Clinical trial NCT03692325
Conditions: Leukoplakia, Oral
Sponsor: Dana-Farber Cancer Institute
Start date: 2018-12-05; Completion date: 2024-08-30
Enrollment: 33 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This research study is studying an immunotherapy drug, as a possible treatment for oral proliferative verrucous leukoplakia (OPVL).

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

The purpose of this study is to evaluate effectiveness (how well the drug works) of nivolumab in treating OPVL and or prolonging the onset of possible malignancy.

Nivolumab is a type of immunotherapy. Immunotherapy works by encouraging the body's own immune system to attack cancer cells. Nivolumab has been demonstrated to activate the immune system to attack cancer cells in participants with different types of cancers. OPVL has a high risk for turning into cancer and the investigators are testing if nivolumab may help to shrink the white lesions in the participant's mouth and reduce cancer risk.

In November 2016, the Food and Drug Administration (FDA) approved nivolumab for the treatment of participants with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Squamous cell carcinoma is the kind of cancer that OPVL can transform into.

Arms: arm 1: * Nivolumab will be administered by IV infusion on Day 1 of each 28-day cycle
* Treatment with the study drug will continue for a maximum of 4 cycles or until unacceptable toxicity or withdrawal of consent
Interventions: intervention 1: Nivolumab
Intervention descriptions: intervention 1: Nivolumab is a type of immunotherapy. Immunotherapy works by encouraging the body's own immune system to attack cancer cells.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
Title: Safety and efficacy of nivolumab in treating high-risk oral leukoplakia 
NCT Number: NCT03692325 
IRB Approval Date: 05/25/2021 


NCI Protocol #: N/A 
DF/HCC Protocol #: 
18-387 
 
Title: Safety and efficacy of nivolumab in treating high-risk oral leukoplakia 
Coordinating Center: Dana-Farber Cancer Institute 
 
Principal Investigator (PI): 
Glenn Hanna, MD 
Dana-Farber Cancer Institute 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Agents: Nivolumab; supplied by Bristol-Myers Squibb 
IND #: 140030 
 
IND Sponsor: Glenn Hanna, MD 
 
Protocol Type / Version Date: Amendment # 7, April 22, 2021. 
 
 
 
 
 
 
 
 
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SCHEMA 
 
 
 
 


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TABLE OF CONTENTS 
1. 
OBJECTIVES ...................................................................................................................... 5 
1.1 
Study Design ............................................................................................................ 5 
1.2 
Primary Objectives ................................................................................................... 5 
1.3 
Secondary Objectives ............................................................................................... 5 
2. 
BACKGROUND .................................................................................................................. 5 
2.1 
Study Disease(s) ....................................................................................................... 5 
2.2 
IND Agents .............................................................................................................. 6 
3. 
PARTICIPANT SELECTION ........................................................................................... 11 
3.1 
Eligibility Criteria .................................................................................................. 11 
3.2 
Exclusion Criteria ................................................................................................... 14 
3.3 
Inclusion of Women and Minorities ....................................................................... 14 
4. 
REGISTRATION PROCEDURES .................................................................................... 15 
4.1 
General Guidelines for DF/HCC Institutions ......................................................... 15 
4.2 
Registration Process for DF/HCC Institutions ....................................................... 15 
4.3 
General Guidelines for Other Investigative Sites ................................................... 15 
4.4 
Registration Process for Other Investigative Sites ................................................. 15 
5. 
TREATMENT PLAN ........................................................................................................ 15 
5.1 
Pre-Treatment Criteria ............................................................................................ 15 
5.2 
Treatment Regimen ................................................................................................ 16 
5.3 
Agent Administration ............................................................................................. 16 
5.4 
General Concomitant Medication and Supportive Care Guidelines ...................... 16 
5.5 
Criteria for Taking a Participant Off Protocol Therapy ......................................... 17 
5.6 
Duration of Follow-Up ........................................................................................... 18 
5.7 
Criteria for Taking a Participant Off Study ............................................................ 18 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ................................................................ 18 
7. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS ............................. 19 
7.1 
Adverse Event Characteristics ................................................................................ 19 
7.2 
Serious Adverse Events .......................................................................................... 19 
7.3 
Expected Toxicities ................................................................................................ 20 
7.4 
Routine Adverse Event Reporting .......................................................................... 21 
7.5 
Serious Adverse Event Collection and Reporting .................................................. 21 
7.6 
Expedited Adverse Event Reporting to Overall PI ................................................ 22 
7.7 
Expedited Adverse Event Reporting to the Food and Drug Administration 
(FDA) ..................................................................................................................... 22 
7.8 
Expedited Adverse Event Reporting to Hospital Risk Management ..................... 22 
7.9 
Expedited Adverse Event Reporting to BMS......................................................... 23 
8. 
PHARMACEUTICAL INFORMATION .......................................................................... 23 
8.1 
Storage and Stability .............................................................................................. 24 
8.2 
Handling ................................................................................................................. 24 


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8.3 
Availability ............................................................................................................. 24 
8.4 
Ordering ................................................................................................................. 24 
8.5 
Accountability ........................................................................................................ 24 
8.6 
Destruction and Return .......................................................................................... 25 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ......................................... 25 
10. 
STUDY CALENDAR ........................................................................................................ 27 
11. 
MEASUREMENT OF EFFECT ........................................................................................ 29 
11.1 
Measurement of Effect – OPVL lesions................................................................. 29 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ............................................ 35 
12.1 
Data Reporting ....................................................................................................... 35 
12.2 
Data Safety Monitoring .......................................................................................... 35 
12.3 
Multicenter Guidelines ........................................................................................... 35 
13. 
STATISTICAL CONSIDERATIONS ............................................................................... 35 
14. 
PUBLICATION PLAN ...................................................................................................... 37 
15. 
REFERENCES ................................................................................................................... 37 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................... 40 
APPENDIX B 
GUIDANCE ON CONTRACEPTION ....................................................... 42 
APPENDIX C 
TOXICITY MANAGEMENT ALGORITHMS .......................................... 43 


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1. OBJECTIVES 
 
1.1 
Study Design 
 
This is a phase II, open label, non-randomized, trial of nivolumab (anti-PD-1) in patients with 
high-risk oral (precancerous) lesions, specifically oral proliferative verrucous leukoplakia (PVL), 
leukoplakia with moderate dysplasia, and erythroleukoplakic lesions. Following initial biopsy of 
up to 3 sites per patient, four monthly doses of the nivolumab will be given. Patients will be 
followed for evidence of clinical regression (in bidimensional measurement) of lesions. After 
treatment, patients will undergo re-biopsy of the same leukoplakia site(s) which will be evaluated 
for regression of the degree of dysplasia (if applicable). The primary endpoint of the study is to 
evaluate the best overall response rate to nivolumab in high-risk oral leukoplakia patients. 
Secondary endpoints will include safety, toxicity assessments, quality of life scores, time to next 
head & neck cancer surgery, cancer-free survival (CFS), overall survival (OS) , and genomic and 
immune correlates of response. 
 
We hypothesize that nivolumab will cause regression in both the size and the degree of dysplasia 
of high-risk oral precancerous lesions, leading to a longer time to the next head & neck surgery, 
as well as improved quality of life and improved survival. 
 
1.2 
Primary Objectives 
 
• To evaluate the efficacy of nivolumab in treating high-risk oral leukoplakia (by 
bidirectional measurement and degree of dysplasia) based on best overall response 
1.3 
Secondary Objectives 
• To evaluate safety and toxicity, and quality of life scores 
• To evaluate the time to the next surgery for a head and neck malignancy 
• To estimate CFS from the time of study registration 
• To estimate OS from the time of study registration 
• To characterize distinct tumor and circulating immunophentoypes and correlate these 
findings with outcomes 
 
2. BACKGROUND 
 
2.1 
Study Disease(s) 
 
Leukoplakia as defined by the World Health Organization (WHO) is “a white plaque of 
questionable risk having excluded (other) known diseases or disorders that carry no increased 
risk for cancer” [1]. Oral proliferative verrucous leukoplakia (PVL) is recognized as an 
aggressive variant of leukoplakia with a higher malignant potential [2]. Oral PVL can involve a 
single site, but is frequently multifocal and often occurs on the gingiva, oral mucosa and tongue 
in both contiguous and noncontiguous regions of the oral cavity [1-4]. 


