Conditions: Head and Neck Cancer
Keywords: Head and Neck Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 6
Healthy volunteers: no

Brief summary:
This research is being performed to treat patient for head and neck cancer patients who have not received prior chemotherapy.

Detailed description:
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific disease. "Investigational" means that the drug or combination of interventions is being studied.

Nivolumab is approved by the U.S. Food and Drug Administration (FDA) for the treatment of recurrent or advanced head and neck cancer (head and neck cancer that has come back or is incurable) but is considered investigational for head and neck cancer patients who have not received prior chemotherapy.

Arms:
arm 1: Participants received 3 cycles of induction with docetaxel, cisplatin and nivolumab (TPN) every 3 weeks (or 21 days): docetaxel 75 mg/m2 IV day 1, cisplatin 100 mg/m2 IV day 1, and nivolumab 240 mg IV flat dose day 1.

Induction was followed by clinical and radiologic assessment of response. Participants without partial response or better based on RECIST 1.1 were offered salvage laryngectomy and/or pharyngectomy. Participants with partial or complete response per RECIST 1.1 proceeded with immunoradiotherapy concurrently with nivolumab. Intensity-modulated radiotherapy (IMRT) was preferred and proton beam radiotherapy not permitted. Nivolumab 240 mg IV flat dose day 1 was repeated every 2 weeks concurrently with IMRT (for a total of 3-4 doses).

Participants then received adjuvant nivolumab (480 mg IV flat dose day 1) every 4 weeks within 3-8 weeks from the last day of IMRT for up to 6 cycles or until disease progression or recurrence.

Interventions: intervention 1: Nivolumab intervention 2: Cisplatin intervention 3: Docetaxel intervention 4: Intensity-modulated radiotherapy
Intervention descriptions: intervention 1: Nivolumab is a type of immunotherapy. intervention 2: Cisplatin is a chemotherapy drug. intervention 3: Docetaxel is a chemotherapy drug. intervention 4: IMRT is definitive treatment for head and neck cancer.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
Title: Induction TPN Followed by Nivolumab With Radiation in Locoregionally 
Advanced Laryngeal and Hypopharyngeal Cancer 
NCT Number: NCT03894891 
IRB Approval Date: 4/28/2020 


 
 
 
 
 
NCI Protocol #: N/A 
 
DF/HCC Protocol #: 18-652 
 
 
TITLE: Sequential therapy with induction TPN followed by nivolumab with radiation in 
locoregionally advanced laryngeal and hypopharyngeal cancer 
 
Coordinating Center: 
Dana-Farber Cancer Institute 
450 Brookline Avenue 
Boston, MA02215 
 
Principal Investigator (PI): 
Robert Haddad, MD 
Dana-Farber Cancer Institute 
robert_haddad@dfci.harvard.edu 
 
 
 
 
Agent(s): Nivolumab; supplied by Bristol-Myers Squibb 
 
IND #: 140607 
 
IND Sponsor: Robert Haddad, MD 
 
Protocol Version # / Version Date: Amendment 2/January 28, 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
i 


* Tumor tissue and blood will be collected at the time of biopsy for correlative studies 
** Imaging is required prior to definitive immunoradiotherapy or salvage surgery 
 
 
 
 
 
SCHEMA 
 
 
 
 
 
 
Archival 
permitted 
≥ PR 
 
 
< PR 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 
Salvage 
surgery 
Docetaxel 
+ Cisplatin + 
Nivolumab 
(3 cycles every 
21 days)** 
B 
I 
O 
P 
S 
Y 
* 
IMRT (to 
69.96-70 
Gy) 
+ 
concurrent 
Nivolumab 
Patients with locoregionally 
advanced (stage III, IV) 
squamous cell carcinoma of 
the larynx or hypopharynx 
Key Eligibility: 
• 
no evidence of distant 
disease 
• 
regardless of smoking 
status 
• 
no prior immunotherapy 
• 
ECOG PS ≤ 1 
Adjuvant 
Nivolumab 
3-8 weeks from the 
completion of IMRT 
(every 28 days, for a 
maximum of 6 cycles or 
until disease progression 
or recurrence) 
Follow for best overall 
response until first 
local or locoregional 
progression and/or 
larynx or hypopharynx 
removal, for 
development of first 
distant recurrence and 
for survival for 4 years 
from the time of study 
registration 


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TABLE OF CONTENTS 
1. 
OBJECTIVES .............................................................................................. 4 
1.1 
Study Design ............................................................................................................ 4 
1.2 
Primary Objectives. .................................................................................................. 4 
1.3 
Secondary Objectives. .............................................................................................. 4 
2. 
BACKGROUND .......................................................................................... 4 
2.1 
Study Disease ........................................................................................................... 4 
2.2 
IND Agent ................................................................................................................ 5 
2.3 
Other Agents ............................................................................................................ 8 
2.4 
Radiation Therapy .................................................................................................... 9 
2.5 
Rationale ................................................................................................................... 9 
2.6 
Correlative Studies Background ............................................................................. 11 
3. 
PARTICIPANT SELECTION ................................................................... 12 
3.1 
Eligibility Criteria .................................................................................................. 12 
3.2 
Exclusion Criteria ................................................................................................... 13 
3.3 
Inclusion of Women and Minorities ....................................................................... 14 
4. 
REGISTRATION And Randomization PROCEDURES ........................... 14 
4.1 
General Guidelines for DF/HCC Institutions ......................................................... 14 
4.1 
Registration Process for DF/HCC Institutions ....................................................... 14 
4.2 
General Guidelines for Other Investigative Sites ................................................... 14 
4.3 
Registration Process for Other Investigative Sites. ................................................ 15 
5. 
TREATMENT PLAN ................................................................................ 15 
5.1 
Treatment Regimen ................................................................................................ 15 
5.2 
Pre-Treatment Criteria ............................................................................................ 20 
5.3 
Chemotherapy Administration ............................................................................... 20 
5.4 
Nivolumab Administration ..................................................................................... 20 
5.5 
General Concomitant Medication and Supportive Care Guidelines ....................... 21 
5.6 
Criteria for Taking a Participant Off Protocol Therapy .......................................... 22 
5.7 
Duration of Follow Up ........................................................................................... 23 
5.8 
Criteria for Taking a Participant Off Study ............................................................ 23 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ........................................ 23 
6.1 
Dose Delays or Modifications for TPN .................................................................. 23 
6.2 
Dose Delays for Nivolumab. .................................................................................. 25 
7. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS ..... 26 
7.1 
Adverse Event Characteristics: ............................................................................... 26 
7.2 
Adverse Event Reporting ....................................................................................... 26 
7.3 
Serious Adverse Events .......................................................................................... 27 
7.4 
Expected Toxicities ................................................................................................ 28 
7.5 
Adverse Events List ................................................................................................ 28 


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7.6 
Routine Adverse Event Reporting .......................................................................... 29 
7.7 
Routine Adverse Event Reporting to BMS ............................................................ 29 
7.8 
Serious Adverse Event Collection and Reporting .................................................. 29 
7.9 
Expedited Adverse Event Reporting to Overall PI ................................................. 30 
7.10 
DF/HCC Expedited Reporting Guidelines ............................................................. 30 
7.11 
Expedited Adverse Event Reporting to the Food and Drug Administration (FDA)31 
7.12 
Expedited Adverse Event Reporting to Hospital Risk Management ...................... 31 
7.13 
Expedited Adverse Event Reporting to BMS ......................................................... 31 
8. 
PHARMACEUTICAL INFORMATION ................................................. 32 
8.1 
IND Agent Nivolumab .......................................................................................... 32 
8.2 
Other Agents .......................................................................................................... 33 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ................. 33 
9.1 
Biomarker Studies .................................................................................................. 34 
10. 
STUDY CALENDAR ................................................................................ 36 
11. 
MEASUREMENT OF EFFECT ................................................................ 38 
11.1 
Antitumor Effect – Solid Tumors ........................................................................... 38 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS .................... 45 
12.1 
Data Reporting ....................................................................................................... 45 
12.2 
Data Safety Monitoring .......................................................................................... 45 
12.3 
Multi-Center Guidelines ......................................................................................... 46 
13. 
STATISTICAL CONSIDERATIONS ....................................................... 46 
14. 
PUBLICATION PLAN .............................................................................. 48 
15. 
REFERENCES ........................................................................................... 49 


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1. OBJECTIVES 
 
1.1 
Study Design 
 
This is a phase II, open label, non-randomized, multi-institutional study of nivolumab (anti-PD-1) 
incorporated into a definitive immunoradiotherapy program following modified induction chemotherapy 
using nivolumab for locoregionally advanced larynx and hypopharynx squamous cell carcinoma of the 
head and neck (SCCHN). Patients with confirmed locoregionally advanced SCCHN arising in the larynx 
or hypopharynx will receive 2-3 cycles of induction docetaxel (T), cisplatin (P) and nivolumab (N) every 
3 weeks followed by clinical and radiologic assessment of response. Patients with at least a partial 
response (PR) defined by RECIST 1.1 will proceed with immunoradiotherapy concurrently with 
nivolumab. This will then be followed by an adjuvant phase of nivolumab dosed every 28 days for up to 
6-cycles or until disease progression or recurrence. Those patients with less than a PR to induction TPN 
will be offered salvage laryngectomy and/or pharyngectomy. The primary objective of this study is to 
improve efficacy with respect to the endpoint of laryngectomy-free survival (LFS) in this population. The 
primary endpoint is to evaluate LFS at 2-years from study registration. Secondary endpoints will include 
overall survival (OS), locoregional control rate (LRC), and laryngo-esophageal dysfunction-free survival 
(LEDFS). 
 
We hypothesize that the combination of nivolumab and radiotherapy used as definitive treatment 
following induction TPN in patients with locoregionally SCCHN arising in the larynx or hypopharynx 
will improve 2-year LFS relative to sequential induction TP + 5-fluorouracil (F) followed by platinum- 
based chemoradiotherapy. 
 
1.2 
Primary Objectives 
 
• To improve efficacy with respect to laryngectomy-free survival (LFS) at 2-years from time of 
study registration as the primary endpoint. 
 
1.3 
Secondary Objectives 
 
• To evaluate clinicopathologic and radiologic response 
• To estimate OS 
• To estimate LEDFS 
• To evaluate safety and toxicity, and quality of life scores 
• To characterize distinct tumor immunophentoypes and correlate these findings with outcomes 
 
2. BACKGROUND 
 
2.1 
Study Disease 
 
There are roughly 13,000 cases of laryngeal cancer each year in the United States, the majority of which 
arise in the supraglottic or glottic region [1]. Hypopharyngeal cancers arise in the pharyngeal wall, 
piriform sinuses, and post-cricoid region which encompasses the lateral, inferior, and posterior borders of 


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the larynx, respectively – but overall are less common. While cancers arising along the vocal cords or 
glottic region can present with early-stage disease due to the recognition of dysphonia or voice hoarseness, 
supraglottic and hypopharyngeal cancers are often detected in the locoregionally advanced stages given 
the delay in symptom development and the rich lymphatic drainage of this anatomic region. 
 
