease hydroxyurea to 50% of the full dose. On subsequent 
cycles, a reduced starting dose of hydroxyurea should be used. For ANC of ≤ 500/μl 
on Day 0 – 5 of any cycle, omit hydroxyurea, and administer 600 mg/m2/day of 5-FU 
and radiotherapy only. On subsequent cycles, a reduced starting dose of hydroxyurea 
by 50% should be used. 
 
Thrombocytopenia: For a platelet count of 50,000/ μl to 74,000/μl on Day 0 – 5 of 
each cycle, decrease hydroxyurea to 50% of full dose. On subsequent cycles, a 
reduced starting dose of hydroxyurea may be used. For a platelet count ≤ 50,000/μl on 
Day 0 – 5 of any cycle, omit hydroxyurea, and administer 600 mg/m2/day of 5-FU and 
radiotherapy only. On subsequent cycles, a reduced starting dose of hydroxyurea by 
50% should be used. 
 
7.2.4.2 Hematologic Dose Modifications for Paclitaxel  
 For ANC ≤ 1000 or platelets count of 50-74 on day 0-5 of each cycle, decrease 
paclitaxel by one dose level. For ANC ≤ 500 or platelet count of less than 50 on day 0 
-5 of any cycle, hold paclitaxel for that cycle and decrease by one dose level in 
subsequent cycles. Discontinue paclitaxel if further dose reduction is required.  Dose 
level 0 = 100 mg/m2; dose level -1 = 75 mg/m2; dose level -2 = 50 mg/m2, dose level -
3 = discontinue  
 
7.2.4.3 Non-Hematologic Dose Modifications for 5-FU, Hydroxyurea, and Paclitaxel 
 Mucositis, Dysphagia, Dermatitis, Diarrhea: Treatment cycles should not be 
delayed for mucositis, dysphagia, dermatitis, or diarrhea. For grade 4 mucositis, 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
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dysphagia, and dermatitis exceeding 7 days duration or persisting on Day 1 of a 
subsequent cycle, decrease 5-FU to 500 mg/m2/day. For grade 4 diarrhea 
exceeding 7 days duration or persisting on Day 1 of a subsequent cycle, decrease 
5-FU to 500 mg/m2/day. Doses will not be increased on subsequent cycles. 
 Nephrotoxicity: If grade 2 renal toxicity, administer 50% hydroxyurea dose. If 
grade 3 or 4 renal toxicity, hold hydroxyurea. 
 Hepatotoxicity: If grade 3 or 4 on day 0, hold hydroxyurea and adjust paclitaxel 
according to section 7.2.1.5. 
 Peripheral neuropathy: For paclitaxel, refer to section 7.2.1.2.  
 Chemoradiotherapy should not be interrupted for non-hematologic toxicity except 
as judged necessary on a case-by-case basis by the treating radiation, medical 
oncologists, and Principal Investigator.  
 In the presence of a persisting fever ≥ 38C or other clinically apparent infection a 
cycle can be postponed for 1 week or interrupted (if treatment cycle has already 
started) if this is necessary in the opinion of the treating medical and radiation 
oncologists.  
 Cutaneous vasculitic toxicities, including vasculitic ulcerations and gangrene, have 
occurred in patients with myeloproliferative disorders during therapy with 
hydroxyurea. These vasculitic toxicities were reported most often in patients with a 
history of, or currently receiving, interferon therapy. Due to potentially severe 
clinical outcomes for the cutaneous vasculitic ulcers reported in patients with 
myeloproliferative disease, hydroxyurea should be discontinued if cutaneous 
vasculitic ulcerations develop.  
 Geriatric Use: Elderly patients may be more sensitive to the effects of 
hydroxyurea, and may require a lower dose regimen. This drug is known to be 
excreted by the kidney, and the risk of toxic reactions to this drug may be greater 
in patients with impaired renal function. Because elderly patients are more likely to 
have decreased renal function, care should be taken in dose selection, and it may 
be useful to monitor renal function. 
 
7.2.4.4 Dose Modifications for Cisplatin 
 Nephrotoxicity: If CrCl 46-60, 25% dose reduction. If CrCl 31-45, 50% dose 
reduction 
 Myelosuppression: If the ANC is < 1000 on day 1 of each cycle, hold cisplatin and 
when counts recover > 1000 ANC, then decrease cisplatin 25%. On subsequent 
cycles, a reduced starting dose of cisplatin should be used.  
 Peripheral Neuropathy: If grade 2, then decrease cisplatin 25%. On subsequent 
cycles, a reduced starting dose of cisplatin should be used. If grade 3 or more, hold 
cisplatin and when neuropathy recovers to grade 2 or better, then decrease cisplatin 
25%. On subsequent cycles, a reduced starting dose of cisplatin should be used.  
 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
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7.2.4.5 General Toxicity Information 
 Any other significant toxicity that is felt to be potentially drug related should be 
discussed between the PI and the treating physician and dose reduction can be 
implemented for the benefit and safety of the patient.  
 Radiotherapy should not be interrupted for non-hematologic toxicities except when 
judged necessary on a case-by-case basis by the treating radiation and medical 
oncologist in consultation with the PI.  
 All interruptions or changes to study drug administration must be recorded.  
 It will be documented whether or not each patient completed the clinical study. If 
for any patient either study treatment or observations were discontinued the reason 
will be recorded. Reasons that a patient may discontinue participation in a clinical 
study are considered to constitute one of the following: 1) adverse events, 2) 
abnormal laboratory value(s), 3) abnormal test procedure result(s), 4) disease 
progression, 5) protocol violation, 6) patient withdrew consent, 7) lost to follow-
up, 8) death 
8 
PHARMACEUTICAL INFORMATION  
 
8.1  
Carboplatin 
 Supply: supplied commercially as a sterile lyophilized powder available in single-
dose vials containing 50 mg, 150 mg and 450 mg of carboplatin. Each vial 
contains equal parts by weight of carboplatin and mannitol. Please refer to package 
insert for information on preparation. 
 Side effects: listed in section 7.1.2. Please refer to the package insert for full 
prescribing information.  
 Preparation: Immediately before use, the content of each vial must be reconstituted 
with either sterile water for injection, USP, 5% dextrose in water, or 0.9% sodium 
chloride injection, USP to produce a carboplatin concentration of 10 mg/ml. When 
prepared as directed, carboplatin solutions are stable for 8 hours at room 
temperature. Since no antibacterial preservative is contained in the formulation, it 
is recommended that carboplatin solutions be discarded 8 hours after dilution.  
 Storage and Stability: Unopened vials of carboplatin are stable for the life 
indicated on the package when stored at controlled room temperature and protected 
from light.  
 Administration: Administer over 30-60 minutes after completing the paclitaxel 
infusion. The Calvert Equation (Dose=AUC (CC+25) will be used to achieve the 
desired dose where CC = Wt*(140-age)/72/creatinine (if female use 85%). 
 


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8.2 
Fluorouracil 
 Commercially available as 10 ml ampules containing 500 mg/10 ml. No dilution is 
necessary for administration, but it may be further diluted in D5W or normal 
saline. It is stored at room temperature and is stable for 24 hours. It will be 
administered by intravenous continuous infusion as described in section 7.1.4. 
Please refer to the package insert for full prescribing information. 
 
8.3  
Hydroxyurea  
 Hydroxyurea (Bristol-Myers Squibb, Princeton, NJ): commercially available as 500 
mg capsules. It is stored at room temperature and will be administered. Please refer to 
the package insert for solution preparation and expected AE. Please refer to the 
package insert for full prescribing information. 
 
8.4  
Paclitaxel  
 Chemistry: Paclitaxel is a natural product with antitumor activity. The chemical 
name for paclitaxel is 5,20‐Epoxy‐1,2 hexahydroxytax‐11‐en 9‐one 4, 10 
diacetate 2‐ benzoate 13‐ester with (2R,3S)‐N‐benzoyl‐3‐phenylisoserine. 
Paclitaxel is a white to off‐white crystalline powder with the empirical formula 
C47H51NO14 and a molecular weight of 853.9. It is extremely lipophilic and 
melts at around 216‐217°C. Paclitaxel is highly insoluble in water. 
 Mechanisms of Action: Microtubules have been demonstrated to be very strategic 
targets for antineoplastic agents; however, few antimicrotubule agents have been 
discovered and encompassed into standard chemotherapeutic regimens. Paclitaxel, 
a diterpenoid plant product extracted from the bark of the western yew (Taxus 
brevifolia), has a unique mechanism of action. Unlike other antimicrotubule agents 
in clinical use (e.g. colchicine, vincristine, and vinblastine) that shift the 
equilibrium between microtubules and tubulin subunits toward microtubule 
disassembly, paclitaxel promotes assembly of microtubules from tubulin dimers 
and stabilizes microtubules by preventing depolymerization. These microtubules 
are stable even when treated with low temperatures or calcium, conditions that 
usually promote disassembly. This unusual stability results in the inhibition of the 
normal dynamic reorganization of the microtubule network that is essential for 
vital interphase and mitotic cellular functions. In addition, paclitaxel induces 
abnormal arrays or "bundles" of microtubules during mitosis. 
 Human Toxicology: The dose limiting toxicities and MTD of paclitaxel 
administered on a variety of schedules to patients with solid neoplasms were 
previously evaluated in phase I trials. In these studies, paclitaxel was infused over 
1, 3, 6, and 24 h, but severe acute reactions, characterized by bronchospasm, 
hypotension, stridor, tachy‐ and bradyarrhythmias, and death, resulted in the 
temporary discontinuation of all trials. These reactions were attributed to 
paclitaxel's Cremophor vehicle, since identical reactions were observed with other 


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drugs formulated with it and when the vehicle alone was administered to animals. 
Since a higher incidence of these acute reactions was observed with shorter 
durations of infusion, studies that used shorter infusions were permanently 
discontinued, and trials that evaluated longer infusion durations (24 h) were 
resumed using antiallergic pre‐medications consisting of corticosteroids, H1‐ and 
H2‐ histamine antagonists. These modifications were associated with a marked 
reduction in the incidence of acute reactions. Neutropenia was the major dose‐
limiting toxicity for paclitaxel in phase I solid tumor trials. In addition, a sensory 
neuropathy, characterized by a glove‐and‐sock distribution of numbness and 
paresthesias, was observed at higher doses. Nausea and vomiting, myalgias, 
mucositis, total‐body alopecia, diarrhea, and phlebitis were also observed. 
 Pharmaceutical Data: Formulation: Paclitaxel (TAXOL®) for Injection 
Concentrate is a clear colorless to slightly yellow viscous solution. It is 
commercially supplied as a solution in a nonaqueous medium. It is intended for 
dilution with a suitable parenteral fluid prior to intravenous infusion. Paclitaxel is 
available in 30 mg (5mL) vials. Each mL of sterile non‐pyrogenic solution 
contains 6 mg paclitaxel, 527 mg of Cremophor®EL (polyoxyethylated castor oil) 
and 49.7% (v/v) dehydrated alcohol, USP. 
 Storage and Stability: Unopened vials of Paclitaxel for Injection Concentrate are 
stable until the date indicated on the package when stored under refrigeration, 2°‐ 
8°C (36°47° F). Refrigeration is not required for shipping. Freezing does not 
adversely affect the concentrate. Solutions for infusion which are prepared as 
recommended are stable at ambient temperature and lighting for up to 27 hours. 
 Administration: Commercially available. Paclitaxel should be given after the 
patient has received the appropriate premedication as per institutional standards. 
Paclitaxel: supplied in 5 ml vials containing 30 mg of drug (6mg/ml). Please refer 
to the package insert for information on preparation and for full prescribing 
information. 
 Drug interactions: There is a potential for interaction with Ketoconazole, which 
might interfere with paclitaxel metabolism. 
 Contraindications: Known hypersensitivity to either paclitaxel or Cremaphor EL. 
 