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Lesions of oral PVL have a nodular or verrucous appearance and affect females more with no 
racial predilection [5-7]. The mean age at the time of diagnosis is in the seventh decade [8], 
approximately two-thirds occur in never smokers and there is no substantial association with 
alcohol consumption [3]. The diagnosis is based on expert oral clinicopathologic examination. 
Oral PVL is thought to progress in a step-wise fashion from hyperkeratosis or hyperplasia (now 
termed keratosis of undetermined significance [KUS]), to various degrees of dysplasia, and 
ultimately carcinoma in situ and/or invasive oral squamous cell carcinoma (OSCC) [8-10]. The 
estimated pooled prevalence of oral leukoplakia in the general population appears to be between 
1.5% (1.4%-1.6%, 95% confidence interval [CI]) and 2.6% (1.7%-2.7%, 95%CI) [11]. 
 
The etiology of oral PVL remains largely unknown. In terms of molecular profiling, 
overexpression of p53 and deletions or mutations of the p16INK4a and p14ARF have been noted 
[12-14]. Lesions also develop aneuploidy and alterations in the Mcm2 complex [15, 16]. A 
causal relationship with the human papillomavirus (HPV) and oral PVL has not been established 
[13, 17-19]. A recent systematic review of 25 studies on oral PVL showed a mean malignant 
transformation (MT) rate of 63.9% with a mean follow-up time of 7.4 years [8]. The annual MT 
rate of oral PVL is approximately 10% per year [10] with an overall 40% mortality rate [3, 8]. 
Recent data from our group (n = 43) have shown that in patients with oral PVL a median of three 
biopsies (range: 1-26) was performed before MT occurred [20]. MT to invasive OSCC occurred 
in 71.4% patients (30/42) after a median of 37 months (range: 1-210) from their initial clinic 
visit. By far, the most common histopathologic diagnosis from biopsies taken at the initial visit 
(i.e. baseline) was hyperkeratosis without dysplasia (also known as KUS; n = 22; 56.4%) [21]. 
This was followed by mild (n = 14; 35.9%), moderate (n = 2; 5.1%) and severe dysplasia (n = 1; 
2.6%). In addition to oral PVL, the extent and degree of dysplasia correlates with risk of 
transformation; and erythroplakia is a clinical feature that portends the highest risk of malignant 
transformation [10]. 
 
Management of high-risk oral leukoplakia conditions remains challenging. In oral PVL in 
particular, management is complicated by the multi-focality of this condition and surgical 
treatment has not been shown to impact the natural history of malignant transformation [22]. 
Patients are monitored closely every 3-6 months (depending of the histopathological diagnosis) 
with periodic biopsies to rule out dysplasia or invasive OSCC, especially when there has been a 
change in the character of the lesion(s): such as development of red and/or nodular/verrucous 
areas, induration and involvement of other sites [10]. Surgery is the most utilized treatment 
option, but recurrence rates remain high at 71.2%, particularly in oral PVL [8]. Other modalities 
of treatment that have been reported include: laser ablation, photodynamic therapy and medical 
therapy although none of these have demonstrated significant efficacy [23-25]. 
2.2 
IND Agents 
 
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 [26]. Mechanisms of tumor evasion include 
the development of T cell tolerance, modulation of inflammatory and angiogenic cytokines, 


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downregulation of antigen-processing machinery, and changes in immune checkpoint receptor 
ligands or receptors that can all facilitate tumor immune evasion [27-29]. 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 
[30]. 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 [31]. 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 [32]. Beyond PD-1 deficient models, antibody blockade in several mouse models 
have demonstrated the emergence of similar autoimmune phenomena [33]. 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 [34, 35], studies have estimated PD-L1 
expression in squamous cell carcinoma of the head and neck (SCCHN) at 30–70% with human 
papillomavirus (HPV) positive tumors more frequently harboring infiltrating immune cells that 
express PD-1 [36, 37]. 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 [38]. Additionally, elevated PD-L1 expression levels correlate with a poor 
prognosis in some solid tumor malignancies [39]. 
 
Beyond invasive carcinoma of the head and neck, recent studies have suggested that early 
immunologic intervention may benefit premalignant oral mucosal sites. Preclinical murine 
models harboring 4NQO-induced oral PVL have been treated with anti-PD-1 therapy and 
blockade of the PD-1 axis resulted in diminished progression of low-grade oral SCCHN lesions 
to high-grade lesions [40]. More infiltrating CD8+ T cells and T-regulatory cells were observed 
in the low-grade lesions following PD-1 blockade. Further, increased production of interferon-γ 
and granzyme B in the treated mice suggested that CD8+ T cell cytotoxic activity increased as 
well. 
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 [41]. 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 [42]. 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 


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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 [43]. 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 to 4 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 [41]. Additionally, PPK and exposure response analyses have been performed to 
support the use of 240 mg IV flat dosing every 2 weeks and 480 mg IV flat dosing every 4 weeks 
in addition to the 3 mg/kg every 2 week regimen. Using the PPK model, exposure to nivolumab 
at 240 mg IV flat dose (every 2 weeks) or 480 mg IV flat dose (every 4 weeks) 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 [44]. 
 
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 [45]. 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 [46, 47]. Treatment-related adverse events of grade 3 or 4 were 


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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. 
 
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) [44]. 
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 six 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) [45]. Nivolumab (at a dose of 3 
mg/kg body weight IV) every 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. 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, 
although benefit was seen regardless of PD-L1 expression or HPV status in some patients. This 
study led to the approval of nivolumab in this setting in April of 2016. 
2.3 Rationale 
 
Oral proliferative verrucous leukoplakia (PVL), localized leukoplakia with moderate dysplasia, 
and erythroplakia are aggressive oral precancerous entities that are associated with a high rate of 
malignant transformation: up to 60-70% of affected patients are diagnosed with invasive oral 
cancer within a period of 3-5 years [5, 8, 9, 48]. The management of oral PVL in particular 
remains challenging due to the fact that no available treatments impact the natural progression to 
invasive cancer and there is also no consensus or “best practice” guidelines for treatment of 


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dysplastic lesions [49]. Current strategies focus on surgical excision, laser ablation techniques, 
photodynamic and topical therapies with variable success [25, 50-52]. Importantly, surgical 
excision of oral PVL has not been shown to improve rates of malignant transformation [9]. 
Therefore, patients are generally monitored with frequent sequential oral biopsies to evaluate for 
progression to cancer [5, 8]. When cancer is diagnosed, referral to a head & neck surgeon for 
oncologic resection is warranted. Despite adequate cancer treatment, recurrence rates exceed 
70% in this high-risk population [8-10]. 
 
The evolution from oral precancerous or dysplastic changes in these conditions to invasive 
OSCC is not well understood, but is thought to progress in a step-wise accumulation of somatic 
gene alterations, DNA double-strand breaks and copy-number alterations [53, 54]. More 
recently, preclinical data has suggested that immune modulation plays a critical role in oral 
carcinogenesis [55]. With advances in immuno-oncology demonstrating the efficacy of immune 
checkpoint inhibitors targeting the programmed cell death protein-1 (PD-1) axis in advanced 
SCCHN [56, 57], there is significant interest in understanding the impact of PD-1 blockade in 
early SCCHN and in cancer prevention, particularly for those at high-risk for malignant 
transformation. 
 