The treatment approach to locoregionally advanced laryngeal and hypopharyngeal cancers is complex: 
with treatment guided by the anatomic location and extent of the tumor, along with patient-specific 
circumstances (such as age, functional status, psychosocial elements, and comorbid medical conditions). 
Input from a multidisciplinary team that includes a medical oncologist, radiation oncologist, and head & 
neck surgeon is crucial to individualizing the treatment strategy [2]. Functional organ preservation has 
been favored in recent years, owing to several landmark studies demonstrating that larynx preservation 
rates (LPR) are favorable with a non-surgical treatment approach without jeopardizing survival outcomes 
[3-4]. A series of trials have clarified that definitive concurrent platinum-based chemoradiotherapy (CRT) 
or a sequential treatment approach using induction chemotherapy followed by definitive CRT offers 
similar outcomes in locoregionally advanced laryngeal and hypopharyngeal cancers [5]. The favored 
regimen for induction chemotherapy has been established: a combination of a taxane added to a platinum- 
fluoropyrimidine backbone [6-9]. While neither definitive CRT nor sequential therapy are superior, 
induction chemotherapy might be favored in those with bulky primary tumors or in those with low cervical 
neck adenopathy owing to the risk of distant metastatic spread [10]. Despite the treatment options 
summarized above, 5- and 10-year overall survival (OS) rates for locoregionally advanced laryngeal and 
hypopharyngeal cancer patients are guarded (5-year OS: 54-58%, 10-year OS: 28-39%). These outcomes 
speak to the significant rate of locoregional failure in this population, with surgery offered as a salvage 
strategy in appropriate patients [11]. 
 
2.2 
IND Agent 
 
2.2.1 Nivolumab 
 
2.2.1.1 Mechanism of action and pharmacology 
 
It has become evident that tumor progression is promoted by immune evasion and abrogation of an 
effective immune response against cancer cells [6]. Mechanisms of tumor evasion include the 
development of T cell tolerance, modulation of inflammatory and angiogenic cytokines, downregulation 
of antigen-processing machinery, and changes in immune checkpoint receptor ligands or receptors that 
can all facilitate tumor immune evasion [7-9]. These mechanisms serve to define immunotherapy targets 
for clinical development. Immune checkpoint receptors block normal T cell activation and costimulation 
to maintain a homeostatic immune response [10]. Programmed cell death protein-1 (PD-1, CD279), one 
such receptor, is expressed on the surface of immune cells and interact with its cognate ligands on antigen- 
presenting or tumor cells. High tumor expression of the ligands of PD-1 (PD-L1 or B7-H1/CD274 and 
PD-L2 or B7-DC/CD273) and/or PD-1 expression by T lymphocytes can attenuate T cell activation and 
drive T cell exhaustion to favor tumor immune evasion [11]. By modulating these inhibitory immune 
receptor-ligand interactions, the goal is to overcome tumor mediated immunosuppression and facilitate an 
anti-tumor response. Preclinical evidence to support the negative regulatory effects of PD-1 comes from 
murine models. PD-1 knockout mice develop organ-specific autoimmunity which can mimic known 
autoimmune disease, such as systemic lupus erythematosus and acute graft versus host disease (GVHD) 
– but this can present at various time points and relies on host genetic factors [12]. Beyond PD-1 deficient 


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models, antibody blockade in several mouse models have demonstrated the emergence of similar 
autoimmune phenomena [13]. These findings strengthen the argument that PD-1 inhibition permits 
enhancement of antigen-specific T cell response, but also indicate that responses can be variable and 
depend largely on underlying host biology. 
 
Efforts have focused on understanding PD-1/L1 expression patterns among various tumor types, in order 
to predict benefit from PD-1 blocking mechanisms. While estimates of tumor cell PD-L1 expression vary 
considerably based on tumor type [14, 15], studies have estimated PD-L1 expression in SCCHN at 30– 
70% with human papillomavirus (HPV) positive tumors more frequently harboring infiltrating immune 
cells that express PD-1 [16, 17]. Upregulation of PD-L1 expression by tumor cells may offer a strategy 
for evasion and protect the cell from apoptotic demise mediated by T cells, and itself may facilitate T cell 
apoptosis [18]. Additionally, elevated PD-L1 expression levels correlate with a poor prognosis in some 
solid tumor malignancies [19]. However, several studies have demonstrated that even tumors with 
minimal PD-L1 expression may respond to PD-1 focused inhibitory mechanisms, and thus PD-1:L1 
interactions are only one component that dictate response to these inhibitory immune signals in a complex 
tumor immune microenvironment [20, 21]. 
 
Nivolumab (BMS-936558, MDX-1106) is a fully human monoclonal antibody targeting the PD-1 or 
CD279 cell surface receptor that binds to PD-1 with nanomolar affinity and a high degree of specificity. 
This therefore precludes binding to cognate ligands, PD-L1 or PD-L2 [22]. In chronic simian 
immunodeficiency virus (SIV) infection in macaques, studies have shown that PD-1 blockade using an 
antibody to PD-1 was well tolerated and resulted in rapid expansion of virus-specific CD8 T cells [23]. 
PD-1 blockade also resulted in proliferation of memory B cells and increases in SIV envelope-specific 
antibody. These improved immune responses were associated with significant reductions in plasma viral 
load and also prolonged the survival of SIV-infected macaques. In vitro assays have demonstrated the 
ability of nivolumab to potently enhance T-cell response and cytokine production (such as interferon alpha 
release); when later given to cynomolgus macaques at high concentrations, there were no adverse immune- 
related events, independent of circulating levels of anti-nivolumab antibodies [24]. In intravenous (IV) 
repeat-dose toxicology studies in cynomolgus macaques, nivolumab was well tolerated at doses up to 50 
mg/kg, administered weekly for 5 weeks, and at doses up to 50 mg/kg, administered twice weekly for 27 
doses. 
 
The pharmacokinetics of nivolumab have been reported in human subjects over a dose range of 0.1 to 10 
mg/kg administered as a single dose or as subsequent doses at 2 or 3 week intervals. The geometric mean 
(% CV%) clearance (CL) was 9.5 mL/h (49.7%), geometric mean volume of distribution at steady state 
(Vss) was 8.0 L (30.4%), and geometric mean elimination half-life (t1/2) was 26.7 days (101%). Steady- 
state concentrations of nivolumab were reached by 12 weeks when administered at 3 mg/kg every 2 weeks 
and systemic accumulation was approximately 3-fold. The exposure to nivolumab increased dose 
proportionally over the dose range of 0.1 to 10 mg/kg administered every 2 weeks. The clearance of 
nivolumab increased with increasing body weight. The population pharmacokinetic (PPK) analysis 
suggested that the following factors had no clinically meaningful effect on the clearance of nivolumab: 
age (29 to 87 years), gender, race, baseline LDH, and PD-L1 expression. Although patient performance 
status, baseline glomerular filtration rate (GFR), albumin, body weight, and mild hepatic impairment did 
have a mild effect on nivolumab clearance, the effect was not clinically meaningful [22]. Additionally, 
PPK and exposure response analyses have been performed to support the use of 240 mg IV flat dosing 
every 2 weeks in addition to the 3 mg/kg every 2 week regimen. Using the PPK model, exposure to 


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nivolumab at 240 mg IV flat dose was identical to a dose of 3 mg/kg for subjects weighing 80 kg. 
 
2.2.1.2 Clinical safety 
 
In an early phase I study investigating a single IV infusion of anti-PD-1 (MDX-1106) in dose-escalating 
six-patient cohorts at 0.3, 1, 3, or 10 mg/kg, followed by a 15-patient expansion cohort at 10 mg/kg (for a 
total of 39 patients), treatment was well tolerated. There was one serious adverse event, inflammatory 
colitis, observed in a patient with melanoma who received five doses at 1 mg/kg [25]. 
 
In a large registration trial which randomized advanced, platinum-refractory SCCHN patients to either 
nivolumab or single-agent standard chemotherapy, treatment-related grade 3 or 4 adverse events occurred 
in 13.1% of the patients in the nivolumab group versus 35.1% of those in the standard arm [26]. In the 
nivolumab treated group, the most common adverse events were fatigue, nausea, rash, decreased appetite, 
and pruritis. Gastrointestinal events were less common than with standard chemotherapy. Pneumonitis 
was observed in 2.1% of nivolumab-treated patients and two treatment-related deaths occurred (one from 
hypercalcemia and one from pneumonitis). 
 
The overall safety experience with nivolumab as monotherapy is based on experience from more than 
8,000 subjects treated to-date in patients with varied cancer types. The safety profile appears similar across 
cancer types [27, 28]. Treatment-related adverse events of grade 3 or 4 were reported in 7% of patients 
treated with nivolumab in advanced non-small cell lung cancer (NSCLC) of squamous histology and in 
16.3% of unresectable, advanced stage melanoma patients. 
 
The safety of combining PD-1 inhibition with radiation therapy (RT) has been demonstrated in several 
reports and is being investigated in several ongoing clinical trials. Fiorica and colleagues showed the 
safety of nivolumab with definitive RT retrospectively in 35 patients treated with anti-PD-1 therapy after 
hypofractionated RT at an interval of at least 1 week from the end of RT [34]. Toxicity rates between 
patients receiving RT alone and the combination of nivolumab-RT were similar. 
 
2.2.1.3 Clinical efficacy 
 
Results from an early phase I trial demonstrated a wide range of clinical activity, including complete, 
partial and mixed response rates in advanced solid tumor patients; including individuals with colorectal 
cancer, NSCLC, melanoma, and renal cell carcinoma (RCC) [25]. Thirty-nine patients received a single 
IV infusion of anti-PD-1 (MDX-1106) in dose-escalating six-patient cohorts at 0.3, 1, 3, or 10 mg/kg, 
followed by a 15-patient expansion cohort at 10 mg/kg. Patients with evidence of clinical benefit at 3 
months were eligible for repeated therapy. One durable complete response (CR) and two partial responses 
(PRs; melanoma, RCC) were observed. Two additional patients (melanoma, NSCLC) had significant 
tumor regression not meeting defined PR criteria. Following this early signal, numerous clinical trials 
emerged to investigate the clinical efficacy of nivolumab in advanced solid tumor and hematologic 
malignancies – with nivolumab (Opdivo™) now approved in multiple cancer types owing to its 
demonstrated clinical efficacy. 
 
In a randomized phase III study (Checkmate-141) of patients with recurrent or metastatic, platinum- 
refractory SCCHN, 361 patients were assigned to nivolumab or standard chemotherapy in a 2:1 ratio with 
a primary endpoint of overall survival (OS) [26]. Nivolumab (at a dose of 3 mg/kg body weight IV) every 


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2 weeks or standard, single-agent systemic therapy (methotrexate, docetaxel, or cetuximab) was 
administered. Additional end points included progression-free survival (PFS), objective response rate 
(ORR), safety, and patient-reported quality of life (QOL). The median OS was 7.5 months (95% 
confidence interval [CI], 5.5 to 9.1) in the nivolumab group versus 5.1 months (95% CI, 4.0 to 6.0) in the 
group that received standard therapy. OS was significantly longer with nivolumab than with standard 
therapy (hazard ratio [HR] for death, 0.70; 97.73% CI, 0.51 to 0.96; p = 0.01), and the estimates of the 1- 
year survival rate were approximately 19 percentage points higher with nivolumab than with standard 
therapy (36.0% vs. 16.6%). Median PFS was 2.0 months (95% CI, 1.9 to 2.1) with nivolumab versus 2.3 
months (95% CI, 1.9 to 3.1) with standard therapy (HR for disease progression or death, 0.89; 95% CI, 
0.70 to 1.13; p = 0.32). The rate of PFS at 6 months was 19.7% with nivolumab versus 9.9% with standard 
therapy. The response rate was 13.3% in the nivolumab group versus 5.8% in the standard-therapy group. 
Additionally, individuals in the study who were PD-L1 (≥ 1% of tumor or immune cells by 
immunohistochemistry [IHC]) or HPV positive appeared to have improved outcomes. That said, 
regardless of PD-L1 expression or HPV status, patients treated with nivolumab experienced a reduction 
in the risk of death compared with standard chemotherapies. This study led to the approval of nivolumab 
in this setting in November of 2016. 
 