8.5 
Cisplatin 
 Formulation: Cisplatin is a sterile aqueous solution, each mL containing 1 mg 
cisplatin and 9 mg sodium chloride. Cisplatin is supplied in multidose vials of 50 
mg and 100 mg cisplatin. Please refer to package insert for information on 
preparation. NOTE: Aluminum reacts with cisplatin causing precipitate formation 
and loss of potency; therefore, needles or intravenous sets containing aluminum 
parts that may come in contact with the drug must not be used for the preparation 
or administration of cisplatin. 


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 Storage: Store at 15C to 20C. Do not refrigerate. Protect unopened container from 
light. The cisplatin remaining in the amber vial following initial entry is stable for 
28 days from light or for 7 days under fluorescent room light. 
 Availability: Commercially available. Administration should follow institutional 
guidelines and may depend on renal function, and ability to give pre- and post-
hydration as appropriate. Typically, a bolus injection will be given over 2-3 hours, 
but injection time may be extended to minimize adverse events. Pre- and post-
hydration is required.   
 
8.6 
Filgrastim  
 Packaging and Formulation: G-CSF (Filgrastim) is commercially available. 
Filgrastim is a sterile, clear, colorless, preservative-free liquid for parenteral 
administration, containing Filgrastim at a specific activity of 1.0 ± 0.6 x 108 U/mg 
(as measured by a cell mitogenesis assay). The product is available in single use 
vial form and prefilled syringe. The single use vial contains 480 mcg Filgrastim at 
a fill volume of 1.6 mL. The formulation is: 480 mcg of Filgrastim (r-methHuG-
CSF), containing acetate (0.94 mg), sorbitol (80.0 mg), Tween® 80 (0.004%), 
sodium (0.056 mg) in water for injection, USP q.s. ad (1.6 mL). The single use 
prefilled syringe contains 0.6 mg Filgrastim at a fill volume of 0.8 mL. The 
formulation is: 480 mcg of Filgrastim (r-methHuG-CSF), containing acetate (0.472 
mg), sorbitol (40.0 mg), Tween® 80 (0.004%), sodium (0.028 mg) in water for 
injection, USP q.s. ad (0.8 mL).  
 Storage Conditions and Stability: Filgrastim should be stored in the refrigerator at 
2o to 8oC (36o to 46o F). Avoid shaking. Prior to injection, Filgrastim may be 
allowed to reach room temperature for a maximum of 24 hours. Any vial or pre-
filled syringe left at room temperature for greater than 24 hours should be 
discarded. Parenteral drug products should be inspected visually for particulate 
matter and discoloration prior to administration, whenever solution and container 
permit; if particulate or discoloration are observed, the container should not be 
used. At a concentration of 5 mcg/ml or greater in D5W, filgrastim is stable for 7 
days at room or refrigerator temperatures. At dilutions from 5 to 15 mcg/ml, 
albumin in a final concentration if 2mg/ml should be added to protect against 
adsorption to plastic materials. Addition of albumin is unnecessary when the drug 
is diluted to a concentration greater than 15 mcg/ml in D5W. Dilutions in D5W are 
stable in glass bottles, polyvinyl chloride, polyolefin or polypropylene bags and IV 
sets, and Travenol Infusors. Dilution of Neupogen® to a final concentration of less 
than 5 mcg/mL is not recommended at any time. Do not dilute with saline at any 
time because the product may precipitate.  
 Preparation and Administration: If using the vial, draw the appropriate dose into a 
syringe for subcutaneous injection. If using the pre-filled syringe, select the 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
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appropriate pre-filled syringe for subcutaneous injection. Inject only the 
appropriate dose, discard the unused drug. Incompatibilities: Normal saline.  
 Adverse Reactions: The following events are associated with Filgrastim and meet 
the regulatory definition of “expected.” The only consistently observed clinical 
toxicity described with Filgrastim is medullary bone pain. Other clinical adverse 
events that have been described include skin rash, and cutaneous vasculitis. Since 
commercial introduction of Neupogen®, there have been rare reports of allergic-
type reactions. Biochemical abnormalities that may occur include increases in 
alkaline phosphatase, uric acid, and lactate dehydrogenase.  
 Overdosage: The maximum amount of Filgrastim that can be safely administered 
has not been determined. Efficacy was demonstrated at doses of 4 to 8 mcg/kg/day 
in the phase 3 study of nonmyeloablative chemotherapy. Patients in bone marrow 
transplant studies received up to 138 mcg/kg/day without toxic effects, although 
there was a flattening of the dose response curve above daily doses of greater than 
10 mcg/kg/day. In Filgrastim clinical trials of cancer patients receiving 
myelosuppressive chemotherapy, WBC > 100,000/mm3 have been reported in less 
than 5% of patients but were not associated with any reported adverse clinical 
effects. In cancer patients receiving myelosuppressive chemotherapy, 
discontinuation of Filgrastim therapy usually results in a 50% decrease in 
circulating neutrophils within 1 to 2 days, with a return to pretreatment levels in 1 
to 7 days.  
 Toxicity/Warnings: Filgrastim is contraindicated inpatients with known 
hypersensitivity to E coli-derived proteins, pegfilgrastim, Neupogen®, or any other 
component of the product. Rare cases of splenic rupture have been reported 
following the administration of colony stimulating factors, including Filgrastim, 
for peripheral blood progenitor cell (PBPC) mobilization in both healthy donors 
and patients with cancer. Some of these cases were fatal. Individuals receiving 
Filgrastim who report abdominal or shoulder tip pain, particularly healthy donors 
receiving Filgrastim for PBPC mobilization, should be evaluated for an enlarged 
spleen or splenic rupture. Adult respiratory distress syndrome (ARDS) has been 
reported in neutropenic patients with sepsis receiving Filgrastim and is postulated 
to be secondary to an influx of neutrophils to sites of inflammation in the lungs. 
Neutropenic patients receiving Filgrastim who develop fever, lung infiltrates, or 
respiratory distress should be evaluated for the possibility of ARDS. In the event 
that ARDS occurs, Filgrastim should be discontinued until resolution of ARDS 
and patients should receive appropriate medical management for this condition.  
Allergic-type reactions occurring on initial or subsequent treatment have been 
reported in < 1 in 4000 patients treated with Filgrastim. These have generally been 
characterized by systemic symptoms involving at least 2 body systems, most often 
skin (rash, urticaria, facial edema), respiratory (wheezing, dyspnea), and 
cardiovascular (hypotension, tachycardia). Some reactions occurred on initial 
exposure. Reactions tended to occur within the first 30 minutes after 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
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administration and appeared to occur more frequently in patients receiving 
Filgrastim IV. Rapid resolution of symptoms occurred in most cases after 
administration of anti-histamines, steroids, bronchodilators, and/or epinephrine. 
Symptoms recurred in more than half the patients who were rechallenged. Severe 
sickle cell crisis has been reported in patients with sickle cell disease (specifically 
homozygous sickle cell anemia, sickle/hemoglobin C disease, and sickle/beta+ 
thalassemia) who received Filgrastim for PBPC mobilization or following 
chemotherapy. One of these cases was fatal.  
 Pregnancy and Lactation: Since there are no adequate and well-controlled studies 
in pregnant women, the effect, if any, of Filgrastim on the developing fetus or the 
reproductive capacity of the mother is unknown. It is not known whether 
Filgrastim is excreted in human milk. Because many drugs are excreted in human 
milk, caution should be exercised when Filgrastim is administered to a nursing 
woman.  
 Drug Interactions: No formal drug interaction studies between pegfilgrastim and 
other drugs have been performed. Drugs which may potentiate the release of 
neutrophils, such as lithium, should be used with caution. Patients receiving 
lithium and Filgrastim should have more frequent monitoring of neutrophil counts.  
 Nursing Guidelines: Filgrastim should be kept in the refrigerator until needed and 
the vials or Pre-filled Syringe should not be shaken. The drug should be 
administered at the same time each day. Vials and Pre-filled Syringes of filgrastim 
are single-dose and the remaining drug should be discarded. Refer to protocol text 
for information regarding requirements for documentation of doses administered, 
temperatures, side effects, etc. Acetaminophen is the recommended analgesic for 
mild bone pain. Duration of therapy will be determined by the return of blood 
counts (WBC/ANC) to specific values. 
 