Recent data suggests that nearly 50% of high-grade oral leukoplakia samples are ligand of PD-1 
(PD-L1) positive [58]. Moreover, PD-L1 positivity and CD8+ T cell count are significantly 
associated with the degree of dysplasia among these samples (p < 0.001) [58]. These findings 
suggest that anti-tumor immunity can be suppressed through upregulation of PD-L1 among 
dysplastic lesions which could promote malignant transformation – confirming the importance of 
immunoediting in oral carcinogenesis. Currently, a phase II trial [NCT02882282] is active but 
not enrolling patients with oral intra-epithelial neoplasia and the molecular high-risk profile of 
loss of heterozygosity (LOH) at 3p14 and/or 9p21, plus at least at one additional chromosomal 
site (4q, 8p, 11p, 13q, or 17p) for patients with no prior oral cancer, or LOH at 3p14 and/or 9p21 
for those with a prior history of invasive oral cancer. Eligible patients receive four doses of 
pembrolizumab. In addition, a phase II trial of pembrolizumab is enrolling patients with a 
diagnosis of leukoplakia, erythroleukoplakia, or PVL with measurable lesions to receive therapy 
for 6-months with a primary endpoint of clinical response at 6- and 12-months [NCT03603223]. 
These studies provide a strong rationale for the early use of therapies targeting the PD-1:L1 axis 
in patients with high-grade oral precancerous lesions, such as oral PVL. Demonstrated efficacy 
or a response signal in this critical population would have significant implications regarding 
immune checkpoint blockade to delay or prevent oral carcinogenesis. 
 
2.4 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 [59]. More 
recently, whole-exome sequencing of NSCLC tumors treated with PD-1 blockade revealed that 
higher mutational burden correlated with improved objective response rates [60]. 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 


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PD-L1 negative patients may respond to treatment – suggesting important mechanisms beyond 
PD-1:L1 interactions [61, 62]. 
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 [63, 64]. Studies confirming these findings in head and neck cancer patients 
are not yet published, although our own preliminary work has shown 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 [65]. We hypothesize that similar 
immunophenotypes can be discerned in early invasive SCCHN samples and even in high-risk 
oral precancerous lesions. The design of the proposed study will allow evaluation of pre- and 
post-immunotherapy biopsy samples in high-risk oral leukoplakia patients, permitting 
investigation of immune microenvironment alterations to potentially identify mechanisms of 
response. Additionally, whether the circulating peripheral immune environment recapitulates the 
oral immune microenvironment remains an unanswered question. By evaluating both the oral 
biopsy and circulating immune profile, we hope to evaluate whether early peripheral blood 
changes in immune parameters could parallel an early indication of treatment response, avoiding 
the cost and risk of sequential biopsies. Understanding the genomic determinants which drive 
immunophenotype appear crucial and therefore whole exome and bulk RNA sequencing are also 
planned. 
 
3. PARTICIPANT SELECTION 
 
Participants must meet the following eligibility criteria on screening examination to be eligible to 
participate in the study: 
 
Eligibility Criteria 
 
3.1.1 Subject must have have a confirmed diagnosis of high-risk oral leukoplakia which is 
defined by any of the following: 
(1) Diagnosis of oral PVL with multifocal lesions (≥2) or contiguous lesions ≥3 cm or 
a single lesion ≥4 cm in largest diameter (at least one lesion with any degree of 
dysplasia) 
(2) Diagnosis of oral PVL without dysplasia on biopsy but with 4 oral cavity quadrant 
involvement 
(3) Diagnosis of leukoplakia in at least 1 lesion with moderate dysplasia (without a 
diagnosis of oral PVL) for which surgery is indicated, but not feasible or patient 
refused. 
(4) Diagnosis of erythroplakia or erythroleukoplakia with any degree of dysplasia for 
which surgery is indicated, but not feasible or patient refused. 
3.1.2 Willing to provide blood and tissue from diagnostic biopsies 


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3.1.3 Any smoking history is permitted. A history of prior or current tobacco use is not an 
exclusion criteria. While discouraged, patients are permitted to continue tobacco use 
while on the study. 
 
3.1.4 Age 18 years or older 
 
3.1.5 ECOG performance status ≤ 2 (Karnofsky ≥60%, see Appendix A) 
 
3.1.6 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 
≥1,000/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 
 
3.1.7 Ability to understand and the willingness to sign a written informed consent document 
 
3.1.8 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 
 
3.1.9 Women of childbearing potential must have a negative serum or urine pregnancy test 
(minimum sensitivity 25 iu/l or equivalent units of hcg) at screening. Pregnancy test will 
be repeated on the day of the first dose of study drug (before administration), although 
results of this test are not required for registration. 
 
“Women of childbearing potential (WOCBP)” is defined as any female who has 
experienced menarche and who has not undergone surgical sterilization (hysterectomy or 
bilateral oophorectomy) or who is not postmenopausal. Menopause is defined clinically 
as 12 months of amenorrhea in a woman over 45 in the absence of other biological or 
physiological causes. In addition, women under the age of 55 must have a documented 
serum follicle stimulating hormone (FSH) level greater than 40 mIU/mL 
 
3.1.10 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 


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See Appendix B for further guidance on contraception. 


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Exclusion Criteria 
 
3.1.11 Known carcinoma in situ (CIS) or invasive squamous cell carcinoma of the oral cavity. A 
history of a prior stage III (T1-2N1, T3N0) or IV (T1-3N2, T4N0) invasive head & neck 
squamous cell carcinoma treated with surgery and radiation with or without 
chemotherapy. Patients with prior locoregionally advanced tumors treated with surgery 
alone are eligible. 
 
3.1.12 Existing significant autoimmune conditions. Patients with a history of Hashimoto 
thyroiditis who are stable on replacement hormone therapy are not excluded. Patients 
cannot be on long-term (> 4 weeks) corticosteroids at doses exceeding prednisone 20 mg 
(or its equivalent) prior to enrollment. Short-term corticosteroid dosing is permitted as 
long as steroids are discontinued within 2 weeks of study registration. 
 
3.1.13 Subject who has had chemotherapy or radiotherapy within 4 weeks (6 weeks for 
nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered 
from adverse events due to agents administered more than 4 weeks earlier. 
 
3.1.14 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 checkpoint pathways. 
 
3.1.15 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. 
 
3.1.16 Known human immunodeficiency virus carrier or a diagnosis of immunodeficiency. 
 
3.1.17 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 is negative). 
 
3.2.7 A personal history of hematopoietic stem cell or solid organ transplant. 
 
3.2.8 Known non-infectious pneumonitis or any history of interstitial lung disease. 
 
3.2.9 A personal history of other active malignancies, with the exception of non-melanomatous 
skin cancers, low-risk prostate adenocarcinoma on active surveillance, or treated cancers 
in remission for the last 5 years. 
 
3.2 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this study. 


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4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines for DF/HCC Institutions 
 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist. 
 
Eligible subjects will be registered by a member of the study team in the Clinical Trials 
Management System (CTMS) “OnCore”. Registrations must occur prior to the initiation of 
protocol therapy. Any subject not registered to the protocol before protocol therapy begins will 
be considered ineligible and registration will be denied. 
 
Following registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study must be canceled. Registration cancellations must be made in OnCore as soon as possible. 
 
4.2 
Registration Process for DF/HCC Institutions 
 
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed. 
 
5. TREATMENT PLAN 
 
Treatment will be administered on an outpatient basis. No investigational or commercial agents 
or therapies other than nivolumab (BMS-936558) may be administered with the intent to treat the 
participant’s oral high-risk leukoplakia during the course of treatment. 
 
5.1 
Pre-Treatment Criteria 
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 focused medical histories. 
 
5.2 
Treatment Regimen 
Pre-medications are not required. There is no need to wait for the result of TSH level to treat. 
Each treatment cycle will be 28 days long. Nivolumab infusion must be promptly followed by a 
saline flush to clear the line of nivolumab. Participants should be carefully monitored for 


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infusion reactions during nivolumab administration. If an acute infusion reaction is noted, 
participants should be managed according to the algorithm described in Appendix D. 
Nivolumab 480 mg will be administered by IV infusion on Day 1 of each 28-day cycle. 
Treatment with the study drug will continue for a maximum of 4 cycles or until unacceptable 
toxicity or withdrawal of consent. Nivolumab will be administered over 60 +/-10 minutes via a 
low protein binding infusion set with 0.2-1.2 micron in-line filter. 
 