2.3 
Other Agents 
 
Multiple trials have clarified the three-drug combination of cisplatin, fluorouracil, plus a taxane as the 
preferred approach when using induction chemotherapy in SCCHN. Early clinical trials found that 
cisplatin (100 mg/m2 IV) and 5-fluorouracil (1000 mg/m2/day IV continuous over a 24-hour infusion for 
five days) given for three cycles as induction achieved higher overall response rates and improved 
outcomes compared with other two-drug platinum based regimens [28]. Later trials found that the addition 
of a taxane (docetaxel or paclitaxel) to the platinum-doublet backbone with 5-fluorouracil enhanced 
efficacy. The most extensive data was from the TAX-324 trial where TPF (docetaxel 75 mg/m2 IV day 1, 
cisplatin 100 mg/m2 IV day 1, and continuous infusion 5-fluorouracil 1000 mg/m2/day for days 1-4) was 
the studied regimen, which showed improved survival compared with a doublet platinum-based regimen 
[6,7]. Additionally, a combined meta-analysis incorporating data from 1,772 patients in 5 trials confirmed 
that adding a taxane to the induction regimen improved survival and decreased rates of locoregional failure 
[29]. 
 
Data from the locoregionally advanced, recurrent or metastatic setting supports the combination of 
cisplatin with docetaxel (or taxanes) without infusional 5-fluorouracil (5-FU). The EORTC performed a 
multicenter phase II study using cisplatin (75 mg/m2 IV day 1) and docetaxel (100 mg/m2 IV day 1) every 
21 days and noted objective response rates of 54%, with 5 complete responses and 14 partial responses 
(overall response rate of 86%) among the untreated locoregionally advanced or metastatic subgroup (n = 
22) [36]. Glisson and colleagues similarly demonstrated that the TP (docetaxel, cisplatin) combination 
yielded a 40% response rate among advanced, incurable SCCHN patients [37]. The combination of 
cisplatin-docetaxel has been prospectively studied as induction and has demonstrated a 70% response rate 
(26% CRs, 44% PRs) but with 34% of patients experiencing grade 3+ neutropenia [38]. Even in an elderly 
population, response rates of up to 88% have been described with the TP induction backbone, without 5- 
FU (F) [39]. These data support the choice of drugs and schedule of administration for TP in the current 
study, combined with nivolumab (N) at standard dosing to replace the 5-fluorouracil infusion which 
requires port-a-cath placement or inpatient admission with added toxicity concerns. 


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2.4 
Radiation Therapy 
 
A combined multimodality approach that incorporates both chemotherapy and radiation therapy (RT) has 
long been established as the backbone of definitive treatment based on the results of multiple clinical trials 
in SCCHN and specifically in larynx and hypopharynx cancer [3, 27]. RTOG 0129 clarified that an altered 
RT fractionation schedule when combined with chemotherapy did not improve outcomes. In fact, standard 
RT fractionation as part of a concurrent chemoradiation program appears superior [30,31]. RTOG 0129 
outlined a total dose of 70 Gray (Gy) in 35 fractions over seven weeks, which is the schedule of radiation 
proposed in the current study – which will be concurrently administered with nivolumab as part of 
definitive immunoradiotherapy. 
 
Preclinical data, particularly in melanoma, have highlighted the potential synergism when utilizing 
immune checkpoint blockade with RT. In fact, cases of immunotherapy exposure followed by targeted 
RT has shown reductions in distant tumor sites, the abscopal effect [32]. Studies have shown that tumor 
PD-L1 expression can increase following RT exposure and that the combination enhances anti-tumor 
immunity [33]. 
 
2.5 
Rationale 
 
The primary rationale for the use of induction chemotherapy (IC) in locoregionally advanced larynx and 
hypopharynx cancers is to avoid radical surgery. With a goal of organ preservation, two initial landmark 
trials published in the 1990s investigated the role of IC followed by radiation [3-4]. In both studies, 
patients were randomized to a platinum-5-fluorouracil (PF) IC regimen followed by radiation (permitting 
salvage surgery) vs. conventional laryngectomy and radiation alone. These studies demonstrated that 
larynx preservation was feasible (larynx preservation rate [LPR] between 40-60%) without jeopardizing 
long-term survival [5]. This was followed by the RTOG 91-11 study comparing a PF IC regimen followed 
by radiation, concurrent chemoradiation (CRT), and radiation alone which showed comparable long-term 
survival among all three treatment arms [11-12]. Of note, 
the composite endpoint of laryngectomy-free survival 
(LFS) was similar in both chemotherapy-containing arms 
(5-year LFS, IC: 44.1% vs. CRT: 47%, p = 0.68);10-year 
LFS, IC: 28.9% vs. CRT: 23.5%, p = 0.68) [Figure right]. 
It should be noted that the RTOG 91-11 study utilized PF 
(cisplatin, 5-FU) and not TPF for induction therapy. A 
similar study compared PF IC followed by radiation to an 
alternating 
platinum-based 
CRT 
schedule 
and 
demonstrated similar 3-year LFS rates [13]. Larynx 
preservation was an important milestone achieved with the 
use of IC, and these early trials led to updated national 
guidelines supporting the role of IC as an initial approach in these patients. 
 
Early observations with taxanes in head and neck cancer then led to trials combining these agents with a 
PF backbone as IC. In addition, there was significant interest in using IC followed by concurrent CRT 
given the increase in locoregional control offered by a concomitant treatment program [12]. The TAX- 
324 study randomized patients with locoregionally advanced head and neck cancer, including larynx and 
hypopharynx tumors, to receive docetaxel plus PF (TPF) followed by concurrent CRT vs. PF followed by 


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the same concurrent regimen. Results showed improved 
overall survival in favor of the TPF arm (5-year OS, TPF: 
52% vs. PF: 42%) with a manageable side effect profile [6- 
7], establishing TPF as the preferred IC regimen in SCCHN. 
Two additional trials utilized the TPF regimen specifically 
in larynx and hypopharynx patients: GORTEC 2000-01 
randomized patients to TPF vs. PF followed by radiation if 
they had any initial response to IC [8] and the LPR was 
significantly improved favoring TPF (70.3%). TREMPLIN 
was a phase II study using TPF for organ preservation with 
responders randomly assigned to either concurrent CRT or 
cetuximab with radiation [9]. LPR exceeded 90% overall 
with no difference in larynx function preservation or survival among each arm. In the GORTEC study, 
larynx dysfunction-free survival (LDFFS) rates favored the TPF arm in long-term follow-up (5-year 
LDFFS, TPF: 67.2% vs. PF: 46.5%) [14]. TPF followed by either radiation or concurrent CRT is an 
acceptable approach for organ preservation based on these results, with TPF followed by radiation favored 
in Europe. 
 
It is now widely recognized that tumors harbor immune checkpoint receptors to escape immune 
recognition, and immune checkpoint receptor inhibitors that block inhibitory immune cell interactions 
have demonstrated efficacy in advanced head and neck cancer [16-17] prompting clinical trials to explore 
their potential in other head and neck cancer populations. Recognizing that the risk of toxicity can be 
significant with TPF IC followed by chemoradiotherapy (so-called sequential treatment), and in the hopes 
of improving LFS here we propose a multicenter, non-randomized phase II study replacing 5-fluorouracil 
in TPF with the anti-PD-1 inhibitor nivolumab as TPN followed by definitive intensity-modulated 
radiation therapy (IMRT) with nivolumab and subsequent adjuvant PD-1 blockade. The rationale for using 
2-3 induction doses of immunotherapy with a TP backbone stems from early studies showing that few 
doses of checkpoint blockade may be all that is necessary to trigger immunomodulation prior to definitive 
therapy [35]. Maintaining a platinum-taxane based IC regimen and adding active immunotherapy is aimed 
at decreasing cytotoxic side effects while preserving response rates and improving patient tolerability 
(such as avoiding a port-a-cath or committing the patient to infusional therapy). Several trials have 
combined taxane-platinum combinations alone (specifically docetaxel, cisplatin or TP) in the advanced 
setting and untreated, locoregionally advanced setting with favorable efficacy [37, 40-41]– including an 
86% overall response among untreated locoregionally advanced and metastatic patients [36]. More recent 
studies have investigated docetaxel-cisplatin (TP) induction and together have shown overall response 
rates to induction TP of 70-88%, but with notable rates of neutropenia [38-39]. Given rates of grade 3+ 
neutropenia in many docetaxel-cisplatin (TP) trials, we favor the option of granulocyte-colony stimulating 
factor (GCSF) support in combination with PD-1 blockade in the current study. 
 
Posner and colleagues published a further analysis of the TAX-324 data in 2009 [42] which was aimed at 
characterizing LFS rates among TPF treated patients. Among operable stage III and IV larynx or 
hypopharynx cancer patients in their analysis (n = 123), the 3-year LFS rate was significantly higher 
among patients who received induction TPF (52%) vs. PF (32%) in TAX-324 [Figure below right]. 
Further, the 2-year LFS rate among the TPF arm was 58% vs. 37% in the PF arm. The authors note they 
chose the operable TAX-324 subgroup and not the entire cohort because they wanted to more closely 
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They make the point that TAX-324 included patients with more advanced primary tumors and nodal 
disease than these other trials. They also suggest that using the LFS endpoint in an inoperable population 
is not feasible since inoperable patients don't have a surgical salvage option and would present with more 
advanced disease characteristics. Finally, the authors point out that the lower 2-year LFS results in this 
TAX-324 subanalysis for the PF arm (37%) as compared to RTOG 91-11 (2-year LFS for the PF arm was 
60%) resulted from the more liberal entry criteria for TAX-324 which allowed patients with borderline 
operable or more advanced disease. Since the proposed trial using induction TPN will not select patients 
based on upfront operability (and therefore may enroll a more advanced stage cohort) and will select HPV 
negative participants, we consider a 2-year LFS estimate of 55% for induction TPF both reasonable and 
conservative for comparison. 
 
In summary, we hope to demonstrate an improvement in the 2-year LFS rate compared with the preferred 
sequential therapy approach of TPF followed by CRT. Secondary endpoints will include OS at 2-years 
and the important composite endpoint of laryngo-esophageal dysfunction-free survival (LEDFS) at 2- 
years which attempts to capture long-term, patient-focused functional outcomes. If this immunotherapy- 
based sequential treatment program proves beneficial, it could stand next to or replace TPF followed by 
definitive chemoradiotherapy. 
 
2.6 
Correlative Studies Background 
 
Given that response rates to PD-1 blockade in the advanced, platinum-refractory SCCHN setting approach 
20%, there is strong interest in identifying biomarkers that predict clinical benefit. In a NSCLC population, 
PD-L1 expression in at least 50% of tumor cells yielded a response rate of 45.2%, compared with an 
objective response rate of 19.4% among all treated patients [17]. More recently, whole-exome sequencing 
of NSCLC tumors treated with PD-1 blockade revealed that higher mutational burden correlated with 
improved objective response rates [18]. Somatic alterations in tumor cells yield neoantigens which are 
thought to facilitate antigen-specific CD8+ T cell responses – suggesting that the genomic landscape of 
the tumor impacts PD-1 response. In SCCHN, stromal or tumor PD-L1 expression does appear to partially 
impact response, but even PD-L1 negative patients may respond to treatment – suggesting important 
mechanisms beyond PD-1:L1 interactions [15, 19]. 
 
Early preclinical and clinical studies have also demonstrated potential synergy between high dose per 
fraction radiotherapy and immunotherapy [20]. Radiation delivered in a limited number of fractions has 
been shown to impact circulating immunologic cytokines and have local immunologic effects on the 
primary tumor [21]. Some reports even suggest that hypofractionated radiation can potentiate 
immunologic effects following PD-1/L1 exposure leading to responses outside the targeted radiation field 
(so-called abscopal effect) [22-23]. Curiously, circulating levels of activated T cells appear increased and 
myeloid-derived suppressor cells (MDSCs) decreased among melanoma patients with abscopal responses 
following radiation [22]. 
 