8.7  
Nivolumab  
 Supply: Nivolumab is investigational and supplied by BMS  
 Storage Conditions and Handling: Nivolumab should be stored at between 2-8 
degrees Celsius (36-46 degrees Fahrenheit), and protected from light and freezing. 
If any temperature excursions are encountered during storage, they should be 
reported to BMS. As with all injectable drugs, care should be taken when handling 
and preparing Nivolumab. Whenever possible, Nivolumab should be prepared in a 
laminar flow hood or safety cabinet using standard precautions for the safe 
handling of intravenous agents applying aseptic technique. Partially used vials 
should be disposed at the time following procedures for the disposal of anticancer 
drugs.  
 Preparation and Administration: Nivolumab injection is to be administered using a 
volumetric pump with a 0.2/0.22 micron pore size, low protein binding 
polyethersulfone membrane in-line filter at the protocol-specific doses. The line 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
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should be flushed at the end of the infusion with sufficient quantity of normal 
saline per institution SOC. Nivolumab is not to be administered as an IV push or 
bolus injection. At the dose of 360 or 480mg, the total dose needed will be diluted 
to a minimum total volume of 100 ml in 0.9% Sodium Chloride injection solution. 
Care must be taken to assure sterility of the prepared solution as the produce not 
contain any anti-microbial preservative or bacteriostatic agent. Nivolumab should 
be administered over 30 minutes but 60 minutes would still be acceptable; 
infusions will be controlled by a volumetric pump. No incompatibilities between 
Nivolumab and polyolefin bags have been observed. IV bags/containers should 
specify they are made of polyolefin. If this is not clearly specified, please check 
with the manufacturer of the IV bag/container. 1) Allow the appropriate number of 
vials of Nivolumab to stand at room temperature for approximately 5 minutes 
before preparation. 2) Ensure that Nivolumab solution is clear, colorless, and 
essentially free from particulate matter. 3) Aseptically withdraw the require 
volume of Nivolumab into a syringe and dispense into an IV bag. a. Add the 
appropriate volume of 0.9% Sodium Chloride injection solution. b. Mix by gently 
inverting several times. DO NOT shake. c. Record the time the Nivolumab was 
prepared on the IV bag label. d. Attach the IV bag containing the Nivolumab 
solution to the infusion set, in-line filter, and infusion pump. e. The infusion rate of 
the infusion pump should be adjusted to allow for a total infusion time of 30-60 
minutes. f. At the end of the infusion period, flush the line with a sufficient 
quantity of 0.9% Sodium Chloride injection solution. 4) Pharmacy supplies 
required: a. Empty IV bags-50mg, 100mL, 200 mL b. 0.9% NaCl bags c. 0.2 or 
0.22 micron in line filter and infusion tubing d. Volumetric infusion pumps. 
 Use Time/Stability: After preparation, nivolumab infusion should be stored at 
room temperature for no more than 8 hours from the time of preparation. This 
includes room temperature storage of the infusion in the IV container and time for 
administration of the infusion. An alternation option is storage under refrigeration 
at 2-8 degrees Celsius for no more than 24 hours from the time of infusion 
preparation. Do not freeze.  
 Investigational supply of Nivolumab is obtained from Bristol Myers Squibb. Drug 
supplies will be kept in a secure, limited access storage area under the storage 
conditions. Where necessary, a temperature log must be maintained to make 
certain that the drug supplies are stored at the correct temperature. 
 The responsible person must maintain records of the product’s delivery to the 
study site, the inventory at the site and the use by each patient. The Principal 
Investigator (and participating site investigators) are responsible for all 
destructions/disposals of partially used and unused supplies.  Supplies are not to be 
shipped back to BMS.  A copy of the drug destruction certificate must be 
maintained for provision to BMS at the end of the study. 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
54
 These records will include dates, quantities, batch/serial numbers, expiry (“use 
by”) dates, and study patients. The responsible person will maintain records that 
document adequately that the patients were provided the doses specified by the 
CSP and reconcile all investigational product(s) received from BMS. 
 
9 
CORRELATIVE STUDIES  
 
9.1 
Objectives 
Correlative studies will be explorative in nature and will focus on tissue (serial samples) 
as well as blood based markers. The overreaching goal is in a descriptive manner to 
identify changes to the tumor microenvironment with chemoimmunotherapy using serial 
samples, and also evaluating potential predictive candidate biomarkers.  
 
We will collect plasma samples to monitor treatment progress using cell free circulating 
tumor DNA (ctDNA). This will be monitored by measuring somatic mutations. In addition 
to providing a marker of treatment efficacy, it will also be used to assess patients after 
treatment serially to assess any evidence of early recurrence but will not be used for 
clinical decision making at this point.  
 
9.2 
Correlative Analysis 
 
9.2.1 Tissue 
Baseline archival (or if not available alternatively fresh) tissue will be collected on all 
patients as well as a biopsy around day 8 of cycle 2 to assess synergistic immunotherapy 
relevant changes in the tumor micro-environment. In the curative intent setting, biopsy is 
readily doable in virtually all head and neck cancer patients with stage IV HNSCC as 
enrolled in this trial. 
 
9.2.1.1 Multicolor immunofluorescence based assessment of immune 
microenvironment 
Using both archival or fresh tumor samples and then the on-treatment paired biopsy during 
induction chemoimmunotherapy, we will analyze dynamic changes in the immune 
microenvironment.  
 
The analyses may include determination of CD8, PD-L1, FOXP3, IDO, CD168 and other 
immune related markers via immunofluorescence. Results will be digitally assessed, and 
results descriptively compared with results from flow cytometry and mRNA analysis. 
 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
55
9.2.1.2 mRNA Analysis / Immune Signatures  
Analysis will be performed using the Nanostring Counter (or similar approach) using the 
Nanostring immune panel. Briefly, from 3-5 FFPE slides, RNA will be extracted using the 
Qiagen RNA/DNA FFPE kit and protocol. 
 
9.2.1.3 Tumor DNA Analysis 
Exome sequencing from tumor and normal blood white cells will be performed on the 
tumor samples for an exploratory analysis of correlation of genetic aberrations, immune 
phenotype, tumor response, and tumor mutational burden. In addition, tumor RNAseq 
analysis will be performed from tumor tissue. Specific processing information will be 
made available in a continually updated SOP for tissue collection and processing. 
 
9.2.1.4 Germline DNA Analysis 
Blood will be obtained from all patients for exome sequencing of normal DNA. Specific 
processing information will be made available in a continually updated SOP for tissue 
collection and processing. 
 
9.2.1.5 Analysis of Tumor Digests 
Fresh tumor samples will be digested using a protocol for tumor digestion employing the 
Miltenyi GentleMACS system available in the HIM Core facility. Single cell suspension 
will be stored for subsequent FACS or similar analysis. Specific processing information 
will be made available in a continually updated SOP for tissue collection and processing.  
 
9.2.2  Blood 
 
9.2.2.1 ctDNA Analysis 
Using cell free circulating DNA (ctDNA), we will measure somatic mutations. This will 
be assessed as a candidate marker of treatment efficacy e.g. during induction with 
chemoimmunotherapy (baseline versus 3 weeks into treatment (cycle 2, day 1)). 
 
Furthermore, it will also be used to assess patients after treatment serially to assess any 
evidence of early recurrence (early detection) but will not be used for clinical decision 
making at this point. Especially as part of a de-escalation protocol, early detection in the 
future may prove invaluable in order to identify patients at risk for recurrence who may 
benefit from additional therapy. 
 
The option to add time points to ctDNA exists at the discretion of the primary investigator 
with the permission of the patient.  
 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
56
9.2.2.2 RNA Analysis  
Blood samples will be obtained at baseline and after 3 weeks (cycle 2, day 1). Samples 
will be processed for RNA extraction (e.g. using the PAXgene RNA kit/tubes). RNA will 
be analyzed by Nanostring or RNAseq in an exploratory fashion comparing baseline with 
on-treatment inflammatory markers. Specific processing information will be made 
available in a continually updated SOP for tissue collection and processing.  
 
9.3 
Sample and Tissue Procurement 
 
9.3.1 Archival Tumor Collection 
All patients at the time of enrollment need to provide 10 or more 5-micron un-stained 
slides for correlative analysis. Patients who cannot fulfill this requirement will need to 
undergo a new biopsy prior to enrollment on study.  
 
9.3.2 Tissue Biopsy 
Tumor biopsy will be performed prior to starting therapy or archival tissue will be 
obtained for all patients. At the time of surgical resection or biopsy, tissue in excess of 
what is necessary for diagnostic purposes will be obtained < 15 min after removal from 
the patient. Furthermore, an optional on-treatment biopsy during induction 
chemoimmunotherapy will be performed sometime around day 8 of cycle 2 as clinically 
feasible.  
 
Tissues will be instantaneously frozen and stored anonymously with a unique barcode at -
80C in a locked freezer in Biospecimen Shared Resource (Tissue Bank) at the University 
of Chicago. Additional alternative processing (e.g. tissue digestion) and cell suspension 
generation for flow analyses is also acceptable.  
 
After obtaining sample: 
 Write study number, patient initials, and date on plastic cryomold 
 Weigh or estimate sample weight and slice sample into less than 0.5 cm thick 
fragments 
 Place tissue into cryotube labeled with study number, patient initials, and date 
filled with RNAlater reagent from Qiagen 
 Freeze over liquid nitrogen vapors or in -80C freezer 
 
9.3.3 Blood Isolation 
Blood will be obtained from all patients enrolled in the study for pharmacogenomics and 
biomarker evaluation. Investigation of the relevant polymorphisms will take place in 
germline DNA extracted from peripheral whole blood (10 mL) collected in EDTA (purple 
top) plastic vacutainer tubes (i.e. BD catalog #366643). Investigation of cytokine markers 
will be from peripheral blood (10 mL) collected in a red top vacutainer tube. Blood should 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
57
be stored at -80C and sent to Biospecimen Shared Resource (Tissue Bank) at the 
University of Chicago for DNA extraction and plasma isolation following standard HTRC 
protocols.  
 
Isolated DNA will be stored anonymously with a unique barcode at -80C at the University 
of Chicago for future genotype analysis. 
 
Patients will have blood samples collected prior to induction chemoimmunotherapy and 2-
3 weeks into induction therapy. Samples will also be collected prior to radiotherapy 
initiation, and 4 and 12 weeks post-chemoradiation.  
 