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 cycle 1 day 1 visit and cycle 1 day 1 labs do not need to be performed. Day 1 labs 
do not need to re-meet eligibility criteria. 
 
5.3 
Agent Administration 
 
Detailed administration instructions will be provided separately, in the Investigator’s Brochures. 
5.4 
General Concomitant Medication and Supportive Care Guidelines 
Because there is a potential for interaction of IND agents with other concomitantly administered 
drugs through the cytochrome P450 system, the Overall PI should be alerted if the participant is 
taking such agents prior to beginning protocol treatment. 
5.4.1 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 
• Any anti-neoplastic therapy (i.e., chemotherapy, hormonal therapy, immunotherapy, 
extensive, non-palliative radiation therapy, or standard or investigational agents for treatment 
of NSCLC) 
5.4.2 Other Restrictions and Precautions 
 
Participants with a condition requiring systemic treatment with either corticosteroids (> 20 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of the first 
dose of study 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. 
5.4.3 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 brief (less than 3 weeks) course of corticosteroids for 


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prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., 
delayed-type hypersensitivity reaction caused by a contact allergen) is permitted. 
5.5 
Criteria for Taking a Participant Off Protocol Therapy 
 
Adverse events will be continuously monitored throughout the trial by the study team with 
decisions made accordingly regarding the study status and patient entry throughout the duration 
of the trial. 
 
Any adverse event(s) attributed to the study medication should result in a delay in future dosing. 
Therapy can be resumed at the discretion of the treating physician or PI. Duration of therapy will 
depend on individual tolerance and response. In the absence of treatment delays due to adverse 
event(s), treatment may continue for four cycles or until one of the following criteria applies: 
 
• 
A diagnosis of invasive squamous cell carcinoma of the head and neck is confirmed 
at any point during study screening or on study. Note: if pre-treatment target lesions 
are increasing in size during the study period then the patient is permitted to continue 
with treatment until formal response assessment after the four planned doses of 
nivolumab. However, it is at the discretion of the treating physician whether to re- 
biopsy any target site before completion of the four planned doses of study treatment. 
If the patient develops a new measurable site during the treatment period, the patient 
can receive the four planned doses of treatment if an on-study biopsy of the new site 
confirms dysplasia without carcinoma in situ or invasive squamous cell carcinoma. A 
diagnosis of invasive squamous cell carcinoma at any point during the study warrants 
referral to a head & neck surgeon for consideration of oncologic resection. 
 
• 
Intercurrent illness that prevents further administration of treatment 
 
• 
Unacceptable adverse event(s) 
 
• 
Participant demonstrates an inability or unwillingness to comply with the medication 
regimen and/or documentation requirements 
 
• 
Participant decides to withdraw from the protocol therapy 
 
• 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator 
 
Participants will be removed from the protocol therapy when any of these criteria apply. The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant. 
 
When a participant is removed from protocol therapy and/or is off of the study, the relevant Off- 
Treatment/Off-Study information will be updated in OnCore. 


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In the event of unusual or life-threatening complications, treating investigators must immediately 
notify Glenn Hanna, MD 
5.6 
Duration of Follow-Up 
 
Participants, regardless if they receive the full course of therapy, will be followed for best overall 
response and development of first invasive OSCC and for survival for 5 years from the time of 
study registration throughout the course of the trial. Participants removed from protocol therapy 
for unacceptable adverse event and if they have not developed first invasive OSCC at time of 
discontinuation of protocol therapy, will continue to be followed until first invasive OSCC and 
survival until death or 5 years from study registration (whichever occurs first). 
 
5.7 
Criteria for Taking a Participant Off Study 
 
Participants will be removed from study when any of the following criteria apply: 
• Lost to follow-up 
• Withdrawal of consent for data submission 
• Death 
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). In addition, the study team will ensure Off 
Treatment/Off Study information is updated in OnCore in accordance with DF/HCC policy 
REGIST-101. 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
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. 
 
Although this is not a phase I protocol, the use of these drugs and the combination in the 
oral precancerous setting is relatively novel, and therefore we plan to include a safety run-in to 
ensure that treatment is well tolerated in this setting. A separate safety run in will be performed 
for the initial study participants, as described in detail in Section 13, Statistical Considerations. 
 
Administration of the study drug 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 D for guidelines on managing immune-related toxicities 


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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 10 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. 
 
7. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. 
 
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 
5.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP website 
[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. 
• In the event of an unanticipated problem or life-threatening complications treating 
investigators must immediately notify the Overall PI 
7.2 
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). 
 
7.3 
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. Management of expected 
toxicities is described in Appendix D. 
 
Most common adverse reactions (>20%) related to nivolumab 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. 
− 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 


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7.4 
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 5.0) will be utilized for AE reporting. 
The CTEP Active Version of the CTCAE version 5.0 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. 
 
7.4.1 
Routine Adverse Event Reporting to BMS 
 
Adverse Events that are routinely collected according to GCP shall be submitted to BMS every 
three (3) months by the last working day of the third month. 
 
The Adverse Event information required to be sent to BMS is noted in an attached ‘Bristol- 
Myers Squibb Early Asset Investigator Sponsored Research (ISR) Import Plan’ (Appendix D) 
which describes the method of collection and submission to BMS via the mailbox: 
 
 
When the file is submitted to BMS, it must be noted that the file contains all “Non Serious 
Adverse Events” (only adverse events not previously submitted to BMS within the 3 months) 
 
7.5 
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 must be collected that occur within 90 days of 
discontinuation of dosing. All SAEs should be followed to resolution or stabilization. 
 
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. 


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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 or fax 
upon request from 
the Investigator, the GPV&E reconciliation report. Requests for reconciliation should be sent to 
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. 
 
7.6 
Expedited Adverse Event Reporting to Overall PI 
 
Investigators must report to the Overall PI any serious adverse event (SAE) that occurs after the 
initial dose of study treatment, during treatment, or within 90 days of the last dose of treatment 
on the local institutional SAE form. 
 
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. 
 
7.7 
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. 
 
Report any unexpected fatal or life-threatening suspected adverse reactions to the Division of 
Oncology Products 2, Office of Hematology and Oncology Products, Center for Drug Evaluation 
and Research, no later than 7 calendar days after initial receipt of the information. 
 
Report any (1) serious, unexpected suspected adverse reactions, (2) findings from other clinical, 
animal, or in-vitro studies that suggest significant human risk, and (3) a clinically important 
increase in the rate of a serious suspected adverse reaction to this Division and to all 
investigators no later than 15 calendar days after determining that the information qualifies for 
reporting. 
 
7.8 
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. 
7.9 
Expedited Adverse Event Reporting to BMS 
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS 
within 24 hours. SAEs must be recorded on the MedWatch form (Form FDA 3500) ; pregnancies 
on a Pregnancy Surveillance Form. 
SAE Email Address: 


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SAE Facsimile Number: 
 
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.) 
 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to the BMS (or 
designee) using the same procedure used for transmitting the initial SAE report. 
 
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 7.3 and the details can be found in the 
Investigator’s Brochures (IBs), provided by BMS. 
 