More recent work has sought to use more comprehensive immune-based metrics to characterize the tumor 
microenvironment. 
Cytometric 
profiling 
has 
identified 
immunologically 
‘hot’ 
and 
‘cold’ 
immunophenotypes which may identify tumors more likely to respond to immunotherapies [24-25]. We 
have demonstrated similar findings in head and neck cancer patients: showing that a robust CD8+ T cell 
infiltrate and pattern of immune checkpoint co-expression may predict clinical benefit to PD-1 blockade 
in an advanced SCCHN population [26]. 


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3. PARTICIPANT SELECTION 
 
Participants must meet the following eligibility criteria on screening examination to be eligible to 
participate in the study: 
 
3.1 
Eligibility Criteria 
 
3.1.1 Subject must have histologically or cytologically confirmed, resectable or unresectable, Stage III 
or Stage IV locoregionally advanced squamous cell carcinoma of the larynx or hypopharynx, as 
defined by 2017 American Joint Committee on Cancer (AJCC), 8th edition 
 
3.1.2 Willing to provide tissue from diagnostic biopsy and blood samples before, during, and after 
treatment 
 
3.1.3 Any smoking history is permitted 
 
3.1.4 Patients must have HPV negative disease. Those patients with a supraglottic primary are required 
to undergo HPV testing with p16 immunohistochemistry and/or confirmatory HPV PCR or ISH 
testing to rule out oropharyngeal origin with laryngeal extension 
 
3.1.5 Age 18 years or older 
 
3.1.6 ECOG performance status ≤ 1 (Karnofsky ≥ 80%, see Appendix A) 
 
3.1.7 Participant must have normal organ and marrow function as defined below within 21 days prior to 
study registration: 
 
− 
leukocytes 
≥3,000/mcL 
− 
absolute neutrophil count 
≥1,500/mcL 
− 
platelets 
≥100,000/mcL 
− 
total bilirubin 
≤2.0 g/dL 
− 
AST(SGOT)/ALT(SGPT) 
≤2.5 × institutional upper limit of normal 
− 
creatinine within normal institutional limits 
OR 
− 
creatinine clearance 
≥60 mL/min/1.73 m2 for participants with creatinine levels 
above institutional normal 


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3.1.8 Ability to understand and the willingness to sign a written informed consent document 
 
3.1.9 Women of childbearing potential (WOCBP) must agree to use appropriate method(s) of 
contraception. WOCBP should plan to use an adequate method to avoid pregnancy for 5 months 
(30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of 
investigational drug 
 
3.1.10 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 nivolumab 
 
“Women of childbearing potential (WOCBP)” is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12 months of 
amenorrhea in a woman over 45 in the absence of other biological or physiological causes. In 
addition, women under the age of 55 must have a documented serum follicle stimulating hormone 
(FSH) level less than 40 mIU/mL 
 
3.1.11 Men who are sexually active with WOCBP must agree to use any contraceptive method with a 
failure rate of less than 1% per year. Men who are sexually active with WOCBP will be instructed 
to adhere to contraception for a period of 7 months after the last dose of investigational product. 
Women who are not of childbearing potential (ie, who are postmenopausal or surgically sterile as 
well as azoospermic men) do not require contraception 
 
See Appendix B for further guidance on contraception. 
 
3.2 
Exclusion Criteria 
 
3.2.1 Existing severe autoimmune conditions (at the discretion of the treating physician). Patients with 
a history of Hashimoto thyroiditis who are stable on replacement hormone therapy are not 
excluded. Short-term corticosteroid dosing is permitted (i.e. dexamethasone for chemotherapy- 
induced nausea prevention during induction chemotherapy) as long as steroids are discontinued 
within 1 week (7 days) of receiving the first dose of nivolumab during the induction phase of 
treatment. 
 
3.2.2 Subject who has had prior chemotherapy for head and neck cancer and/or radiotherapy to the head 
and neck. 
 
3.2.3 Subject who has been treated with immunotherapy. This includes prior treatment with anti-PD-1, 
anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically 
targeting T-cell co-stimulation or immune checkpoint pathways. 
 
3.2.4 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric 
illness/social situations that would limit compliance with study requirements. 


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3.2.5 Known human immunodeficiency virus carrier or a diagnosis of immunodeficiency. Any positive 
test result for hepatitis B virus or hepatitis C virus indicating presence of virus, e.g., Hepatitis B 
surface antigen (HBsAg, Australia antigen) positive, or Hepatitis C antibody (anti-HCV) positive 
(except if HCV-RNA negative). 
 
3.2.7 Known non-infectious pneumonitis or any history of interstitial lung disease. 
 
3.2.8 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, and low-risk prostate 
adenocarcinoma being managed with active surveillance. A history of another separate 
malignancy in remission without evidence of active disease in the last 5 years is permitted. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
 
4. REGISTRATION AND RANDOMIZATION PROCEDURES 
 
4.1 
General Guidelines for DF/HCC Institutions 
 
Eligible participants will be registered in the Clinical Trials Management System (CTMS) OnCore. 
Registrations must occur prior to the initiation of any protocol-specific therapy or intervention. Any 
participant not registered to the protocol before protocol-specific therapy or intervention begins will be 
considered ineligible and registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will complete the protocol- 
specific eligibility checklist. 
 
Following registration, participants may begin protocol-specific therapy and/or intervention. Issues that 
would cause treatment delays should be discussed with the Overall Principal Investigator (PI). If the 
subject does not receive protocol therapy following registration, the subject must be taken off-study in the 
CTMS (OnCore) with an appropriate date and reason entered. 
 
4.1 
Registration Process for DF/HCC Institutions 
 
Applicable DF/HCC policy (REGIST-101) must be followed. 
 
4.2 
General Guidelines for Other Investigative Sites 
 
Eligible participants will be entered on study centrally at Dana-Farber Cancer Institute, the Coordinating 
Center, by the Study Coordinator. All sites should call the Study Coordinator to verify eligibility and 
registration status. 


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Following registration, participants should begin protocol therapy within 5 days. Issues that would cause 
treatment delays should be discussed with the Overall PI. If the subject does not receive protocol therapy 
following registration, the subject must be taken off-study in the CTMS (OnCore) with an appropriate 
date and reason entered. 
 
4.3 
Registration Process for Other Investigative Sites 
 
To register a participant, the following documents should be completed by the participating site and 
faxed or e-mailed to the Study Coordinator: 
• Copy of lab results 
• Signed participant consent form 
• HIPAA authorization form 
• Eligibility checklist 
 
The participating site will then call or e-mail the Study Coordinator to verify eligibility. The Study 
Coordinator will follow DF/HCC policy (REGIST-101) and register the participant on the protocol. The 
Study Coordinator will fax or e-mail the participant study number, and if applicable the dose treatment 
level, to the participating site. The Study Coordinator will also contact the participating site and verbally 
confirm registration. 
 
 
5. TREATMENT PLAN 
 
Eligibility and exclusion criteria are provided in Section 3. These criteria will be assessed 21 days prior 
to study registration to establish eligibility and baseline values. 
 
Informed consent will be obtained after the study has been fully explained to the subject and before the 
conduct of any screening procedures or assessments. 
 
Demographic information and baseline characteristics will be collected at the Screening Visit. Standard 
demographic parameters include age, sex, and race/ethnicity (recorded in accordance with prevailing 
regulations). Baseline characteristics will include ECOG PS (Appendix A), disease status, and medical 
histories. 
 
5.1 
Treatment Regimen 
 
5.1.1 
C1D1 of TPN Induction Therapy 
 
No investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the participant's malignancy. 
 
The induction TPN cycle will be 21 days long, and nivolumab cycles thereafter will be 28 days long. 
 
Below are the specific laboratory criteria patients will need to meet in order to begin a subsequent cycle 
of TPN (docetaxel, cisplatin and nivolumab): 


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• Leukocytes ≥3,000/mcL 
• Absolute neutrophil count ≥1,500/mcL 
• Platelets ≥100,000/mcL 
• Total bilirubin ≤2.0 g/dL 
• AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal 
• Creatinine within normal institutional limits 
OR 
• Creatinine clearance ≥60 mL/min/1.73 m2 for participants with creatinine levels above 
institutional normal 
• Thyroid function tests (TSH) should be reviewed prior to the start of TPN therapy. If abnormal 
then replacement hormone therapy can be utilized without delaying the start of induction TPN. 
Thyroid function test abnormalities generally should not interrupt dosing on protocol unless the 
patient is severely symptomatic from hypo- or hyperthyroidism. 
• 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 nivolumab. 
 
5.1.2 
Dose and schedule of TPN Cycles, and Pre-medications 
 
Patients with confirmed locoregionally advanced SCCHN arising in the larynx or hypopharynx will 
receive 3 cycles of induction docetaxel, cisplatin and nivolumab (TPN) every 3 weeks (or 21 days), 
followed by clinical and radiologic assessment of response. 
 
TPN dosing will consist of docetaxel 75 mg/m2 IV day 1, cisplatin 100 mg/m2 IV day 1, and nivolumab 
240 mg IV flat dose day 1 of a 21 day cycle. 
 
Standard pre-medications including dexamethasone, palonosetron or ondansetron, and fosaprepitant are 
permitted for anti-emetic effect. Pre-medication with dexamethasone prior to taxane exposure is permitted 
and strongly encouraged. 
 
5.1.2.1 
Antibiotic prophylaxis and GCSF support 
 
Following each TPN cycle administered, patients will receive oral levofloxacin 500 mg daily by mouth 
on day 5 through day 15 of the cycle for antibiotic prophylaxis. 
 
In addition, granulocyte-colony stimulating factor (GCSF) support can be administered (at the treating 
physician’s discretion, see Section 2.5) at least 24 hours (but no later than 72 hours) after completion of 
the TPN infusion in the form of pegfilgastrim 6 mg subcutaneously once or as tbo-filgastrim administered 
subcutaneously daily at least 24 hours after the completion of the TPN infusion (but no later than 72 
hours). Tbo-filgastrim should be given for at least 5 days and continued for a maximum of 14 days or until 
the ANC is at or above 1000. Tbo-filgrastim should not be given with 24 hours of the start of the next 
cycle of TPN. 


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5.1.2.2 
Dose Reductions and Delays for TPN 
 
• If laboratory criteria are not met or patient experienced toxicity prohibits the administration of a 
subsequent TPN cycle, the next cycle can be delayed up to 14 days (2 weeks) and then resumed 
at chemotherapy dose attenuation (at the discretion of the treating physician and per protocol 
standards in Section 6.0). 
• If laboratory criteria or treatment-related side effects limit the administration of cycle 2 of TPN 
for more than 14 days, the subject should be removed from the study treatment. 
• If administration of cycle 3 of TPN is delayed more than 14 days, the treating physician or PI may 
allow the subject to proceed to the definitive radioimmunotherapy phase of treatment (i.e. 2 cycles 
of TPN are required to proceed to the definitive radioimmunotherapy phase of treatment). 
• Individual cytotoxic agents (docetaxel or cisplatin) can be modified or dose reduced at the 
discretion of the treating physician (see Section 6.0), but should not be individually omitted from 
the TPN regimen. Nivolumab should not be dose reduced but rather held for patient experienced 
toxicity during the induction TPN phase. 
 
5.1.3 
Post-TPN Imaging for Response Assessment 
Subjects will undergo repeat neck CT or MRI or PET-CT following the completion of the induction phase 
of treatment (at least 10 days after the completion of the last TPN infusion). 
• Partial or Complete Response: Patients with a radiographic partial response (PR) defined by 
RECIST 1.1 following 2-3 cycles of induction TPN, will proceed with immunoradiotherapy 
concurrently with nivolumab. 
• Stable Disease or Progression: Those patients in whom at least a radiographic PR is not achieved 
will be offered surgical salvage comprised of laryngectomy and/or pharyngectomy at the discretion 
of the involved head & neck surgeon, if their disease is deemed resectable. In the case of salvage 
surgery, the patient will not proceed with further study treatments and will receive standard post- 
operative radiation with or without chemotherapy off protocol. If the patient has less than a 
radiographic PR to induction TPN and declines salvage surgery or is deemed unresectable, the 
patient is likely to be considered palliative or incurable and may continue cytotoxic therapy or 
immunotherapy, or even consider radiation or chemoradiotherapy, at the discretion of the treating 
physician. 
 