Plasma will be used for identification of cell free circulating tumor DNA, e.g. for somatic 
mutations to be assessed as a candidate biomarker for monitoring during treatment for 
efficacy and surveillance after completion of treatment for detection of early recurrence. 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
58
10 
STUDY CALENDAR 
 
Induction Chemotherapy 
CRT 
Post-treatment Follow Up 
 
Pre-
Stu
dy$  
C1 
D1 
C1 
D8 
C1 
D15 
C2 
D1 
C2 
D8 
C2 
D15 
 
C3 
D1 
C3 
D8 
C3 
D15 
Pre-
RT 
RT 
C1 
RT 
C2 
RT 
C3 
RT 
C4 
RT 
C5 
4 weeks 
post-
chemoRT 
(15) 
12 weeks 
post-
chemoRT 
(15) 
Q3-6 mo f/u 
2 years post-
chemoRT 
(15) 
 
 
 
 
 
Scheduling Window 
(Days) 
-28 
to -
1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
 
±3 
±3 
±3 
±3 
±3 
 
±10 
 
Induction Chemo
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
CRT(1) 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
Adjuvant nivolumab 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Q4 weeks for 9 months (13) 
Panendoscopy (14) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biopsy(2) 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
PET/PET-CT(3) 
X 
 
 
 
 
 
 
 
 
 
X* 
 
 
 
 
 
 
X  
 
MRI/CT Neck 
X 
 
 
 
 
 
 
 
 
 
X* 
 
 
 
 
 
 
 
X(11) 
CT Chest 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X(11) 
Metastatic workup (4) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Correlative blood(5) 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent Meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Swallowing Eval. (6) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Dental Exam (6) 
Anytime before CRT 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TSH(7) 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
X 
CBC  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistries (8)   
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE evaluation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tumor Measurement 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
QoL Evaluations 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
b-hCG(9) 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
HPV testing 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Surgery(10) 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
$All baseline testing is to be conducted within 4 weeks prior to start of protocol therapy unless otherwise specified.  
*Pre-chemoradiation imaging should occur on or within 10 days of cycle 3 day 15 
(1)CRT: Please refer to dedicated treatment section.  Briefly, RT duration varies depending on allocated treatment arm and choice of 
regimen – cisplatin-RT vs TFHX.  
(2)Biopsy should be performed if no adequate archival tissue is available pre-study. A second optional biopsy for purposes of 
correlative tissue analysis should be performed around cycle 2 day 8 of induction chemotherapy.   
(3) At baseline PET/PET-CT is optional. On study PETs between induction/chemoRT and after chemoRT are optional. 
(4) As appropriate per treating physician – this may include but is not limited to abdominal imaging, PET, bone scan. 
(5) Correlative blood draws will occur pre-treatment, day 1 of cycle 2, pre-chemoradiation, and at 4 and 12 weeks after chemoradiation.   
(6) These tests can occur at any time before radiation starts – before start of induction therapy or during induction therapy. 
(7) TSH should be repeated q2mo while on consolidative nivolumab, and annually after post-CRT, and as part of standard of care 
considered to be continued beyond this protocol.  
(8) Standard comprehensive metabolic panel includes electrolytes, kidney function, liver function, glucose, and calcium 
(9) To be done within 24 hr of starting therapy. 
(10) Although unlikely to be necessary, an option for surgical neck dissection will be allowed after induction therapy prior to radiation 
to reduce the radiotherapy field size.  In addition, biopsy and/or salvage surgical procedures may be indicated for persistent disease after 
completion of definitive chemoradiation.  
(11) Follow up imaging of the head, neck, and optionally, the chest via CT and/or MRI is indicated after completion of chemoradiation 
every 3 months for the first year, every 6 months for years 2-3, and annually for years 4-5.   
(13) A chemistry and CBC will be drawn every 4 weeks (at each dose) of consolidative nivolumab. These are the only required tests 
specific for consolidative visits.  Imaging and TSH may occur on these visits if they fall in line with the post-chemoradiation imaging 
schedule.   


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
59
(14) If clinically indicated by multidisciplinary tumor board. 
(15) The first post-chemoRT follow up scan should occur three months after completing chemoRT. The remaining follow up imaging 
may occur within 1 month of the specified time points. 
(16) HPV testing is required prior to C1D1 for oropharyngeal primary tumor patients only. Other anatomic sites will be classified as 
HPV- unless requested per treating physician. 
(17) CT chest required only if PET/CT not performed. 
 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
60
11 
CRITERIA FOR OUTCOME ASSESSMENT/THERAPEUTIC 
RESPONSE  
 
11.1 
Outcome Response 
All baseline evaluations will be performed within the first 28 days. For subsequent 
evaluation, the method of assessment and techniques will be the same as those used at 
baseline. We will use radiographic response rates per RECIST v1.1 and we will further 
quantify tumor shrinkage ≥ 50% defined as deep response. 
 
11.2  Therapeutic Response  
Response will be evaluated in this study using the international criteria proposed by the 
RECIST committee for measurable disease. Patients will be evaluated for response 
according to the guidelines below.  
 
11.2.1 Response Evaluation Criteria in Solid Tumors (RECIST)  
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised RECIST guideline (version 1.1). Changes in the largest 
diameter (uni-dimensional measurement) of the tumor lesions and the shortest diameter in 
the case of malignant lymph nodes are used in the RECIST criteria.  
 
11.2.1.1 
Disease Parameters 
 Measurable disease: Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) on 
radiography or by calipers on clinical exam.  
 Malignant lymph nodes: To be considered pathologically enlarged and measurable, 
a lymph node must be > 15 mm in short axis when assessed by CT scan. At 
baseline and in follow-up, only the short axis will be measured and followed.  
 Non-measurable disease: All other lesions (or sites of disease), including small 
lesions (longest diameter < 10 mm or pathological lymph nodes with ≥ 10 to < 15 
mm short axis), are considered non-measurable disease.  
 Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 
5 lesions in total, representative of all involved organs, should be identified as 
target lesions and recorded and measured at baseline. Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements. A sum of the diameters for all 
target lesions will be calculated and reported as the baseline sum diameters. If 
lymph nodes are to be included in the sum, then only the short axis is added to the 
sum. The baseline sum diameters will be used as a reference to further characterize 
any objective tumor regression in the measurable dimension of the disease. 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
61
 Non-target lesions: All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target 
lesions and should also be recorded at baseline. Measurements of these lesions are 
not required, but the presence, absence, or in rare cases unequivocal progression of 
each should be noted throughout follow-up.  
 
11.2.1.2 
Methods for Evaluation of Measurable Disease  
All measurements should be taken and recorded in metric notation using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are accessible by clinical exam.  
 
Clinical Lesions. Clinical lesions will only be considered measurable when they are 
superficial (e.g. skin nodules and palpable lymph nodes) and ≥ 10 mm diameter as 
assessed using calipers (e.g. skin nodules).  
 
Conventional CT and MRI: Diagnostic imaging plays an important role in the assessment 
of head and neck squamous cell carcinomas before and after treatment. Currently, 
computed tomography (CT) with contrast, fluorodeoxyglucose positron emission 
tomography (FDG-PET), and magnetic resonance imaging (MRI) are routinely used to 
evaluate patients with this type of cancer. 
 
11.2.1.3 
Evaluation of Target Lesions 
 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 the diameters of 
target lesions, taking as reference the baseline sum diameters. 
 Deep Response (DR): At least a 50% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters.  
 Progressive Disease (PD): At least a 20% increase in the sum of the 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. The 
appearance of one or more new lesions is also considered progression. 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
62
 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.   
12 
REGULATORY AND REPORTING REQUIREMENTS  
 
12.1 
Regulatory Guidelines  
 
Food and Drug Administration (FDA) Approval 
This study will be conducted under an IND held by Dr. Everett Vokes at the University of 
Chicago. The University of Chicago CCTO will be responsible for facilitating all 
communications with the FDA on behalf of the IND holder. Participating sites should not 
communicate directly with the FDA.  
 
New Protocol Distribution and IRB Submission 
Once final BMS and University of Chicago (U of C) IRB approval is received, the protocol 
and consent form will be distributed to the participating affiliate institutions electronically. 
Upon receipt of the email, the affiliate institution is expected to do the following: 
 The affiliate institution is expected to submit the protocol to their IRB as soon as 
possible after receipt. 
 The U of C version date must appear on the affiliate consent form and on the 
affiliate IRB approval letter. The version dates can be found on every page of the 
protocol and consent form.  
 
Before the study can be initiated at any site, the following documentation must be 
provided to the Cancer Clinical Trials Office (CCTO) at the U of C Comprehensive 
Cancer Center. 
 A copy of the official local IRB approval letter for the protocol and informed 
consent 
 IRB membership list 
 CVs and medical licensure for the principal investigator and any sub-investigators 
who will be involved in the study 
 Form FDA 1572 appropriately filled out and signed with appropriate 
documentation 
 CAP and CLIA Laboratory certification numbers and institutions lab normal 
values 
 Investigational drug accountability standard operating procedures  
 Additionally, before the study can be initiated at any site, the required executed 
research contract/subcontract must be on file with the University of Chicago. 
 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
63
Amendment Distribution and IRB Submission 
All modifications to the protocol, consent form, will be submitted to the University of 
Chicago IRB for review and approval. A list of the proposed modifications or 
amendments to the protocol and/or an explanation of the need of these modifications will 
be submitted, along with a revised protocol incorporating the modifications. Only the 
Study Lead PI can authorize any modifications, amendments, or termination of the 
protocol. Once a protocol amendment has been approved by the University of Chicago 
IRB, the Regulatory Manager will send the amended protocol and consent form (if 
applicable) to the affiliate institutions electronically. Upon receipt of the packet the 
affiliate institution is expected to do the following: 
 The affiliate must reply to the email from the Regulatory Manager indicating that 
the amendment was received by the institution and that it will be submitted to the 
local IRB. 
 The amendment should be submitted to the affiliate institution’s IRB as soon as 
possible after receipt. The amendment must be IRB approved by the institution 
within 3 months from the date that it was received.  
 The University of Chicago version date and/or amendment number must appear on 
the affiliate consent form and on the affiliate IRB approval letter. The version 
dates can be found on the header of every page of the protocol and consent form. 
The amendment number can be found on the University of Chicago IRB 
amendment approval letter that is sent with the protocol/amendment mailing. 
 The IRB approval for the amendment and the amended consent form (if amended 
consent is necessary) for the affiliate institution must be sent to the designated UC 
Regulatory Manager as soon as it is received.  
 
Annual IRB Renewals, Continuing Review and Final Reports 
A continuing review of the protocol will be completed by the University of Chicago IRB 
and the affiliates’ IRBs at least once a year for the duration of the study. The annual IRB 
renewals for the affiliate institution should be emailed promptly to the Regulatory Affairs 
Administrator. If the institution’s IRB requires a new version of the consent form with the 
annual renewal the consent form should be included with the renewal letter. 
 