Product information table: please also see respective product investigator brochures 
 
Table 1. Product Description 
Product 
Potency 
Primary 
Secondary 
Appearance 
Storage 
Description 
Packaging 
Packaging 
Conditions 
and Dosage 
(Volume)/ 
(Qty) /Label 
(per label) 
Form 
Label Type 
Type 
Nivolumab 
100 mg 
10 mL vial 
5 vials per 
Clear to opalescent 
2 to 8°C. 
(BMS- 
(10 
carton/ 
colorless to pale 
Protect form 
936558-01) 
mg/mL) 
Open-label 
yellow liquid. May 
light and 
Solution for 
contain particles 
freezing 
Injection 
 
 
8.1 
Storage and Stability 
 
Nivolumab must be stored at 2º-8ºC (36º-46ºF) and protected from light and freezing. IV bags 
containing undiluted and diluted solutions of Nivolumab prepared for dosing may be stored up to 
20 hours in a refrigerator at 2°-8°C (36°-46°F) and used within 8 hours at room temperature and 
under room light. The maximum 8-hour period under room temperature and room light 
conditions for undiluted and diluted solutions of Nivolumab injection in the IV bag should be 
inclusive of the product administration period. 
 
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 the BMS-936558-01(nivolumab) investigator 
brochure section for “recommended storage and use conditions”. 


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8.2 
Preparation 
 
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 to 10 mg/ml. Mix diluted 
solution by gentle infusion. Do not shake. The maximum allowable volume of final infusion is 
120 ml. 
 
8.3 
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. 
 
8.4 
Availability 
 
Free of cost, investigational supply of nivolumab, will be provided by Bristol-Myers Squibb. 
 
8.5 
Ordering 
 
Dana-Farber Research Pharmacy will request supply of nivolumab from Bristol-Myers Squibb, 
by submitting an order form, provided by Bristol-Myers Squibb. 
 
8.6 
Accountability 
Accountability for investigational agents at the study site is the responsibility of the sponsor- 
investigator. Study drug will be dispensed only to eligible patients by Dana-Farber Research 
Pharmacy. The appropriate study personnel will maintain records of study drug receipt and 
dispensing at Dana-Farber Research Pharmacy. A careful record of the inventory and disposition 
of the agent will be maintained, using the NCI Drug Accountability Record Form (DARF). 
 
8.7 
Destruction and Return 
 
Unused supplies and expired supplies of the investigational agents will be destroyed on site, by 
the Dana-Farber Research Pharmacy, per DFCI institutional policy. 
 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
Correlative studies are planned as part of this study. At the time of initial biopsy (before study 
drug dosing), oral precancerous tissue (obtained from up to 3 sites per patient) will be sent for 
multiparametric flow cytometry 
DFCI), a portion of 
fresh-frozen, paraffin-embedded (FFPE) tissue will be obtained for genomic sequencing and for 
immunohistochemistry (IHC) for immune marker staining (e.g. PD-1, PD-L1/L2) and/or 
multiplexed immunofluorescence (MIF). Flow cytometry, sequencing and IHC/MIF data will be 
gathered to characterize distinct immunophentoypes and these findings will be correlated with 
outcomes. Additionally, peripheral blood samples will be collected at various time points for 
circulating immune profiling. 


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9.1 Biomarker Studies 
 
Oral precancerous high-risk leukoplakia is a requirement to be enrolled on this study. A separate, 
fresh research biopsy (and up to 3 per patient) is mandatory prior to starting treatment on study, 
archival tissue will not be accepted. At the time of biopsy, after adequate tissue for pathological 
assessment has been harvested as deemed appropriate by the proceduralist, remaining tissue will 
be collected for research purposes. If relevant, tissue may also be obtained at the time of an 
invasive oral cancer diagnosis for research purposes. 
 
Oral mucosal biopsies should not generally be performed late on Friday afternoons, as there may 
not be time for processing of fresh tissue samples. 
 
 
 
Each oral biopsy 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. 
 
At the time of oral mucosal biopsy (see Study calendar), 4 cores are requested from the dominant 
or largest precancerous lesion: 
1. 2 cores each in its own Roswell Park Memorial Institute (RPMI) containing 10% fetal 
bovine serum (FBS) 5 mL microcentrifuge tube for multiparametric flow cytometry 
2. 1 core in 10% neutral buffered formalin in a standard orange-top specimen cup for 
tissue block and slide preparation allowing for immunohistochemistry 
3. 1 core in 5 mL of RPMI media in a 5-15 mL conical tube for genomic sequencing 
If the patient has 2 or 3 oral mucosal biopsy sites for characterization of dysplasia, only the 
dominant or largest lesion requires 4 cores for correlative studies. The remaining 1-2 sites are 
only biopsied to evaluate the degree of dysplasia and monitor for invasive transformation. 
At the time of blood sample collection (see Study calendar), 2 tubes are requested: 
• 2 tubes drawn in 8 mL whole blood, purple top tubes for circulating immune profiling 
 
Multiparametric flow cytometry 
At the time of pre- and post-treatment biopsy, two cores of fresh tissue will be allocated to two 
1.5 mL centrifuge tubes (one core in each tube) in RPMI containing 10% fetal bovine serum 
(FBS). The specimen will be de-identified and labeled with the participant’s initials, study ID 
number and the date of acquisition. After collection, the two tubes should be delivered 


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immediately to the lab of 
 
The specimen must arrive in a timely fashion to 
facilitate processing for evaluation of immune cells. Tissue will be prepared as a cell suspension 
that will be stained using fluorescently-conjugated antibody cocktails for human immune 
markers (surface antibodies include: CD45, CD3, CD4, CD8, CD69, CD38, CCR7, LAG-3, 
TIM-3, PD-1, CD45RA, CTLA-4, CD16, CD158b, CD158, CD56, CD160, PD-L1, GITR, 
CD15, CD19, and CD14). Cells will be analyzed within 72 hours of fixation on a BD Fortessa 
cell analyzer with FACSDiva software v8.0.1 (BD Biosciences) and gated using FlowJo software 
v10. 
 
Circulating immune profiling 
 
At the time of pre- and post-treatment biopsy and a specified time points during and after 
treatment, two tubes of peripheral blood (obtained at a minimum of 3 time points during the 
study) will be obtained per standard collection protocols – drawn in phlebotomy or clinic and 
captured in 8 mL whole blood, purple top tubes. The volume of blood to be collected per blood 
draw for study purposes will not exceed 40 mL. The specimen will be de-identified and labeled 
with the participant’s initials, study ID number and the date of acquisition. After collection, the 
blood sample should be delivered immediately to lab 
The specimen must 
arrive in a timely fashion to facilitate processing for evaluation of immune cells. Blood must be 
spun within 3 hours of collection for 15 min at 3000 rpm. The plasma is then aliquoted into 2 x 
60 µL aliquots and immediately frozen at -80ºC. Plasma is thawed on ice prior to usage. 50 µL 
of plasma is sufficient for each assay, where triplicate measurements per sample per time point 
are envisaged. Plasma is diluted 1:4 (15 µL in 50 µL reaction) prior to transfer to plate-based 
assay. We will utilize a multiplex magnetic bead-based sandwich ELISA assay to simultaneously 
measure the soluble form of 14 immune checkpoint molecules (BTLA, CTLA-4, PD-1, PD-L1, 
PD-L2, GITR, HVEM, IDO, LAG-3, TIM-3, CD27, CD28, CD80 and CD137). Each bead is 
encoded with a ratiometric concentration of 2 IR dyes and act as a barcode, unique to each 
protein. The final detection complex is formed with the addition of streptavidin-phycoerythrin 
(SA-PE) conjugate, where the phycoerythrin serves as the fluorescent reporter. Plasma 
concentration levels, measured in pg/mL, for each protein are derived from 5-parameter curve 
fitting models. Fold change relative to pre-treated baseline are calculated and plotted as log2FC 
to establish biological significance. The changes in secretion levels will be correlated with tumor 
immune parameters and clinical response. 
 