5.1.4 
Concurrent Radioimmunotherapy with Nivolumab 
At least 21 days or 3 weeks after completion of the last cycle (cycle 2 or 3) of TPN and after completion 
of reimaging, patients will start concurrent radioimmunotherapy. Intensity-modulated radiotherapy 
(IMRT) is preferred, and proton beam radiotherapy is not permitted. If a patient completes the induction 
phase of the study but elects to come off protocol for proton beam radiotherapy, this will be logged and 
tracked, and annually reported. Six months after study initiation, the PI and co-investigators should review 
proton use data. 
 
Treatment planning CT scans should be performed with neck and shoulder immobilization that will also 
be used during daily treatment. Treatment planning scans should at least encompass the region from the 
orbits to below the clavicles. CT scan thickness should be 0.3 cm or thinner in the area of the target 
volumes. 


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5.1.4.1 
Radiation Therapy Planning and Delivery 
 
Target volumes should be delineated on each CT slice where present. The Gross Tumor Volume (GTV) 
is specifically defined as all known gross disease determined from pre-chemotherapy evaluations 
including clinical information and imaging (CT, MRI or PET). Clinical target volumes (CTV) are defined 
as either the GTV with an anatomical margin or areas at risk of harboring microscopic disease. Generally, 
these volumes will include a high-risk clinical target volume (CTV1) including volumes of potential tumor 
extension (adjacent to primary or nodal GTV) and nodal areas at highest risk for microscopic involvement 
abutting areas of gross disease. The exact margins will be determined on a case by case basis. There will 
also generally be a CTV2 including lymph node or other regions at lesser risk of nodal involvement. In 
general, the entire larynx and both sides of the neck (including most or all of levels 2-4) should be treated 
as part of GTV, CTV1 or CTV2 in all cases, and depending on the location of primary tumor and/or 
involved lymph nodes, consideration should be given to include nodal levels VI, and the upper 
mediastinum a tracheostomy/stoma if present, as well as levels 1b and 5 and the lateral retropharyngeal 
lymph nodes in the node positive neck. The planning target volumes (PTV) will provide a margin to 
account for variation in daily set up and are in general expected to be approximately 3-5mm. The following 
normal structures should also be defined and delineated in all cases: spinal cord, brainstem, right and left 
parotid and submandibular glands, larynx, mandible, oral cavity, esophagus, left and right brachial plexus, 
left and right cochlea, constrictor muscles, or postcricoid. 
 
The GTV should be prescribed either 70 Gy in 35 fractions or 69.96 Gy in 33 fractions and CTV1 and 
CTV2 should be prescribed approximately between 59-63 Gy, and 46-54 Gy, respectively. Definitive 
immunoradiation should be delivered in 33-35 fractions with intensity-modulated radiotherapy (IMRT). 
Either dose-painting IMRT or a sequential boost approach are permitted. No more than 20% of the PTV 
should receive >110% of the prescription dose. In most cases, no more than 5% of the PTV should receive 
< 95% of the prescription dose. 
 
The following normal tissue limits are recommended: 
Brainstem 
maximum < 54 Gy 
Spinal Cord 
maximum < 45 Gy 
Mandible 
maximum < 70 Gy 
Cochlea 
maximum < 30 Gy 
Brachial plexus 
maximum < 66 Gy 
Parotid 
mean dose to one of the parotid glands < 26 Gy 
 
Note: In cases with a conflict and/or overlap between target and normal tissue, target dose considerations 
should take priority at the discretion of the treating physician. Exceptions to this include the brainstem 
and spinal cord, which take priority. 
 
Treatment should be delivered with megavoltage equipment capable of delivering static or dynamic 
intensity modulation or other techniques capable of meeting dose specifications and constraints and 
delivering highly conformal radiation. Treatment should generally be delivered once daily, Monday- 
Friday, over a period of approximately 7 weeks. Treatment breaks are strongly discouraged. Images should 
be obtained prior to the first treatment to verify the treatment position. During treatment, imaging should 
be repeated at least once per week for setup verification, although daily image guided radiation therapy is 


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suggested. 
 
Real time radiation plan review is not required. However, for verification purposes, it is requested that 
sites submit digital radiation data within two weeks following the completion of radiation therapy. This 
should be transferred via secure Partners Healthcare Interface (transfer.partners.org). Participating centers 
will be invited to create an account within this system by study staff. These data should include: treatment 
plan in DICOM format including the complete radiation structure set and radiation dose matrix in absolute 
dose, as well as supportive diagnostic imaging used to create the radiation treatment plan (e.g. imaging 
performed prior to induction chemotherapy); a dose volume histogram (DVH) including all treatment 
targets and organs at risk; and summary document(s) which includes: the date of first and last treatment, 
the prescribed dose to each target (GTV, CTV1, CTV2), treatment planning system, and method of IGRT, 
if applicable. 
 
5.1.4.2 
Radiation Timing and Schedule 
 
The first fraction of RT should be administered no later than 6 weeks (or 42 days) after the last cycle of 
TPN. The planned 33-35 fractions of RT are to be administered on a continuous weekday schedule for a 
total of approximately 7 weeks (permitting holiday and weekend day interruptions). 
 
5.1.4.3 
Concurrent Nivolumab Dosign and Schedule with Radiation 
 
 
 
 
 
 
 
 
5.1.5 
Adjuvant Nivolumab Phase 
 
 
 
 
 
 
 
 
 
5.1.6 
Stopping Rules 
 
In addition to the continuous routine toxicity monitoring by the study team throughout the duration of the 
trial, the following 


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These events and rates will be continuously monitored and decisions made regarding the overall status of 
the trial. 
 
5.2 
Pre-Treatment Criteria 
 
5.2.1 Cycle 1, Day 1 
If screening assessments occur within a week before start of study treatment, then they may serve as the 
baseline or cycle 1 day 1 visit. Laboratory evaluations do not need to be repeated to meet eligibility criteria 
on cycle 1 day 1, if they were done within 3 days of the first treatment dose. 
 
5.3 
Chemotherapy Administration 
 
When administering TPN cycles, the T (docetaxel) should be administered per standard institutional 
guidelines first, followed by a 30 minute wait period to evaluate for infusion reaction. P (cisplatin) should 
be administered second per institutional standards, followed by a 30 minute wait period. Nivolumab 
should be administered last as outlined in Section 5.4 below, and given over 30 minutes. 
 
For both docetaxel and cisplatin, standard operating procedure should be applied when recalculating 
weight-based dosing at the beginning of each cycle. Nivolumab is to be used at a flat dose. 
 
5.4 
Nivolumab Administration 
 
5.4.1 
Description of the Dosage Form 
Nivolumab injection, 100 mg/10 mL (10 mg/mL): Nivolumab injection, 100 mg/10 mL (10 mg/mL) is 
a clear to opalescent, colorless to pale yellow liquid, which may contain light (few) particulates. The drug 
product is a sterile, non-pyrogenic, single-use, isotonic aqueous solution formulated at 10 mg/mL in 
sodium citrate, sodium chloride, mannitol, diethylenetriaminepentacetic acid (pentetic acid), and 
polysorbate 80 (Tween 80), at pH 6.0 and includes an overfill to account for vial, needle, and syringe 


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holdup. It is supplied in 10-cc Type I flint glass vials, stoppered with butyl rubber stoppers and sealed 
with aluminum seals. 
 
5.4.2 
Drug Product Preparation 
Nivolumab Injection, 100 mg/10 mL (10 mg/mL): Nivolumab injection is to be administered over 30 
minutes (± 10 minutes) as an IV infusion through a 0.2 to 0.22 micron pore size, low-protein binding 
(polyethersulfone membrane) in-line filter at the protocol-specified doses and infusion times. It is not to 
be administered as an IV push or bolus injection. Dilute nivolumab with either 0.9% sodium chloride 
injection, USP or 5% dextrose injection, USP to prepare an infusion with a final concentration ranging 
from 1 mg/mL to 10 mg/mL. The total infusion volume must not exceed 160 mL. 
 
During drug product preparation and handling, vigorous mixing or shaking is to be avoided. 
 
Care must be taken to assure sterility of the prepared solution as the product does not contain any 
antimicrobial preservative or bacteriostatic agent. Nivolumab infusions are compatible with polyvinyl 
chloride (PVC) or polyolefin containers and infusion sets, and glass bottles. 
 
5.4.3 
Recommended Storage and Use Conditions 
Nivolumab Injection, 100 mg/10 mL (10 mg/mL): Vials of nivolumab injection must be stored at 2°C 
to 8°C (36°F to 46°F) and protected from light and freezing. 
 
The administration of nivolumab infusion must be completed within 24 hours of preparation. If not used 
immediately, the infusion solution may be stored under refrigeration conditions (2°C to 8°C, 36°F to 46°F) 
for up to 24 hours, and a maximum of 8 hours of the total 24 hours can be at room temperature (20°C to 
25°C, 68°F to 77°F) and room light. The maximum of 8 hours under room temperature and room light 
conditions includes the product administration period. 
 
5.5 
General Concomitant Medication and Supportive Care Guidelines 
 
5.5.1 CYP 450 Drug Interactions 
 
Because there is a potential for interaction of nivolumab with other concomitantly administered drugs 
through the cytochrome P450 system, the case report form must capture the concurrent use of all other 
drugs, over-the-counter medications, or alternative therapies. 
 
The Overall PI should be alerted if the participant is taking any agent known to affect or with the potential 
to affect selected CYP450 isoenzymes. 
 
5.5.2 
Prohibited and/or Restricted Treatments 
 
The following medications are prohibited during the study (unless utilized to treat a drug related adverse 
event): 
• Immunosuppressive agents 
• Immunosuppressive doses of systemic corticosteroids with the exception of during the induction phase 
of treatment for pre-medication and anti-emetic purposes 


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− Note: In regards to cisplatin anti-emetic prevention: dexamethasone is permitted on days 1-4 of 
the induction or TPN cycle (up to 12 mg IV/po on day 1) and reduced to a total dose of 8 mg daily 
for up to 3 days after cisplatin dosing. Delayed emesis can be managed in a subsequent TPN cycle 
using dexamethasone 8 mg twice daily x 2-days followed by 4 mg twice daily x 2-days starting 
the day after chemotherapy dosing. 
• Any concurrent anti-neoplastic therapy (i.e., chemotherapy, hormonal therapy, immunotherapy, 
extensive, non-palliative radiation therapy, or standard or investigational agents 
 
5.5.3 
Other Restrictions and Precautions 
 
Participants with a condition requiring systemic treatment with either corticosteroids (> 20 mg daily 
prednisone equivalent) or other immunosuppressive medications within 7 days of the first dose of 
nivolumab treatment are excluded. Inhaled or topical steroids, and adrenal replacement steroid doses ≤ 20 
mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease. 
 
5.5.4 
Permitted Therapy 
 
Participants are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Adrenal replacement steroid doses ≤ 20 mg daily 
prednisone are permitted. A course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for 
treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity reaction caused by a contact 
allergen) is permitted. 
 
