Clinical trial NCT03107182
Conditions: HPV-Related Squamous Cell Carcinoma HNSCC
Keywords: HPV- positive HNSCC head and neck squamous cell carcinoma
Sponsor: University of Chicago
Start date: 2017-06-27; Completion date: 2024-09-06
Enrollment: 72 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Carboplatin, nab-paclitaxel, and nivolumab combination will be administered for three cycles of three weeks duration each. TORS or RT/CRT will be performed after induction chemotherapy (i.e. day 64 of therapy). Patients with low risk and small volume tonsillar disease (T1-T2, non-bulky N2A-N2B with ≤2 non-lower neck lymph nodes measuring ≤5 cm in size) or base of tongue disease (T1-2 with lateralized primary ≤3 cm, non-bulky N2A-N2B with ≤2 non-lower neck lymph nodes measuring ≤5 cm in size) who have ≥50% reduction by RECIST following induction chemotherapy will undergo TORS and selective nodal dissection. De-intensified adjuvant RT will be given for adverse pathologic features. Patients may refuse TORS treatment.

Patients with low risk, who do not qualify for TORS (due to volume of disease or poor visualization/access) or refuse TORS, who have ≥50% reduction by RECIST following induction chemotherapy will be given de-intensified treatment with radiation alone to 50 Gy.

Before induction chemotherapy, patients will undergo examination under anesthesia and direct laryngoscopy to tattoo and photograph the primary tumor to plan the post-induction resection. Adjuvant nivolumab will be offered to all patients for 6-months post completion of definitive therapy (7 doses given as a flat dose of 480mg, every four weeks).

Detailed description:
A phase II trial in human papillomavirus (HPV)-positive oropharyngeal squamous cell cancer (as determined by p16 immunohistochemistry with confirmatory ISH or PCR) to determine radiologic response to induction chemotherapy with nivolumab. Patients will undergo evaluation by a multidisciplinary team prior to risk assessment. The patients will be assigned to high or low risk groups based on tumor size, lymph node involvement, and smoking history. Patients will be assigned to treatment with induction chemotherapy with carboplatin, nab-paclitaxel, and nivolumab. Radiologic response to induction chemotherapy according to RECIST measurement of tumor shrinkage will then be used for therapeutic stratification of locoregional therapy, consisting of either transoral robotic surgery (TORS) or radiation with or without chemotherapy. Patients with low risk disease (see table above) and small volume tonsillar/BOT disease (T1-2 primary, non-bulky N2A-N2B nodal status) who have ≥50% reduction by RECIST following induction chemotherapy will undergo TORS for primary site resection and selective nodal dissection as a definitive treatment if technically feasible with adjuvant radiation for adverse pathologic features. Patients with other low risk tumors e.g. with higher volume disease, or who refuse surgery, who also have ≥50% reduction by RECIST following induction chemotherapy will be given de-intensified treatment with radiation alone to 50 Gy (no chemotherapy). Patients with low risk features and \<50% but ≥30% reduction OR high risk features (T4, bulky N2B or N2C-N3, \>10 pack-years tobacco use) with ≥50% reduction will receive de-intensified chemoradiation with concurrent cisplatin-RT to 50 Gy (5 weeks) or TFHX to 45 Gy (3 cycles/6 weeks). Patients with low risk features and \<30% reduction OR high risk disease with \<50% reduction or any patients with progressive disease during induction chemotherapy will undergo chemoradiotherapy with concurrent cisplatin-RT to 70 Gy (7 weeks) or TFHX to 75 Gy (5 cycles/10 weeks). Patients with both high and low risk features who have ≥50% reduction will receive locoregional therapy targeting the pre-chemotherapy extent of disease only. Adjuvant nivolumab will be offered to all patients for 6-months post completion of definitive therapy (7 doses given as a flat dose of 480mg, every four weeks).

Arms: arm 1: All enrolled patients will receive three 21-day cycles of chemotherapy consisting of nab-paclitaxel (100 mg/m2 on days 1, 8, 15; 9 doses total), carboplatin (AUC 5 on day 1; 3 doses total), and nivolumab (360 mg on days 1; 3 doses total). Growth factor support will be provided using G-CSF administered on days 16-18.

Adjuvant nivolumab will be offered to all patients for 6-months post completion of locoregional therapy. arm 2: Following the induction treatments (carboplatin, nab-paclitaxel, and nivolumab), patients will be assessed based on response to chemotherapy and high or low risk status.

Patients with low risk and small volume tonsillar disease (T1-T2, non-bulky N2A-N2B with ≤2 non-lower neck lymph nodes measuring ≤5 cm in size) or base of tongue disease (T1-2 with lateralized primary ≤3 cm, non-bulky N2A-N2B with ≤2 non-lower neck lymph nodes measuring ≤5 cm in size) who have ≥50% reduction by RECIST following induction chemotherapy will undergo TORS and selective nodal dissection. De-intensified adjuvant RT will be given for adverse pathologic features. Patients may refuse TORS treatment.

Patients with low risk, who do not qualify for TORS (due to volume of disease or poor visualization/access) or refuse TORS, who have ≥50% reduction by RECIST following induction chemotherapy will be given de-intensified treatment with radiation alone to 50 G. arm 3: Following the induction treatments (carboplatin, nab-paclitaxel, and nivolumab), patients will be assessed based on response to chemotherapy and high or low risk status.

Patients who have low risk disease with \<50% but ≥30% reduction of tumor by RECIST with induction chemotherapy will receive CRT to 50 Gy with concurrent bolus cisplatin (x2 doses) or TFHX (paclitaxel, 5-FU, hydroxyurea, dexamethasone, famotidine, and diphenhydramine) to 45 Gy (3 cycles).

Patients who have high risk disease and ≥50% reduction of tumor by RECIST with induction chemotherapy will receive CRT to 50 Gy with concurrent bolus cisplatin (x2 doses) or TFHX to 45 Gy (3 cycles). arm 4: Following the induction treatments (carboplatin, nab-paclitaxel, and nivolumab), patients will be assessed based on response to chemotherapy and high or low risk status.

Patients who have low risk disease and \<30% reduction of tumor by RECIST with induction chemotherapy will receive CRT to 70 Gy with concurrent bolus cisplatin (x3 doses) or TFHX (paclitaxel, 5-FU, hydroxyurea, dexamethasone, famotidine, and diphenhydramine) to 75 Gy (5 cycles).

Patients who have high risk disease and \<50% reduction of tumor by RECIST with induction chemotherapy will receive CRT to 70 Gy with concurrent bolus cisplatin (x3 doses) or TFHX to 75 Gy (5 cycles).

Any patient who has progressive disease will receive CRT to 70 Gy with concurrent bolus cisplatin (x3 doses) or TFHX to 75 Gy (5 cycles).
Interventions: intervention 1: nab-paclitaxel intervention 2: Carboplatin intervention 3: Nivolumab intervention 4: Cisplatin intervention 5: Hydroxyurea intervention 6: 5-FU intervention 7: Dexamethasone intervention 8: Famotidine intervention 9: Diphenhydramine intervention 10: Paclitaxel intervention 11: Transoral robotic surgery (TORS) intervention 12: Adjuvant RT intervention 13: Chemoradiotherapy
Intervention descriptions: intervention 1: All enrolled patients will receive three 21-day cycles of nab-paclitaxel (100 mg/m2 on days 1, 8, 15; 9 doses total) intervention 2: All enrolled patients will receive three 21-day cycles of carboplatin (AUC 6 on day 1; 3 doses total). intervention 3: All enrolled patients will receive three 21-day cycles of nivolumab (360 mg on days 1; 3 doses total).

Adjuvant nivolumab will be offered to all patients for 6-months post completion of locoregional therapy for a total of 7 doses. intervention 4: Cisplatin will be given on an every 3 weeks basis at a dose of 100 mg/m2 IV over 3-4 hrs day 1 (or 2) and 22 (or 23). Only for patients on the Intermediate Dose Arm and additionally on day 43 (or 44) for patients on the Regular Dose Arm. intervention 5: Patients on the Intermediate or Regular Dose Arms will receive chemoradiation for 3-5 cycles (6-10 weeks). On day 0 patients will start hydroxyurea at 500 mg PO q 12 hours x 6 days (11 doses). The first daily dose of hydroxyurea on days 1 - 5 is given 2 hours prior to the first fraction of daily radiotherapy. intervention 6: Patients on the Intermediate or Regular Dose Arms will receive chemoradiation for 3-5 cycles (6-10 weeks). On day 0 at 1800 patients will start continuous infusion of 5-FU at 600 mg/m2/day x 5 days (120 hours). intervention 7: Patients on the Intermediate or Regular Dose Arms will receive chemoradiation for 3-5 cycles (6-10 weeks). On days 1-5 patients will receive dexamethasone 20 mg PO (IV) in am Day 1, 1 hr prior to paclitaxel intervention 8: Patients on the Intermediate or Regular Dose Arms will receive chemoradiation for 3-5 cycles (6-10 weeks). On days 1-5 patients will receive famotidine 20 mg PO (IV) in am Day 1, 1 hr prior to paclitaxel. intervention 9: Patients on the Intermediate or Regular Dose Arms will receive chemoradiation for 3-5 cycles (6-10 weeks). On days 1-5 patients will receive diphenhydramine 50 mg PO (IV) in am Day 1, 30 mins prior to paclitaxel. intervention 10: Patients on the Intermediate or Regular Dose Arms will receive chemoradiation for 3-5 cycles (6-10 weeks). On days 1-5 patients will start paclitaxel 100 mg/m2 after first RT fraction on day 1 of each cycle. Paclitaxel should be administered in 250 ml 0.9% NaCl over 60 minutes. intervention 11: Patients with low risk and small volume tonsillar disease (T1-T2, non-bulky N2A-N2B with ≤2 non-lower neck lymph nodes measuring ≤5 cm in size) or base of tongue disease (T1-2 with lateralized primary ≤3 cm, non-bulky N2A-N2B with ≤2 non-lower neck lymph nodes measuring ≤5 cm in size) who have ≥50% reduction by RECIST following induction chemotherapy will undergo TORS and selective nodal dissection. Patients may refuse TORS treatment. Patients will receive RT or TORS. intervention 12: Patients with low risk, who do not qualify for TORS (due to volume of disease or poor visualization/access) or refuse TORS, who have ≥50% reduction by RECIST following induction chemotherapy will be given de-intensified treatment with radiation alone to 50 Gy. Patients will receive RT or TORS. intervention 13: Patients who have low risk disease with \<50% but ≥30% reduction, or patients who have high risk disease and ≥50% reduction of tumor by RECIST with induction chemotherapy will receive CRT to 50 Gy with concurrent bolus cisplatin (x2 doses) or TFHX to 45 Gy (3 cycles).

Patients who have low risk disease and \<30% reduction of tumor, patients who have high risk disease and \<50% reduction of tumor by RECIST, or any patient who has progressive disease with induction chemotherapy will receive CRT to 70 Gy with concurrent bolus cisplatin (x3 doses) or TFHX to 75 Gy (5 cycles).

Protocol documents:
Prot_SAP_000.pdf: 
SPONSOR: The University of Chicago 
 
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A phase II trial of nivolumab/nab-paclitaxel/carboplatin 
induction chemotherapy followed by response-stratified 
locoregional 
therapy 
for 
patients 
with 
locoregionally 
advanced HPV-related oropharyngeal cancer – the OPTIMA II 
Trial 
 
OPTIMA = OroPharyngeal Tumor Induction chemotherapy and response-
stratified locoregional therapy trial in order to Minimize long-term Adverse 
events 
 
 
 
 
 
UCCCC IRB Number: 
IRB17-0104 
 
Coordinating Center: 
The University of Chicago  
 
Principal Investigator: 
Everett Vokes  
 
 
 
 
Section of Hematology/Oncology,  
University of Chicago Medical Center  
 
 
 
 
5841 S Maryland Avenue; MC6092, Chicago, IL 60637 
 
 
 
 
Phone: 773-702-9306  
E-mail: evokes@medicine.bsd.uchicago.edu 
 
Co-Investigators:  
 
Alexander T. Pearson 
Daniel Haraf (Radiation Oncology PI) 
 
 
 
 
Nishant Agrawal (ENT PI) 
 
 
 
 
Michael Spiotto 
 
 
 
 
 
Zhen Gooi 
 
Louis Portugal 
Elizabeth Blair 
Nicole Cipriani 
Mark Lingen 
Statistician:   
 
Theodore Karrison 
Research Nurse: 
 
Courtney Mccampbell  
Study Coordinator:  
Elaine Klema 
Data Manager: 
 
Melody Jones 
 
 
 


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Table of Contents 
 
1 
PROTOCOL SYNOPSIS & SCHEMATA......................................................................6 
1.1 
Brief Trial Schema .................................................................................................6 
1.2 
Brief Schema for Response-Stratified Locoregional Therapy ...........................6 
1.3 
Brief Overview of Risk Classification ..................................................................7 
1.4 
Brief Trial Design Overview .................................................................................7 
1.5 
Brief Background and Rationale ..........................................................................8 
1.6 
Brief Definition of Subject Population .................................................................9 
1.7 
Brief Overview of Objectives ................................................................................9 
1.8 
Key Inclusion Criteria .........................................................................................10 
1.9 
Brief Overview of Treatment Plan .....................................................................10 
1.10 Brief Summary of Treatment Duration .............................................................12 
1.11 Brief Overview of Statistical analysis .................................................................12 
2 
OBJECTIVES ..................................................................................................................14 
2.1 
Primary Objective ................................................................................................14 
2.2 
Secondary Objectives ...........................................................................................14 
2.3 
Laboratory Objectives .........................................................................................15 
2.4 
Exploratory Objectives ........................................................................................15 
3 
BACKGROUND ..............................................................................................................16 
3.1 
Locally Advanced Head and Neck Cancer ........................................................16 
3.2 
Chemoradiotherapy .............................................................................................16 
3.2.1 CRT Platforms: Concurrent Cisplatin-Radiation or TFHX ...........................17 
3.3 
Induction Chemotherapy ....................................................................................18 
3.4 
Human Papillomavirus (HPV) and HNSCC .....................................................19 
3.5 
Response-Adapted Volume De-escalation (RAVD) ..........................................20 
3.6 
Dose De-escalation for HPV-related Oropharynx Cancer ...............................21 
3.7 
Transoral Robotic Surgery (TORS) ...................................................................21 
3.8 
Positron Emission Tomography (PET)-Based Surveillance ............................23 
3.9 
Nivolumab / anti-PD-1 .........................................................................................23 
3.10 Study Rationale ....................................................................................................24 
3.10.1 Risk Status ............................................................................................................26 
3.10.2 Group A1: Single-Modality De-escalation Arm (SDA) -- TORS B: Single-
Modality De-escalation Arm (SDA) –RT ..........................................26 
3.10.3 Group A2: Single-Modality De-escalation Arm (SDA) –RT ............................26 
3.10.4 Group B: Intermediate De-escalation Arm (IDA) – Intermediate dose CRT 26 
3.10.5 Group C: Regular Dose Arm (RDA) – Standard dose CRT: ..........................27 


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3.10.6 Adjuvant Treatment with Nivolumab/anti-PD-1 ..............................................27 
4 
SUBJECT SELECTION .................................................................................................28 
4.1 
Eligibility Criteria ................................................................................................28 
4.2 
Exclusion Criteria ................................................................................................29 
4.3 
Criteria for discontinuation/withdrawal of informed consent .........................31 
4.4 
HPV testing ...........................................................................................................32 
5 
TREATMENT PLAN ......................................................................................................33 
5.1 
General Considerations .......................................................................................33 
5.2 
Pre-treatment evaluation .....................................................................................33 
5.3 
Study evaluations .................................................................................................34 
5.4 
Induction Chemotherapy Details and Guidelines .............................................35 
5.5 
Surgical Details and Guidelines ..........................................................................35 
5.5.1 Indications for Adjuvant Radiation post-operatively .......................................36 
5.6 
Definitive Radiation/Chemoradiation Details and Guidelines.........................36 
5.6.1 Risk Status ............................................................................................................36 
5.6.2 Response Stratified Grouping: ...........................................................................37 
5.6.3 Concurrent Cisplatin-Radiation:........................................................................39 
5.6.4 TFHX Regimen: ...................................................................................................39 
5.6.5 Radiation Therapy Guidelines ............................................................................40 
5.6.6 Nodal Planning Target Volume Delineation: ....................................................43 
5.7 
Adjuvant Immunotherapy Details and Guidelines ...........................................46 
5.8 
Supportive Guidelines..........................................................................................47 
5.9 
Post-therapy Follow-up .......................................................................................48 
5.10 Duration of Therapy ............................................................................................49 
5.11 Late Toxicity Assessment ....................................................................................49 
5.11.1 Late Toxicity Assessment Schedule ....................................................................49 
5.11.2 Assessment of Late Toxicity ................................................................................49 
5.11.3 Quality of Life Assessments and Performance Measures ................................50 
6 
EXPECTED ADVERSE EVENTS, RISKS AND DOSE MODIFICATIONS ..........51 
6.1 
Expected Adverse Events ....................................................................................51 
6.1.1 Nab-Paclitaxel.......................................................................................................51 
6.1.2 Carboplatin ...........................................................................................................52 
6.1.3 5-Fluorouracil .......................................................................................................52 
6.1.4 Paclitaxel (during TFHX concurrent chemoradiation) ....................................53 
6.1.5 Hydroxyurea .........................................................................................................54 
6.1.6 Cisplatin 55 
6.1.7 Filgrastim ..............................................................................................................55 