Departure from the Protocol 
An investigator cannot modify the protocol without satisfying procedures in this protocol 
as outlined in the study calendar.  Any changes in research activity, except those 
necessary to remove an apparent, immediate hazard to the study subject, must be 
reviewed and approved by the local IRB.  When a variation from the protocol is deemed 
necessary for an individual subject, the principal investigator or study chair must be 
contacted by phone or email (Everett Vokes, 773-702-9306 / 312-823-7990, 
evokes@medicine.bsd.uchicago.edu).  Such contact must be made as soon as possible to 
permit a decision as to whether or not the subject is to continue in the study. 
 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
64
The principal investigator or study chair must be informed of all intentional or 
unintentional departures from the protocol and will decide whether or not the subject is to 
continue in the study (Everett Vokes, 773-702-9306 / 312-823-7990, 
evokes@medicine.bsd.uchicago.edu).  All departures from the protocol, intentional and 
unintentional, along with the decision of the principal investigator will be submitted to 
the local and University of Chicago IRB per institutional guidelines. 
 
12.2 
Adverse Event Characteristics 
CTCAE term (AE description) and grade 
The descriptions and grading sales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5 will be utilized for AE reporting. All 
appropriate treating areas will have access to a copy of the CTCAE version 5. A copy of 
the CTCAE version 5 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
Attribution of the AE 
 Definite (5) – The AE is clearly related to the study treatment. 
 Probable (4) – The AE is likely related to the study treatment. 
 Possible (3) – The AE may be related to the study treatment. 
 Unlikely (2) – The AE is doubtfully related to the study treatment. 
 Unrelated (1) – The AE is clearly NOT related to the study treatment. 
 
12.3  Adverse Event Definitions  
 
12.3.1  Adverse Event  
An adverse event is any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product that does not necessarily have a causal 
relationship with the treatment. An adverse event can be any unfavorable and unintended 
sign (including a laboratory finding), symptom or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.  
 
At each evaluation patients should be interviewed in a non-directed manner to elicit 
potential adverse reactions from the patient. The occurrence of an adverse event will be 
based on changes in the patient’s physical examination, laboratory results, and/or signs 
and symptoms, and review of the patient’s own record of adverse events.  
 
Adverse events will be followed until resolution while the patient remains on-study. Once 
the patient is removed from study, events thought to be related to the study medication 
will be followed until resolution or stabilization of the adverse event, or until the patient 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
65
starts a new treatment regimen, or death, whichever comes first. Patients will be followed 
for AEs/SAEs for 100 days after their last dose of study drug(s). 
 
12.3.2  Serious Adverse Events (SAE) 
An adverse event is considered serious if it results in ANY of the following outcomes 
 
Death  
 
Life-threatening (e.g. places patient at immediate risk of death, this does not 
include events that might have caused death if they occurred a greater severity) 
 
Results in inpatients hospitalization or prolongation of existing hospitalization for 
≥ 24 hours 
 
A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
 
A congenital anomaly/birth defect  
 
Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon 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 
events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, bloody dyscrasias or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse.  
 
In addition to those events meeting the definitions above, the following will be considered 
an SAE for the purposes of this study:  
 Suspected transmission of an infectious agent (e.g. pathogenic or nonpathogenic) 
via the study drug 
 Pregnancy within 6 months completion of chemoradiation or the last dose of 
consolidative nivolumab, whichever occurs latest 
 Overdose to any medication required for cancer treatment or supportive measures  
 Grade 3 or more infusion reaction due to nivolumab  
 
12.3.3 Relatedness  
The definition of “related” being that there is a reasonable possibility that the drug caused 
the adverse experience.  
 
12.3.4  Adverse Reactions 
An adverse event is considered to be an adverse reaction if there is evidence to suggest a 
causal relationship to the study agent. This may include a single occurrence of an event 
strongly associated with drug exposure (e.g. Stevens-Johnson Syndrome), one or more 
occurrence of an event otherwise uncommon is the study population, or an aggregate analysis 
of specific events occurring at greater than expected frequency. 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
66
 
12.4  Adverse Event Reporting Requirements 
 
12.4.1 Routine Adverse Event Reporting  
All adverse events must be reported in routine study data submissions. AEs reported using the 
Serious Event Reporting Form and/or MedWatch Form discussed below must also be reported 
in routine study data submissions. 
 
All adverse events (except grade 1 and 2 laboratory abnormalities that do not require an 
investigation), regardless of causal relationship, are to be recorded in the case report form and 
source documentation. The Investigator must determine the intensity of any adverse events 
according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 
5.0 and their causal relationship.  
 
12.4.2  Serious Adverse Event Reporting to Coordinating Center 
Use the UC CCC protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
All serious adverse events (as defined in section 12.3.2) occurring on this study require 
expedited reporting to the University of Chicago Comprehensive Cancer Center (UCCCC). 
The responsible Research Nurse or other designated individual at the treating site should 
report the SAE to the Study Lead Investigator, the University of Chicago CRC, and the CCTO 
by the end of the business day when the team becomes aware of the event. Events occurring 
after business hours should be reported to the CCTO by 12pm the next business day. Reports 
should be made using the “Serious Event Report” Form. Please scan and send via email 
(preferred) or fax to the following: 
 
University of Chicago Phase II CRA General: 
PhaseIICRA@medicine.bsd.uchicago.edu 
Fax: 773-702-4889 
 
UC CCC Cancer Clinical Trials Office Quality Assurance: 
qaccto@bsd.uchicago.edu 
 
All unexpected adverse reactions must be reported to the IND holder so that the University of 
Chicago CCTO can inform the FDA. The responsible Research Nurse or other designated 
individual at the treating site should provide a complete written report using the FDA 
MedWatch 3500A from. The completed form should be sent to the CCTO at 
qaccto@bsd.uchicago.edu and to the Phase II CRA at 
PhaseIICRA@medicine.bsd.uchicago.edu within the specified timelines below regardless of 
whether all information regarding the event is available. If applicable, a follow-up report 
should be provided to the CCTO if additional information on the event becomes available.  
 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
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Participating sites should not forward any adverse event reports directly to the FDA. The 
CCTO will report all events to the FDA as per the current FDA guidelines.  
 
All serious adverse events should also be reported to the local IRB of record according to their 
policies and procedures.  
 
12.4.3 Serious and Unexpected Adverse Event Reporting by the Coordinating 
Center 
The designated UC CCC Regulatory Manager will notify all participating sites of all 
unexpected and serious adverse reactions that occur on this clinical trial and which are 
reported to the FDA and/or UC Institutional Review Board (IRB).  When reported to the 
FDA, a copy of the completed Form 3500A (MedWatch) will be provided to the 
responsible Regulatory Manager by the CCTO IND Coordinator for distribution to all 
participating sites. 
 
12.4.4 Serious Adverse Event Reporting to BMS 
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS 
within 24 hours of investigator knowledge of the event. SAEs must be recorded on BMS or an 
approved form; pregnancies 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 the BMS (or designee) 
using the same procedure used for transmitting the initial SAE report. All SAEs should be 
followed to resolution or stabilization.  
 
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. The Sponsor will reconcile the clinical database SAE cases (case level only) 
transmitted to BMS Global Pharamacovigilance (WoldwideWorldwide.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. 
 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
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12.5 
Data Submission  
Data reporting will be performed utilizing the RedCap electronic data capture system. The 
University of Chicago CRC will provide you with the applicable user registration 
information. 
 
All required data must be recorded in the RedCap database at the completion of each 
cycle. AEs are to be entered in real time. SAEs are to be entered on the Serious Event 
Form within 24 hours of the site’s knowledge of the event and sent via email (preferred) 
or fax to the University of Chicago (PhaseIICRA@medicine.bsd.uchicago.edu or 
qaccto@bsd.uchicago.edu; Fax: 773-702-4889). All case report forms must be completed 
by designated study personnel.  
 
Each screened (consented) patients is to be entered into RedCap within 48 hours of patient 
registration. The site will prepare and maintain adequate and accurate source documents. 
Source records are original documents, data, and records (e.g. medical records, raw data 
collection forms, pharmacy dispensing records, recorded data from automated 
instruments, laboratory data) that are relevant to the clinical trial. These documents are 
designed to record all observations and other pertinent data for each patient enrolled in 
this clinical trial. Source records must be adequate to reconstruct all data transcribed onto 
the case report form.  
 
12.6  Data and Safety Monitoring  
This study will be monitored by the designated University of Chicago Clinical Research 
Coordinator (CRC) in accordance with the University of Chicago, Section of 
Hematology/Oncology standard operating procedure titled Monitoring of Multi-
Institutional Investigator Initiated Clinical Trials.  
 
Prior to subject recruitment, and unless otherwise specified, a participating site will 
undergo a Site Initiation Teleconference to be conducted by the designated University of 
Chicago research team. The site’s principal investigator and their study staff must attend 
the site initiation meeting.  
 
Monitoring will be conducted to verify the following: 
 
 Adherence to the protocol 
 Completeness and accuracy of study data and samples collected 
 Compliance with regulations  
 Submission of required source documents  
 
Participating sites will also undergo a site close-out teleconference upon completion, 
termination or cancellation of a study to ensure fulfillment of study obligations during the 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
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conduct of the study, and to ensure that the site Investigator is aware of his/her ongoing 
responsibilities. 
 
Unless otherwise specified, this protocol will undergo weekly review at the multi-
institutional data and safety monitoring teleconference as per procedures specified by the 
UC CCC NCI-approved Data and Safety Monitoring Plan. The conference will review: 
 
 Enrollment rate relative to expectations, characteristics of participants 
 Safety of study participants (Serious Adverse Event & Adverse Event reporting) 
 Adherence to protocol (protocol deviations) 
 Completeness, validity and integrity of study data 
 Retention of study participants 
 
Protocol deviations are to be documented using the Protocol Deviation Form and sent via 
email to PhaseIICRA@medicine.bsd.uchicago.edu. Deviations that are considered major 
because they impact subject safety or alter the risk/benefit ratio, compromise the integrity 
of the study data, and/or affect subjects’ willingness to participate in the study must be 
reported within 7 days. Please contact the University of Chicago CRA 
(PhaseIICRA@medicine.bsd.uchicago.edu) if you have questions about how to report 
deviations.  All major protocol deviations should also be reported to the local IRB of 
record according to their policies and procedures. 
 