Immunohistochemistry 
At the time of pre- and post-treatment biopsy, one core of fresh tissue will be allocated to a 
standard orange-top specimen cup containing 10% neutral buffered formalin. The specimen will 
be labeled with the participant’s initials, medical record number and the date of acquisition. After 
collection, the specimen will be sent to the Brigham & Women’s Hospital (BWH) pathology 
division for processing. Following standard tissue processing, sectioning and slide preparation 
for histopathologic review, the specimen will be stored in accordance with BWH protocols (both 
tissue blocks and tissue slides). At a later time, we will then request tissue block retrieval through 
the Pathology Specimen Locator Core with preparation of 5 unstained slides through the 
Specialized Histopathology (SHP) Core service at BWH. SHP will then prepare 1 stained 


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hematoxylin & eosin slide, 1 slide stained for PD-1, 1 slide stained for PD-L1 and 2 unstained 
slides will be stored for additional studies. These slides will be retrieved from the SHP in Thorn 
Building, 6th floor, room 603 at the BWH by the study principal investigator. In collaboration 
with an oral maxillofacial pathologist, Dr. Sook-Bin Woo of the BWH Department of Oral 
Medicine and Dentistry, the slides will be analyzed and scored based on stained immune 
parameters. 
 
Genomic sequencing 
 
At the time of pre- and post-treatment biopsy, one core of fresh tissue will be allocated to 5 mL 
of RPMI media in a 5-15 mL conical tube for the purposes of DNA and RNA sequencing efforts. 
Once prepared, aliquoted core material for sequencing will be delivered immediately to the 
laboratory of Dr. Ravindra Uppaluri at the DFCI 
 
 
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 
and x-rays must be done <4 weeks prior to study registration. 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. Each treatment cycle in this study is 28 days long. 
 
Assessments must be performed prior to administration of any study agent. Study assessments 
and agents should be administered within + 3 days of the protocol-specified date, unless 
otherwise noted. 
 
Studies 
Screening 
Enrollment 
Treatment phase 
End of 
Treatmenth 
Follow up 
visit 30 days 
after the last 
doseh 
Survival 
Follow up 
Cycle 
1 
Cycle 
2 
Cycle 
3 
Cycle 
4 
Day 
Day 
Day 
Day 
Informed consent 
X 
Medical History 
X 
Physical exam 
(Ht, Wt, VS, PS) 
X 
X 
X 
X 
X 
X 
X 
Routine labs b 
X 
X 
X 
X 
X 
X 
X 
B-HCG 
(WOCBP only) c 
X 
X 
X 
X 
X 
X 
X 
FSH test d 
X 
ECG 
X 
X 


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Photographs, 
measurements e 
X 
X 
X 
X 
X 
X h 
X h 
Biopsy samples f 
X 
X 
X h 
Correlative 
biopsies f 
X 
X 
X h 
Correlative blood 
X 
X 
X 
X 
X 
Nivolumab 
X 
X 
X 
X 
Quality of life 
survey g 
X 
X 
X 
X 
Adverse event 
evaluation 
X 
X 
X 
X 
X 
X 
Survival Status 
X h 
a) Physical exam is symptom directed. Height measured at screening only. 
b) Routine labs include: CBC with differential, LFTs, chemistries, TSH, phosphorous. Baseline HCV antibody, hepatitis B 
surface antigen, hepatitis B surface antibody, and hepatitis B core antibody testing is required at screening only. 
c) Serum or urine within 24 hours prior to first dose. 
d) Follicle Stimulating Hormone test will be performed only on women who are under 55 years of age. 
e)  Color digital photographs capturing all oral precancerous sites but including the entire oral cavity (any site biopsied should 
be photographed). Bidimensional measurements of each oral precancerous lesion should be obtained and recorded, using 
the largest maximum diameter of each site. 
f) Baseline biopsy can be performed any time after the subject has consented up until C1D1. Archival tissue is not acceptable. 
Fresh biopsy is mandatory (at up to three sites per patient). Fresh tissue is also collected following completion of treatment. 
Biopsy will also be recommended if the patient progresses to invasive squamous cell carcinoma of the head and neck. 
Fresh tissue may also be collected at time of progression. 
g) Quality of life surveys will be completed at screening, after 2 cycles of treatment, at the end of treatment, and at 30-day 
follow-up. Patients will complete the chronic oral mucosal diseases quality of life questionnaire (COMD QLQ [66]). This is 
a validated instrument that assesses various aspects of oral health and function that has been shown to perform well in 
patients with oral mucosal diseases, including oral precancerous conditions. See Appendix C for the full questionnaire. 
h) Participants, regardless if they receive the full course of prescribed therapy, will be followed for best overall response and 
development of first invasive OSCC every cycle during treatment (including a survival status update). Post end-of-protocol 
treatment, if first invasive OSCC has not been confirmed, assessments will continue every 3-6 months until best overall 
response and first invasive OSCC are documented (with survival status updates during this time period as well). After 
documentation of first invasive OSCC, survival status will continue to be updated every 3 months until death or 5 years 
from study registration (whichever occurs first). Photographs and measurements may continue at PI discretion after first 
invasive OSCC and during survival follow up. Clinically indicated biopsies that occur at or following first invasive OSCC 
can be used for study correlatives at PI discretion during survival follow up. 
 
 
11. MEASUREMENT OF EFFECT 
 
11.1 
Measurement of Effect – OPVL lesions 
 
For the purposes of this study, participants will be re-evaluated for change in the measurements 
of each oral leukoplakia site at every study visit following initial study drug dosing. In addition, 
re-biopsy of initial oral leukoplakia sites (up to 3 per patient) will be obtained at the end of 
treatment, and to development of invasive oral cancer up to 5 years form study registration. 
Timelines are described in Section 10. 
 
Response will be measured by: (1) measuring the change in size of each oral leukoplakia lesion, 


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and (2) by assessing histopathological change (a change in the degree of dysplasia as defined by 
histologic features) [modified from Wan der Waal I, et al. Oral Oncol 2000; 36(3)264-6]. See 
Response Criteria below. 
 
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 
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 ≥ 10 mm by 
bidirectional measurements on oral examination. All lesion measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
 
Non-measurable disease. All other lesions (or sites of leukoplakia), including small 
lesions (longest diameter < 10 mm), are considered non-measurable disease. 
 
Target lesions. All measurable lesions up to a maximum of 3 lesions 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 
the degree of high-risk oral leukoplakia, 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 all oral leukoplakia lesions) for all target lesions will be 
calculated and reported as the baseline sum diameters. 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 leukoplakia) including any measurable 
lesions over and above the 3 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. 


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11.1.3 Methods for Evaluation of Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or a 
digital (photographic) 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. 
 
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. Color photographs 
of target lesions is preferred at each follow-up visit to accompany measurements. 
 
11.1.4 Response Criteria 
 
11.1.4.1 
Evaluation of Target Lesions 
 
STEP 1: Grade each individual lesion by size and histology to achieve the individual 
score of each site (up to 3 per patient). 
 
Size 
Criteria 
L1 
A lesion measuring < 2 cm in largest diameter 
L2 
A lesion measuring 2-3 cm in largest diameter 
L3 
A lesion measuring > 3 cm in largest diameter 
 
Histology Criteria 
P0 
Keratosis of unknown significance with or without mild atypia 
(hyperkeratosis should not be reactive, such as from friction or factitial 
injury) 
P1 
Mild dysplasia 
P2 
Moderate dysplasia 
P3 
Severe dysplasia 
 
Examples: 
Patient A has 3 sites (1 cm, mild dysplasia = L1P1; 2.5 cm, mild dysplasia = L2P1; 2 
cm, severe dysplasia = L2P3) 
Patient B has 1 site (4 cm, moderate dysplasia = L3P2) 
STEP 2: Score the patients individual sites using the below grid. A higher score 
reflects more advanced disease. 
Points 
Composite of Size / Histology 
2 
L1 P0 
4 
L1 P1 
6 
L1 P2 
8 
L1 P3 
12 
L2 P0 
14 
L2 P1 
16 
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18 
L2 P3 
22 
L3 P0 
24 
L3 P1 
26 
L3 P2 
28 
L3 P3 
 
Examples: 
Patient A has 3 sites (L1P1 = 4; L2P1 = 16; L2P3 = 18; total points = 38 is the 
composite score) 
Patient B has 1 site (L3P2 = 26; total points = 26 is the composite score) 
 
STEP 3: Following nivolumab, repeat measurements and histologic assessments. 
Recalculate the above score for each patient to assess the change in the composite 
score. Then calculate the change over the total baseline composite score as a (%) to 
the first decimal place. 
 