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6.1.8 Nivolumab .............................................................................................................55 
6.1.9 Radiation ...............................................................................................................56 
6.2 
Dose modifications ...............................................................................................56 
6.2.1 Induction Chemotherapy Dose Modifications ...................................................57 
6.2.2 Dose Modifications Immunotherapy/Nivolumab during Induction Phase .....59 
6.2.3 Adverse Event Management Algorithms for Immunotherapy/Nivolumab ....59 
6.2.4 Dose Modifications During Concurrent Chemoradiotherapy .........................66 
6.2.5 Dose 
Modifications 
Immunotherapy/Nivolumab 
during 
Adjuvant 
Nivolumab Treatment .........................................................................69 
7 
AGENT FORMULATION AND PROCUREMENT ...................................................70 
7.1 
Nab-paclitaxel .......................................................................................................70 
7.2 
Carboplatin ...........................................................................................................73 
7.3 
Fluorouracil ..........................................................................................................73 
7.4 
Hydroxyurea .........................................................................................................73 
7.5 
Paclitaxel ...............................................................................................................73 
7.6 
Cisplatin ................................................................................................................75 
7.7 
Filgrastim (Neupogen) Drug Information ......................................................76 
7.8 
Nivolumab .............................................................................................................78 
8 
CORRELATIVE/SPECIAL STUDIES .........................................................................81 
8.1 
Objectives ..............................................................................................................81 
8.2 
Correlative analysis..............................................................................................81 
8.2.1 Tissue: 
81 
8.2.2 Blood: 
82 
8.2.3 Radiological Correlatives ........................................ Error! Bookmark not defined. 
8.3 
Sample and Tissue Procurement ........................................................................83 
8.3.1 Archival tumor collection ....................................................................................83 
8.3.2 Tissue Biopsy ........................................................................................................83 
8.3.3 Blood Isolation ......................................................................................................83 
9 
STUDY CALENDAR / FLOWCHART ........................................................................85 
10 MEASUREMENT OF EFFECT ....................................................................................92 
10.1 Measurement of Target Lesions .........................................................................92 
10.2 Measurement of Response ...................................................................................92 
10.2.1 Details about diagnostic imaging ........................................................................92 
10.3 Progression-Free and Overall Survival..............................................................94 
11 REGULATORY AND REPORTING REQUIREMENTS ..........................................95 
11.1 Regulatory Guidelines .........................................................................................95 
11.1.1 Food and Drug Administration (FDA) Approval .............................................95 


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11.2 Expedited Adverse Event Reporting ..................................................................95 
11.3 Adverse Event Definitions ...................................................................................95 
11.3.1 Adverse Event .......................................................................................................95 
11.3.2 Serious Adverse Event (SAE)..............................................................................95 
11.3.3 Relatedness ...........................................................................................................96 
11.3.4 Adverse Reactions ................................................................................................96 
11.4 Adverse Event Reporting ....................................................................................97 
11.4.1 Routine Adverse Event Reporting ......................................................................97 
11.4.2 Serious Adverse Event Reporting .......................................................................97 
11.4.3 Serious Adverse Event Reporting to BMS .........................................................97 
11.4.4 Serious Adverse Event Reporting to Celgene ....................................................98 
11.5 Subject registration and data submission ..........................................................99 
11.5.1 Registration...........................................................................................................99 
11.5.2 Data management ................................................................................................99 
11.6 Data and safety monitoring .................................................................................99 
11.7 Auditing.................................................................................................................99 
11.8 Record Retention................................................................................................100 
11.9 Obligations of Study Site Investigations ..........................................................100 
12 STATISTICAL CONSIDERATIONS .........................................................................101 
12.1 Statistical methods .............................................................................................101 
12.1.1 Primary Endpoint: Deep Response Rate (DRR) .............................................101 
12.1.2 Secondary Endpoints .........................................................................................101 
12.1.3 Exploratory Objectives/Endpoints/Analyses ...................................................103 
12.1.4 Laboratory/Translational Objectives ...............................................................103 
12.1.5 Visual Aid Objectives.........................................................................................103 
13 REFERENCES: .............................................................................................................105 
APPENDIX A: Performance Status Criteria .....................................................................112 
APPENDIX B: RTOG/NRG Early Toxicity Grading .......................................................113 
APPENDIX C: RTOG Late Toxicity Grading ...................................................................115 
APPENDIX D: Sample Transmission Form and Instructions .........................................116 
APPENDIX E: Accepted Forms of Birth Control .............................................................118 
APPENDIX F: Quality of Life Forms and Performance Measures .................................119 
 
 
 


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1 
PROTOCOL SYNOPSIS & SCHEMATA 
1.1 
Brief Trial Schema 
 
*For concurrent chemoradiotherapy a choice of either cisplatin-based or a paclitaxel/5-
FU/hydroxyurea-based backbone is acceptable. Both regimens are considered equivalent 
choices and are dependent on physician/subject preference (dealer’s choice). 
1.2 
Brief Schema for Response-Stratified Locoregional Therapy  
 
AUC=6, d1 
1. Carboplatin AUC=6, d1 
2. Nab-paclitaxel 100mg/m2  
    d1/d8/d15 
3. Nivolumab, 360mg(flat), d1 
 
      21-day cycle for 3 cycles 


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1.3 
Brief Overview of Risk Classification 
 
→ N3/bulky nodal disease is defined radiologically or on clinical exam. 
1.4 
Brief Trial Design Overview 
 
A phase II trial in human papillomavirus (HPV)-positive oropharyngeal squamous 
cell cancer (as determined by p16 immunohistochemistry with confirmatory ISH or PCR) 
to determine radiologic response to induction chemotherapy with nivolumab. Subjects will 
undergo evaluation by a multidisciplinary team prior to risk assessment. The subjects will 
be assigned to high or low risk groups based on tumor size, lymph node involvement, and 
smoking history. Subjects will be assigned to treatment with induction chemotherapy with 
carboplatin, nab-paclitaxel, and nivolumab. Radiologic response to induction 
chemotherapy according to RECIST measurement of tumor shrinkage will then be used 
for therapeutic stratification of locoregional therapy, consisting of either transoral robotic 
surgery (TORS) or radiation with or without chemotherapy .  Subjects with low risk disease 
(see table above) and small volume tonsillar/BOT disease (T1-2 primary, non-bulky N2A-
N2B nodal status) who have ≥50% reduction by RECIST following induction 
chemotherapy will undergo TORS for primary site resection and selective nodal 
dissection as a definitive treatment if technically feasible with adjuvant radiation for 
adverse pathologic features. Subjects with other low risk tumors e.g. with higher volume 
disease, or who refuse surgery, who also have ≥50% reduction by RECIST following 
induction chemotherapy will be given de-intensified treatment with radiation alone to 50 
Gy (no chemotherapy). Subjects with low risk features and <50% but ≥30% reduction OR 
high risk features (T4, bulky N2B or N2C-N3, >20 pack-years tobacco use) with ≥50% 
reduction will receive de-intensified chemoradiation with concurrent cisplatin-RT to 50 Gy 
(5 weeks) or TFHX to 45 Gy (3 cycles/6 weeks). Subjects with low risk features and <30% 
reduction OR high risk disease with <50% reduction or any subjects with progressive 
disease during induction chemotherapy will undergo chemoradiotherapy with concurrent 
cisplatin-RT to 70 Gy (7 weeks) or TFHX to 75 Gy (5 cycles/10 weeks). Subjects with 
both high and low risk features who have ≥50% reduction will receive locoregional therapy 
targeting the pre-chemotherapy extent of disease only. Adjuvant nivolumab will be offered 


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to all subjects for 6-months post completion of definitive therapy (7 doses given as a flat 
dose of 480mg, every four weeks). 
1.5 
Brief Background and Rationale 
 
The incidence of HPV-positive oropharyngeal cancer is rising rapidly in the United 
States and Europe.1 HPV-positive tumors occur in younger, healthier subjects often with 
higher socioeconomic status. Subjects with HPV-positive tumors have excellent 
prognosis and we may be currently over-treating this younger subject population.2,3 
Recently, it has been shown that induction chemotherapy may be used for treatment 
stratification in HPV-positive subjects.4,5 A good response to induction chemotherapy 
indicates improved prognosis overall with decreased risks of locoregional and distant 
recurrence.6 As such, subjects with favorable response to induction chemotherapy may 
be candidates for de-intensified locoregional therapy. The goal of de-intensified 
locoregional therapy is to decrease the late toxicity associated with treatment.  
 
In our recently published response-adapted volume de-escalation (RAVD) trial, 
treatment was stratified based on response to induction chemotherapy.5 Subjects with 
favorable response to induction chemotherapy received concurrent chemotherapy and 
radiation targeted to only gross disease. In this novel approach, elimination of elective 
nodal coverage did not compromise outcomes and resulted in significantly improved late 
toxicity. In a specific subset analysis of HPV-positive oropharynx subjects, outcomes were 
excellent with 2-year locoregional control and progression-free survival rates of 100% and 
93%, respectively, in good responders to induction chemotherapy.   
 
In a subsequent study (OPTIMA I), we sought to further decrease the toxicity of 
definitive chemoradiation for HPV-positive oropharyngeal cancer by decreasing the 
radiotherapy dose.7 In this study, subjects were first stratified based on subject and tumor 
characteristics. Treatment for each strata was then determined by response to an 
induction chemotherapy regimen consisting of nab-paclitaxel and carboplatin. In this trial, 
low-risk subjects with favorable response to induction chemotherapy received definitive 
radiation and high-risk subjects received chemoradiation. Both low- and high-risk subjects 
with favorable response to induction chemotherapy received radiotherapy dose de-
escalation. Preliminary data based on post-treatment pathology specimens indicate a 
high degree of control using this approach although an analysis of the complete cohort is 
still pending. 
 
Monoclonal antibodies targeting the programmed death (PD)-1 immune 
checkpoint receptor have shown remarkable activity in multiple cancer types including 
head and neck cancer.8,9 The goal of PD-1 blockade is to promote tumor recognition and 
destruction by the immune system. Nivolumab, a PD-1 inhibitor, is approved in 
melanoma, Hodgkin lymphoma, lung carcinoma, and renal cell carcinoma, and has 
recently been approved by the U.S. Food and Drug Administration (FDA) for head and 
neck cancer. Results of the phase III CheckMate-141 study investigating nivolumab after 
platinum-based chemotherapy were recently published.8 In this trial, the ORR was 13.3% 
with nivolumab and a 2.4 month benefit in median overall survival (OS) was observed 
versus investigator’s choice of therapy (P = 0.01). 


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Given the above, we hypothesize that the addition of the checkpoint inhibitor 
nivolumab to induction chemotherapy will increase the response rate to neoadjuvant 
therapy and therefore increase the proportion of subjects who may qualify for de-
intensified locoregional therapy. Additionally, we believe that further de-intensification of 
locoregional therapy compared to Optima I by limiting treatment to only the pre-
chemotherapy extent of disease (in subjects with ≥50% induction response) will further 
reduce the toxicity associated with curative-intent therapy without compromising disease 
control. An additional goal of this trial will be to assess the comparative efficacy and 
toxicity profiles of locoregional therapy with TORS versus RT in low-risk subjects with 
favorable induction response. 
 
1.6 
Brief Definition of Subject Population 
 
• Subjects with HPV-positive HNSCC 
 
1.7 
Brief Overview of Objectives 
 
Primary Objectives: 
• To measure the deep response rate (DRR) to induction chemotherapy with 
carboplatin/nab-paclitaxel/nivolumab and determine its activity compared to the 
DRR using carboplatin/nab-paclitaxel in the Optima I trial. 
 
• In the predecessor Optima 1 study, deep responses were defined as ≥50% tumor 
shrinkage by RECIST 1.1 and this is believed to approximate a clinical complete 
response (CR) as utilized in the ECOG 1308 study (which was the primary 
outcome for E1308). Hence in this study, deep responses are also defined as 
≥50% tumor shrinkage by RECIST 1.1. Linked to this we will evaluate the overall 
percentage of subjects treated with dose-reduced radiotherapy or TORS. 
Secondary Objectives: 
• To determine the tolerability of the nivolumab/carboplatin/nab-paclitaxel induction 
chemotherapy regimen and its impact on subsequent receipt of definitive 
chemoradiotherapy. 
 
• To determine 2-year progression-free survival (PFS) for the entire cohort and all 
arms and compare them to the entire cohort and corresponding arms in Optima I. 
 
• To determine 2-year overall survival (OS) for the entire cohort and all arms and 
compare them to the entire cohort and corresponding arms in Optima I. 
 


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• To determine 2-year rates of locoregional and distant control for the entire cohort 
and all arms and compare them to the entire cohort and corresponding arms in 
Optima I. 
 
• To determine rates of acute and late toxicity and compare them to rates of G-tube 
dependency on the Optima I and RAVD trials. 
 
• To determine quality of life scores in subjects and compare them to quality of life 
scores on the RAVD trial. 
 
• To determine the comparative efficacy and toxicity profiles of TORS versus RT for 
management of low risk disease. 
 
1.8 
Key Inclusion Criteria  
• Subjects with locoregionally advanced HPV-positive squamous cell carcinoma. 
HPV positivity will be determined by p16 IHC and HPV PCR for validation and HPV 
type determination. 
 
• Normal organ function 
 
• Measurable disease by RECIST 1.1 
 
• No previous radiation or chemotherapy for a head and neck cancer 
 
• ECOG performance status 0-1 (Karnofsky 80%) 
 
• Age ≥18 years  
 
• Ability to obtained informed consent 
 
• Availability of baseline tissue (as listed below in section 4.0) 
 
 
1.9 
Brief Overview of Treatment Plan 
Induction therapy: All enrolled subjects will receive three 21-day cycles of 
chemotherapy consisting of nab-paclitaxel (100 mg/m2 on days 1, 8, 15; 9 doses total), 
carboplatin (AUC 5 on day 1; 3 doses total), and nivolumab (360 mg on days 1; 3 
doses total). Growth factor support will be provided using G-CSF administered on 
days 16-18 if clinically indicated. 
 


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TORS/RT/CRT: The subjects will be assigned to treatment arms based on response 
to induction chemotherapy and high or low risk status. High or low risk status is based 
on tumor size, lymph node involvement, and smoking history at enrollment on study. 
 
Risk Status: 
 
Low Risk Status (all of the below): 
o T1-3 
o N0-N2B (unless N3 equivalent lymph nodal conglomerate*) 
o ≤20 pack year history tobacco use 
o HPV16 
 
 
High Risk Status (any of the below): 
o T4 
o N2C-N3 
o Bulky N2B disease with N3 equivalent nodal conglomerate* 
o >20 pack year history tobacco use 
o Non-HPV16 HPV type (e.g. HPV31, 18, etc) 
 
*N3/bulky nodal disease is defined radiologically or on clinical exam. 
 
Response Stratified Grouping: 
 
Subjects will be assigned to TORS, RT, or CRT based on response to induction 
chemotherapy and risk category (see schemas 1.1 and 1.2). Decision between RT or 
TORS in the single modality arm (SDA) will be individualized (see details below). 
Chemoradiation will be done using either outpatient cisplatin (100mg/m2 every 3 
weeks), or alternatively the inpatient TFHX platform consisting of 2-week cycles of 
paclitaxel (100 mg/m2, day 1), 5-FU (continuous infusion at 600 mg/m2/day  5 days), 
and hydroxyurea (500 mg PO BID days 0-5, 11 doses/cycle) with twice daily radiation 
(150 cGy per fraction). Both chemoradiation platforms are considered equivalent and 
treatment on either regimen will depend on subject preference. 
 
Group A1: Single-Modality De-escalation Arm (SDA) --TORS 
 
Subjects with low risk and small volume tonsillar disease (T1-T2, non-bulky N2A-N2B 
with ≤2 non-lower neck lymph nodes measuring ≤5 cm in size) or base of tongue 
disease (T1-2 with lateralized primary ≤3 cm, non-bulky N2A-N2B with ≤2 non-lower 
neck lymph nodes measuring ≤5 cm in size) who have ≥50% reduction by RECIST 
following induction chemotherapy will undergo TORS and selective nodal dissection. 
De-intensified adjuvant RT will be given for adverse pathologic features. Subjects may 
refuse TORS treatment (see treatment next paragraph). 
 
Group A2: Single-Modality De-escalation Arm (SDA) –RT 
Subjects with low risk, who do not qualify for TORS (due to volume of disease or poor 
visualization/access) or refuse TORS, who have ≥50% reduction by RECIST following 


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induction chemotherapy will be given de-intensified treatment with radiation alone to 
50 Gy (see schema page 5). 
 
Group B: Intermediate De-escalation Arm (IDA) – Low dose CRT 
Subjects who have low risk disease with <50% but ≥30% reduction of tumor by 
RECIST with induction chemotherapy will receive CRT to 50 Gy with concurrent bolus 
cisplatin (x2 doses) or TFHX to 45 Gy (3 cycles). 
 
Subjects who have high risk disease and ≥50% reduction of tumor by RECIST with 
induction chemotherapy will receive CRT to 50 Gy with concurrent bolus cisplatin (x2 
doses) or TFHX to 45 Gy (3 cycles). 
 
Group C: Regular Dose Arm (RDA) – Standard dose CRT: 
Subjects who have low risk disease and <30% reduction of tumor by RECIST with 
induction chemotherapy will receive CRT to 70 Gy with concurrent bolus cisplatin (x3 
doses) or TFHX to 75 Gy (5 cycles). 
 
Subjects who have high risk disease and <50% reduction of tumor by RECIST with 
induction chemotherapy will receive CRT to 70 Gy with concurrent bolus cisplatin (x3 
doses) or TFHX to 75 Gy (5 cycles). 
 
Any subject who has progressive disease will receive CRT to 70 Gy with concurrent 
bolus cisplatin (x3 doses) or TFHX to 75 Gy (5 cycles). 
 
Adjuvant therapy: Adjuvant nivolumab 480mg iv every 4 weeks will be offered to all 
subjects for 6-months post completion of locoregional therapy (= doses). 
 
1.10 
Brief Summary of Treatment Duration 
Induction chemotherapy: 9 weeks 
Definitive radiation therapy: 5 weeks 
Definitive chemoradiotherapy: 5-10 weeks 
Adjuvant radiation therapy (if indicated after TORS): 4-4.5 weeks 
Adjuvant immunotherapy: 6 months (=7 doses) 
 
1.11 
Brief Overview of Statistical analysis 
Subjects will receive induction chemotherapy for three cycles followed by radiologic 
evaluation and response-based allocation to definitive locoregional therapy.  
Response will be assessed after completion of induction chemotherapy by radiological 
examination.  
We expect to enroll and start treatment in 3-5 subjects per month for a total of 56 
subjects over a period of approximately 18 months. This study is designed to accrue 


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56 evaluable subjects for the primary endpoint to allow sufficient statistical power. 
However the trial is to be extended to up to 74 patients to fulfull sufficient enrollment 
on the RT-alone (A1) and TORS (A2) arms (at least 10 subjects each, unless the trial 
reaches N=74 subjects first). 
Overall Primary Objective: To demonstrate an increased rate of deep responses (deep 
response rate=DRR) to induction chemotherapy with the addition of nivolumab to the 
carboplatin/nab-paclitaxel backbone used in the Optima I trial. 
• In the predecessor Optima 1 study, deep responses were defined as ≥50% tumor 
shrinkage by RECIST 1.1 and this is believed to be equivalent to a clinical complete 
response (CR) as utilized in the ECOG 1308 study (which was the primary 
outcome for E1308). Hence in this study, deep responses are also defined as 
≥50% tumor shrinkage by RECIST 1.1. 
• 
We will employ a superiority test in which the objective is to establish that the 
response rate to carboplatin/nab-paclitaxel/nivolumab induction chemotherapy is 
15% higher than the response rate of 60% in Optima I which utilized a 
carboplatin/nab-paclitaxel induction regimen. 
• We will test: H0: DRR=60% (based on data from Optima 1 trial) vs HA: DRR=75% 
with addition of nivolumab to the carboplatin/nab-paclitaxel induction regimen. 
• Using Power Analysis and Sample Size (PASS v11) software, a sample of 56 
subjects will provide 87% power to test this hypothesis using a (one-sided) type I 
error rate of 0.10. Essentially, H0 will be rejected and nivolumab/carboplatin/nab-
paclitaxel based induction regimen declared superior if the lower, one-sided 90% 
confidence limit for the response rate exceeds 75%. No interim analysis will be 
conducted. 
NB: A minimum of 10 patients will be enrolled on the RT only and also TORS arm to 
allow for descriptive interpretation of the pathology results in tabular form. The overall 
trial may overenroll up to 18 patients (N=74) to fulfill this enrollment goal for the RT-only 
and TORS arms. 
 