12.7 
Auditing 
In addition to the clinical monitoring procedure, the University of Chicago 
Comprehensive Cancer Center (UCCCC) will perform routing Quality Assurance Audits 
of investigator-initiated clinical trials as described in the NCI-approved UCCCC DSM 
Plan. Audits provide assurance that trials are conducted and study data are collected, 
documented and reported in compliance with the protocol. Further, quality assurance 
audits ensure that study data are collected, documented and reported in compliance with 
Good Clinical Practices (GCP) Guidelines and regulatory requirements. The audit will 
review patients enrolled at the University of Chicago in accordance with audit procedures 
specified in the UCCCC Data and Safety Monitoring plan. For institutions who are formal 
members of the Personalized Cancer Care Consortium (PCCC), the UC CCC will conduct 
on site quality assurance audits on average every two years during the enrollment and 
treatment phase of the study.  
 
A regulatory authority (e.g. FDA) may also wish to conduct an inspection of the study, 
during its conduct or even after its completion. If an inspection has been requested by a 
regulatory authority, the site investigator must immediately inform the University of 
Chicago Cancer Clinical Trials Office and Regulatory Manager that such a request has 
been made. 


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13 
STATISTICAL PLAN 
 
13.1 
Analysis Populations 
 All Enrolled Patients: All patients who sign an informed consent form and are 
registered onto the trial 
 Safety Population: All patients who receive at least one dose of chemo- or 
immunotherapy (i.e. carboplatin, paclitaxel, and nivolumab). 
 Evaluable Population: All patients who receive at least one dose of carboplatin, 
paclitaxel, and nivolumab.  
 
13.2 
Endpoints 
 
13.2.1 Primary Endpoint  
 Objective: To intensify induction chemotherapy with the addition of an immune 
checkpoint inhibitor aimed at increasing the proportion of patients achieving a 
deep tumor response in order to subsequently allow risk-adapted definitive 
chemoradiotherapy in advanced stage HPV negative head and neck squamous cell 
cancer patients.  
 Definition: Deep Response Rate (DRR) is defined as a 50% or greater response to 
induction therapy based on RECIST v1.1 criteria.  
 Analysis: The proportion of patients who achieve a deep response will be 
calculated along 95% exact confidence intervals for ORR on binomial distribution.  
 Sample Size: The DRR will be compared against a historical control of a 
platinum/taxane induction regimen. The DRR of our historical control is 22%11. 
This trial consisted of HPV positive and negative patients receiving induction 
cisplatin, paclitaxel, everolimus, and cetuximab. As noted in the study, there were 
89 evaluable patients who completed induction therapy. In unpublished data, 32 of 
the 89 patients who completed induction therapy were HPV negative. Seven of 
those 32 patients had a deep response. To further provide evidence of response rate 
to induction therapy, we recently completed a phase I induction therapy trial using 
carboplatin, paclitaxel, and veliparib. Eighteen HPV negative patients were 
enrolled on this portion of the trial. Four of the 18 (22%) had a deep response to 
this regimen. Our hypothesis is that the addition of immunotherapy will increase 
the deep response rate to 40% based on the ~15% response rate seen with 
nivolumab in the metastatic setting. In addition, an increase from 38% to 58% was 
recently reported in a trial evaluating the addition of a PD-1 inhibitor to 
carboplatin and paclitaxel in squamous cell lung cancer.49 Assessment of DRR will 
occur within 1-2 weeks of receiving the final dose of paclitaxel (the final dose of 
induction therapy). We will use a Simon two-stage design to test the null 
hypothesis that P ≤ 0.220 versus the alternative that p ≥ 0.400 has an expected 
sample size of 22.32 and a probability of early termination of 0.687. If the drug is 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
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actually not effective, there is a 0.090 probability of concluding that it is (the target 
for this value was 0.100). If the drug is actually effective, there is a 0.197 
probability of concluding that it is not (the target for this value was 0.200). After 
testing the drug on 17 patients in the first stage, the trial will be terminated if 4 or 
fewer have a deep response. If the trial goes on to the second stage, a total of 34 
patients will be studied. If the total number responding is less than or equal to 10, 
the drug is rejected. Two additional patients will be enrolled to account for drop 
out prior to starting any treatment.  
 
13.2.2 Secondary Endpoints 
 Objective: Assess survival outcomes in all patients receiving induction 
chemoimmunotherapy and compare survival between radiation arms.  
o Endpoint: Progression free survival at 24 months after completing 
chemoradiation.  
 Definition: Progression-free survival will be defined as the time 
from registration to the date of first documented disease 
progression, clinical progression, or death due to any cause, 
whichever occurs first. 
 Analysis: PFS will be estimated by Kaplan-Meier methodology in 
all evaluable patients. PFS will be calculated for the entire cohort 
and for each radiation treatment arm. Comparison between the two 
radiation treatment arms will be made using the log-rank test. 
Patients who died without reported progression will be considered 
to have progressed on the date of their death. Patients who did not 
progress or die will be censored on the date of their last evaluable 
tumor assessment. Patients who started any subsequent anti-cancer 
therapy, including tumor-directed radiotherapy and tumor-directed 
surgery outside of the context of this trial, without a prior reported 
progression will be censored at the last evaluable tumor assessment 
prior to/on initiation of the subsequent anti-cancer therapy. For 
patient who have not progressed or are still alive, the date of 
documented last follow-up will be recorded.  
o Endpoint: Overall survival at 24 months after completing 
chemoradiation.  
 Definition: Overall survival will be defined as the time between the 
date of registration and the date of death.  
 Analysis: OS will be estimated by Kaplan-Meier methodology in all 
evaluable patients. OS will be calculated for the entire cohort and 
for each radiation treatment arm. Comparison between the two 
radiation treatment arms will be made using the log-rank test. For 


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patients without documentation of death, overall survival will be 
censored on the last date the patient was known to be alive. 
 Objective: Assess disease control in all patients receiving induction 
chemoimmunotherapy and compare disease control between radiation arms.  
o Endpoint: Locoregional control at 24 months after completing 
chemoradiation.  
 Definition: Locoregional control will be defined as the time from 
registration to the date of first documented disease progression in 
the head and neck.  
 Analysis: Locoregional control will be estimated by Kaplan-Meier 
methodology in all evaluable patients. Locoregional control will be 
calculated for the entire cohort and for each radiation treatment arm. 
Comparison between the two treatment arms will be made using the 
log-rank test.  
o Endpoint: Distant control at 24 months after completing 
chemoradiation  
 Definition: Distant control will be defined as the time from 
registration to the date of first documented disease progression 
below the clavicles. 
 Analysis: Distant control will be estimated by Kaplan-Meier 
methodology in all evaluable patients. Distant control will be 
calculated for the entire cohort and for each radiation treatment arm. 
Comparison between the two radiation treatment arms will be made 
using the log-rank test.  
 
13.2.3 Exploratory Endpoints  
 Objective: Assess long-term/late toxicities including enteral tube dependence in all 
patients receiving induction chemoimmunotherapy.  
 Objective: Assess acute and long-term toxicity in patients who received risk-
adapted chemoradiotherapy after deep response to induction 
chemoimmunotherapy. 
o Endpoint: Acute and late toxicity during treatment and at 1 month, 3 
months, and 1 year post-chemoradiation  
 Definition: Acute and late toxicities will be defined using the 
National Cancer Institute Common Terminology Criteria for 
Adverse Events (CTCAE) v5.0 
 Analysis: Acute and late toxicity will be assessed in the safety 
population and for each radiation treatment arm. All AEs, drug-
related AEs, SAEs and drug-related SAEs will be tabulated using 
the worst grade by CTCAE v5.0 by system and organ class. 
Comparisons will be made using Fisher’s exact test. 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
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o Endpoint: Enteral tube dependency at 3 months and 1 year 
 Definition: Enteral tube dependency will be defined as continued 
necessity of any nutrition through enteral tube to maintain weight.  
 Analysis: The incidence of enteral tube dependency will be 
described within the safety population and among each radiation 
treatment arm. Comparisons will be made using Fisher’s exact test. 
 Objective: Evaluate quality of life in patients who receive dose-reduced 
chemoradiotherapy after a deep response to induction therapy. 
o Endpoint: Overall and domain subset scores of the PSS-HN and FACT 
H&N quality of life assessments  
 Analysis: Quality of life assessments will be measured in the safety 
population. Results will be tabulated and compared using Fisher’s 
exact test.  
 Objective: Interrogate and understand the immune micro-environment at baseline 
and 2-3 weeks into induction therapy with extensive immunohistological and 
serum biomarkers.  
o Analysis: Potential relationships between biomarker data and efficacy will 
be investigated as part of an exploratory analysis aimed at identifying 
baseline biomarkers that may be used to prospectively identify patients 
likely or not likely to respond to induction carboplatin, paclitaxel, and 
nivolumab. These exploratory predictive biomarker analyses will be 
completed with biomarkers measured in the blood and in tumor samples 
obtained prior to and near completion of induction therapy. The main 
tumor biomarkers measured will be PD-L1, tumor mutation burden, and T-
cell activated gene signatures. Cell free DNA will also be collected via 
peripheral blood. Associations between biomarkers and efficacy measures 
will be analyzed on all evaluable patients with available biomarker data. 
The relationship between binary measures and candidate biomarkers will 
be investigated using logistic regression. Models to predict clinical activity 
based on combinations of biomarkers may also be investigated. Additional 
post hoc statistical analyses not specified in the protocol, such as 
alternative modeling approaches or unmentioned biomarkers may be 
completed.  Details are outlined in section 8.0.  
 
13.3  Accrual Rate and Study Duration 
o We will accrue up to 36 patients to this trial to account for any drop out 
prior to starting therapy. Based on the number of patients seen at our 
institution, we hope to accrue over the course of 1.5-2 years.  
o The study will end 2 years after the final patient has completed 
chemoradiation. 
o Continued follow up will be allowed beyond the end of the trial.  


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
74
 
13.4 
Safety Analysis Plan 
 The safety of adding nivolumab to induction chemotherapy will be assessed by 
evaluation of nivolumab exposure, adverse events, serious adverse events, deaths, 
and changes from baseline in laboratory determinations. Safety analyses will be 
performed for all patients who take at least one dose of study drug. 
 