Examples: 
Patient A has 3 sites now (1 cm, mild dysplasia = L1P1; 2 cm, no dysplasia = L2P0; 1 
cm, mild dysplasia = L1P1) 
Patient B has 1 site now (2 cm, moderate dysplasia = L2P2) 
 
Patient A has 3 sites now (L1P1 = 4; L2P0 = 12; L1P1 = 4; total points = 20 is the 
new composite score) 
Patient B has 1 site now (L2P2 = 16; total points = 16 is the new composite score) 
 
Patient A has 3 sites (38 – 20 points = ∆18), 18/38 = 47.4% 
Patient B has 1 site (26 – 16 points = ∆10), 10/26 = 38.5% 
 
STEP 4: Using the difference in the composite score for each patient, match to the 
response grid below. 
 
Definition Best Overall Response 
A decrease of > 80% or more 
CR 
A decrease of 40-80% 
PR 
Neither PR or PD 
SD 
An increase of 10% or more 
PD 
Examples: 
Patient A has 3 sites (38 – 20 points = ∆18), 18/38 = 47.4%, called PR 
Patient B has 1 site (26 – 16 points = ∆10), 10/26 = 38.5%, called SD 
Complete Response (CR): A decrease of >80% in the total composite score, for at 
least 4 weeks. 
Partial Response (PR): A decrease of 40-80% in the total composite score. 
 
Progressive Disease (PD): At least a 10% increase in the total composite score. 


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(Note: the appearance of one or more new lesions is also considered progression). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD. 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): 
Disappearance of all non-target lesions, as assessed 
visually, for at least 4 weeks. 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s). 
 
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. 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 documentation when the lesion was discovered. 
 
11.1.4.4 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from study registration until 
first disease progression/diagnosis of invasive OSCC (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 histologic criteria. 
 
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 
> 4 wks Confirmation** 
CR 
Non-CR/Non- 
PD 
No 
PR 
> 4 wks Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non- 
PD/not 
No 
PR 


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evaluated 
SD 
Non-CR/Non- 
PD/not 
evaluated 
No 
SD 
Documented at least once > 4 
weeks from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See manuscript for further details on what is evidence of a new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
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. 
 
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. 


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11.1.6 Cancer-Free Survival and Overall Survival 
 
Overall Survival: Overall Survival (OS) is defined as the time from study registration to 
death due to any cause, or censored at date last known alive. 
 
Cancer-Free Survival: Cancer-Free Survival (DFS) is defined as the time from study 
registration to development of invasive oral cancer or death due to any cause. Participants 
alive without disease progression or recurrence (of invasive oral cancer) are censored at 
date of last disease evaluation. 
 
11.1.7 Time to Next Surgery 
 
Time to Next Surgery: Time to Next Surgery is defined as the time from the first study 
treatment to any head & neck surgery or resection for biopsy-proven carcinoma in situ 
(CIS) or invasive oral carcinoma (including all stages). 
 
11.1.8 Quality of life Assessment 
 
Quality of Life Assessment: The chronic oral mucosal diseases quality of life 
questionnaire (COMD QLQ, see Appendix C) will be used to assess the effect of the 
participants mouth condition on daily life activities. The survey consists of 24 questions 
with five response options per item. The response for each item is coded from 0 to 4 with 
“not at all = 0” and “extremely = 4” (at time of scoring, for 3 questions, the likert scale is 
reversed). The summary of the overall score ranges from 0 to 104, with a higher score 
indicating a poorer patient-assessed quality of life score. 
 
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 
Study team is responsible for entering data in the eDC system (InForm), within the 
timeframe, in accordance with DF/HCC SOPs. 
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 clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 


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raises any questions about participant safety will be addressed with the Overall PI and study 
team. 
The DSMC will review each protocol up to four times a year or more often if required to review 
toxicity and accrual data. 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 with 30 
days of intervention 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. 
 
13. STATISTICAL CONSIDERATIONS 
 
The primary objective of this trial is to evaluate best overall response rate (CR+PR). A two-stage 
design (Simon’s optimal design) will be used to minimize the number of patients enrolled. 
Sixteen eligible patients who start protocol treatment are to be accrued in the first stage. If there 
are ≤ 1 patients with disease in response, accrual to this trial will be closed with the expectation 
that there is little evidence that the response rate will reach 25%. The probability that the trial 
will close early is 51.5% if the true response rate is 10%. If there are >1 patients with disease in 
response, accrual will continue until a total of 33 eligible patients who start protocol treatment 
are entered. If there are > 5 patients with disease in response among 33 eligible patients who 
began protocol treatment, further testing of this regimen will be considered. If the true response 
rate is 25%, the probability of concluding the regimen is effective is 84.3%, if the true response 
rate is 10%, the probability of concluding the regimen is effective is 9.8%. Allowing for patients 
to be declared ineligible or to not start protocol treatment after registration, a total of 35 patients 
will be entered. 
 
The primary efficacy population includes all eligible patients who begin protocol treatment. Best 
overall response will be summarized as a proportion with a corresponding exact 95% confidence 
interval (CI) (if the trial closes to accrual after the first stage), or a corresponding 95% (two- 
stage) CI if the trial closes to accrual after the second stage. 
 
For secondary objectives: 
• Adverse events will be classified and graded according to the CTCAE v.5.0. Frequencies 
of adverse events will be summarized among patients who begin protocol therapy. The 
following stopping rule will be used to monitor excessive protocol related toxicity: if 3 or 
more of the first 10 patients who begin protocol treatment experience treatment related 
toxicities which cause extreme delays (protocol treatment needed to be stopped >10 weeks) 
or excessive treatment related toxicities, accrual to the trial will be suspended to further 
evaluate the events and decisions made regarding the overall status of the trial. If the true 
rate due to toxicity is 10% then the probability of suspending accrual is 7%; if the true rate 
is 20%, then the probability of suspending accrual is 32%; if the true delay rate is 30% then 
the probability of suspending accrual is 62%. Adverse events will be continuously 
monitored throughout the trial by the study team with decisions made accordingly 
regarding the study status and patient entry throughout the duration of the trial. 


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• The distributions of time-to-event endpoints will be estimated using the Kaplan-Meier 
method with corresponding 95% confidence intervals for the median or time-specific event 
time. 
 
• Another endpoint is to assess quality of life (QOL). QOL will be assessed via self-report 
questionnaires at the timepoints outlined in the Study Calendar. Descriptive statistics from 
the questionnaires will be summarized across timepoints of assessment. Rates of drop- 
out/non-response to QOL assessments and corresponding reason will also be summarized 
across timepoints of assessment. 
 
• Several correlative studies are also planned. Given the small sample size of this trial, 
these studies are exploratory. Samples will be collected at baseline and at post-baseline 
timepoints as outlined in the Study Calendar. Human immune cell markers (see 9.1 
Biomarker Studies) from patients with evaluable tumor and peripheral blood samples will 
be summarized descriptively and graphically. Within subject changes in these markers will 
also be analyzed. Correlation between immune checkpoint receptor ligands and best overall 
response will be analyzed. Assuming 27 evaluable patients with baseline and a post- 
baseline value provides 80% power to detect .58 SD mean difference (Wilcoxon sign rank 
test two-sided 0.05 alpha level) in any given circulating or tumor immune marker. 
 