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2 
OBJECTIVES 
2.1 
Primary Objective 
• To measure the deep response rate (DRR) to induction chemotherapy with 
carboplatin/nab-paclitaxel/nivolumab and determine its activity compared to the 
DRR using carboplatin/nab-paclitaxel in the Optima I trial. 
 
• In the predecessor Optima 1 study, deep responses were defined as ≥50% tumor 
shrinkage by RECIST 1.1 and this is believed to approximate a clinical complete 
response (CR) as utilized in the ECOG 1308 study (which was the primary 
outcome for E1308). Hence in this study, deep responses are also defined as 
≥50% tumor shrinkage by RECIST 1.1. Linked to this we will evaluate the overall 
percentage of subjects treated with dose-reduced radiotherapy or TORS. 
 
2.2 
Secondary Objectives 
• To determine the tolerability of the nivolumab/carboplatin/nab-paclitaxel induction 
chemotherapy regimen and its impact on subsequent receipt of definitive 
chemoradiotherapy. 
• To determine 2-year progression-free survival (PFS) for the entire cohort and all 
arms and compare them to the entire cohort and corresponding arms in Optima I. 
• To determine 2-year overall survival (OS) for the entire cohort and all arms and 
compare them to the entire cohort and corresponding arms in Optima I. 
• To determine 2-year rates of locoregional and distant control for the entire cohort 
and all arms and compare them to the entire cohort and corresponding arms in 
Optima I. 
• To determine rates of acute and late toxicity and compare them to rates of G-tube 
dependency on the Optima I and RAVD trials. 
• To determine quality of life scores in subjects and compare them to quality of life 
scores on the RAVD trial. 
• To determine the comparative efficacy and toxicity profiles of TORS versus RT for 
management of low risk disease. A minimum of 10 patients will be enrolled on the 
RT only and also TORS arm to allow for descriptive interpretation of the pathology 
results in tabular form. The overall trial may overenroll up to 18 patients (N=74) to 
fulfill this enrollment goal for the RT-only and TORS arms. 
 


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2.3 
Laboratory Objectives 
• To evaluate quantitative HPV titers pre-treatment, post-induction, and post-
definitive locoregional therapy at defined intervals on blood and saliva samples. 
This will be used to assess treatment efficacy (e.g. during nivolumab based 
induction chemotherapy), as well as a potential marker for early recurrence. 
 
• To evaluate changes in the immune micro-environment at a) baseline and b) 
during combined anti-PD-1/chemotherapy induction (paired biopsies). This will 
performed in an exploratory fashion: 
o Multicolor IF to assess changes in the immune microenvironment 
o mRNA analysis (Nanostring) 
o Mutational Load 
o Blood based markers over time 
 
2.4 
Exploratory Objectives 
• To evaluate the efficacy and utility of a visual aid used during the consent 
process by anonymous and optional subject and provider questionnaires.  
 
• To determine whether MRI (namely diffusion weighted imaging, and radiomics) 
can predict response to induction (chemotherapy + immunotherapy). 


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3 
BACKGROUND 
3.1 
Locally Advanced Head and Neck Cancer 
Approximately 50,000 new cases of head and neck cancer are diagnosed annually in the 
United States.10 The majority (90-95%) of these cases are squamous cell carcinomas of 
the head and neck (HNSCC) and approximately two-thirds are locoregionally advanced 
cancers (AJCC Stage III-IV). Despite advances in the multimodality treatment of 
locoregionally advanced HNSCC (LA-HNSCC) over the past two decades, these subjects 
still experience significant morbidity and mortality. 
 
Historically, locoregionally advanced tumors were treated with surgery, radiation therapy, 
or both. Locoregional failure rates were approximately 30% at 2 years and locoregional 
failures accounted for nearly 60% of failures. Survival at 5 years was reported to be only 
40%. Approximately 20% of subjects developed metastatic disease and nearly one-fifth 
of these subjects died of distant metastases without evidence of locoregional 
recurrence.11-14 
 
3.2 
Chemoradiotherapy  
Given the discouraging outcomes with surgery and radiation, investigators became 
increasingly interested in the incorporation of chemotherapy for the treatment of LA-
HNSCC. The feasibility of a non-surgical, organ preservation approach with concomitant 
chemoradiation was first established by the landmark Veterans Affairs Laryngeal Cancer 
Study.15,16 Since then, several randomized trials and meta-analyses have demonstrated 
improved disease-free and/or overall survival with concomitant chemoradiotherapy and 
confirmed its role as standard therapy for subjects with locoregionally advanced un-
resectable disease.17-22 The positive effects on disease-free and overall survival seem to 
be predominantly mediated through improved locoregional control, thus affecting the 
traditionally predominant pattern of failure for this disease. 
 
Concurrent chemoradiotherapy attempts to capitalize on both the radiosensitizing 
properties of chemotherapy at sites of known disease targeted by radiation in addition to 
delivering agents that function systemically to treat occult metastatic disease. However, 
sensitizing effects are not tumor specific and exert both locoregional effects on adjacent 
normal tissues within the radiation field as well as systemic effects, particularly on the 
bone marrow and peripheral nervous system. Concurrent chemoradiotherapy trials have 
consistently reported an increased incidence of acute grade 3 and 4 toxic effects, with 
mucositis, dermatitis, and cytopenias being the most prominent.23 This rise creates 
concern about chronic toxic effects, including consequential late effects, which evolve 
from persistent severe acute toxic effects.  
 
Optimizing the therapeutic ratio of treatment benefit to toxicity has thus become a focus 
of recent investigation. Advances in the delivery of conformal radiation, including the 
development of intensity modulated radiation therapy (IMRT), have allowed significant 
improvements in sparing normal tissue structures. This is best exemplified by the 


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reduction in rates of xerostomia with sparing of the parotid glands.24 However, other 
treatment-related morbidities such as dysphagia are still problematic. Rates of feeding 
tube dependence at 1-year in the 3D-conformal era have been reported to be 
approximately 25%.25 This is particularly significant given recent data that quality of life 
among subjects with HNSCC treated with radiotherapy is substantially affected by 
swallowing dysfunction and the need for enteral nutrition support.26 In the IMRT-era, 
efforts have been focused on decreasing the dose of radiation to dysphagia-related 
structures, particularly the pharyngeal constrictors, which are prone to stricture formation 
with doses ≥50 Gy.27 Single-institution reports of treatment of oropharyngeal cancer in 
the IMRT-era demonstrate long-term feeding tube dependence rates of approximately 5-
10%.28 
 
3.2.1 
CRT Platforms: Concurrent Cisplatin-Radiation or TFHX  
Chemoradiotherapy with concurrent bolus cisplatin (100 mg/m2 delivered q3weeks) and 
conventionally fractionated radiotherapy remains the commonly accepted standard of 
care for the treatment of LA-HNSCC. This is due to the prevalence of randomized studies, 
including the Head and Neck Intergroup trial and RTOG 91-11, which observed that 
concurrent chemoradiotherapy with every-3-weeks cisplatin improved locoregional 
control and overall survival for unresectable HNSCC and resectable laryngeal cancers, 
respectively.29,30  
 
At the University of Chicago, we have investigated multiple intensive concomitant 
chemoradiotherapy regimens. We initially studied the interaction of 5-FU, hydroxyurea 
and radiotherapy (FHX).31,32 Both chemotherapy agents have known systemic activity and 
have been shown to act as radiation enhancers in vitro and in vivo.14,33,34 Cytotoxic activity 
is synergistic as hydroxyurea modulates the activity of 5-FU by depleting cellular pools of 
deoxyuridine monophosphate (dUMP) and facilitating binding of the 5-FU metabolite 5-
FdUMP to its target enzyme thymidylate synthase.35 Paclitaxel was subsequently added 
to the FHX regimen (TFHX) and the radiation scheme changed to twice daily to further 
intensify the treatment.36-39  
 
The TFHX regimen was demonstrated to be a highly active and tolerable concomitant 
chemotherapy and hyperfractionated radiation regimen: overall survival and locoregional 
control rates at 3 years were 60% and 86%, respectively.38,40 Since surgery was used 
primarily as a salvage procedure, excellent organ preservation was also achieved. Acute 
toxicities were severe in a majority of subjects but were considered tolerable overall. 
Mucositis (84% grade 3/4), “in-field” dermatitis (38% grade 3/4), leukopenia (34% grade 
3/4), and anemia (22% required transfusion) were the most common serious side effects. 
At 1 year post-treatment, 61% of subjects had severe xerostomia and 47% had 
compromised swallowing; the rate of feeding tube dependence was 20%. 
 
In an attempt to decrease the toxicity of concomitant chemoradiation, we conducted 
prospective investigations into reducing the radiation dose in sequential cohorts to areas 
at risk for microscopic disease.6,41 The cohort receiving 75 Gy to gross disease (high risk), 
54 Gy to intermediate-risk volumes, and 39 Gy to low-risk volumes experienced the best 


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therapeutic ratio. Again, high locoregional and distant control rates were seen, though the 
rate of dermatitis (45%) was significantly lower. 
 
With improved locoregional control, the systemic control of micrometastatic disease 
emerged as an important treatment goal that was not achieved optimally with the 
chemotherapy doses applied during concomitant chemoradiotherapy. Indeed, 
approximately 20% of subjects were noted to recur distantly, despite the addition of 
cytotoxic chemotherapy to radiation therapy as part of the TFHX regimen. 
 
3.3 
Induction Chemotherapy 
On the basis of the aforementioned studies, induction chemotherapy was investigated as 
a method of successfully eradicating micrometastatic disease. At the University of 
Chicago, carboplatin and paclitaxel were initially chosen as an induction chemotherapy 
regimen because they are typically well-tolerated with low rates of mucositis. The first 
report of this regimen demonstrated both high locoregional control and improved distant 
control.42 Systemic disease progression was noted in 7% of subjects; this translated into 
improved 3-year progression-free and overall survival rates of 80% and 77%, 
respectively.  
 
Currently, the triplet combination of a taxane (docetaxel or paclitaxel), cisplatin, and 5-FU 
(TPF) is considered one standard induction regimen (if induction therapy is considered). 
This is largely based on the results of a meta-analysis demonstrating a 5% increase in 
survival for cohorts using a cisplatin/fluorouracil (5-FU) combination and published phase 
III trials demonstrating the superiority of induction docetaxel, cisplatin, and 5-fluorouracil 
over 
cisplatin 
and 
5-fluorouracil 
when 
followed 
by 
radiotherapy 
or 
chemoradiotherapy.21,43-45  
 
Controversy still exists regarding the overall survival benefit of adding induction TPF to 
chemoradiotherapy. Recent studies demonstrating no additional survival benefit are 
limited by methodological deficiencies.46-48 Additionally, recent data demonstrate that TPF 
and carboplatin/paclitaxel seem to have equivalent activity while the latter platform is 
associated with decreased toxicity.49 Two studies evaluating carboplatin/paclitaxel 
induction demonstrated 82% and 87% response rates compared to our DeCIDE trial 64% 
response to TPF.41,42,50  
 
Paclitaxel and nab-paclitaxel have the same activity based on response rates with better 
delivery and a favorable toxicity profile (especially with nab-paclitaxel). Compared with 
solvent-based paclitaxel, nab-paclitaxel delivers 33% higher drug concentration to tumors 
in preclinical xenograft models, and demonstrates enhanced transport across endothelial 
cell monolayers.51 The Cremophor-free medium enables nab-paclitaxel to be given in a 
shorter duration without the need for premedication to prevent solvent-related 
hypersensitivity reactions.   Standard IV bags and tubing may be used for the delivery of 
nab-paclitaxel. Preliminary data from our Optima I trial using a nab-paclitaxel/carboplatin 
induction backbone indicate a high degree of tolerability and efficacy with a deep 
response rate of approximately 60%. Importantly with relation to immunotherapy, nab-


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paclitaxel can be administered without steroid premedication, and concerns exist for 
immunotherapy efficacy with steroid pre-medication. 
 
3.4 
Human Papillomavirus (HPV) and HNSCC 
Both epidemiologic and molecular evidence have elucidated the causative role of HPV in 
oropharynx SCC over the past decade. The incidence of oropharyngeal cancer has risen 
dramatically over the past two decades and it is now the most common HNSCC.1 Both 
seropositivity and oral infection with high-risk type HPV (HPV-16) have been shown to 
increase the risk of developing oropharyngeal cancer (OPC).52,53 HPV-positive tumors 
have a unique molecular profile: wild-type p53, upregulated p16, and downregulated 
pRb.54 There is direct evidence that HPV-16 is oncogenic, mechanistically driving the 
development and viability of cancer cells.55-57 
 
There is concern for an HNSCC-epidemic due to HPV. Extrapolating recent trends, the 
annual number of HPV-positive OPC is expected to surpass the annual number of 
cervical cancers by the year 2020.1,58 This is especially concerning in light of the fact that 
subjects with HPV-related OPC are approximately ten years younger on average than 
their HPV-negative OPC counterparts.59 
 
Recently, studies have demonstrated that subjects with HPV-related OPC have superior 
response to therapy and survival compared to HPV-negative OPC. In retrospective 
analyses of survival and HPV status from three phase III trials, unprecedented overall 
survival of approximately 80-90% at three years was obtained.2,60,61  Improved survival in 
these studies was largely due to markedly improved local-regional control as a biologic 
consequence of the HPV-origin of these tumors. With the improvement in locoregional 
control, distant metastasis is now gaining recognition as a leading cause of death in HPV-
positive subjects and the rate of distant relapse is the same for both HPV-related OPC 
and non-HPV related tumors.2,3,62 
 
Recursive partitioning analysis has helped to stratify HPV-related OPC subjects for both 
risk of death and distant relapse. In a retrospective analysis of the association between 
tumor HPV status and survival among subjects with stage III/IV OPC who were enrolled 
in a randomized trial comparing accelerated-fractionation radiotherapy with standard-
fractionation radiotherapy as part of concomitant chemoradiation with cisplatin, HPV 
status of the tumor was the major determinant of overall survival, followed by the number 
of pack-years of tobacco smoking (≤10 vs >10), and then nodal stage (N0-N2A vs N2B-
N3) for HPV-positive tumors.2 In another retrospective analysis of  the association 
between tumor HPV status and distant metastatic risk in a prospectively assembled 
cohort of OPC subjects treated with radiotherapy alone or concurrent chemoradiotherapy, 
the distant control rates for HPV-positive, low-risk N0-2A or less than 10 pack-year N2B 
subjects were similar for RT alone and CRT, but the rate was lower in the N2C subset 
managed by RT alone.3 Subsequent studies however have found a higher threshold of 
20-pack years, which is now commonly used, and other studies have found no 
relationship with tobacco use at all, and hence tobacco use was not integrated into the 


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new staging system for HPV-positive OPC subjects (ICONS-S / AJCC 8th edition) for that 
reason.3,64 
 
Preliminary results of our Optima I trial indicate that risk stratification using nodal stage 
(N0-N2B vs N2C-N3), tumor size (T0-3 vs T4), and tobacco use history (≤10 vs >10 pack 
years) appropriately selected subjects for de-intensified locoregional therapy without 
compromising outcomes. Additionally, this risk stratification is echoed in recent proposals 
for a new staging classification for HPV-related OPC as part of the AJCC 8th edition.63,64 
In a multi-institutional development and validation study, adjusted hazard ratio methods 
were found to best model a proposed staging system in which T1-T2/N0-N2B is classified 
as stage I (5-year survival 85%), T3/N2C is classified as stage II (5-year survival 78%), 
and T4/N3 is classified as stage III (5-year survival 53%).64 Additionally, there are recent 
data demonstrating the prognostic significance of HPV-genotype, with superior survival 
outcomes for subjects with HPV-16.65 
 
3.5 
Response-Adapted Volume De-escalation (RAVD) 
It has been shown that subjects with favorable response to IC have superior prognosis 
and are less likely to experience locoregional failure after definitive chemoradiation.6 
Strategies to decrease the late toxicity associated with CRT have focused on radiotherapy 
(RT) dose reduction and constraints for organs at risk. It has also been shown that the 
majority of locoregional failures after CRT are “in-field” and occur within the highest-risk 
RT treatment volume.66 
 
Conventional head and neck RT elective nodal volumes are based on historic surgical 
data regarding the risk of occult LN involvement. Several series have investigated 
decreasing elective nodal RT coverage. For subjects with limited tonsillar cancer, 
elimination of contralateral elective neck RT has shown to be feasible.67 Additionally, it 
has recently been shown that elimination of elective RT to the retropharyngeal and high 
level II lymph nodes in the contralateral uninvolved neck is feasible and results in 
decreased toxicity.68 In our RAVD trial, we utilized radically reduced RT volumes entirely 
omitting elective nodal coverage in good responders to IC and significantly decreasing 
coverage in non-responders.5  
 
Outcomes of the RAVD trial were specifically investigated in subjects with HPV+ 
oropharyngeal SCC. 2-year PFS and OS for HPV+ oropharynx good responders were 
93.1% and 92.1%, respectively. 2-year PFS and OS for HPV+ oropharynx non-
responders were 74.0% and 95.2%, respectively. The majority of locoregional failures 
(12/13—92.3%) in this trial were in-field failures within the RT treatment volume and 11/12 
(91.7%) occurred in the highest-risk PTV1. With respect to late toxicity, non-responders 
were significantly more likely to undergo G-tube placement during treatment (50.0% GR 
vs 73.5% NR, P = 0.040) and be G-tube dependent at 3-month (22.9% GR vs 57.1% NR, 
P = 0.002) and 6-month follow-up (5.7% GR vs 32.6% NR, P = 0.005). On multivariate 
analysis, good response to IC was the only significant predictor of G-tube dependency on 
treatment (OR 0.36, P = 0.028) and at 3-month (OR 0.22, P = 0.002) and 6-month follow-
up (OR 0.12, P = 0.009). 