13.5 
Handling of Missing Data 
 Every attempt will be made to obtain data at the defined time points as described in 
the primary and secondary endpoints. For time points that have no data, we will 
evaluate whether or not the other time points can be used to fulfill the primary and 
secondary data. If the data are not sufficient to analyze specific endpoints, the 
participant’s data may be excluded entirely or partially, depending on the specific 
endpoints in questions and in consultation with the biostatistician. No missing data 
will be imputed. Whenever possible, all available data will be included in the 
analysis. A sample size for each analysis will be clearly stated along with the 
reason for exclusion, if any participant is excluded from the analysis due to 
missing data.  
 
14 
STUDY MANAGEMENT AND REGULATORY AFFAIRS  
  
14.1 
Multicenter Guidelines  
The specific responsibilities of the Principal Investigator and the Coordinating Center are 
presented in section 16.3. Clinical studies coordinated by The University of Chicago must 
be conducted in accordance with the ethical principles that are consistent with Good 
Clinical Practices (GCP) and in compliance with other applicable regulatory requirements 
The Study Lead PI/Coordinating Center is responsible for distributing all official 
protocols, amendments, and IND Action Letters or Safety Reports to all participating 
institutions for submission to their individual IRBs for action as required.   
 
14.2 
Institutional Review Board (IRB) Approval and Consent  
Unless otherwise specified, each participating institution must obtain its own IRB 
approval. It is expected that the IRB will have the proper representation and function in 
accordance with federally mandated regulations. The IRB should approve the consent 
form and protocol. 
 


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In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki. 
 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the patient and the investigator is assured that the patient understands the 
implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing an IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the patient and by the person who conducted the informed 
consent discussion. 
 
14.3  Food and Drug Administration (FDA) Approval  
This study will be conducted under an investigator-held IND held at the University of 
Chicago.  The University of Chicago CCTO will be responsible for facilitating all 
communications with the FDA on behalf of the IND holder.   Participating sites should not 
communicate directly with the FDA.   
 
14.4  Amendments to the Protocol  
All modifications to the protocol, consent form, and/or questionnaires will be submitted 
to the University of Chicago IRB for review and approval. A list of the proposed 
modifications or amendments to the protocol and/or an explanation of the need of these 
modifications will be submitted, along with a revised protocol incorporating the 
modifications. Only the Study Lead PI can authorize any modifications, amendments, or 
termination of the protocol. Once a protocol amendment has been approved by the 
University of Chicago IRB, the Regulatory Manager will send the amended protocol 
and consent form (if applicable) to the affiliate institutions electronically. Upon receipt 
of the packet the affiliate institution is expected to do the following: 
 
 The affiliate must reply to the email from the Regulatory Manager indicating that 
the amendment was received by the institution and that it will be submitted to the 
local IRB.  
 
 The amendment should be submitted to the affiliate institution’s IRB as soon as 
possible after receipt. The amendment must be IRB approved by the institution 
within 3 months from the date that it was received.  
 


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76
 The  University  of  Chicago  version  date  and/or  amendment  number  must  
appear  on  the  affiliate consent form and on the affiliate IRB approval letter.  
The version dates can be found on the footer of every page of the protocol and 
consent form.  The amendment number can be found on the University of Chicago 
IRB amendment approval letter that is sent with the protocol/amendment mailing.  
 
 The IRB approval for the amendment and the amended consent form (if amended 
consent is necessary) for the affiliate institution must be sent to the designated UC 
Regulatory Manager as soon as it is received. 
 
14.5 
Annual IRB Renewals, Continuing Review and Final Reports 
A continuing review of the protocol will be completed by the University of Chicago IRB 
and the participating institutions’ IRBs at least once a year for the duration of the 
study. The annual IRB renewal approvals for participating institutions should be 
forwarded promptly to the Regulatory Manager. If the institution’s IRB requires a new 
version of the consent form with the annual renewal, the consent form should be 
included with the renewal letter. 
  
14.6 
Record Retention 
Study documentation includes all CRFs, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory 
documents (e.g., protocol and amendments, IRB correspondence and approval, signed 
patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. 
 
Government agency regulations and directives require that all study documentation 
pertaining to the conduct of a clinical trial must be retained by the study investigator.  In 
the case of a study with a drug seeking regulatory approval and marketing, these 
documents shall be retained for at least two years after the last approval of marketing 
application in an International Conference on Harmonization (ICH) region.  In all other 
cases, study documents should be kept on file until three years after the completion and 
final study report of this investigational study. 
 
14.7  Obligations of Study Site Investigators 
the site in accordance with Title 21 of the Code of Federal Regulations and/or the 
Declaration of Helsinki.  The Study Site Principal Investigator is responsible for 
personally overseeing the treatment of all study patients.  He/she must assure that all study 
site personnel, including sub-investigators and other study staff members, adhere to the 


Protocol v2.0 07/27/2020 
 
 
 
 
 
 
 
 
 
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study protocol and all FDA/GCP/NCI regulations and guidelines regarding clinical trials 
both during and after study completion. 
 
The Study Site Principal Investigator at each institution or site will be responsible for 
assuring that all the required data will be collected and entered into the CRFs. 
Periodically, monitoring visits or audits will be conducted and he/she must provide access 
to original records to permit verification of proper entry of data.  
15  
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therapy for locoregionally advanced head and neck cancer. J Clin Oncol. 
2000;18(8):1652-1661. 
29. 
Rosen FR, Haraf DJ, Kies MS, et al. Multicenter randomized Phase II study of 
paclitaxel (1-hour infusion), fluorouracil, hydroxyurea, and concomitant twice daily 


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radiation with or without erythropoietin for advanced head and neck cancer. Clin Cancer 
Res. 2003;9(5):1689-1697. 
30. 
Salama JK, Stenson KM, Kistner EO, et al. Induction chemotherapy and 
concurrent chemoradiotherapy for locoregionally advanced head and neck cancer: a multi-
institutional phase II trial investigating three radiotherapy dose levels. Ann Oncol. 
2008;19(10):1787-1794. 
31. 
Haraf DJ, Rosen FR, Stenson K, et al. Induction chemotherapy followed by 
concomitant TFHX chemoradiotherapy with reduced dose radiation in advanced head and 
neck cancer. Clin Cancer Res. 2003;9(16 Pt 1):5936-5943. 
32. 
Vokes EE, Stenson K, Rosen FR, et al. Weekly carboplatin and paclitaxel followed 
by concomitant paclitaxel, fluorouracil, and hydroxyurea chemoradiotherapy: curative and 
organ-preserving therapy for advanced head and neck cancer. J Clin Oncol. 
2003;21(2):320-326. 
33. 
Pointreau Y, Garaud P, Chapet S, et al. Randomized trial of induction 
chemotherapy with cisplatin and 5-fluorouracil with or without docetaxel for larynx 
preservation. J Natl Cancer Inst. 2009;101(7):498-506. 
34. 
Posner MR, Hershock DM, Blajman CR, et al. Cisplatin and fluorouracil alone or 
with docetaxel in head and neck cancer. N Engl J Med. 2007;357(17):1705-1715. 
35. 
Vermorken JB, Remenar E, van Herpen C, et al. Cisplatin, fluorouracil, and 
docetaxel in unresectable head and neck cancer. N Engl J Med. 2007;357(17):1695-1704. 
36. 
Cohen EE, Karrison TG, Kocherginsky M, et al. Phase III randomized trial of 
induction chemotherapy in patients with N2 or N3 locally advanced head and neck cancer. 
J Clin Oncol. 2014;32(25):2735-2743. 
37. 
Haddad R, O'Neill A, Rabinowits G, et al. Induction chemotherapy followed by 
concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent 
chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a 
randomised phase 3 trial. Lancet Oncol. 2013;14(3):257-264. 
38. 
Hitt R, Grau JJ, Lopez-Pousa A, et al. A randomized phase III trial comparing 
induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone 
as treatment of unresectable head and neck cancer. Ann Oncol. 2014;25(1):216-225. 
39. 
Herman LC, Chen L, Garnett A, et al. Comparison of carboplatin-paclitaxel to 
docetaxel-cisplatin-5-flurouracil induction chemotherapy followed by concurrent 
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40. 
Dawson LA, Anzai Y, Marsh L, et al. Patterns of local-regional recurrence 
following parotid-sparing conformal and segmental intensity-modulated radiotherapy for 
head and neck cancer. Int J Radiat Oncol Biol Phys. 2000;46(5):1117-1126. 
41. 
O'Sullivan B, Warde P, Grice B, et al. The benefits and pitfalls of ipsilateral 
radiotherapy in carcinoma of the tonsillar region. Int J Radiat Oncol Biol Phys. 
2001;51(2):332-343. 
42. 
Spencer CR, Gay HA, Haughey BH, et al. Eliminating radiotherapy to the 
contralateral retropharyngeal and high level II lymph nodes in head and neck squamous 
cell carcinoma is safe and improves quality of life. Cancer. 2014;120(24):3994-4002. 
43. 
Villaflor VM, Melotek JM, Karrison TG, et al. Response-adapted volume de-
escalation (RAVD) in locally advanced head and neck cancer. Ann Oncol. 
2016;27(5):908-913. 
44. 
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat 
Rev Cancer. 2012;12(4):252-264. 
45. 
Ferris RL, Blumenschein G, Jr., Fayette J, et al. Nivolumab for Recurrent 
Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med. 2016;375(19):1856-
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46. 
Seiwert TY, Foster CC, Blair EA, et al. OPTIMA: A Phase II Dose and Volume 
De-Escalation Trial for Human Papillomavirus-Positive Oropharyngeal Cancer. Annals of 
Oncology. 2018:mdy522-mdy522. 
47. 
Fu KK, Pajak TF, Trotti A, et al. A Radiation Therapy Oncology Group (RTOG) 
phase III randomized study to compare hyperfractionation and two variants of accelerated 
fractionation to standard fractionation radiotherapy for head and neck squamous cell 
carcinomas: first report of RTOG 9003. Int J Radiat Oncol Biol Phys. 2000;48(1):7-16. 
48. 
Lacas B, Bourhis J, Overgaard J, et al. Role of radiotherapy fractionation in head 
and neck cancers (MARCH): an updated meta-analysis. Lancet Oncol. 2017;18(9):1221-
1237. 
49. 
Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus Chemotherapy for 
Squamous Non-Small-Cell Lung Cancer. N Engl J Med. 2018;379(21):2040-2051. 
 