5.6 
Criteria for Taking a Participant Off Protocol Therapy 


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5.7 
Duration of Follow Up 
 
 
 
 
 
 
5.8 
Criteria for Taking a Participant Off Study 
 
 
 
 
 
 
 
 
 
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
6.1 
Dose Delays or Modifications for TPN 
 
Dose modifications for the docetaxel-cisplatin (TP) component of the TPN regimen are permitted and 
should follow institutional standards based on toxicity, with the following suggested modifications: 


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• When dose reductions in TP (docetaxel and cisplatin) occur they should include the appropriate 
dose level reductions of both or either agent as specified in Table B below (each row of Table B 
indicates the recommended single or dual agent reduction). In Table B, the toxicity listed in the 
first column on the left corresponds to the recommended dose attenuation in the middle and right 
columns. 
• A maximum of 2 dose reductions per individual study chemotherapy drugs are permitted: if 
additional reductions are required, the induction TPN regimen should be discontinued. 
• If this occurs in cycle 3 of the TPN phase, the patient may proceed to definitive radioimmunotherpy 
on protocol. 
• If this occurs during cycles 1 or 2 of induction TPN, the patient will be removed from the protocol. 
• Once a dose has been decreased, it should remain reduced for all subsequent dosing unless dose is 
further reduced. No dose escalations will be allowed. 
• If one or more of the study drugs is delayed due to drug related toxicities during a treatment cycle, 
the other study drugs (TP or N) in the regimen may be administered at the discretion of the 
investigator; when dosing is resumed, dose reduction should only be applied to the study drug that 
was withheld. 
 
Table A. Recommended Dose Levels: 
Cisplatin dose 
Docetaxel dose 
Starting dose 
100 mg/m2 
75 mg/m2 
Dose Level -1 
75 mg/m2 
56 mg/m2 
Dose Level -2 
56 mg/m2 
37 mg/m2 
 
Table B. Recommended Dose Modifications for Toxicity: 
Cisplatin 
Docetaxel 
Neutrophils (ANC) < 500/mm3 lasting 
≥ 5 days 
Decreased by -1 dose level 
Decreased by -1 dose level 
Febrile neutropenia (body temperature 
≥ 38.5C and ANC < 1000/mm3) 
Decreased by -1 dose level 
Decreased by -1 dose level 
Platelets < 25,000/mm3 
Decreased by -1 dose level 
Decreased by -1 dose level 
Platelets < 50,000/mm3 with 
significant bleeding or requiring 
transfusion 
Decreased by -1 dose level 
Decreased by -1 dose level 
Grade 4 hemoglobin (< 6.5 g/100 mL) 
Decreased by -1 dose level 
Decreased by -1 dose level 
Nausea or emesis ≥ grade 3 despite 
optimal medical management 
Decreased by -1 dose level 
Decreased by -1 dose level 
Stomatitis ≥ grade 3 
Decreased by -1 dose level 
Decreased by -1 dose level 
Diarrhea ≥ grade 3 despite optimal 
medical management 
Decreased by -1 dose level 
Decreased by -1 dose level 
Neuropathy (sensory or motor) grade 2 
lasting > 7 days or grade 3 lasting 7 
days or less 
Decreased by -1 dose level 
Decreased by -1 dose level 
Nephrotoxicity (creatinine clearance 
50-59 mL/min or grade 3 creatinine 
elevation) 
Decreased by -1 dose level 
No modification 
Total bilirubin > 1.5x ULN 
No modification 
No modification 
Total bilirubin > 2.5x ULN 
No modification 
75% of previous dose 
Total bilirubin > 4x ULN 
No modification 
50% of previous dose 
Other grade ≥ 3 toxicities (except 
fatigue or transient arthralgias, 
Decreased by -1 dose level 
Decreased by -1 dose level 


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myalgias) 
 
6.2 
Dose Delays for Nivolumab 
 
There will be no dose reductions for nivolumab permitted. Doses of nivolumab may be interrupted, 
delayed, or discontinued depending on how well the participant tolerates the treatment. Dosing visits are 
not skipped, only delayed. 
Administration of nivolumab should be delayed for the following adverse events: 
• Grade 2 non-skin, drug-related adverse event, with the exception of fatigue 
• Grade 2 drug-related creatinine, AST, ALT and/or Total Bilirubin abnormalities 
• Grade 3 skin, drug-related adverse event 
• Grade 3 drug-related laboratory abnormality, with the following exceptions: 
− Grade 3 lymphopenia or asymptomatic amylase or lipase does not require dose delay 
− Grade  3 AST, ALT, Total Bilirubin will require dose discontinuation 
• Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, warrants delaying the dose of study medication. 
Note: see Appendix C for guidelines on managing immune-related toxicities 
 
Participants who require delay of nivolumab should be re-evaluated weekly or more frequently if clinically 
indicated and resume nivolumab dosing when re-treatment criteria (as described below) are met. 
Participants with a delay in dosing beyond 6 weeks should be considered for discontinuation of protocol 
treatment and discussed with the Overall PI. 
 
Subsequent dosing may be re-started if subjects continue to meet laboratory criteria (baseline values). The 
investigator will determine if subsequent dosing is appropriate for subjects who have laboratory or clinical 
abnormalities that do not meet dose discontinuation criteria (described below). All related grade 2 
toxicities should be discussed with the Overall PI, prior to subsequent dosing. 
 
6.2.1 Administration of nivolumab should be permanently discontinued for the 
following adverse events: 
 
• Any grade encephalitis, grade 3 adrenal insufficiency, and grade 3 myocarditis, or any reoccurrence 
of the same grade 3 adverse reaction will require discontinuation of nivolumab. 
• A grade 3 pneumonitis and grade 3 uveitis will require permanent discontinuation. 
• Any grade 4 adverse event will require permanent discontinuation with the following 
exceptions: 
− 
Grade 4 electrolyte abnormalities that < 72 hours in duration 
− 
Grade 4 neutropenia or lymphopenia < 5 days in duration 
− 
Grade 4 increase in amylase or lipase that is not associated with clinical or radiographic 
evidence of pancreatitis 
 
The consideration to re-initiate study therapy under these exceptions will be made on a case by 
case basis after considering the overall benefit/risk profile and in consultation with the Overall PI. 


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7. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The following list of 
reported and/or potential AEs and the characteristics of an observed AE will determine whether the event 
requires expedited reporting in addition to routine reporting. 
 
7.1 
Adverse Event Characteristics: 
• CTCAE term (AE description) and grade: The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for AE reporting. All appropriate treatment areas should have access to a copy of the 
CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP web 
site http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.2 
Adverse Event Reporting 
 
7.2.1 In the event of an unanticipated problem or life-threatening complications treating investigators 
must immediately notify the Overall PI. 
 
7.2.2 Investigators must report to the Overall PI any adverse event (AE) that occurs after the initial dose 
of study treatment, during treatment, or within 30 days of the last dose of treatment. 
SAEs should be reported on MedWatch Form 3500A, which can be accessed at: 
http://www.accessdata.fda.gov/scripts/medwatch/. Send the SAE forms as follows: 
 
 
 
 
 
 
 
 
 
7.2.3 For Multi-Center Trials where a DF/HCC investigator is serving as the Sponsor, each participating 
institution must abide by the reporting requirements set by the DF/HCC. This applies to any 
medical event equivalent to an unexpected grade 2 or 3 with a possible, probable or definite 
attribution, unexpected grade 4 toxicities, and grade 5 (death) regardless of study phase or 
attribution. 


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7.2.4 DF/HCC Adverse Event Reporting Guidelines 
 
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for Human 
Research Studies (OHRS) per the DFCI IRB reporting policy. 
 
Other investigative sites will report AEs to their respective IRB according to the local IRB’s 
policies and procedures in reporting adverse events. A copy of the submitted institutional AE form 
should be forwarded to the Overall PI within the timeframes detailed in the table below. 
 
Attribution 
DF/HCC Reportable Adverse Events(AEs) 
Gr. 2 & 3 
AE 
Expected 
Gr. 2 & 3 AE 
Unexpected 
Gr. 4 AE 
Expected 
Gr. 4 AE 
Unexpected 
Gr. 5 AE 
Expected or 
Unexpected 
Unrelated 
Unlikely 
Not required 
Not required 
5 calendar 
days# 
5 calendar 
days 
24 hours* 
Possible 
Probable 
Definite 
Not required 
5 calendar 
days 
5 calendar 
days# 
5 calendar 
days 
24 hours* 
# If listed in protocol as expected and not requiring expedited reporting, event does not need to 
be reported. 
* For participants enrolled and actively participating in the study or for AEs occurring within 
30 days of the last intervention, the AE should be reported within 1 business day of learning of 
the event. 
 
The Overall PI will submit AE reports from outside institutions to the DFCI OHRS according to 
DFCI IRB policies and procedures in reporting adverse events. 
 
7.3 
Serious Adverse Events 
 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening (defined as an event in which the participant was at risk of death at the time of the 
event; it does not refer to an event which hypothetically might have caused death if it were more 
severe) 
• Requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE 
below) 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 


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• Is an important medical event (defined as a medical event(s) that may not be immediately life- 
threatening or result in death or hospitalization but, based upon appropriate medical and scientific 
judgment, may jeopardize the subject or may require intervention [eg, medical, surgical] to prevent 
one of the other serious outcomes listed in the definition above.) Examples of such events include, 
but are not limited to, intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization.) 
• Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study drug 
is an SAE. 
 
Although pregnancy, overdose, potential drug-induced liver injury (DILI), and cancer are not always 
serious by regulatory definition, these events must be handled as SAEs. 
Any component of a study endpoint that is considered related to study therapy should be reported as an 
SAE (eg, death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported). 
 
7.4 
Expected Toxicities 
 
Expected adverse events are those that have been previously identified as resulting from administration of 
the agent. For the purposes of this study, an adverse event is considered expected when it appears in the 
current adverse event list in the Investigator’s Brochure or is included in the informed consent document 
as a potential risk. Most common adverse events or expected toxicities are listed below. Details are found 
in the respective IBs. Management of expected toxicities is described in Appendix C. 
 
Toxicities related to cisplatin and docetaxel will be managed according to their respective USPI. 
 
7.5 
Adverse Events List 
 
Most common adverse reactions (>20%) related to nivolumab alone were: fatigue, rash, 
musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased 
appetite, back pain, arthralgia, upper respiratory tract infection, pyrexia. 
 
The following hospitalizations are not considered SAEs in BMS supported clinical studies: 
 
− A visit to the emergency room or other hospital department < 24 hours, that does not result in 
admission (unless considered an important medical or life-threatening event) 
− Elective surgery, planned prior to signing consent 
− Admissions as per protocol for a planned medical/surgical procedure 
− Routine health assessment requiring admission for baseline/trending of health status (eg, routine 
colonoscopy) 
− Medical/surgical admission other than to remedy ill health and planned prior to entry into the study. 
Appropriate documentation is required in these cases. 


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− Admission encountered for another life circumstance that carries no bearing on health status and 
requires no medical/surgical intervention (eg, lack of housing, economic inadequacy, caregiver 
respite, family circumstances, administrative reason). 
− Admission for administration of anticancer therapy in the absence of any other SAES 
7.6 
Routine Adverse Event Reporting 
 
Investigators will assess the occurrence of AEs and SAEs at all participant evaluation time points during 
the study. 
 
All AEs and SAEs whether reported by the participant, discovered during questioning, directly observed, 
or detected by physical examination, laboratory test or other means, will be recorded in the participant’s 
medical record and on the appropriate study-specific case report forms. 
 
The descriptions and grading scales found in the CTEP Active Version of the NCI Common Terminology 
Criteria for Adverse Events (CTCAE version 4.0) will be utilized for AE reporting. The CTEP Active 
Version of the CTCAE version 4.0 is identified and located on the CTEP website at: 
 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
All appropriate treatment areas should have access to a copy of the CTEP Active Version of CTCAE. 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the toxicity 
case report forms. AEs reported through expedited processes (e.g., reported to the IRB, FDA, etc.) 
must also be reported in routine study data submissions. 
 