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3.6 
Dose De-escalation for HPV-related Oropharynx Cancer 
Given the excellent cancer control and survival in HPV-associated oropharynx cancer, 
there has been a wave of recent efforts to decrease the intensity of treatment without 
compromising cancer control. Alternative dose de-intensification strategies have been 
recently published or presented. 
 
In the University of North Carolina/University of Florida experience, subjects with 
favorable-risk HPV-associated oropharynx cancer were treated with weekly cisplatin and 
60 Gy RT (10 Gy dose de-escalation) followed by pathologic evaluation.69 The pathologic 
complete response rate was 86% and non-inferior to the null hypothesis of 87%. In the 
ECOG 1308 trial, subjects with resectable stage III/IV disease received induction 
chemotherapy followed by risk-stratified locoregional therapy (54 Gy with cetuximab for 
complete responders versus 69.3 Gy for partial responders).4 Preliminary results of this 
trial indicate a 2-year progression-free survival of 84% and locoregional control greater 
than 90%. Additionally, preliminary results of our Optima I trial significantly de-escalating 
dose for both high and low risk HPV-related oropharynx cancer after favorable response 
to induction chemotherapy indicate a high degree of control without compromised 
efficacy.  
 
3.7 
Transoral Robotic Surgery (TORS) 
Compared to traditional open surgical approaches, transoral robotic surgery (TORS) has 
been shown to improve Quality of Life (QOL) outcomes and functional outcomes in 
speech and swallowing, while maintaining good oncologic outcomes.70 Favorable 
gastrostomy tube rates (0-9,5% at one year and 0% at 2 years after treatment) have been 


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reported following TORS. T1-2 tumors of the oropharynx, especially those arising within 
the tonsillar fossa and lateral pharyngeal wall, glossopharyngeal sulcus, and lateral 
tongue base, are amenable to TORS when adequate oral access can be obtained. 
 
There are limited retrospective and no randomized data comparing TORS versus RT/CRT 
for definitive treatment of oropharynx cancer. A recently published meta-analysis 
suggests equivalent efficacy of both TORS and RT in terms of disease control for early 
stage oropharyngeal SCC.71 A small retrospective analysis of quality of life outcomes 
published by the UCLA group showed similar quality of life among subjects treated by 
transoral surgery or chemoradiotherapy.72 The currently accruing ORATOR phase II 
study which randomizes subjects with early-stage SCC of the oropharynx to RT of TORS 
will provide valuable prospective data.73 
 
A novel approach using induction chemotherapy followed by transoral surgery was 
recently published by the George Washington University group.74 In this series of 17 
subjects with advanced oropharyngeal cancer who were treated with neoadjuvant 
chemotherapy followed by transoral surgery of the pre-chemotherapy extent of disease 
plus selective neck dissection, 16/17 subjects were alive without recurrence at median 
follow-up of 31 months (3-year disease-specific survival 94.1%).  
 
Additionally, multiple trials are currently examining the role of adjuvant therapy de-
intensification for subjects with HPV-related oropharynx cancer after TORS. Standardly, 
post-operative RT is delivered to a dose of 60-66 Gy for adverse features including 
extracapsular extension (ECE), positive surgical margins, perineural invasion (PNI), or 
lymphovascular invasion (LVI). Concomitant chemotherapy is also added for subjects 
with ECE or positive margins, based on joint analysis of the EORTC and RTOG trials 
demonstrating a significant survival benefit for this subset.75   
 
The Eastern Cooperative Group (ECOG) 3311 trial is examining transoral surgery 
followed by low-dose of standard-dose RT with or without chemotherapy for subjects with 
HPV-related stage III/IVA oropharynx cancer.76 Subjects with intermediate adverse 
features (≤1 mm ECE, 2-3 involved nodes, PNI, or LVI) are randomized to RT alone to 50 
Gy versus 60 Gy. Subjects with high risk adverse features (positive margins, >1 mm ECE, 
or ≥4 involved nodes) are treated to 66 Gy with concurrent cisplatin (40 mg/m2). In the 
phase II trial from the Mayo Clinic, subjects with p16-positive oropharynx cancer with less 
than a ten pack-year smoking history who have had a complete surgical resection are 
also treated with de-intensified adjuvant therapy.77 Subjects with intermediate risk 
disease (≥T3, ≥N2, LVI, or PNI) are treated with 30 Gy RT (1.5 Gy BID) and concurrent 
weekly docetaxel while subjects with ECE receive a similar treatment regimen but also 
have the nodal level with positive ECE concurrently boosted to 36 Gy in 1.8 Gy twice-
daily fractions. 
 
In this trial we are seeking to use TORS as a substitution for XRT in good prognosis cases 
with excellent response to induction with reduced longterm toxicities (such as fibrosis, 
xerostomia, dental issues, and dysphagia, etc (see 5.11.2).  
 


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3.8 
Positron Emission Tomography (PET)-Based Surveillance 
Post-chemoradiotherapy neck dissection can be associated with significant morbidity 
because of the associated scarring and fibrosis. In our published experience at the 
University of Chicago, 10% of subjects developed wound healing complications and other 
complications occurred in 16% of subjects and included need for tracheotomy, nerve 
transection and paresis, and permanent hypocalcemia.78 
 
Computed tomography (CT) has been previously shown to spare subjects with 
radiographic complete response from post-RT neck dissection, regardless of initial nodal 
stage.79 This has been adopted as the routine post-CRT surveillance at the University of 
Chicago over the past decade. Recently, positron emission tomography (PET)-CT has 
been adopted at several institutions as a method of avoiding neck dissection after 
definitive chemoradiotherapy.  
 
A prospective, randomized, controlled trial, assessing the noninferiority of PET-CT guided 
surveillance (performed 12 weeks after the end of chemoradiotherapy, with neck 
dissection performed only if PET-CT showed an incomplete or equivocal response) to 
planned neck dissection in subjects with stage N2 or N3 disease was recently published.80 
The hazard ratio for death slightly favored PET-CT–guided surveillance and indicated 
noninferiority. Survival was similar among subjects who underwent PET-CT–guided 
surveillance and those who underwent planned neck dissection, but surveillance resulted 
in considerably fewer operations and it was more cost-effective. 
 
3.9 
Nivolumab / anti-PD-1 
Nivolumab is a fully humanized, IgG4 (kappa) isotype monoclonal antibody (mAb) that 
binds the programmed death receptor-1 (PD-1).81 PD-1 is a transmembrane protein 
primarily expressed on activated immune cells. In its usual function, the binding of PD-1 
(found on activated T-cells) to its ligands PD-L1 (B7-H1) and PD-L2 (B7-DC) inhibits T-
cell proliferation and activation. Upregulation of PD-1 ligands can occur in tumors and is 
thought to serve as a means of immune evasion by the tumor.82 Nivolumab blocks the 
interaction of the PD-1 T-cell receptor with its ligands, potentially enabling the reactivation 
of immunosurveillance and cancer eradication. 
 
Nivolumab is approved by the U.S Food and Drug Administration (FDA) in melanoma, 
Hodgkin lymphoma, lung carcinoma, and renal cell carcinoma. It has received approval 
for head and neck cancer based on the results of the CheckMate 141 study.8 In this phase 
III randomized trial, eligibility criteria included recurrent/metastatic HNSCC of the oral 
cavity, pharynx, or larynx with progression on or within 6 months of the last dose of 
platinum-based therapy (irrespective of number of prior lines of therapy or PD-L1 status. 
Subjects were randomized to receive nivolumab (3 mg/kg IV q2week) versus 
investigator’s choice of therapy. Approximately one-quarter of subjects enrolled were p16 
positive. Median overall survival was 7.5 months for nivolumab versus 5.1 months for 
investigator’s choice therapy (HR 0.70, P=0.01). The 1-year overall survival rate was 
36.0% for nivolumab versus 16.6% for investigator’s choice. The objective response rate 


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with nivolumab was 13.3% (2.5% complete, 10.8% partial). For subjects with p16 positive 
disease, the HR for overall survival was 0.56 (95% CI 0.32-0.99). Overall, nivolumab was 
well-tolerated with 3.8% of subjects not continuing treatment due to study drug toxicity 
and 13.1% of subjects experiencing any treatment-related grade 3-4 adverse event. The 
most common grade 3-4 treatment related adverse events were fatigue (2.1%), anemia 
(1.3%), and asthenia (0.4%). 
 
Currently, there is great interest in integrating nivolumab into the curative-intent setting. 
The Radiation Therapy Oncology Group (RTOG) will soon activate a phase III trial with a 
phase I dose finding lead-in study to evaluate whether the addition of nivolumab will 
improve the overall survival for subjects with newly diagnosed intermediate-risk or high-
risk HNSCC when treated with radiation therapy and cisplatin-based or cetuximab-based 
chemotherapy or with radiation alone.83  
 
Chemotherapy leads to tumor lysis and release of tumor antigens, which may prime the 
immune system for checkpoint inhibitors. The combination of a taxane and immune 
checkpoint inhibitor has been reported to improve response in non-small cell lung cancer 
(NSCLC). In a recently presented phase I study of nivolumab with nab-paclitaxel and 
carboplatin in advanced NSCLC (ABI-007-ST-001), subjects received 4 cycles of nab-
paclitaxel (100 mg/m2 on days 1, 8, 15), carboplatin (AUC 6 on day 1 of a 21-day cycle), 
and nivolumab (5 mg/kg on day 15 starting at cycle 1).84 No dose-limiting toxicities were 
observed. The most frequent grade ≥3 treatment-related adverse events were 
neutropenia (28.6%) and anemia (19%). No pneumonitis has been reported to date. 
 
3.10 
Study Rationale 
HPV-positive oropharynx cancer is a distinct clinical entity based on differing 
demographics, biology, and prognosis. The overall survival benefit in subjects with HPV-
related oropharynx cancer is due largely to a marked improvement in locoregional control. 
Given the younger demographic and the significant long-term morbidity incurred with 
standard locoregional therapy, treatment de-intensification is currently an area of active 
investigation. 
 
Multiple approaches for treatment de-intensification of HPV-positive oropharynx cancer 
have recently been presented or are currently under investigation in multi-institutional 
settings. These strategies may be classified as follows: 
 
1. Chemotherapy and RT dose de-escalation for select subjects with low-risk 
disease (UNC/UF study69, NRG HN00285) 
2. Substitution of cetuximab in place of cisplatin as the concurrent agent (RTOG 
101686, TROG 12.0187) 
3. Transoral surgical resection followed by de-intensified adjuvant therapy (ECOG 
331176) 
4. Induction chemotherapy followed by response-stratified locoregional therapy 
(ECOG 13084, University of Chicago RAVD5 and Optima I88 studies) 
 


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Our published results using induction chemotherapy to stratify subjects for receipt of 
radical radiotherapy volume de-escalation demonstrate excellent locoregional control and 
significantly improved treatment toxicity and quality of life outcomes.5 Notably, subjects 
with both high- and low-risk HPV-positive oropharynx cancer, as well as HPV-negative 
HNSCC, were candidates for radical volume de-escalation in this trial. In the subset 
analysis of HPV-positive oropharynx subjects, outcomes were excellent with 2-year 
locoregional control and progression-free survival rates of 100% and 93%, respectively, 
for subjects with favorable response to induction chemotherapy in whom elective nodal 
coverage was omitted. Preliminary results of our subsequent study investigating 
significant RT dose de-escalation in subjects with response to induction chemotherapy 
also indicate a high degree of control without compromised outcomes. 
 
Increasing the response rate to neoadjuvant therapy is an important endpoint to increase 
the proportion of subjects who qualify for de-intensified locoregional therapy. Monoclonal 
antibodies targeting the programmed death (PD)-1 immune checkpoint receptor have 
shown remarkable activity in multiple cancer types including head and neck cancer. The 
goal of PD-1 blockade is to promote tumor recognition and destruction by the immune 
system. Nivolumab has received breakthrough designation for head and neck cancer 
based on phase III results demonstrating a survival benefit with an objective response 
rate of 13.3%.8  
 
Chemotherapy leads to tumor lysis and release of tumor antigens, which may prime the 
immune system for checkpoint inhibitors. Synergy of anti-PD-1 with chemotherapy is 
supported by early data combining nivolumab with nab-paclitaxel and carboplatin.84 
These data suggest a marked increase in the response rate and depth of response, 
perhaps related to the use of steroid sparing chemotherapy (in particular steroid sparing 
nab-paclitaxel) which allows for synergy with PD-1/PD-L1 checkpoint blockade. 
 
Given the above, we hypothesize that the addition of a checkpoint inhibitor, nivolumab, 
to induction chemotherapy will increase the response rate to neoadjuvant therapy and 
therefore increase the proportion of subjects who may qualify for de-intensified 
locoregional therapy. Additionally, we hypothesize that de-intensified locoregional 
therapy for subjects with favorable response to induction chemotherapy (including TORS 
or dose- and volume- de-escalated C/RT) will not compromise control outcomes but will 
result in significantly decreased treatment toxicity.  
 
In this study, we will specifically evaluate subjects with locoregionally advanced HPV-
positive squamous cell cancer of the oropharynx. Subjects will be given 3 cycles of 
neoadjuvant nivolumab, carboplatin, and nab-paclitaxel followed by clinical and 
radiographic assessment of response. The subjects will be assigned to treatment arms 
based on response to induction chemotherapy and high or low risk status, as outlined 
below: 
 


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3.10.1 
Risk Status 
3.10.1.1 
 
Low Risk Status (all of the below): 
o T1-3 
o N0-N2B (unless N3 equivalent lymph nodal conglomerate*) 
o ≤20 pack year history tobacco use 
o HPV16 
 
3.10.1.2 
 
High Risk Status (any of the below): 
o T4 
o N2C-N3 
o Bulky N2B disease with N3 equivalent nodal conglomerate* 
o >20 pack year history tobacco use 
o Non-HPV16 HPV type (e.g. HPV18, HPV31, etc) 
  
*N3/bulky nodal disease is defined radiologically or on clinical exam 
 
3.10.2 
Group A1: Single-Modality De-escalation Arm (SDA) -- TORS: Single-
Modality De-escalation Arm (SDA) –RT 
Subjects with low risk and small volume tonsillar disease (T1-T2, non-bulky N2A-
N2B with ≤2 non-lower neck lymph nodes measuring ≤5 cm in size) or base of 
tongue disease (T1-2 with lateralized primary ≤3 cm, non-bulky N2A-N2B with ≤2 
non-lower neck lymph nodes measuring ≤5 cm in size) who have ≥50% reduction 
by RECIST following induction chemotherapy will undergo TORS and selective 
nodal dissection. De-intensified adjuvant RT will be given for adverse pathologic 
features. Subjects may refuse TORS treatment.  
 
3.10.3 
Group A2: Single-Modality De-escalation Arm (SDA) –RT 
Subjects with low risk, who do not qualify for TORS (due to volume of disease or 
poor visualization/access) or refuse TORS, who have ≥50% reduction by RECIST 
following induction chemotherapy will be given de-intensified treatment with 
radiation alone to 50 Gy (see schema page 5). 
 
3.10.4 
Group B: Intermediate De-escalation Arm (IDA) – Intermediate dose 
CRT 
Subjects who have low risk disease with <50% but ≥30% reduction of tumor by 
RECIST with induction chemotherapy will receive CRT to 50 Gy with concurrent 
bolus cisplatin (x2 doses) or TFHX to 45 Gy (3 cycles). 
 


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Subjects who have high risk disease and ≥50% reduction of tumor by RECIST with 
induction chemotherapy will receive CRT to 50 Gy with concurrent bolus cisplatin 
(x2 doses) or TFHX to 45 Gy (3 cycles). 
  
3.10.5 
Group C: Regular Dose Arm (RDA) – Standard dose CRT: 
Subjects who have low risk disease and <30% reduction of tumor by RECIST with 
induction chemotherapy will receive CRT to 70 Gy with concurrent bolus cisplatin 
(x3 doses) or TFHX to 75 Gy (5 cycles). 
 
 
 
 
 
 
Subjects who have high risk disease and <50% reduction of tumor by RECIST with 
induction chemotherapy will receive CRT to 70 Gy with concurrent bolus cisplatin 
(x3 doses) or TFHX to 75 Gy (5 cycles). 
 
 
 
 
 
 
Any subject who has progressive disease will receive CRT to 70 Gy with 
concurrent bolus cisplatin (x3 doses) or TFHX to 75 Gy (5 cycles). 
 
3.10.6 
Adjuvant Treatment with Nivolumab/anti-PD-1 
Adjuvant nivolumab will be offered to all subjects for 6-months post completion of 
locoregional therapy for additional systemic activity. 
 


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4 
SUBJECT SELECTION 
4.1 
Eligibility Criteria 
• Subjects must have pathologically confirmed HPV-positive head and neck 
squamous cell carcinoma of the oropharynx. Confirmed HPV-positive disease of 
other subsites are uncommon but also eligible.  
 
• HPV testing must be compliant with the following criteria: 
• p16 IHC positivity is sufficient to enroll and initiate treatment (p16 IHC 
interpretation to follow guidelines by Jordan and Lingen et al89).   
• p16 IHC positivity is to be validated using an HPV PCR during the induction 
phase. This is essential as HPV genotype influences treatment arm 
allocation, with non-HPV16 HPV strains being considered high risk. 
 
• Availability of ≥10 unstained 5 micron slides (to be provided to HTRC at the 
University of Chicago). Subjects who cannot fulfill this requirement will need to 
undergo a new biopsy prior to enrollment on study. 
 
• Subjects must be at least 18 years of age. 
 
• Subjects with AJCC (7th edition, 2010) N2-N3 nodal disease or T3-T4 primary 
tumor. Those with AJCC (8th edition 2018) TXNX are also allowed. 
 
• Measurable disease (either primary site and/or nodal disease) by RECIST 1.1 
criteria.  
 
• No previous radiation or chemotherapy for a head and neck cancer. 
 
• No complete surgical resection for a head and neck cancer within 8 weeks of 
enrollment (although lymph node biopsy including excision of an individual node 
with presence of residual nodal disease, or surgical biopsy/excision of the tumor 
with residual disease is acceptable). 
 
• ECOG performance status 0-1 (Karnofsky 80%). 
 