 
 


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16 
APPENDIX 
 
16.1  PSS-HN 
 
 
 
 
 
 
 
 
 
PERFORMANCE STATUS SCALE FOR HEAD & NECK 
CANCER PATIENTS - PSS-HN 
 
Suggestions for Administration 
 
These performance scales may be rated by health professionals (e.g., physicians, nurses, nutritionists) or 
other personnel (e.g., clerks, data managers). Ratings are determined through use of an unstructured 
interview format. 
 
Normalcy of Diet 
Begin by asking the patient what kinds of foods (s)he has been eating. Ask what foods are difficult to eat. 
Based on the patient's response, choose an item at the low end of the scale. Move up the scale giving 
examples of foods in each category and asking the patient if (s)he is eating those food items. Even if the 
patient says that (s)he eats everything, inquire about specific items beginning with 50, soft chewable foods 
and moving upwards. Stop at the item at, and above which the patient cannot eat. The patient then receives 
the score below that. If the patient indicates that (s)he is eating a full diet, also inquire whether (s)he needs 
to drink more liquids than usual with meals; eating a full diet with intake of extra fluids is scored 90. If the 
patient can take foods orally, but is also using a feeding tube, score based on solid food. 
 
Public Eating 
Score the Public Eating scale by asking the patient where (s)he eats (in a restaurant, at home, at 
friends/relatives' homes, etc.) and with whom (s)he eats (always alone, with family/friends, etc). Ask patient 
if (s)he chooses different foods (softer, less messy, etc.) when eating with others. When was the last time the 
patient ate in a restaurant, cafeteria, MacDonald's, picnic, family reunion? Choose the score beside the 
description that best fits the patient.  A patient on a restricted diet, (e.g., tube feeding, pureed foods) who 
does not eat in public but will join others in a public eating setting should be rated 75. Score 999 for 
inpatients. 
 
Understandability of Speech 
This scale is scored based on the interviewer's ability to understand the patient during conversation (in this 
case, based on conversation about patient's diet and social activities). Choose the score beside the 
description that best fits the patient. See if you can understand the patient if you are looking away while 
(s)he is talking. 
 
Special Considerations for Inpatients: Administration of the PSS-HN varies somewhat for inpatients. Score 
the Normalcy of Diet and Understandability of Speech Scale as indicated. The Eating in Public Scale is not 
applicable as inpatients generally have little opportunity to eat with others or leave their hospital rooms. 
Inpatients receive a score of 999 on the Eating in Public Scale.


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PERFORMANCE STATUS SCALE FOR 
HEAD AND NECK CANCER PATIENTS: PSS-HN 
 
 
 
Patient Name  
 
ID# /    /    / /   /   / /    /    /    / 
Date / / / / / /  / 
 
 
 
 
 
NORMALCY OF DIET /    /   /   / 
PUBLIC EATING / / / / 
 
100
90 
Full diet (no restrictions)
Full diet (liquid assist) 
100
No restriction of place, food or
companion (eats out at any 
opportunity) 
80 
70 
All meat 
Raw carrots, celery 
75 
No restriction of place, but restricts 
diet when in public (eats anywhere, 
but may limit intake to less "messy" 
60 
Dry bread and crackers 
foods (e.g., liquids)
50 
Soft chewable foods (e.g., macaroni, 
50
Eats only in presence of selected
persons in selected places 
canned/soft fruits, cooked vegetables,
fish, hamburger, small pieces of meat) 
25 
Eats only at home in presence of 
40 
Soft foods requiring no chewing 
selected persons
(e.g., mashed potatoes, apple
sauce, pudding) 
0
999 
Always eats alone
Inpatient 
30
Pureed foods (in blender)
20 
Warm liquids 
UNDERSTANDABILITY OF SPEECH / / / / 
 
10 
Cold liquids 
 
0 
Non-oral feeding (tube fed) 
 
100 
Always understandable 
 
75 
Understandable most of the time; 
occasional repetition necessary 
 
50 
Usually understandable; face-to-face 
contact necessary 
 
25 
Difficult to understand 
 
0 
Never understandable; may use written 
communication 
 
 
List MA, Ritter-Sterr C, Lansky SB. A Performance Status Scale for Head and Neck Cancer Patients. 
Cancer. 66:564-569, 1990 


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16.2 
FACT H&N
 
FACT-H&N (Version 4)
English (Universal) 
Copyright 1987, 1997 
16 November 2007 
Page 1 of 3 
 
Below is a list of statements that other people with your illness have said are important. Please circle 
or mark one number per line to indicate your response as it applies to the past 7 days. 
 
 
PHYSICAL WELL-BEING
Not
at all 
A little
bit 
Some-
what 
Quite a
bit 
Very
much 
GP1 
I have a lack of energy ....................................................... 
0 
1 
2 
3 
4 
GP2 
I have nausea ...................................................................... 
0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I have trouble 
meeting the needs of my family ......................................... 
0 
1 
2 
3 
4 
GP4 
I have pain .......................................................................... 
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of treatment ......................... 
0 
1 
2 
3 
4 
GP6 
I feel ill ............................................................................... 
0 
1 
2 
3 
4 
GP7 
I am forced to spend time in bed ........................................ 
0 
1 
2 
3 
4 
SOCIAL/FAMILY WELL-BEING 
Not 
at all 
A little 
bit 
Some-
what 
Quite a
bit 
Very 
much 
GS1 
I feel close to my friends .................................................... 
0 
1 
2 
3 
4 
GS2 
I get emotional support from my family ............................ 
0 
1 
2 
3 
4 
GS3 
I get support from my friends............................................. 
0 
1 
2 
3 
4 
GS4 
My family has accepted my illness .................................... 
0 
1 
2 
3 
4 
GS5 
I am satisfied with family communication about my 
illness.................................................................................. 
0 
1 
2 
3 
4 
GS6 
I feel close to my partner (or the person who is my main 
support) .............................................................................. 
0 
1 
2 
3 
4 
Q1 
Regardless of your current level of sexual activity, please 
answer the following question. If you prefer not to answer it, 
please mark this box 
and go to the next section. 
GS7 
I am satisfied with my sex life ............................................ 
0 
1 
2 
3 
4 
 


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FACT-H&N (Version 4)
English (Universal) 
Copyright 1987, 1997 
16 November 2007 
Page 1 of 3 
 
Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
 
 
EMOTIONAL WELL-BEING 
Not at
all 
A little 
bit 
Some-
what 
Quite a
bit 
Very 
much 
GE1 
I feel sad ............................................................................. 
0 
1 
2 
3 
4 
GE2 
I am satisfied with how I am coping with my illness......... 
0 
1 
2 
3 
4 
GE3 
I am losing hope in the fight against my illness................. 
0 
1 
2 
3 
4 
GE4 
I feel nervous ...................................................................... 
0 
1 
2 
3 
4 
GE5 
I worry about dying ............................................................ 
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get worse ........................... 
0 
1 
2 
3 
4 
FUNCTIONAL WELL-BEING 
 
Not at
all 
A little 
bit 
Some-
what 
Quite a
bit 
Very 
much 
GF1 
I am able to work (include work at home) ......................... 
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is fulfilling.................... 
0 
1 
2 
3 
4 
GF3 
I am able to enjoy life......................................................... 
0 
1 
2 
3 
4 
GF4 
I have accepted my illness.................................................. 
0 
1 
2 
3 
4 
GF5 
I am sleeping well .............................................................. 
0 
1 
2 
3 
4 
GF6 
I am enjoying the things I usually do for fun ..................... 
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right now............. 
0 
1 
2 
3 
4 


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FACT-H&N (Version 4)
English (Universal) 
Copyright 1987, 1997 
16 November 2007 
Page 1 of 3 
 
Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
 
 
ADDITIONAL CONCERNS 
Not at 
all 
A little 
bit 
Some-
what 
Quite a
bit 
Very 
much 
H&N1 
I am able to eat the foods that I like ...................................
0 
1 
2 
3 
4 
H&N2 
My mouth is dry .................................................................
0 
1 
2 
3 
4 
H&N3 
I have trouble breathing .....................................................
0 
1 
2 
3 
4 
H&N4 
My voice has its usual quality and strength .......................
0 
1 
2 
3 
4 
H&N5 
I am able to eat as much food as I want .............................
0 
1 
2 
3 
4 
H&N6 
I am unhappy with how my face and neck look.................
0 
1 
2 
3 
4 
H&N7 
I can swallow naturally and easily .....................................
0 
1 
2 
3 
4 
H&N8 
I smoke cigarettes or other tobacco products .....................
0 
1 
2 
3 
4 
H&N9 
I drink alcohol (e.g. beer, wine, etc.)..................................
0 
1 
2 
3 
4 
H&N 
10 
I am able to communicate with others ...............................
0 
1 
2 
3 
4 
H&N 
11 
I can eat solid foods............................................................
0 
1 
2 
3 
4 
H&N 
12 
I have pain in my mouth, throat or neck ............................
0 
1 
2 
3 
4 
 
 


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16.3  Multicenter Guidelines 
Responsibility of the Study Lead PI  
 The Study Lead PI will be the single liaison with regulatory and data management 
staff, outside sponsor/s, FDA, and funding agencies  The Study Lead PI is 
responsible for the coordination, development, submission, and approval of the 
protocol as well as its subsequent amendments.  The protocol must not be rewritten 
or modified by anyone other than the Study Lead PI.  There will be only one 
version of the protocol, and each participating institution will use that document.  
The Study Lead PI is responsible for assuring that all participating institutions are 
using the correct version of the protocol. 
 The Study Lead PI is responsible for the overall conduct of the study at all 
participating institutions and for monitoring its progress.  All reporting 
requirements are the responsibility of the Study Lead PI.  
 The Study Lead PI is responsible for the timely review of Adverse Events (AE) to 
assure safety of the patients. 
 The Study Lead PI will be responsible for the review of and timely submission of 
data for study analysis. 
 
Responsibilities of the Coordinating Center 
 The Coordinating Center is responsible for maintaining copies of IRB approvals 
from each participating site.  
 The Coordinating Center is responsible for central patient registration.  The 
Coordinating Center is responsible for assuring that IRB approval has been 
obtained at each participating site prior to the first patient registration from that 
site. 
 The Coordinating Center is responsible for the preparation of all submitted data for 
review by the Study Lead PI. 
 The Coordinating Center will maintain documentation of AE reports.  The 
Coordinating Center will submit AE reports to the Study Lead PI for timely 
review.