7.7 
Routine Adverse Event Reporting to BMS 
 
 
 
 
 
 
 
 
 
 
7.8 
Serious Adverse Event Collection and Reporting 
 
Following the subject’s written consent to participate in the study, all SAEs, whether related or not related 
to study drug, must be collected, including those thought to be associated with protocol-specified 
procedures. 
. All SAEs 
should be followed to resolution or stabilization. 


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All SAEs must be collected that occur during the screening period. If applicable, SAEs must be collected 
that relate to any protocol-specified procedure (e.g., a follow-up skin biopsy). The sponsor-investigator 
should report any SAE that occurs after these time periods that is believed to be related to study drug or 
protocol-specified procedure. 
 
The sponsor-investigator will reconcile the clinical database SAE cases (case level only) transmitted to 
BMS Global Pharmacovigilance 
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 
a 
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. 
 
7.9 
Expedited Adverse Event Reporting to Overall PI 
 
Investigators must report to the 
 
 
Investigators will report AEs directly to the DFCI Office for Human Research Studies (OHRS) per the 
DFCI IRB reporting policy, using the local institutional SAE form. 
 
7.10 
DF/HCC Expedited Reporting Guidelines 
 
For Multi-Center Trials where a DF/HCC investigator is serving as the Sponsor, each participating 
institution must abide by the reporting requirements set by the DF/HCC. This applies to any medical event 
equivalent to an unexpected grade 2 or 3 with a possible, probable or definite attribution, unexpected grade 
4 toxicities, and grade 5 (death) regardless of study phase or attribution. 
 
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for Human Research 
Studies (OHRS) per the DFCI IRB reporting policy. 
 
Other investigative sites will report AEs to their respective IRB according to the local IRB’s policies and 
procedures in reporting adverse events. A copy of the submitted institutional AE form should be forwarded 
to the Overall PI within the timeframes detailed in the table below. 
 
Attribution 
DF/HCC Reportable AEs 
Gr. 1 AE 
Unexpected 
Gr. 1 & 2 
& 3 AE 
Expected 
Gr. 2 & 3 
AE 
Unexpected 
Gr. 4 AE 
Expected 
Gr. 4 AE 
Unexpected 
Gr. 5 AE 
Expected or 
Unexpected 
Unrelated 
/ Unlikely 
Not 
required 
Not 
required 
Not 
required 
5 calendar 
days# 
5 calendar 
days 
24 hours* 
Possible 
/ Probable 
/ Definite 
Not 
required 
Not 
required 
5 calendar 
days 
5 calendar 
days# 
5 calendar 
days 
24 hours* 


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The Overall PI will submit AE reports from outside institutions to the DFCI OHRS according to DFCI 
IRB policies and procedures in reporting adverse events. 
 
7.11 
Expedited Adverse Event Reporting to the Food and Drug Administration 
(FDA) 
 
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The Overall 
PI will report to the FDA, regardless of the site of occurrence, any serious adverse event that meets the 
FDA’s criteria below for expedited reporting: 
 
Any unexpected fatal or life-threatening suspected adverse reactions should be reported no later than 7 
calendar days after initial receipt of the information. Address each submission to the Regulatory Project 
Manager and/or to the Chief, Project Management Staff; 
 
 
 
 
 
 
 
 
 
7.12 
Expedited Adverse Event Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any participant safety reports 
or sentinel events that require reporting according to institutional policy. 
 
7.13 
Expedited Adverse Event Reporting to BMS 
 
SAEs, whether related or not related to study drug, and pregnancies must be reported 
* For participants enrolled and actively participating in the study or for AEs occurring within 30 days 
of the last intervention, the AE should be reported within 24 hours of learning of the event. 
# If listed in protocol as expected and not requiring expedited reporting, event does not need to be 
reported. 


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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 
 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agent administered in 
this study can be found in Section 7. 
 
8.1 
IND Agent Nivolumab 
 
8.1.1 Description 
 
Nivolumab, also referred to as BMS-936558-01 or BMS-936558, is a soluble protein consisting of 4 
polypeptide chains, which include 2 identical heavy chains and 2 identical light chains. A description of 
the physical and chemical properties of nivolumab are provided below. 
 
Product Description 1 
BMS Number 
BMS-936558-01 or BMS-936558 
Other Names 
Opdivo®, nivolumab, BMS-936558, MDX1106, ONO-4538, 
anti-PD-1 
Molecular Weight 
146,221 daltons (143,619.17 daltons, protein portion) 
Appearance 
Clear to opalescent, colorless to pale yellow liquid, light (few) 
particulates may 
be present 
Solution pH 
5.5 to 6.5 
 
 
Product 
Description 
and 
Dosage 
Form 
Potency 
Primary 
Packaging 
(Volume)/ 
Label Type 
Appearance 
Storage Conditions 
(per label) 
Nivolumab 
100 
mg 10 mL vial 
Clear to opalescent colorless to 2 to 8°C. Protect form 
(BMS-936558- 
(10 
pale yellow liquid. May contain light and freezing 
01) 
mg/mL) 
particles 
Solution 
for 
Injection 


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8.1.2 Storage and Stability 
 
If stored in a glass front refrigerator, vials should be stored in the carton. Recommended safety measures 
for preparation and handling of nivolumab include laboratory coats and gloves. 
 
For additional details on prepared drug storage and use time of nivolumab under room temperature/light 
and refrigeration, please refer to section 5 of this protocol. 
 
8.1.3 Handling 
 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and the 
environment, should undertake the preparation, handling, and safe disposal of the chemotherapeutic 
agent in a self-contained and protective environment. 
 
8.1.4 Availability 
 
 
8.1.5 Ordering 
 
Pharmacies at all participating sites will request supply of nivolumab, directly from Bristol-Myers Squibb, 
by submitting an order form, provided by Bristol-Myers Squibb. 
 
8.1.6 Accountability 
 
The investigator, or a responsible party designated by the investigator, should maintain a careful record 
of the inventory and disposition of the agent using the NCI Drug Accountability Record Form (DARF) 
or another comparable drug accountability form. (See the NCI Investigator’s Handbook for Procedures 
for Drug Accountability and Storage.) 
 
8.1.7 Destruction and Return 
 
Unused supplies and expired supplies of the investigational agents will be destroyed on site, by the 
pharmacy, per institutional SOP. 
 
8.2 
Other Agents 
 
TPN regimen will be stored, prepared, and administered per standard of care/institutional standard. 
 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
Correlative studies are planned as part of this study. 


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9.1 
Biomarker Studies 
 
Biopsy confirmed squamous cell carcinoma of the larynx or hypopharynx is a requirement to be enrolled 
on this study. 
 
 
Tumor biopsies and/or surgery should not generally be performed on Friday afternoons, as there may not 
be time for 
If a biopsy or surgical resection is performed 
, 
of the Belfer Center for Applied Cancer Science should be notified ahead of 
time to ensure that there will be adequate time for processing fresh tissue or serum samples, since these 
should not be stored over the weekend. 
 
Each tumor and blood sample obtained will be assigned a unique coded identifier in order to preserve the 
confidentiality of the participant. The coded samples will be linkable to the participant, but the key that 
links that person to the unique identifier will be stored in a database housed on a server at the DFCI. 
Access to participant identity will be provided only to the principal investigator and study staff (not 
laboratory staff). There are multiple firewalls and passwords protecting the data from unwanted viewers. 
Patient privacy will be maintained by strictly curtailing access to the electronic file via passwords and 
firewalls. The coded samples will be cryopreserved and stored in secure locked freezers. Once all research 
is complete, the link between the coded samples and patient identifiers will be destroyed. 
 
If only an archival pre-treatment biopsy sample is obtained, the formalin-fixed paraffin-embedded (FFPE) 
tissue block should be obtained for research sample allocation. Preparation 
from the BWH Specialized Histopathology Core for genomic sequencing and we will request 
preparation of 
 
If a 
 
 
 
 
 
 
 
At the time of each blood sample collection (see Study calendar), 2 tubes are requested: 


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Multiparametric flow cytometry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunohistochemistry 


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Genomic sequencing 
 
 
 
 
 
 
 
10. STUDY CALENDAR 
 
Screening evaluations are to be conducted within 3 weeks prior to study registration. Procedures done 
within a week of study registration don’t need to be repeated to establish baseline. Scans must be done 
Laboratory evaluations do not need to be repeated to meet 
eligibility criteria 
In an event 
that the participant’s condition is deteriorating, laboratory evaluations should be repeated within 48 hours 
prior to initiation of the next cycle of therapy. TPN cycle will be 21 days long, and subsequent nivolumab 
cycles will be 28 days long. 
 
Assessments must be performed prior to administration of any study agent. 
unless otherwise noted. 


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Informed 
consent 
X 
Medical 
History 
X 
Concomitant 
Medicines 
X 
HPV 
TestingA 
X 
Physical 
exam (Ht, 
Wt, VS, 
PS)B 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Routine 
labsC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
B-HCG 
(WOCBP 
only)D 
X 
X 
X 
ECG 
X 
X 
Radiologic 
evaluationE 
X 
XF 
XE 
Biopsy 
sampleG,H 
X 
Correlative 
blood 
X 
X 
X 
X 
X 
X 
X 
TPN 
(docetaxel, 
cisplatin, 
nivolumab)I 
X 
X 
XJ 
Nivolumab 
XK 
X 
X 
XL 
XM 
IMRTN 
X 
X 
X 
X 
X 
X 
X 
Quality of 
life surveyO 
X 
X 
X 
X 
X 
Adverse 
event 
evaluation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a) Patients must have HPV negative disease. Those patients with a supraglottic primary are required to undergo HPV testing with p16 
immunohistochemistry and/or confirmatory HPV PCR or ISH testing to rule out oropharyngeal origin with laryngeal extension 
b) Physical exam is symptom directed. Height measured at screening only. 
c) Routine labs include: CBC with diff, LFTs, CMP, Mg, TSH. Baseline HCV antibody, hepatitis B surface antigen, hepatitis B surface antibody, and 
hepatitis B core antibody testing is required. TSH (and free T4 if TSH is abnormal) is required less frequently according to the following schedule: 
 
d) Serum or urine within 24 hours prior to first dose of induction TPN. 
e) 
 
 
 
 
 
 
 
f) Subjects will undergo repeat neck CT or MRI or PET-CT following the completion of the induction phase of treatment (at least 10 days after the 
completion of the last TPN infusion). 
g) 
h) Fresh biopsy is mandatory (if safe to perform) if archival tissue is not available. FNA cytologic samples are not permitted. 
i) Patients will receive oral levofloxacin 500 mg daily by mouth on D5-15 of the cycle for antibiotic prophylaxis. In addition, granulocyte-colony 
stimulating factor (GCSF) support can be administered (at the treating physician’s discretion) at least 24 hours (but no later than 72 hours) after 
completion of the TPN infusion in the form of pegfilgastrim 6 mg subcutaneously once or as tbo-filgastrim administered subcutaneously daily at least 24 
hours after the completion of the TPN infusion (but no later than 72 hours). Tbo-filgastrim should be given for at least 5 days and continued for a 
maximum of 14 days or until the ANC is at or above 1000. Tbo-filgrastim should not be given with 24 hours of the start of the next cycle of TPN. 
Standard pre-medications including dexamethasone, palonosetron or ondansetron, and fosaprepitant are permitted for anti-emetic effect. Pre-medication 
with dexamethasone prior to taxane exposure is permitted and strongly encouraged. 
j) Of note, 


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k) Nivolumab will start concurrently with IMRT and is repeated every 14 days or 2 weeks during IMRT. If individual RT fractions are canceled or delayed 
at the discretion of the treating radiation oncologist, nivolumab can be continued on a 2 week schedule to overlap with RT until the completion of 
radiation. 
l) Administration of the final dose of nivolumab is permitted +/- 5 days from the last fraction of IMRT. 
m) Adjuvant nivolumab should begin within 3-8 weeks following the completion of nivolumab + IMRT (from the last day of RT). Nivolumab will then be 
dosed every 28 days (4 weeks per cycle) for up to 6 months (or 6 cycles). 
n) IMRT (intensity modulated radiotherapy) begins at least 21 days or 3 weeks after the completion of the last cycle of TPN and after restaging scans. The 
first fraction of RT should be administered no later than 6 weeks (or 42 days) after the last cycle of TPN begins. 
o) Quality of life surveys will be completed at screening, after completion of induction TPN and nivolumab-IMRT, at the end of adjuvant nivolumab 
treatment, and at 30-day follow-up. Patients will complete the EORTC QOL Module for Head and Neck Cancer (QLQ-C30 and HN35). See Appendix D 
for the full questionnaires. 
 