• Normal Organ Function 
• Leukocytes ≥3000/mm3,  
• platelets ≥100,000/mm3,  
• absolute neutrophil count ≥1,500,  
• hemoglobin >9.0 gm/dL,  
• AST and ALT <2.5 X ULN  
• alkaline phosphatase <2.5 X ULN  
• albumin >2.9 gm/dL,  
• total bilirubin ≤1.5 mg/dl,  


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• creatinine clearance >45 mL/min (or SCr <1.5 mg/dL), normal within 2 
weeks prior to start of treatment. 
→The standard Cockcroft and Gault formula or the measured 
glomerular filtration rate must be used to calculate CrCl for enrollment 
or dosing 
• Subjects must sign a study-specific informed consent form prior to study entry. 
Subjects should have the ability to understand and the willingness to sign a written 
informed consent document. 
 
• Age, Sex, and Reproductive Status:  
a) Men and women, ages ≥ 18. 
b) Women of childbearing potential (WOCBP=premenopausal woman capable of 
becoming pregnant) must have a negative serum or urine pregnancy test 
(minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior 
to the start of study drug.   
c) Women must not be breastfeeding.   
d) WOCBP must agree to follow instructions for method(s) of contraception for 
the duration of treatment with study drug(s) plus 5 half-lives of study drug(s) 
plus 30 days (duration of ovulatory cycle) for up to 5 months post-treatment 
completion.   
e) Men who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study drug(s) plus 
5 half-lives of study drug(s) plus 90 days (duration of sperm turnover) for up to 
7 months post treatment completion.   
f)  Azoospermic males and WOCBP who are continuously not heterosexually 
active are exempt from contraceptive requirements. However, they must still 
undergo pregnancy testing as described in this section.   
 
Investigators shall counsel WOCBP and male subjects who are sexually active 
with WOCBP on the importance of pregnancy prevention and the implications of 
an unexpected pregnancy. Investigators shall advise WOCBP and male subjects 
who are sexually active with WOCBP on the use of highly effective methods of 
contraception. Highly effective methods of contraception have a failure rate of 
<1% when used consistently and correctly.  
 
At a minimum subjects must agree to the use of one method of highly effective 
contraception as listed in Appendix E. In addition, male subjects are expected to 
use a condom as noted in Appendix E.  
  
4.2 
Exclusion Criteria 
• Unequivocal demonstration of distant metastases (M1 disease). 
 
• Unidentifiable primary site. 


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• Intercurrent medical illnesses which would impair subject tolerance to therapy or 
limit survival. Including but not limited to ongoing or active infection, 
immunodeficiency, symptomatic congestive heart failure, pulmonary dysfunction, 
cardiomyopathy, unstable angina pectoris, cardiac arrhythmia, or psychiatric 
illness/social situations that would limit compliance. Once clinically stable, as 
defined by the PI, they are eligible. 
 
• Pregnant and nursing women are excluded because of the potential teratogenic 
effects and potential unknown effects on nursing newborns (please see above 
paragraph under inclusion criteria regarding WOCBP) 
 
• Prior surgical therapy other than incisional/excisional biopsy or organ-sparing 
procedures such as debulking of airway-compromising tumors. Residual 
measurable tumor is required for enrollment on study as outlined above 
 
• Subjects receiving other investigational agents. 
 
• Peripheral neuropathy >grade 1 
 
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy in 
excess of physiologic dose or any other form of immunosuppressive therapy within 
7 days prior to the first dose of trial treatment.  
• Has a known history of active tuberculosis (Bacillus Tuberculosis infection) 
 
• Has hypersensitivity to nivolumab or any other drug used in this protocol. 
• Has had a prior systemic anti-cancer treatment within the last 8 weeks 
• Has a known additional malignancy that is progressing or requires active 
treatment.  Exceptions include basal cell carcinoma of the skin or squamous cell 
carcinoma of the skin that has undergone potentially curative therapy or in situ 
cervical cancer or any tumors that are not likely to influence live expectancy in the 
subsequent 3 years without active treatment (e.g. low grade prostate cancer in 
absence of therapy). 
• Has active autoimmune disease that has required systemic treatment in the past 
year (i.e. with use of steroids or immunosuppressive drugs). Replacement therapy 
e.g. levothyroxine, insulin, or physiologic corticosteroid doses for adrenal or 
pituitary insufficiency, etc. are not considered a form of systemic treatment.  
• Has known history of, or any evidence of active, non-infectious pneumonitis. 
• Has a history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 


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• Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). However, if eradicated subject is eligible. 
• Has received a live vaccine within 28 days of planned start of study therapy. 
o Note:  Seasonal influenza vaccines for injection are generally inactivated 
flu vaccines and are allowed; however intranasal influenza vaccines (e.g., 
Flu-Mist®) are live attenuated vaccines, and are not allowed within 28 
days prior to initiation of treatment. 
 
4.3 
Criteria for discontinuation/withdrawal of informed consent 
Subjects may be discontinued from trial treatment at any time, at the discretion of the 
investigator(s). Specific reasons for discontinuing a subject from study treatment include: 
 
• Objective progression of disease if deemed inappropriate for further study 
treatment. 
 
• Unacceptable adverse events. 
 
• Protocol non-compliance. 
 
• Study closure. 
 
• Subject decision to withdraw from the study.  
 
• In the judgment of the investigator, further treatment would not be in the best 
interest of the subject. 
 
All deaths that occur within the trial period or within 100 days after administration of the 
last dose of trial drug are to be reported as SAEs. 
 
All trial treatment-related toxicities and SAEs must be followed up until resolution. All 
subjects who have new or worsening CTCAE grade 3 or 4 laboratory values at the time 
of withdrawal must have additional testing performed for up to 12 months, and the results 
must be recorded in the subject’s medical record. In these cases, the investigators must 
record their opinions regarding relationship to study treatment in the subject’s medical 
record. Laboratory abnormalities should not be reported as adverse events unless a 
criterion for an SAE is fulfilled, the laboratory abnormality causes the subject to 
discontinue from the study, or the investigator insists the abnormality should be reported 
as an AE.   
 


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4.4 
HPV testing 
As this trial makes treatment decisions based on HPV status, the specificity of the HPV 
test used is of critical importance. Therefore, certain HPV testing requirements have to 
be met that take into account varying HPV performance characteristics in oropharyngeal 
primary tumors.  
 
• p16 IHC positivity is sufficient to enroll and initiate treatment (p16 IHC 
interpretation to follow guidelines by Jordan and Lingen et al89).   
• p16 IHC positivity is to be validated using an HPV PCR during the induction 
phase. This is essential as HPV genotype influences treatment arm 
allocation, with non-HPV16 HPV strains being considered high risk. 
 


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5 
TREATMENT PLAN 
5.1 
General Considerations 
Induction chemotherapy will be administered on an outpatient basis. Subjects receiving 
radiation therapy alone will be treated as outpatients whereas chemoradiotherapy may 
be administered on an inpatient basis (using the TFHX regimen) or outpatient basis (with 
cisplatin). Subjects receiving adjuvant nivolumab will receive this on an outpatient basis. 
All subjects will be evaluated by surgical, medical, and radiation oncologists prior to trial 
entry to determine optimal local treatment. Subjects will start induction chemotherapy 
within 4 weeks of signing consent. Three cycles of carboplatin, nab-paclitaxel, and 
nivolumab induction chemotherapy will be followed by response-adjusted locoregional 
therapy.  
 
Subjects in Group A1 (Single-Modality De-escalation Arm) will undergo either TORS (with 
adjuvant radiation therapy 40-44 Gy for adverse features). Subjects in Group A2 will 
receive  radiation therapy alone to 50 Gy in standard daily fractionation. Subjects in Group 
B (Intermediate De-escalation Arm) and Group C (Regular Dose Arm) will receive 
concurrent chemoradiation consisting of cisplatin 100mg/m2 for two (intermediate) or 
three (regular) doses with daily radiation, OR twice daily radiation with paclitaxel, 5-FU, 
and hydroxyurea (TFHX) given on an alternating week basis. Subjects should have a pre-
induction chemotherapy CT simulation (or PET-CT simulation if available) performed. 
Cisplatin-radiation will be given to a total dose of 50 Gy for subjects in Group B and 70 
Gy for subjects in Group C. TFHX will be given to a total dose of 45 Gy for subjects in 
Group B and 75 Gy for subjects in Group C. Adjuvant nivolumab will be offered to all 
subjects for 6 months on an outpatient basis.  
 
5.2 
Pre-treatment evaluation 
Subjects must have completed the following within 4 weeks of signing consent unless 
noted (also see study calendar in section 9 for additional details) : 
 
• Inclusion and exclusion criteria reviewed. 
 
• Physical examination to define measurable disease. 
 
• Pan-endoscopy with biopsy, tumor mapping, and documentation (if clinically 
indicated at PI’s discretion). 
 
• Biopsy proven squamous cell carcinoma of the oropharynx with HPV testing (IHC 
is sufficient for enrollment, but PCR needs to be completed during the first cycle of 
induction to confirm IHC). 
 
• Baseline diagnostic CT or MRI scans of the head and neck that includes entire 
disease extent within 4 weeks before study entry. 


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• PET/CT scan is recommended prior to start of induction chemotherapy, 
though not required. 
 
• 10 days prior to chemotherapy, CBC with differential and platelet count, and 
complete metabolic profile. 
 
• Ultrasound or CT imaging of the liver if chemistries (SGOT, SGPT, and bilirubin) 
are above upper limit of normal. 
 
• Additional studies (bone scan, barium swallow, etc.) to exclude distant metastases 
or second primaries as clinically indicated. 
 
• Complete dental evaluation before the end of induction. 
 
• Speech and swallowing consultation during the first cycle of induction. 
 
• Informed consent. 
 
Refer to section 9 for a complete list of required baseline evaluations.   
 
5.3 
Study evaluations 
Subjects will have the following exams and tests throughout the study at specified time 
points (please see study chart): 
 
• Physical examination. 
 
• Performance status evaluation. 
 
• CBC with differential and platelet count. 
 
• Complete metabolic panel. 
 
• Toxicity and quality of life evaluations. 
 
• Head and Neck staging evaluation and imaging with either MRI or CT within 4 
weeks prior to induction chemotherapy. 
 
• Repeat imaging of the head and neck after the 3rd cycle of induction chemotherapy 
week for stratification of locoregional therapy. In the case of TORS candidates, this 
can be delayed up to 3 weeks. 
 
• Follow-up imaging with head and neck CT/MRI at 4 weeks post-locoregional 
therapy with or without re-staging PET/CT at 12 weeks post-locoregional therapy. 


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5.4 
Induction Chemotherapy Details and Guidelines  
Induction chemotherapy will be administered on an outpatient basis and concurrent 
chemoradiation will be administered on an inpatient basis. Expected adverse events 
(AEs) and appropriate dose modifications for these agents are described in Section 6. No 
other investigational agents or therapies other than those described below may be 
administered with the intent to treat the subject’s malignancy. 
 
 
Carboplatin, nab-paclitaxel, and nivolumab combination will be administered for three 
cycles of three weeks duration each. TORS or RT/CRT will be performed after induction 
chemotherapy (i.e. day 64 of therapy). Dose delays and dose modifications should take 
place as outlined.  In no case should the three cycles of induction chemotherapy be 
given over a period exceeding twelve (12) weeks. 
 
Pre-medications: Premedication with dexamethasone should not be given due to the 
possibility of counteracting the effect of nivolumab, unless absolutely clinically necessary 
(after discussion with the PI). 
 
Nivolumab: 360 mg flat dose on day 1, q21 days (3 doses total) 
 
Nab-Paclitaxel: 100 mg/m2 in 250 ml of NS (or similar per institutional standard) over 30 
minutes on days 1, 8, and 15 (9 doses total) 
Carboplatin: Start after completion of nab-paclitaxel, AUC 5 in 250 ml of D5W (or 
similar per institutional standard) over 30-60 minutes on day 1 (3 doses total) 
A baseline creatinine level should be drawn within 1 week prior to starting chemotherapy.  
Antiemetics: Pre-treatment with a 5 HT-3 antagonist [eg ondansetron hydrochloride 
(Zofran), dolasetron mesylate (Anzemet), or granisetron 
Hydrochloride (Kytril)] prior to chemotherapy on Day 1 is recommended. The use of 
additional antiemetics and the prevention of delayed emesis are left to the discretion of 
the treating physician. Dexamethasone/steroids as anti-emetic therapy should be 
avoided, and only should be given after discussion with the study PI. 
 
Hydration: Hydration is left to the discretion of the treating physician. 
 
For each cycle:  Filgrastim (neupogen) is to be given at the discretion of the treating 
physician as clinically indicated. 
 
5.5 
Surgical Details and Guidelines  
Subjects with low risk and small volume tonsillar disease (T1-T2, non-bulky N2A-N2B 
with ≤2 non-lower neck lymph nodes measuring ≤5 cm in size) or base of tongue disease 
(T1-2 with lateralized primary ≤3 cm, non-bulky N2A-N2B with ≤2 non-lower neck lymph 


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nodes measuring ≤5 cm in size) who have ≥50% reduction by RECIST following induction 
chemotherapy will undergo TORS and selective nodal dissection. De-intensified adjuvant 
RT will be given for adverse pathologic features. Subjects may refuse TORS treatment 
(see treatment next paragraph). 
 
Subjects with low risk, who do not qualify for TORS (due to volume of disease or poor 
visualization/access) or refuse TORS, who have ≥50% reduction by RECIST following 
induction chemotherapy will be given de-intensified treatment with radiation alone to 50 
Gy (see schema page 5). 
 
Before induction chemotherapy, subjects will undergo examination under anesthesia 
and direct laryngoscopy to tattoo and photograph the primary tumor to plan the post-
induction resection.  Surgical resection should be performed within 2 weeks and no later 
than 4 weeks after completion of the third cycle of induction chemotherapy. 
 
Primary site resection by TORS will be limited to the pre-induction extent of 
tumor (as defined with mapping and documentation at the time of pre-induction 
direct laryngoscopy). Selective nodal dissection of levels 2-4 and any other 
previously involved nodal levels as well as nodal levels that are clinically felt to 
be at risk will be performed. 
 
5.5.1 
Indications for Adjuvant Radiation post-operatively  
In the absence of adverse pathologic features, subjects will not receive radiation 
based therapy. 
 
Post-operative radiation will be given for adverse pathologic features as follows: 
 
(1) 40 Gy in 2 Gy once daily fractions for PNI or LVI. 
(2) 44 Gy in 2 Gy once daily fractions for ECE or positive surgical margins. 
 
Post-operative RT volumes will be at the discretion of the treating physician, with approval 
from the Radiation PI, but generally will be targeted toward the surgical bed site with 
adverse pathology. 
 
Post-operative RT should begin within 4 weeks and no later than 6 weeks after surgical 
resection. 
 
 
5.6 
Definitive Radiation/Chemoradiation Details and Guidelines  
5.6.1 
Risk Status 
5.6.1.1 
Low Risk Status (all of the below): 
o T1-3 


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o N0-N2B (unless N3 equivalent lymph nodal conglomerate*) 
o ≤20 pack year history tobacco use 
o HPV16 
 
5.6.1.2 
High Risk Status (any of the below): 
o T4 
o N2C-N3 
o Bulky N2B disease with N3 equivalent nodal conglomerate* 
o >20 pack year history tobacco use 
o Non-HPV16 HPV type (e.g. HPV18, HPV31 etc) 
 
*N3/bulky nodal disease is defined radiologically or on clinical exam. 
 
5.6.2 
Response Stratified Grouping: 
Subjects will be assigned to TORS, RT, or CRT based on response to induction 
chemotherapy.  
 
Chemoradiation will be given with concurrent cisplatin or on the TFHX platform 
based on physician and subject preference, and are considered interchangeable. 
 
• Cisplatin will be given at a dose of 100mg/m2, every 21 days for 2 (IDA arm, 
see below) or 3 doses (RDA arm, see below).  
 
• Chemoradiation on the TFHX platform will consist of 14-day cycles of 
paclitaxel (100 mg/m2 day 1 over 1 hour), 5-FU (continuous infusion at 
600 mg/m2/day  5 days), and hydroxyurea (500 mg PO BID days 0-5, 11 
doses/cycle) with twice daily radiation (150 cGy per fraction). Cisplatin-
based chemoradiation on an outpatient basis will be offered as an 
alternative treatment platform. 
 
 
5.6.2.1 
 
Group A1: Single-Modality De-escalation Arm (SDA) – TORS 
Subjects with low risk tumors and small volume tonsillar disease (T1-T2, up to 
N2B) OR  base of tongue disease (T1-2 with primary ≤3cm, up to N2B) who have 
≥50% reduction by RECIST following induction chemotherapy will undergo 
TORS and selective nodal dissection. De-intensified adjuvant RT will be given 
for adverse pathologic features. Subjects may refuse TORS treatment (see 
treatment next paragraph). 
 
Subjects with low risk, who do not qualify for TORS (due to volume of disease or 
poor visualization/access) or refuse TORS, who have ≥50% reduction by 


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RECIST following induction chemotherapy will be given de-intensified treatment 
with radiation alone to 50 Gy (see schema page 5). 
 
Surgical resection should be performed within 2 weeks and no later than 4 weeks 
after completion of the third cycle of induction chemotherapy. 
 
Primary site resection by TORS will be limited to the pre-induction extent of tumor 
(as defined with mapping and documentation at the time of pre-induction direct 
laryngoscopy). Selective nodal dissection of at least the previously involved 
nodal levels will be performed. 
 
Post-operative radiation will be given for adverse pathologic features as follows: 
 
• 40 Gy in 2 Gy once daily fractions for PNI or LVI. 
• 44 Gy in 2 Gy once daily fractions for ECE or positive surgical margins. 
 
Post-operative RT volumes will be at the discretion of the treating physician, with 
approval from the Radiation PI, but generally will be directed toward the involved 
disease site. 
 
Post-operative RT should begin within 4 weeks and no later than 6 weeks after 
surgical resection.  
 
5.6.2.2 
Group A2: Single-Modality De-escalation Arm (SDA) – RT 
Subjects with low risk, who do not qualify for TORS (due to volume of disease or 
poor visualization/access) or refuse TORS, who have ≥50% reduction by 
RECIST following induction chemotherapy will be given de-intensified treatment 
with radiation alone to 50 Gy (see schema page 5). 
 
5.6.2.3 
Group B: Intermediate De-escalation Arm (IDA) – Low dose CRT 
Subjects who have low risk disease with <50% but ≥30% reduction of tumor by 
RECIST with induction chemotherapy will receive CRT to 50 Gy with concurrent 
cisplatin (x2 doses) or 45 Gy on the TFHX platform (3 cycles). 
 