With an estimated monthly accrual of 3 patients, the first stage is estimated to complete accrual 
in approximately 6 months. Due to possible delays in initiation of approval and/or in initiation of 
accrual itself, accrual to the first stage could take longer. As is customary with this type of 
design, accrual will be suspended after the first stage (n = 16 eligible patients who begin protocol 
therapy) in order to assess outcome; however, this suspension is also dependent on the actual 
observed accrual rate and the number of patients with confirmation of disease response status 
while the first stage of the trial is accruing. 
 
14. PUBLICATION PLAN 
 
The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than three 
(3) years after the end of the study. 
 
15. REFERENCES 
 
1. 
Warnakulasuriya, S., N.W. Johnson, and I. van der Waal, Nomenclature and classification of potentially 
malignant disorders of the oral mucosa. J Oral Pathol Med, 2007. 36(10): p. 575-80. 
2. 
Bagan, J., et al., Proliferative verrucous leukoplakia: a concise update. Oral Dis, 2010. 16(4): p. 328-32. 
3. 
Pentenero, M., et al., Oral proliferative verrucous leucoplakia: are there particular features for such an 
ambiguous entity? A systematic review. Br J Dermatol, 2014. 170(5): p. 1039-47. 


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4. 
Bagan, J.V., et al., Proliferative verrucous leukoplakia: high incidence of gingival squamous cell 
carcinoma. J Oral Pathol Med, 2003. 32(7): p. 379-82. 
5. 
Villa, A., A.R. Kerr, and S.B. Woo, Proliferative erythro-leukoplakia: a variant of proliferative verrucous 
leukoplakia? . Oral Surg Oral Med Oral Pathol Oral Rad, 2016. 122(5): p. e160. 
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Cabay, R.J., T.H. Morton, Jr., and J.B. Epstein, Proliferative verrucous leukoplakia and its progression to 
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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able to carry on 
all 
pre-disease 
performance 
without 
restriction. 
100 
Normal, no complaints, no evidence of disease. 
90 
Able to carry on normal activity; minor signs or 
symptoms of disease. 
1 
Symptoms, but ambulatory. Restricted in 
physically strenuous activity, but ambulatory 
and able to carry out work of a light or 
sedentary nature (e.g., light housework, office 
work). 
80 
Normal activity with effort; some signs or 
symptoms of disease. 
70 
Cares for self, unable to carry on normal activity 
or to do active work. 
2 
In bed <50% of the time. Ambulatory and 
capable of all self-care, but unable to carry out 
any work activities. Up and about more than 
50% of waking hours. 
60 
Requires occasional assistance, but is able to 
care for most of his/her needs. 
50 
Requires considerable assistance and frequent 
medical care. 
3 
In bed >50% of the time. Capable of only 
limited self-care, confined to bed or chair 
more than 50% of waking hours. 
40 
Disabled, requires special care and assistance. 
30 
Severely disabled, hospitalization indicated. 
Death not imminent. 
4 
100% 
bedridden. 
Completely 
disabled. 
Cannot carry on any self-care. Totally 
confined to bed or chair. 
20 
Very sick, hospitalization indicated. Death not 
imminent. 
10 
Moribund, fatal processes progressing rapidly. 
5 
Dead. 
0 
Dead. 


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APPENDIX B    GUIDANCE ON CONTRACEPTION 
 
Highly Effective Methods of Contraception 
Highly effective methods of contraception have a failure rate of < 1% when used consistently 
and correctly. WOCBP and female partners of male subjects, who are WOCBP, are expected to 
use one of the highly effective methods of contraception listed below. Male subjects must inform 
their female partners who are WOCBP of the contraceptive requirements of the protocol and are 
expected to adhere to using contraception with their partner. 
 
At a minimum, subjects must agree to use one highly effective method of contraception as listed 
below: 
 
For WOCBP 
Highly effective methods of birth control include the following: 
• Progestogen only hormonal contraception associated with inhibition of ovulation 
• Hormonal methods of contraception including oral contraceptive pills 
(combination of estrogen and progesterone), vaginal ring, injectables, or implants 
• Intrauterine devices (IUDs) (hormonal or non-hormonal) 
• Intrauterine Hormone-releasing System (IUS) 
• Bilateral tubal ligation 
• Vasectomy 
• Complete abstinence (complete avoidance of heterosexual intercourse) 
 
For male subjects with partners that are WOCBP 
• Condom 
 
All male subjects who have partners who are WOCBP must use condoms as their second method 
of contraception. 
 
Women of childbearing potential (WOCBP) receiving nivolumab will be instructed to adhere to 
contraception for a period of 5 months after the last dose of investigational product. Men 
receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to 
contraception for a period of 31 weeks after the last dose of investigational product. These 
durations have been calculated using the upper limit of the half-life for nivolumab (25 days) and 
are based on the protocol requirement that WOCBP use contraception for 5 half-lives plus 30 
days and men who are sexually active with WOCBP use contraception for 5 half-lives plus 90 
days after the last dose of nivolumab. 


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APPENDIX C 
TOXICITY MANAGEMENT ALGORITHMS 
 
• These general guidelines constitute guidance to the Investigator. The guidance applies to 
all immuno-oncology (I-O) agents and regimens. 
• A general principle is that differential diagnoses should be diligently evaluated according 
to standard medical practice. Non-inflammatory etiologies should be considered and 
appropriately treated. 
• Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. 
The oral equivalent of the recommended IV doses may be considered for ambulatory 
patients with low-grade toxicity. The lower bioavailability of oral corticosteroids should 
be taken into account when switching to the equivalent dose of oral corticosteroids. 
• Consultation with a medical or surgical specialist, especially prior to an invasive 
diagnostic or therapeutic procedure, is recommended. 
• The frequency and severity of the related adverse events covered by these algorithms will 
depend on the immuno-oncology agent or regimen being used. 


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Summary of major changes: Protocol Amendment # 1, dated November 27th, 
2018 
 
Protocol Section 
Change 
Section 5.1 and 5.4 
Removed language mandating reporting of concomitant medications 
within case report forms. 
Section 7.9 
Added clarifying language about reporting SAEs to BMS. 
Section 9.1 
Replaced Dr. Michaela Bowden with Dr. Ravindra Uppaluri and Dr. 
Patrick Lizotte. 
Section 10 
Study calendar updates: Added FSH test at screening visit, moved end 
of treatment biopsy to the 30 day Follow-up visit and consolidated 
correlative blood sample collections at the C1D1 and 30 day Follow-up 
visits. 
 
Summary of major changes: Protocol Amendment # 2, dated January 3rd, 
2019 
 
 
Protocol Section 
Change 
Section 10 
Study calendar updates: Typographical changes to the calendar and 
removed the requirement of performing photographs and lesion 
measurements at the End of Treatment visit. 
 
Summary of major changes: Protocol Amendment # 3, dated January 29th, 
2019 
 
Protocol Section 
Change 
Appendix C 
Added fields for “Patient Name” and “Date” along with formatting 
changes to the survey. 
Section 10 
Study calendar updates: Specified the requirement of performing 
Phosphorous test as part of routine labs. Clarified the timeline of 
performing the screening biopsy procedure. 
Summary of major changes: Protocol Amendment # 6, dated January 29th, 
2020 
 
Protocol Section 
Change 
Appendix C 
Made survey standalone document 
Section 10 
Study calendar updates: Added “Survival Follow up” column. Clarified 
that “photographs and measurements” are to be performed at each 
Survival Follow up visit. Allowed for study team to collect research 
tissue on biopsies performed at potential first invasive OSCC and during 
survival follow up. Added that study team may perform photographs 


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and measurements after first invasive OSCC at PI discretion. Added 
“Survival Status” row to Study Calendar, clarified survival status will be 
collected every 3-4 months. 
Section 9.1 
Clarified tubes used for fresh tissue collection. 
Section 7.5 and 7.6 
Updated SAE reporting from 30 days from last dose to 90 days from last 
dose. SAEs will be reported to Sponsor and to IRB 90 days from last 
dose. 
Cover Page 
Removed Dr. Alessandro Villa, DDS, PhD, MPG as Sub-Investigator