 
11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, participants 
 
following initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international criteria proposed by 
the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [Eur J Ca 45:228- 
247, 2009]. Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the 
shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria. 
 
11.1.1 Definitions 
 
Evaluable for Target Disease response. Only those participants who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their disease re- 
evaluated will be considered evaluable for target disease response. These participants will have 
their response classified according to the definitions stated below. (Note: Participants who exhibit 
objective disease progression prior to the end of cycle 1 of induction TPN will also be considered 
evaluable.) 
 
Evaluable Non-Target Disease Response. Participants who have lesions present at baseline that 
are evaluable but do not meet the definitions of measurable disease, have received at least one 
cycle of therapy, and have had their disease re-evaluated will be considered evaluable for non- 
target disease. The response assessment is based on the presence, absence, or unequivocal 
progression of the lesions. 
 
11.1.2 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) as ≥ 20 mm by chest x-ray or ≥10 mm 
with CT scan, MRI, or calipers by clinical exam. All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 


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Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable. 
 
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 (CT scan slice thickness recommended 
to be no greater than 5 mm). 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. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, abdominal masses (not 
followed by CT or MRI), and cystic lesions are all considered non-measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if 
they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same participant, these are preferred for selection as target lesions. 
 
Target lesions. All measurable lesions up to a 
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. It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected. A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) 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 into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the disease. 
 
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. 
 
11.1.3 Methods for Evaluation of Disease 
 
All measurements should be taken and recorded in metric notation using a ruler, calipers, or a 
digital measurement tool. 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 the treatment. 


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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 assessable 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 in diameter as assessed using calipers 
(e.g., skin nodules). In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended. 
 
Chest x-ray. Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung; however, CT is preferable. 
 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT thickness is 5mm or less. If CT scans have slice thickness greater than 
5 mm, the minimum size of a measurable lesion should be twice the slice thickness. MRI is also 
acceptable in certain situations (e.g. for body scans). 
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; 
however, there are many image acquisition variables involved in MRI, which greatly impact image 
quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable 
globally. As with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of disease. Furthermore, 
as with CT, the modality used at follow-up should be the same as was used at baseline and the 
lesions should be measured/assessed on the same pulse sequence. It is beyond the scope of the 
RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases. Ideally, the same type of scanner should be used and the image acquisition 
protocol should be followed as closely as possible to prior scans. Body scans should be performed 
with breath-hold scanning techniques, if possible. 
 
FDG-PET. While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in assessment 
of progression (particularly possible 'new' disease). New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm: 
(a) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
(b) No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET 
at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT scans are needed to determine if there is truly progression occurring at that site (if so, the 
date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET 
at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD. 
(c) FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or scarring. 
The use of FDG-PET in this circumstance should be prospectively described in the protocol 


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and supported by disease-specific medical literature for the indication. However, it must be 
acknowledged that both approaches may lead to false positive CR due to limitations of FDG- 
PET and biopsy resolution/sensitivity. 
 
Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
 
PET-CT. At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements. However, if the 
site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to 
a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time. Note, however, that the PET portion of the CT introduces 
additional data which may bias an investigator if it is not routinely or serially performed. 
 
MIBG (meta-iodobenzylguanidine). The following is recommended, to assure high quality 
images are obtained. 
 
Patient preparation: Iodides, usually SSKI (saturated solution of potassium iodide), are 
administered to reduce thyroidal accumulation of free radioiodine, preferably beginning the 
day prior to injection and continuing for 3 additional days (4 days total). For infants and 
children, one drop t.i.d. is sufficient, for adolescents 2 drops t.i.d., and for adults 3 drops t.i.d. 
Participants and/or parents are asked about exposure to potential interfering agents. If none is 
noted, an indwelling intravenous line is established. The dose of MIBG is administered by 
slow intravenous injection over 90 seconds. 
 
Images from the head to the distal lower extremities should be obtained. 
 
I-123MIBG scintigraphy is performed to obtain both planar and tomographic images. 
 
Planar: Anterior and posterior views from the top of the head to the proximal lower extremities 
are obtained for 10 minutes at 24 hours and occasionally at 48 hours following injection of 10 
mCi/1.7 square meters of body surface area (~150 μCi/kg, maximum 10 mCi). Anterior views 
of the distal lower extremities are adequate. A large field of view dual head gamma camera 
with low energy collimators is preferred. 
 
SPECT: Most participants receiving I-123 MIBG also undergo SPECT at 24 hours, using a 
single or multi-headed camera with a low energy collimator. The camera is rotated through 
360 degrees, 120 projections at 25 seconds per stop. Data are reconstructed using filtered back 
projections with a Butterworth filter and a cut off frequency of 0.2-0.5. SPECT/CT may be 
performed at institutions with this capacity. 
 
Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 


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independent review at a later data and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or 
MRI is advised. If there is concern about radiation exposure from CT, MRI may be used instead 
of CT in selected instances. 
 
Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor evaluation is not 
advised. However, such techniques may be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint. 
 
Tumor markers. Tumor markers alone cannot be used to assess response. 
 
Cytology, Histology. These techniques can be used to differentiate between partial responses (PR) 
and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell 
tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
 
11.1.4 Response Criteria 
 
11.1.4.1 
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. 
 
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. (Note: the appearance of one or more new lesions is 
also considered progressions). 
 
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. 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). 


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Note: If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not normally 
trump target lesion status. It must be representative of overall disease status change, not a 
single lesion increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
 
11.1.4.3 
Evaluation of New Lesions 
 
The finding of a new lesion should be unequivocal (i.e. not due to difference in scanning 
technique, imaging modality, or findings thought to represent something other than tumor (for 
example, some ‘new’ bone lesions may be simply healing or flare of pre-existing lesions). 
However, a lesion identified on a follow-up scan in an anatomical location that was not scanned 
at baseline is considered new and will indicate PD. If a new lesion is equivocal (because of 
small size etc.), follow-up evaluation will clarify if it truly represents new disease and if PD is 
confirmed, progression should be declared using the date of the initial scan on which the lesion 
was discovered. 
 
11.1.4.4 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient's best response assignment 
will depend on the achievement of both measurement and confirmation criteria. 
 
For Participants with Measurable Disease (i.e., Target Disease) 
 
Target Lesions 
Non-Target 
Lesions 
New Lesions 
Overall 
Response 
Best 
Overall 
Response 
when 
Confirmation is Required* 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non- 
PD/not evaluated 
No 
PR 
SD 
Non-CR/Non- 
PD/not evaluated 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 


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For Participants with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as 
an endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be 
measured is not advised 
 
11.1.5 Duration of Response 
 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started, or death due to any cause. 
Participants without events reported are censored at the last disease evaluation). 
 
Duration of overall complete response: The duration of overall CR is measured from the time 
measurement criteria are first met for CR until the first date that progressive disease is objectively 
documented, or death due to any cause. Participants without events reported are censored at the 
last disease evaluation. 
 
Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements. 
 
11.1.6 Time-to-event Endpoint Definitions 
 
Laryngectomy-Free survival: defined as time from study registration to earlier of surgical removal 
of larynx and/or hypopharynx, or death due to any cause. Participants alive with intact larynx and 
hypopharynx are censored at date of last disease evaluation. 
 
Laryngo-Esophageal Dysfunction-Free Survival: defined as time from study registration to earlier 
of surgical removal of larynx and/or hypopharynx, non-functioning larynx and/or hypopharynx 
(inability to swallow, speak, and/or breath on own), or death from any cause. Participants alive 
 
** 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
Note: Participants with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as “symptomatic deterioration.” 
Every effort should be made to document the objective progression even after discontinuation of treatment. 


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with intact and functioning larynx and hypopharynx and esophagus are censored at date of last 
disease evaluation. 
 
Disease-free survival: defined as time from study registration to earlier of removal of 
larynx/hypopharynx (i.e. local/locoregional recurrence), distant disease recurrence, invasive 
second primary, or death due to any cause. Participants alive without one of these events are 
censored at date last know event-free. 
 
Overall Survival: Overall Survival (OS) is defined as the time from study registration to death due 
to any cause, otherwise, participants are censored at date last known alive. 
 
11.1.7 Quality of life Assessment 
 
Quality of Life Assessment: The EORTC QOL Module for Head and Neck Cancer (QLQ-C30 and 
HN35, see Appendix D) will be used to assess the effect of cancer treatment on physical, social 
and emotional well-being and function. The survey consists of 30 and 35 items, respectively. 
 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 (Adverse 
Events: List and Reporting Requirements). 
 
12.1 
Data Reporting 
 
12.1.1 Method 
 
The Office of Data Quality (ODQ) will collect, manage, and perform quality checks on the data 
for this study. 
 
12.1.2 Responsibility for Data Submission 
 
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or data 
forms to the Office of Data Quality (ODQ) in accordance with DF/HCC policies. 
 
12.2 
Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity and 
accrual data from this study. The committee is composed of medical oncologists, research nurses, 
pharmacists and biostatisticians with direct experience in cancer clinical research. Information that raises 
any questions about participant safety will be addressed with the Overall PI and study team. 
 
 
Information to be provided to the committee may include: up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or higher unexpected 
adverse events that have been reported; summary of all deaths occurring within 30 days of intervention 


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for Phase I or II protocols; for gene therapy protocols, summary of all deaths while being treated and 
during active follow-up; any response information; audit results, and a summary provided by the study 
team. Other information (e.g. scans, laboratory values) will be provided upon request. 
 
12.3 
Multi-Center Guidelines 
 
This protocol will adhere to the policies and requirements of the DF/HCC Multi-Center Data and Safety 
Monitoring Plan. The specific responsibilities of the Overall PI, Coordinating Center, and Participating 
Institutions and the procedures for auditing are presented in Appendix E. 
 
• The Overall PI/Coordinating Center is responsible for distributing all IND Action Letters or Safety 
Reports to all participating institutions for submission to their individual IRBs for action as 
required. 
 
• Mechanisms will be in place to ensure quality assurance, protocol compliance, and adverse event 
reporting at each site. 
 
• Except in very unusual circumstances, each participating institution will order the study agent(s) 
directly from supplier. A participating site may order the agent(s) only after the initial IRB 
approval for the site has been forwarded to the Coordinating Center. 
 
 
13. STATISTICAL CONSIDERATIONS 
 
This is a one arm phase II trial. 
 
 
 
 
 
 
The primary efficacy population includes all eligible patients who begin protocol treatment(the evaluable 
population). 
 
 
Adverse events will be classified and graded according to the CTCAE v.4.0. and frequencies will be 
summarized among patients who begin protocol therapy. 
 
In addition to the continuous routine toxicity monitoring by the study team throughout the duration of the 
trial, the following 


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These events and rates will be continuously monitored and decisions made regarding the overall status of 
the trial. 
 
 
For the primary endpoint, the Kaplan-Meier method will be used to estimate LFS. For other secondary 
objectives: Best overall response will be summarized 
 
 
 
 
Another endpoint is to assess quality of life (QOL 


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14. PUBLICATION PLAN 
 
The results should be made public 


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