Subjects who have high risk disease and ≥50% reduction of tumor by RECIST with 
induction chemotherapy will receive CRT to CRT to 50 Gy with concurrent cisplatin 
(x2 doses) or 45 Gy on the TFHX platform (3 cycles). 
 
5.6.2.4 
 
Group C: Regular Dose Arm (RDA) – Standard dose CRT: 
Subjects who have low risk disease and <30% reduction of tumor by RECIST with 
induction chemotherapy will receive CRT to 70 Gy with concurrent cisplatin (x3 
doses) or 75 Gy on the TFHX platform (5 cycles). 


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Subjects who have high risk disease and <50% reduction of tumor by RECIST with 
induction chemotherapy will receive CRT to CRT to 70 Gy with concurrent cisplatin 
(x3 doses) or 75 Gy on the TFHX platform (5 cycles). 
 
 
 
 
 
 
Any subject who has progressive disease will receive CRT to 70 Gy with 
concurrent cisplatin (x3 doses) or 75 Gy on the TFHX platform (5 cycles). 
 
Expected AEs and appropriate dose modifications for nab-paclitaxel, carboplatin, 
nivolumab, 5-FU, hydroxyurea, and radiation are described in sections 6.1 and 6.2 
and Appendices B and C. No investigational or commercial agents or therapies 
other than those described below may be administered with the intent to treat the 
subject's malignancy. 
 
5.6.3 
 
Concurrent Cisplatin-Radiation: 
Cisplatin will be given on an every-3-weeks basis at a dose of 100mg/m2 IV over 
3-4 hours day 1 (or 2) and 22 (or 23) for subjects on the Intermediate Dose Arm, 
and additionally on day 43 (or 44) for subjects on the Regular Dose Arm. 
Mannitol should be given to decrease risk of toxicity if clinically appropriate. 
  
5.6.4 
TFHX Regimen: 
Subjects on the Intermediate or Regular Dose Arms will receive chemoradiation 
for 3-5 cycles (6-10 weeks) and chemotherapy should be administered during all 
weeks of radiotherapy.   
 
Day 0  
P.M.:  
start hydroxyurea at 500 mg PO q 12 hours  6 days 
(11 doses).  The first daily dose of hydroxyurea on days 
1 – 5 is given 2 hours prior to the first fraction of daily 
radiotherapy. 
 
 
 
6:00 P.M.:  
start continuous infusion of 5-FU at 600 mg/m2/day  5 
days (120 hours). 
 
Day 1 – 5 
dexamethasone 20 mg PO (IV) in am Day 1, 1 hr prior 
to paclitaxel 
 
famotidine 20 mg PO (IV) in am Day 1, 1 hr prior to 
paclitaxel 
 
diphenhydramine 50 mg PO (IV) in am Day 1, 30 mins 
prior to paclitaxel 
 
 


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Start paclitaxel 100 mg/m2 after first RT fraction on day 
1 of each cycle. Paclitaxel should be administered in 
250 ml 0.9% NaCl over 60 minutes. 
 
Radiation therapy is administered twice daily at 
150 cGy per fraction. 
 
Days 6 – 13:  
No chemoradiotherapy. Subjects should be seen 
once on an outpatient basis during these non-
treatment days to monitor for toxicity.  
 
For each cycle:  
Administer 5 g/kg subcutaneously (SQ) of G-CSF 
(filgrastim) daily, beginning on Day 6 through Day 12 
at a minimum of 24 hours after completion of 5-FU in 
subjects who develop grade 3 neutropenia or who have 
neutropenia  grade 2 on Day 0 of any cycle.  In these 
subjects, G-CSF should be utilized in all subsequent 
cycles. G-CSF can be utilized prophylactically from the 
start of chemoradiotherapy in all cycles at the 
discretion of the treating physician. 
 
Chemoradiotherapy cycles are repeated every 14 days until the completion of 
radiotherapy. 
 
5.6.5 
Radiation Therapy Guidelines 
1. All subjects will have a complete dental evaluation prior to the start of radiation 
therapy, ideally prior to the start of chemotherapy. 
 
2. Treatment approaches will use Intensity Modulated Radiotherapy (IMRT) and, in 
selected cases, 3D conformal radiotherapy will be used alone or in combination 
with IMRT. In both instances, the physician will attempt to deliver an even dose 
to the target tissue and minimize doses to surrounding normal structures. The use 
of customized blocks or multileaf collimation for field shaping is strongly 
recommended.  
 
3. Localization requirements: All subjects will be immobilized and simulated in the 
treatment position prior to the start of induction chemotherapy and after induction 
chemotherapy within 1-2 weeks after the last cycle of chemotherapy. A contrast 
enhanced CT simulation scan (or PET-CT simulation scan) with immobilization is 
required for planning. Slice thickness should be optimally 3 mm and no greater 
than 5 mm. The pre- and post-chemotherapy diagnostic scans will be fused to 
define the targets below. Subjects must be reproducibly immobilized. Radio-
opaque markers may be used whenever possible to delineate the surgical scars, 
extent of nodal disease, skin involvement, and any gross disease.  
 


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4. Target volumes: Appropriate volumes will be delineated at the time of simulation 
to treat the pre-chemotherapy extent of gross disease and areas of potential 
microscopic disease. 
 
GTV will be all gross tumor identified by physical exam, additional clinical 
information, and radiographic studies prior to induction chemotherapy.  
 
CTV1 will be an isotropic expansion of the GTV by 1.0 cm and may be modified 
at the discretion of the treating physician to respect anatomic boundaries to 
spread of tumor (e.g., bone or air). 
 
PTV1 will be an isotropic expansion of the CTV1 by 0.5 cm. 
 
CTV2 will include CTV1 plus the next echelon of uninvolved but at risk lymph 
nodes that include the nodal stations at risk for microscopic spread as described 
in the tables below. Inclusion of the retropharyngeal nodes will be at the discretion 
of the treating radiation oncologist. CTV2 may be modified at the discretion of the 
treating physician to respect anatomic boundaries to spread of tumor (e.g., bone 
or air). 
 
PTV2 will be an isotropic expansion of the CTV2 by 0.5 cm. 
 
5. Dose and fractionation: 
 
For subjects treated with RT alone:  
 
i. Single-Modality De-escalation Arm (SDA) -- RT:  PTV1 will be 
treated to 50 Gy (2 Gy QD) with radiation alone over 5 consecutive 
weeks. There will be no PTV2 volume. 
 
For subjects treated with CRT on the TFHX platform: 
 
i. Intermediate De-escalation Arm (IDA): PTV1 will be treated to 45 Gy 
(1.5 Gy BID) over the course of 3 cycles. PTV2 will be treated to 30 Gy 
(1.5 Gy BID) during the first 2 cycles of CRT for low-risk subjects with 
<50% response. There will be no PTV2 volume for high-risk subjects 
with ≥50% response. Chemoradiation will be given on an alternating 
week basis. There should be a minimum of 6 hours between fractions. 
All fields will be treated each day. In the case of mechanical failure or a 
holiday, one day of BID radiotherapy can be replaced with a single QD 
fraction of 2 Gy. Accordingly, the final cumulative dose will be slightly 
less. 
ii. Regular Dosing Arm (RDA): PTV1 will be treated to 75 Gy (1.5 Gy 
BID) over the course of 5 cycles and PTV2 will be treated to 45 Gy (1.5 
Gy BID) during the first 3 cycles of CRT. Chemoradiation will be given 
on an alternating week basis. There should be a minimum of 6 hours 


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between fractions. All fields will be treated each day. In the case of 
mechanical failure or a holiday, one day of BID radiotherapy can be 
replaced with a single QD fraction of 2 Gy. Accordingly, the final 
cumulative dose will be slightly less. 
 
For subjects treated with CRT with cisplatin, RT dose, fractionation, and volume 
delineation will be as follows: 
 
i. Intermediate De-escalation Arm (IDA): PTV1 will be treated to 50 Gy 
(2 Gy QD) over the course of 5 consecutive weeks. PTV2 will be treated 
to 30 Gy (2 Gy QD) during the first 3 weeks of CRT for low-risk subjects 
with <50% response. There will be no PTV2 volume for high-risk 
subjects with ≥50% response. 
ii. Regular Dosing Arm (RDA): PTV1 will be treated to 70 Gy (2 Gy QD) 
over the course of 7 consecutive weeks. PTV2 will be treated to 50 Gy 
(2 Gy QD) during the first 5 weeks of CRT. 
 
6. Field Size: Appropriate volumes will be determined at the time of simulation to 
treat gross disease and areas of potential microscopic disease as indicated. The 
optimal field arrangement will be determined based on the treatment planning 
techniques employed. All fields must be treated during each treatment session. 
 
7. Treatment technique: Blocking will be individualized for each subject.  Either 
custom Cerrobend blocks or multileaf collimator will be acceptable. 
 
Intensity Modulated Radiotherapy: Optimal IMRT planning will depend on the 
planning system employed.  We anticipate the optimal plan will use 7 to 11 gantry 
positions.  Acceptable plans will encompass the PTV with the 95% isodose line.  
No more than 1% of the PTV should receive less than 95% of the prescribed dose.  
Plans should be reviewed to ensure that any part of the PTV getting less than 
95% of the prescribed dose is at the edge of the volume.  In no case should a 
central area of the PTV receive less than 95% of the prescribed dose.  No more 
than 1% of the PTV should receive more than 110% of the prescribed dose. 
 
3D Conformal Radiotherapy: The neck should be treated with opposed lateral 
fields using a half-field technique. The lower neck should be treated with an 
anterior field prescribed to a depth of 3 cm. Opposed fields for the lower neck are 
permitted in order to improve PTV coverage and increase homogeneity.  Wedges, 
tissue compensators, or segmented fields should be used to ensure uniformity of 
PTV coverage. Electron boosts of the posterior neck are permitted to limit the 
dose to the spinal cord. Electron fields shall be prescribed to the depth of 
maximum dose with the energy and field size chosen so that the target volume is 
encompassed within 90% of the prescribed isodose line. A cord block is permitted 
on the anterior or lateral fields provided it does not block tumor. Feathering the 
match line is permitted in cases where a cord block would block tumor. For 3D 
techniques, acceptable plans will encompass the PTV within the 95% isodose 


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line. The dose variation in the PTV will be +7% and -5% of the prescription point 
dose. 
 
8. Normal Tissue Constraints/Dose Volume Histograms: Isodose calculations in 
the axial, sagittal, or coronal planes are required. In addition, dose volume 
histograms for the planning treatment volumes and the spinal cord are required. 
The dose limit to the spinal cord will vary depending upon the technique used. 
Attempts should be made to limit the spinal cord dose to <45 Gy in all cases. 
 
9. Adaptive Re-planning: Subjects on the Regular Dose Arm treated on the TFHX 
platform will undergo repeat CT simulation during cycle 3 for adaptive re-planning 
of treatment volumes. 
 
10. Surrounding critical normal structures should be outlined for study purposes, 
including the brainstem, spinal cord, superior/inferior constrictor muscles, optic 
nerves/chiasm, parotid and submandibular glands, temporo-mandibular (T-M) 
joints and cochlea, oral cavity, mandible, eyes, lens, brachial plexus, esophagus 
(including postcricoid pharynx) and glottic larynx. The normal tissues will be 
contoured and considered as solid organs. DVH plots must be generated for 
relevant critical normal structures, any corresponding PRVs, and the unspecified 
tissues. Institutions that use PRVs must clearly define them as such. Ultimate 
inclusion of the normal structures and exceptions from the above guidelines will 
be made at the discretion of the treating radiation oncologist. 
 
11. Special situations: 3D conformal treatment techniques may be preferable to 
IMRT in certain situations.  Some large primary tumors and some large neck 
nodes may extend up to the skin.  In these situations, it may not be possible to 
add a sufficient margin to the GTV to account for variability in the subject set up. 
In such a situation, 3D conformal treatment techniques may be preferable to 
IMRT. 
 
5.6.6 
Nodal Planning Target Volume Delineation: 
 
Lateralized Base of Tongue 
 
Adenopathy Level 
 
Ipsilateral 
Contralateral 
Involved 
Nodes 
IA 
IB 
II 
III IV 
V 
IA 
IB 
II 
III 
IV 
V 
CTV2 
 
 
 
 
 
 
 
 
 
 
 
 
Ipsilateral 
IB, 
II 
IA,
II 
IB, 
III 
II, 
IV 
II, III 
SCV 
II, 
III 
IA, 
IB, 
II 
II 
II 
II 
II 
II 
Contralateral 
IA 
 II 
II 
II 
II 
II 
IB 
II 
IB 
II, 
IV 
II, III 
SCV 
II, 
III 
 


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Base of Tongue Crossing Midline 
 
Adenopathy Level 
 
Ipsilateral 
Contralateral 
Involved 
Nodes 
IA 
IB 
II 
III IV 
V 
IA 
IB 
II 
III 
IV 
V 
CTV2 
 
 
 
 
 
 
 
 
 
 
 
 
Ipsilateral 
IB, II IA,
II 
IB, 
III 
II, 
IV 
II, 
III, 
SCV 
II, 
III 
IA, 
IB, 
II 
II 
II 
II 
II 
II 
Contralateral 
IA 
 II 
II 
II 
II 
II 
IB 
IA, 
II 
IB, 
III 
II, 
IV 
II, III, 
SCV 
II, 
III 
 
Soft Palate 
 
Adenopathy Level 
 
Ipsilateral 
Contralateral 
Involved 
Nodes 
IA 
IB 
II 
III IV 
V 
IA 
IB 
II 
III 
IV 
V 
CTV2 
 
 
 
 
 
 
 
 
 
 
 
 
Ipsilateral 
IB, II IA, 
II 
IB, 
III 
II, 
IV 
II, 
III, 
SCV 
II, 
III 
IA, 
IB, 
II 
II 
II 
II 
II 
II 
Contralateral 
IA 
 II 
II 
II 
II 
II 
IB 
IA, 
II 
IB, 
III 
II, 
IV 
II, 
III, 
SCV 
II, 
III 
 
Lateralized Tonsil 
 
Adenopathy Level 
 
Ipsilateral 
Contralateral 
Involved 
Nodes 
IA 
IB 
II 
III IV 
V 
IA 
IB 
II 
III 
IV 
V 
CTV2 
 
 
 
 
 
 
 
 
 
 
 
 
Ipsilateral 
IB, II IA, 
II 
IB, 
III 
II, 
IV 
II, 
III, 
SCV 
II, 
III 
IA, 
IB, 
II 
II 
II 
II 
II 
II 
Contralateral 
IA 
--- 
--- 
--
- 
--- 
--
- 
IB 
IA, 
II 
IB, 
III 
II, 
IV 
II, 
III, 
SCV 
II, 
III 
 


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Tonsil with Base of Tongue Invasion 
 
Adenopathy Level 
 
Ipsilateral 
Contralateral 
Involved 
Nodes 
IA 
IB 
II 
III IV 
V 
IA 
IB 
II 
III 
IV 
V 
CTV2 
 
 
 
 
 
 
 
 
 
 
 
 
Ipsilateral 
IB, II IA,
II 
IB, 
III 
II, 
IV 
II, 
III, 
SCV 
II, 
III 
IA, 
IB, 
II 
II 
II 
II 
II 
II 
Contralateral 
IA 
 II 
II 
II 
II 
II 
IB 
II 
IB, 
III 
II, 
IV 
II, 
III, 
SCV 
II, 
III 
 
Oropharynx involving Larynx 
 
Adenopathy Level 
 
Ipsilateral 
Contralateral 
Involved 
Nodes 
IA 
IB 
II 
III IV 
V 
IA 
IB 
II 
III 
IV 
V 
CTV2 
 
 
 
 
 
 
 
 
 
 
 
 
Ipsilateral 
IB, II IA,
II 
 III 
II, 
IV 
II, 
III, 
SCV 
II, 
III 
IA, 
IB, 
II 
II 
II 
III 
III 
II 
Contralateral 
IA 
 II 
II 
II 
II 
II 
IB 
IA, 
II 
IB,
III 
II, 
IV 
II, III, 
SCV 
II, 
III 
 
Oropharynx involving Oral Cavity (Lateralized) 
 
Adenopathy Level 
 
Ipsilateral 
Contralateral 
Involved 
Nodes 
IA 
IB 
II 
III 
IV 
V 
IA IB 
II 
III 
IV 
V 
CTV2 
 
 
 
 
 
 
 
 
 
 
 
 
Ipsilateral 
IB, 
II 
IA, 
II 
IA, 
IB, 
III 
IA, 
IB, 
II, 
IV 
IA, 
IB, 
II, 
III, 
IV, 
SCV 
IA, 
IB, 
II, 
III 
IA
, 
IB
, 
II 
IA, 
IB, 
II 
IA, 
IB, 
II 
IA, 
IB, 
II 
IA, 
IB, II 
IA, 
IB, 
II 
Contralateral 
IA, 
IB 
--- 
--- 
--- 
--- 
--- 
IB
, 
II 
IA, 
II 
IA,
IB, 
III 
IA, 
IB, 
II, 
IV 
IA, 
IB, 
II, 
III, 
SCV 
II, 
III 
 


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Oropharynx involving Oral Cavity (Crosses Midline) 
 
Adenopathy Level 
 
Ipsilateral 
Contralateral 
Involved 
Nodes 
IA 
IB 
II 
III 
IV 
V 
IA 
IB 
II 
III 
IV 
V 
CTV2 
 
 
 
 
 
 
 
 
 
 
 
 
Ipsilateral 
IB, 
II 
IA, 
II 
IA, 
IB, 
III 
IA, 
IB, 
II, 
IV 
IA, 
IB, 
II, 
III, 
IV, 
SCV 
IA
, 
IB
, 
II, 
III 
IA, 
IB, 
II 
IA, 
IB, 
II 
IA, 
IB, 
II 
IA, 
IB, 
II 
IA, 
IB, II 
IA
, 
IB
, 
II 
Contralateral 
IB, 
II 
IB, 
II 
IB, 
II 
IB, 
II 
IB, II IB
, 
II 
IB, 
II 
IA, 
II 
IA,
IB, 
III 
IA, 
IB, 
II, 
IV 
IA, 
IB, II, 
III, 
SCV 
II, 
III 
 
Oropharynx involving Nasopharynx 
 
Adenopathy Level 
 
Ipsilateral 
Contralateral 
Involved 
Nodes 
IA 
IB 
II 
III 
IV 
V 
IA 
IB 
II 
III 
IV 
V 
CTV2 
 
 
 
 
 
 
 
 
 
 
 
 
Ipsilateral 
IB, 
II, 
VA 
IA, 
II, 
VA 
IB, 
III, 
VA 
II, 
IV, 
VA 
II, 
III, 
VA, 
SCV 
II, 
III 
IA, 
IB, 
II, 
VA 
II, 
VA 
II, 
VA 
II, 
VA 
II, VA II, 
VA 
Contralateral IA 
 II 
II 
II 
II 
II 
IB, 
VA 
IA, 
II, 
VA 
IB, 
III, 
VA 
II, 
IV, 
VA 
II, III, 
SCV,
VA 
II, 
III, 
VA 
 
5.7 
Adjuvant Immunotherapy Details and Guidelines 
Nivolumab: 480 mg flat dose every 28 days (7 doses total = 6 months adjuvant 
treatment). The goal is to potentially re-activate a potential antitumor response 
triggered during the induction phase after immunosuppressive RT or CRT 
treatment and eradicate micro-metastatic residual disease. 
 


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5.8 
Supportive Guidelines 
• Antiemetics will be ordered at the discretion of the attending physician. 
 
• Use of growth factor support (G-CSF) on days 16/17/18 of induction if counts drop 
and Physician-recommended.. During the TFHX week-on week-off regimen G-
CSF may be used during the off week at the treating physician’s discretion. 
 
• A double lumen venous access device (e.g., Port-a-Cath) is recommended prior 
to initiation of therapy, although peripheral IV access is acceptable. 
 
• Use of a feeding device is recommended for high-risk subjects. Placement of a 
feeding device is left to the discretion of the treating physician/investigator. 
Commonly applied criteria for feeding device placement include: 
i. Loss of > 10% of body weight from the start of therapy 
ii. Dehydration or inability to maintain adequate oral hydration 
iii. Inability to maintain intake of >25 kcal/kg of ideal body weight 
 
• During chemoradiotherapy subjects should receive instructions for oral hygiene 
and prescriptions to include standard of care treatment typical for the care of HNC 
subjects undergoing radiation or chemoradiation: 
i. Oral nystatin or fluconazole (100mg QD) 
ii. Viscous lidocaine HCl (Xylocaine) solution) and/or Grade I 
mouthwash 10 mL QID, swish and spit 
 
Table: Grade I mouthwash 
Lidocaine, Viscous (2%) 
50 mL 
Diphenhydramine elixir (12.5 mg/5 mL) 50 mL 
Sodium bicarbonate injection 
100 mL 
Normal saline irrigation 
500 mL 
Total volume 
700 mL 
 
iii. Normal saline mouthwash 10ml QID swish and spit 
 
iv. Natural Care Gel (or similar product) BID during chemoradiotherapy 
and TID during rest week. 
 
v. Vigilon (or similar product) to be applied to open wounds during 
chemoradiotherapy. 
 
vi. Silvadene cream to open wounds followed by zinc oxide cream and 
then Telfa dressings BID during rest week (N.B.: discontinue Silvadene 
and zinc oxide creams 1 day prior to radiotherapy). 
 


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vii. Aquaphor (or similar brand) cream to lips PRN. 
 
viii. Adequate analgesia is essential to maintain oral intake and subject 
comfort. Narcotic analgesics are usually necessary and should be used 
at the physician/investigator discretion. 
 
ix. Therabite for trismus if appropriate. 
 
x. Replacement for electrolyte imbalances when applicable.   
 
• Prior to discharge of the subjects after a cycle of chemoradiation, a CBC and 
platelet count, and determination of serum electrolytes, including creatinine will be 
performed. 
 
• A visit to the treating physician is strongly recommended between cycles of  
chemoradiation (i.e., days 6-14)   
 
• Use of intravenous home hydration is strongly recommended in subjects with 
inadequate oral intake: normal saline 1000ml IV QD during rest week (days 6-14). 
 
• If Hgb <10, subjects should generally be transfused an amount sufficient to 
increase Hgb to 10.  The Hgb level should be maintained >10 mg/dl for the 
duration of chemoradiotherapy in all subjects.  
 
• The use of peg-filgrastim is described in section 6 and G-CSF (filgrastim) is 
described in section 5.8.  
 
• The use of amifostine during chemoradiotherapy is not permitted. 
 
5.9 
Post-therapy Follow-up 
Every subject should be followed clinically until taken off study. Subjects will be 
seen in clinical evaluation approximately 4 weeks after completing locoregional 
therapy with repeat imaging of the head and neck at that time. PET-CT at 12 weeks 
post-completion of locoregional therapy may also be optionally performed for 
surveillance of indeterminate findings at 6-week imaging. Salvage surgical 
intervention may be indicated by either 6- or 12-week post-treatment imaging 
findings (upon review in multidisciplinary tumor board).  
 
Subjects should undergo clinical and radiographic disease evaluation every 3 
months in year 1, every 6 months in years 2 and 3, and annually in years 4 and 5. 
Radiographic assessment should include imaging of the head, neck, and chest. 
Laboratory evaluation should consist of at least a CBC, serum electrolytes, serum 
creatinine, liver enzymes (AST, ALT, alkaline phosphatase), serum calcium, and 
serum albumin. TSH should be measured at least annually. This schedule can be 


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altered according to the physician’s discretion. Suspicion of progressive disease 
should be evaluated by radiographic studies whenever possible. 
 
In addition, in an exploratory manner, we will draw blood for cell free circulating 
tumor DNA extraction and evaluation of HPV titers as an exploratory marker of 
early detection of potential recurrences. This is a research/exploratory evaluation 
and will not be used for clinical decision making at this point. 
 
5.10 
Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue 
for the allotted treatment time period (as described above) or until one of the 
following criteria applies: 
 
 
• Disease progression. 
 
• Intercurrent illness that prevents further administration of treatment. 
 
• Unacceptable adverse event(s). 
 
• Subject decides to withdraw from the study. 
 
• General or specific changes in the subject’s condition render the subject 
unacceptable for further treatment in the judgment of the investigator. 
 
5.11 
Late Toxicity Assessment 
5.11.1 
Late Toxicity Assessment Schedule 
 
Swallowing function and speech will be assessed pre-treatment, after induction 
chemotherapy, at first follow-up after completion of definitive locoregional therapy, 
and then at 3, 6, 12, and 24 months post-treatment. 
 
5.11.2 
Assessment of Late Toxicity 
Performance measures will be assessed by determining swallowing function and 
speech. Voice will be assessed as a simple yes/no response from subjects as to 
whether their voice has returned to normal. Swallowing will be determined by a 
subject’s ability to swallow table food. A formal swallow evaluation will be done on 
subjects experiencing dysphagia. Additionally, late toxicity will be determined by 
evaluating presence and degree of xerostomia, dental decay, osteoradionecrosis, 
as well as the presence of G-tube or tracheotomy dependence.  
 


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5.11.3 
Performance Measures 
The proposed regimen aims to decrease treatment toxicity without compromising 
outcomes. Thus, QoL and performance are important treatment endpoints. The 
objective is to describe these dimensions prospectively, pre-treatment, through 
treatment, to long-term follow-up. Specific aims are to document subject’s 
experience of treatment effects; evaluate changes in QoL and performance as a 
function of treatment regimen; determine extensiveness and persistence of QoL 
and function-related treatment effects; and describe the pattern, timing and extent 
of recovery of function and QoL. 
 
Performance measures to be used in this protocol include (Appendix F): 
• Performance Status Scale for Head and Neck Cancer Patients (PSS-
HN) 
• Functional Assessment of Cancer Therapy - Head and Neck Version 4  
(FACT-H&N) 
• Selected questions from the McMaster University Head and Neck 
Radiotherapy Questionnaire Performance Status Scale for Head and 
Neck Cancer (MRQ)  
 
The PSS-HN is a clinician rated instrument consisting of three subscales: 
Normalcy of Diet, Eating in Public, and Understandability of Speech. It has been 
demonstrated to be reliable and valid in head and neck cancer subjects. 
 
Functional Assessment of Cancer Therapy-Head and Neck Version 4 (FACT-
H&N). The FACT-H&N is a multidimensional, self-report QoL instrument 
specifically designed for use with head and neck cancer subjects. The core scale 
(FACT-G) consists of 27 core items assessing subject well-being in four areas: 
Physical, Social/Family, Emotional, and Functional. The Core scale is 
supplemented with site-specific modules, of which the head and neck version (12 
items) will be employed here. 
 
McMaster Radiotherapy Questionnaire. This subject self-report instrument (can be 
clinician administered) quantifies subjects' perception of the frequency and 
severity (troublesomeness) of radiation related side effects. 
 
These instruments will be administered pre-treatment (pre-induction), post-
induction chemotherapy, at first follow-up (4 weeks) after completion of definitive 
locoregional therapy, and then at 3, 6, 12, and 24 months post-treatment. 
 


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6 
EXPECTED ADVERSE EVENTS, RISKS AND DOSE 
MODIFICATIONS 
6.1 
Expected Adverse Events 
6.1.1 
Nab-Paclitaxel 
• Cardiovascular: ECG abnormal (60%; 35% in subjects with a 
normal baseline). Edema /fluid retention (10%), hypotension (5%), 
cardiovascular events (grades 3/4: 3%; included chest pain, 
cardiac 
arrest, 
supraventricular 
tachycardia, 
thrombosis, 
pulmonary 
thromboembolism, 
pulmonary 
emboli, 
and 
hypertension)  
• Dermatologic: Alopecia (90%)  
• Gastrointestinal: Nausea (30%; grades 3/4: 3%), diarrhea (27%; 
grades 3/4: <1%), vomiting (18%; grades 3/4: 4%), mucositis (7%; 
grades 3/4: <1%) 
• Hematologic: Neutropenia (80%; grade 4: 9%), anemia (33%; 
grades 3/4: 1%), myelosuppression (dose-related), bleeding (2%), 
neutropenic fever (2%), thrombocytopenia (2%; grades 3/4: <1%) 
• Hepatic: AST increased (39%), alkaline phosphatase increased 
(36%), GGT increased (grades 3/4: 14%), bilirubin increased (7%) 
• Neuromuscular & skeletal: Sensory neuropathy (71%; grades 3/4: 
10%; dose dependent; cumulative), weakness (47%; severe 8%), 
myalgia/arthralgia (44%), peripheral neuropathy (grade 3: 10%) 
• Ocular: Vision disturbance (13%; severe [keratitis, blurred vision]: 
1%)  
• Renal: Creatinine increased (11%; severe 1%)  
• Respiratory: Dyspnea (12%), cough (7%) 
• Miscellaneous: Infection (24%; primarily included oral candidiasis, 
respiratory tract infection, and pneumonia) Hypersensitivity 
reaction (4%, includes chest pain, dyspnea, flushing, hypotension; 
severe: <1%)  
 


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6.1.2 
Carboplatin 
• Dermatologic: Alopecia (includes other agents in combination with 
carboplatin) 
• Endocrine 
& 
metabolic: 
Hypomagnesemia, 
hypokalemia, 
hyponatremia, hypocalcemia; less severe than those seen after 
cisplatin (usually asymptomatic) 
• Gastrointestinal: Nausea, vomiting, stomatitis, diarrhea, anorexia 
• Hematologic: Myelosuppression is dose related and is the dose-
limiting toxicity; thrombocytopenia is the predominant manifestation, 
with a reported incidence of 37% in subjects receiving 400 mg/m2 as 
a single agent and 80% in subjects receiving 520 mg/m2; leukopenia 
has been reported in 27% to 38% of subjects receiving carboplatin as 
a single agent (nadir: ~21 days following a single dose) 
• Hepatic: Alkaline phosphatase increased, AST increased (usually mild 
and reversible) 
• Otic: Hearing loss at high tones (above speech ranges, up to 19%); 
clinically-important ototoxicity is not usually seen 
• Renal: Increases in creatinine and BUN have been reported; most of 
them are mild and they are commonly reversible; considerably less 
nephrotoxic than cisplatin 
• Neuromuscular & skeletal: Peripheral neuropathy (4% to 6%; up to 
10% in older and/or previously-treated subjects) 
• <1% (Limited to important or life-threatening): Neurotoxicity, urticaria, 
rash, nephrotoxicity, secondary malignancies, anaphylaxis, malaise, 
hypertension 
 
6.1.3 
5-Fluorouracil 
Common toxicities include: 
• Gastrointestinal – diarrhea, mucositis, nausea, and vomiting 
• Hematologic – myelosuppression 
• Dermatologic – photosensitivity, skin dryness, hand-foot syndrome, 
increased pigmentation of skin, increased pigmentation of veins used for 
infusion, nail changes 


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Less commonly observed toxicities include 
• Cardiac – myocardial ischemia, arrhythmias 
• Allergic reactions 
• Neurologic – acute cerebellar syndrome, disorientation, headache 
• Eye – lacrimal duct stenosis, lacrimation, photophobia, and visual 
changes 
 
5-FU may cause birth defects and should not be used in pregnant women.  It is a 
known radiation sensitizer and may potentiate side effects of radiation. 
 
6.1.4 
Paclitaxel (during TFHX concurrent chemoradiation) 
 
Common toxicities include 
• Myleosuppression 
• Anemia 
• Alopecia 
• Myalgias and arthralgias 
• Peripheral neuropathy 
• Nausea and vomiting (usually mild) 
• Diarrhea 
• Mucositis 
• Hypersensitivity reaction  - fever, facial flushing, chills, shortness of 
breath, or hives after Taxol is given.  The majority of these 
reactions occur within the first 10 minutes of an infusion.  Notify your 
healthcare provider immediately (premedication regimen has 
significantly decreased the incidence of this reaction).  
 
Less common side effects 
• Peripheral edema 
• Abnormal liver function tests 


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• Hypotension 
• Skin reactions/darkening of the skin 
• Nail changes/discoloration 
• Electrocardiogram (ECG) abnormalities with bradycardia, heart block, bundle 
branch block, and ventricular tachycardia, 
 
The following are less common side effects (occurring in 10-29%) for subjects 
receiving Taxol: 
• Swelling of the feet or ankles (edema). 
• Increases in blood tests measuring liver function.  These return to normal 
once treatment is discontinued. (see liver problems). 
• Low blood pressure (occurring during the first 3 hours of infusion). 
• Darkening of the skin where previous radiation treatment has been given 
(radiation recall - see skin reactions). 
• Nail changes (discoloration of nail beds - rare) (see skin reactions) 
 
6.1.5 
Hydroxyurea 
Common side effects include: 
• Myelosuppression (mainly leukopenia) 
• Nausea, vomiting 
• Diarrhea or constipation 
• Stomatitis 
 
It may aggravate the inflammation of mucous membranes secondary to irradiation.   
 
Less common side effects include:   
• Dysuria or impairment of renal tubular function 
• Rare neurologic disturbances, e.g., headaches, dizziness, disorientation, 
hallucination and convulsion. 
 


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6.1.6 
Cisplatin 
 
Common side effects include: 
• Nausea and vomiting 
• Renal toxicity 
• Electrolyte wasting (magnesium, calcium, potassium) 
• Myelosuppression 
• Anemia 
Less common side effects include: 
• Peripheral neuropathy 
• Hearing loss 
• Anorexia 
• Dysguesia, metallic taste 
• Elevated liver function tests 
• Alopecia 
 
6.1.7 
Filgrastim 
Common side effects may include chest pain, elevated white count, fatigue, 
dizziness, skin rash, elevated LDH, nausea, thrombocytopenia, bone aches, 
epistaxis, fever 
 
6.1.8 
Nivolumab 
Immuno-Oncology (I-0) agents such as PD-1 inhibitors (e.g. Nivolumab) are 
associated with adverse events that can differ in severity and duration than adverse 
events caused by other therapeutic classes.  Nivolumab is considered an immune-
oncology agent in this protocol.  Early recognition and management of adverse 
events associated with immune-oncology agents may mitigate severe toxicity.  For 
further details please refer to the nivolumab investigator brochure and tables below. 
Management guidelines are provided under 6.2.2. 


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Common side effects include: 
• Fatigue 
• Nausea 
• Anemia 
• Diarrhea 
• Asthenia 
• Endocrinopathies (e.g. hypothyroidism) 
 
Less common side effects include: 
• Hepatic (e.g. transaminase elvation) 
• Pulmonary (e.g. pneumonitis) 
• Renal 
• Skin 
• Hypersensitivity/Infusion Reactions 
 
6.1.9 
Radiation 
Radiation to the head and neck will cause skin irritation, dry mucous membranes due to 
salivary gland dysfunction, mucositis and stomatitis.  The concomitant administration of 
chemotherapy will aggravate these side effects.  Long-term side effects include myelitis, 
osteoradionecrosis, hoarseness, hypothyroidism, trismus, swallowing dysfunction, and 
fibrosis of soft tissues. 
 
6.2 
Dose modifications 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) 
Version 4 for toxicity and Adverse Event reporting.  A copy of the CTCAE Version 4.0 can 
be 
downloaded 
from 
the 
CTEP 
home 
page 
(https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
).This section discusses the general dose modifications in the setting of the most 
commonly observed adverse events with systemic therapy.  These are general guidelines 
to be followed, but deviations from the listed dose modifications are allowed at the 
discretion of the treating physician.  
. 


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6.2.1 
Induction Chemotherapy Dose Modifications 
No more than two dose modifications should be allowed for any subject. If a subject 
requires a third dose-reduction study treatment should be discontinued.  If such a 
subject is clinically benefiting from treatment, and, if the physician believes the toxicity 
will be alleviated sufficiently with dose modification, further treatment will be permitted at 
the discretion of the Principal Investigator.  In no case should the three cycles of 
induction chemotherapy be given over a period exceeding eleven (11) weeks and 
treatment with surgery, radiation, or chemoradiation (as appropriate) should be initiated.   
 
Hematologic toxicity 
• Subjects should not begin a new cycle of induction therapy unless 
the ANC is > 1500 cells/mm3 and the platelet count is > 100,000 
cells/mm3. Repeat counts should be obtained weekly until 
resolved. In the setting of low blood counts as specified above, 
dose reductions on subsequent cycles are provided in the table 
below.  
• A delay in therapy of up to 2 weeks is permitted for count 
recovery.   
• If ANC is <1,500 or platelets <100,000 on day 8 or 15 of each 
cycle, reduce all subsequent doses of nab-paclitaxel and 
carboplatin (if any) to one dose reduction of the previous dose. 
Withhold treatment until counts recover to an absolute neutrophil 
count of at least 500 cells/mm3  and a platelet count of at least 
50,000 cells/mm3 on days 8 or 15 of the cycle.  Growth factor 
support should then be used with subsequent cycles. 
 
Dose Modification Table: 
 
 
Neurotoxicity (Peripheral) 
• Subjects with grade 1 peripheral neuropathy should be carefully watched 
for progression of symptoms. A dose reduction is not necessary in this 
setting. 
100,000/mm3 


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• In the setting of grade 2 peripheral neuropathy – nab-paclitaxel should be 
dose reduced according to the table below.   
• Withhold albumin-bound paclitaxel for grade 3-4 peripheral neuropathy.  
Resume albumin-bound paclitaxel at reduced doses (see table) when 
peripheral neuropathy improves to Grade 1 or completely resolves. 
 
 
 
Ototoxicity:  
• For grade 3 ototoxicity discontinue carboplatin. 
 
Hypersensitivity: 
• Albumin-bound paclitaxel (Nab-paclitaxel):   
 
o  For grade 3 reactions manage the reaction according to institutional 
guidelines. For subsequent doses, use steroid and anti-histamine 
pretreatment and increase the infusion time to 60 minutes. For 
documented grade 4 hypersensitivity reactions, manage the reaction 
according to institutional guidelines and discontinue nab-paclitaxel. 
 
Liver: 
• Albumin-bound paclitaxel (Nab-paclitaxel):   
• Mild impairment (AST or ALT <10 times ULN or bilirubin ≤1.25 
times ULN): No adjustment required. 
• Moderate impairment (AST or ALT <10 times ULN or bilirubin 
1.26-2 times ULN): Reduce dose to 75 mg/m2. 
• Severe impairment: AST or ALT <10 times ULN or bilirubin 2.01-
5 times ULN: Reduce dose to 50 mg/m2. May increase up to 
75mg/m2 in subsequent cycles if liver impairment improves to 
either moderate or mild impairment (based on individual 
tolerance). 
• AST or ALT >10 times ULN or bilirubin >5 times ULN: Discontinue 
nab-paclitaxel. 
 
• No dose adjustment required for Carboplatin 
 Other Toxicities 
• For all other grade ≥ 2 toxicities (except alopecia, nausea, 
vomiting, fatigue and anorexia), reduce carboplatin and albumin-


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bound paclitaxel by 25% for all subsequent doses during 
induction. 
• In the event of recurrent grade 3 or 4 toxicity attributed to 
chemotherapy (excluding transaminase elevation, nausea, 
vomiting, and alopecia) reduce carboplatin and nab-Paclitaxel by 
a further 25% during induction. 
 
6.2.2 
Dose Modifications Immunotherapy/Nivolumab during Induction Phase  
There will be no dose adjustments for nivolumab, however treatment can be held or 
discontinued based on occurrence of immune related adverse events. Please refer to the 
below tables/guidelines for guidance as well as investigator brochure for most up to date 
detailed management guidelines. 
Guidelines for permanent discontinuation or withholding of doses are described in Tables 
below (derived from the IB). Detailed guidelines for the management of immune-related 
adverse reactions are described in the IB). 
6.2.3 
Adverse Event Management Algorithms for Immunotherapy/Nivolumab  
 


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6.2.3.1 
Nivolumab Dose Delay Criteria 
Because of the potential for clinically meaningful nivolumab-related AEs requiring early 
recognition and prompt intervention, management algorithms have been developed for 
suspected AEs of selected categories.  These algorithms are specified above.   
 
Dose delays will occur when nivolumab-related AEs have not resolved upon the next 
cycle of treatment or the subject remains on an equivalent of 10 mg prednisone or 
higher. In the setting of an adverse event  likely due to nivolumab, the treating physician 
has the option to continue induction therapy with carboplatin and nab-paclitaxel while 
holding nivolumab.  
 
In the event there are adverse events related to carboplatin or nab-paclitaxel that 
require holding treatment, nivolumab must also be held and delayed until chemotherapy 
can resume.  
 
Nivolumab should also be permanently discontinued for Grade 2 or 3 immune-related 
adverse reactions that persist despite treatment modifications or for inability to reduce 
corticosteroid dose to 10 mg prednisone or equivalent per day  
 
 


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6.2.3.2 
Treatment of Infusion Reaction 
Since Nivolumab contains only human IgG protein sequences, it is unlikely to be 
immunogenic and induce infusion or hypersensitivity reacitons.  However, if such a 
reaction were to occur, it might manifest with fever, chills, rigors, headache, rash 
pruritus, athralgias, blood pressure shifts, bronchospasms, or other symptoms.  All 
Grade 3,4, or 5 infusion reacitons should be reported within 24 hours to the primary 


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investigator and reported as an SAE if criteria are met.  Infusion reactions should be 
graded according to NCI CTCAE v 4.0 guidelines. 
 
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines as appropriate: 
 
For Grade 1 symptoms: (Mild reaction; infusion interruption not indicated; intervention 
not indicated) 
 
Remain at bedside and monitor subject until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 
mg (or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) at least 30 
minutes before additional nivolumab administrations. 
 
For Grade 2 symptoms: (Moderate reaction requires therapy or infusion interruption 
but responds promptly to symptomatic treatment [eg, antihistamines, non-steroidal anti-
inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic 
medications indicated for  24 hours). 
 
Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the subject 
with diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen); remain at bedside and monitor subject until resolution of symptoms. 
Corticosteroid or bronchodilator therapy may also be administered as appropriate. If the 
infusion is interrupted, then restart the infusion at 50% of the original infusion rate when 
symptoms resolve; if no further complications ensue after 30 minutes, the rate may be 
increased to 100% of the original infusion rate. Monitor subject closely. If symptoms 
recur then no further nivolumab will be administered at that visit. Administer 
diphenhydramine 50 mg IV, and remain at bedside and monitor the subject until 
resolution of symptoms. The amount of study drug infused must be recorded on the 
electronic case report form (eCRF). The following prophylactic premedications are 
recommended for future infusions: diphenhydramine 50 mg (or equivalent) and/or 
paracetamol 325 to 1000 mg (acetaminophen) should be administered at least 30 
minutes before additional nivolumab administrations. If necessary, corticosteroids 
(recommended dose: up to 25 mg of IV hydrocortisone or equivalent) may be used. 
 
For Grade 3 or Grade 4 symptoms: (Severe reaction, Grade 3: prolonged [ie, not 
rapidly responsive to symptomatic medication and/or brief interruption of infusion]; 
recurrence of symptoms following initial improvement; hospitalization indicated for other 
clinical sequelae [eg, renal impairment, pulmonary infiltrates]). Grade 4: (life 
threatening; pressor or ventilatory support indicated).  
 
Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal saline, 
and treat the subject as follows. Recommend bronchodilators, epinephrine 0.2 to 1 mg 
of a 1:1,000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 
solution injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Subject should be monitored 


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until the investigator is comfortable that the symptoms will not recur. Nivolumab will be 
permanently discontinued. Investigators should follow their institutional guidelines for 
the treatment of anaphylaxis. Remain at bedside and monitor subject until recovery from 
symptoms. In the case of late-occurring hypersensitivity symptoms (eg, appearance of a 
localized or generalized pruritis within 1 week after treatment), symptomatic treatment 
may be given (eg, oral antihistamine, or corticosteroids). 
 
6.2.4 
Dose Modifications During Concurrent Chemoradiotherapy 
Hematologic Toxicity Dose Modifications for Hydroxyurea: 
Neutropenia:  
If the absolute neutrophil count (ANC) is between 500 and 1000 on day 0 – 5 of each 
cycle, decrease hydroxyurea to 50% of the full dose. On subsequent cycles, a reduced 
starting dose of hydroxyurea should be used. 
For ANC of  500/l on Day 0 – 5 of any cycle, omit hydroxyurea, and administer 600 
mg/m2/day of 5-FU and radiotherapy only.  On subsequent cycles, a reduced starting 
dose of hydroxyurea by 50% should be used. 
Thrombocytopenia:  
For a platelet count of 50,000/l to 74,000/l on Day 0 – 5 of each cycle, decrease 
hydroxyurea to 50% of full dose.  On subsequent cycles, a reduced starting dose of 
hydroxyurea may be used. 
For a platelet count  50,000/l on Day 0 – 5 of any cycle, omit hydroxyurea, and 
administer 600 mg/m2/day of 5-FU and radiotherapy only.  On subsequent cycles, a 
reduced starting dose of hydroxyurea by 50% should be used. 
Hematologic Dose Modifications for Paclitaxel: 
Dose Level 
Paclitaxel 
(mg/m2) 
  0 
100 
–1 
75 
 -2 
50 
-3 
Discontinue 
 


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Neutropenia and Thrombocytopenia:  
For ANC ≤ to 1000 or platelet count of 50-74 on day 0-5 of each cycle: decrease 
paclitaxel by one dose level.  
 
For ANC </= 500 or platelet count of less than 50 on day 0-5 of any cycle: hold 
paclitaxel for that cycle and decrease by one dose level in subsequent cycles.   
 
Non-Hematologic Dose Modifications for 5-FU, Hydroxyurea, and Paclitaxel: 
Mucositis, Dysphagia, Dermatitis, Diarrhea 
 
Treatment cycles should not be delayed for mucositis, dysphagia, dermatitis or 
diarrhea. 
 
For grade 4 mucositis, dysphagia, and dermatitis exceeding 7 days duration or 
persisting on Day 1 of a subsequent cycle, decrease 5-FU to 500 mg/m2/day.   
 
For grade 4 diarrhea exceeding 7 days duration or persisting on Day 1 of a 
subsequent cycle, decrease 5-FU to 500 mg/m2/day. 
 
Doses will not be increased again on subsequent cycles. 
 
Nephrotoxicity 
 
Grade 2 renal toxicity – administer 50% dose hydroxyurea 
 
Grade 3, 4 renal toxicity – Hold hydroxyurea 
 
Hepatotoxicity on day 0:  Grade 3, 4 – Hold hydroxyurea and adjust paclitaxel per package 
insert 
Peripheral neuropathy: 
For Grade 2 peripheral neuropathy, decrease paclitaxel by one dose level per CRT 
dosing schedule (see hematologic toxicity chart).  
For Grade 3 or greater peripheral neuropathy, discontinue paclitaxel.  
Other Non-hematological Toxicity 
Chemoradiotherapy should not be interrupted for non-hematologic toxicity except as 
judged necessary on a case-by-case basis by the treating radiation, medical oncologists, 
and Principal Investigator. 
In the presence of a persisting fever  38C or other clinically apparent infection a cycle 
can be postponed for 1 week or interrupted (if treatment cycle has already started) if this 
is necessary in the opinion of the treating medical and radiation oncologists. 


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Cutaneous vasculitic toxicities, including vasculitic ulcerations and gangrene, have 
occurred in subjects with myeloproliferative disorders during therapy with hydroxyurea. 
These vasculitic toxicities were reported most often in subjects with a history of, or 
currently receiving, interferon therapy. Due to potentially severe clinical outcomes for 
the cutaneous vasculitic ulcers reported in subjects with myeloproliferative disease, 
hydroxyurea should be discontinued if cutaneous vasculitic ulcerations develop. 
 
Geriatric Use: Elderly subjects may be more sensitive to the effects of hydroxyurea, and 
may require a lower dose regimen. This drug is known to be excreted by the kidney, 
and the risk of toxic reactions to this drug may be greater in subjects with impaired renal 
function. Because elderly subjects are more likely to have decreased renal function, 
care should be taken in dose selection, and it may be useful to monitor renal function. 
 
Dose Modifications for Cisplatin: 
Cisplatin 
Renal Toxicity 
CrCl 46-60 – 25% dose reduction 
CrCl 31-45 – 50% dose reduction 
Myelosuppression 
If the absolute neutrophil count (ANC) is < 1000 on day 1 of each cycle, hold cisplatin and 
when count recover > 1000 ANC, then decrease cisplatin 25%. On subsequent cycles, a 
reduced starting dose of cisplatin should be used. 
Peripheral neuropathy 
If Grade 2 neuropathy on day 1 of each cycle, then decrease cisplatin 25%. On 
subsequent cycles, a reduced starting dose of cisplatin should be used. 
If Grade 3 or greater neuropathy on day 1 of each cycle, hold cisplatin and when 
neuropathy recovers to grade 2 or better, then decrease cisplatin 25%. On subsequent 
cycles, a reduced starting dose of cisplatin should be used. 
General Toxicity Information 
 
Any other significant toxicity that is felt to be potentially drug related should be discussed 
between the PI and the treating physician and dose reduction can be implemented for the 
benefit and safety of the subject.  


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Radiotherapy should not be interrupted for non-hematologic toxicities except when judged 
necessary on a case-by-case basis by the treating radiation and medical oncologist in 
consultation with the PI. 
All interruptions or changes to study drug administration must be recorded. 
It will be documented whether or not each subject completed the clinical study. If for any 
subject either study treatment or observations were discontinued the reason will be 
recorded. Reasons that a subject may discontinue participation in a clinical study are 
considered to constitute one of the following: 
1. adverse event(s) 
2. abnormal laboratory value(s) 
3. abnormal test procedure result(s) 
4. disease progression 
5. protocol violation 
6. subject withdrew consent 
7. lost to follow-up 
8. administrative problems 
9. death 
 
6.2.5 
Dose Modifications Immunotherapy/Nivolumab during Adjuvant 
Nivolumab Treatment 
There will be no dose adjustments for nivolumab, however treatment can be held or 
discontinued based on occurrence of immune related adverse events. Please refer to 
sections/treatment algorithms above for adverse event management during induction for 
further details (management of adverse events and dose delays will be analogous to the 
induction phase for immunotherapy with nivolumab). 
 


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7 
AGENT FORMULATION AND PROCUREMENT 
7.1 
Nab-paclitaxel 
Classification: 
Antineoplastic Agent, Antimicrotubular; Natural Source (Plant) Derivative; Taxane 
Derivative 
Mode of Action: 
Albumin-bound paclitaxel nanoparticle formulation. Paclitaxel promotes microtubule 
assembly by enhancing the action of tubulin dimers, stabilizing existing microtubules, and 
inhibiting their disassembly, interfering with the late G2 mitotic phase, and inhibiting cell 
replication. May also distort mitotic spindles, resulting in the breakage of chromosomes. 
Paclitaxel may also suppress cell proliferation and modulate immune response. 
How Supplied: 
Injection, powder for reconstitution: Abraxane®: 100 mg [contains albumin (human)] 
Storage: 
Store in vials in original cartons at room temperature (20oC-25oC; 68oF to 77oF). Retain 
in the original package to protect from bright light.  
Stability: 
Unopened vials of nab-paclitaxel are stable until the date indicated on the package when 
stored at the above temperature in the original package. Reconstituted vials of albumin-
bound paclitaxel may be refrigerated at 2oC to 8oC (38oF to 46oF) for a maximum of 8 
hours and should be protected from bright light 
Dose Specifics: 
Albumin-bound paclitaxel 100mg/m2 IV over 30, minutes on day 1, 8, and 15 of each 21-
day cycle of induction chemotherapy (total of 3 cycles) 
Preparation: 
Reconstitute each vial with 20 mL of 0.9% sodium chloride injection, USP injected over 
at least 1 minute. Direct the NaCl onto the inside wall of the vial, and not directly onto the 
lyophilized cake, as this will result in foaming. Following reconstitution, allow the vial to 
sit for a minimum of 5 (five) minutes to ensure proper wetting of the lyophilized 
cake/powder. Gently swirl and/or invert the vial slowly for at least 2 minutes until complete 
dissolution of any cake/powder occurs. 
Rapid agitation or shaking will result in foaming. If foaming or clumping occurs, stand 
solution for at least 15 minutes until foam subsides. The reconstituted suspension should 
appear milky and homogeneous without visible particulates. If unsuspended powder is 
visible, the vial should be gently inverted again to ensure complete resuspension, prior to 


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use. Each ml of reconstituted product will contain 5 mg of paclitaxel. Withdraw the desired 
volume and inject the suspension into an empty sterile PVC container. 
Route of Administration 
Albumin-bound paclitaxel will be administered as an IV infusion over 30 minutes. On days 
when carboplatin is given, albumin-bound paclitaxel will be administered first. Filters are 
not required for preparation or administration of albumin-bound paclitaxel. If filters are 
used as part of institutional procedures, the pore size must be ≥ 15 micron. 
Drug Return and Destruction  
Study drug will be disposed of as per the University of Chicago Medical Center 
Investigational Pharmacy drug destruction policy/procedure. The following information 
must be recorded on the site’s pharmacy drug accountability log:  
Quantity of vials destroyed. 
Expiration date 
Lot number.   
 
The pharmacist must document that the study drug was destroyed in accordance with 
their institution’s drug destruction policy or SOP.  A drug destruction memo and the site’s 
drug destruction SOP/policy should be sent to Celgene Medical Operations Dept.  A copy 
of the drug destruction memo should be retained at the clinical site.  In the event of study 
completion or termination, a copy of all pharmacy records (drug dispensing log, drug 
accountability log and any destruction memos) must be mailed to Celgene Medical 
Operations.  
a) Supplier 
Celgene Corporation 
86 Morris Avenue 
Summit, NJ  07901 
 
Industry Contact: 
Martha Kennedy 
Manager, Medical Operations 
Celgene Corporation 
400 Connell Drive, 7th Floor 
Connell Corporate Park 
Berkeley Heights, NJ 07922 
Mobile: 908-723-6919 
Fax: 908-673-2779 
Email: Mkennedy@celgene.com  


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b) Drug Distribution 
ABRAXANE® will be distributed by Celgene Corporation.  No supplies will be 
shipped to any site until regulatory approval has been obtained.  Investigational 
sites will be supplied with ABRAXANE® upon identification and screening of a 
potential trial subject.   
Upon identification of a potential subject, sites must fax a completed Drug 
Request Form to Celgene Corporation.  Allow at least 5 working days for drug 
shipment.  There are no shipments on Fridays or holidays. 
For re-supply of drug, please complete and fax the Drug Request Form to 
Celgene Corporation at 908-673-2779. 
c) Drug Return and Destruction 
If the investigational site does not have a policy, procedure or SOP detailing 
the process to follow for study drug destruction, the study drug must then be 
returned to Celgene using the Drug Return Form provided in the package 
containing the study drug.  The following information must be recorded on the 
site’s pharmacy drug accountability log: quantity of vials to be returned, 
expiration date and lot number.  A copy of the Drug Return Form and the study 
drug should be returned to Celgene Clinical Supplies Dept. using the mailing 
address on the packaging slip that came with the original study drug order.  A 
copy of the Drug Return Form should be retained at the clinical site.  In the 
event of study completion or termination, a copy of all pharmacy records (drug 
dispensing log, drug accountability log and any destruction memos) must be 
mailed to Celgene Medical Operations. 
If the investigational site has a policy, procedure or SOP detailing the process 
to follow for study drug destruction, the pharmacist or designee can choose to 
destroy the study drug on site.  The following information must be recorded on 
the site’s pharmacy drug accountability log: quantity of vials destroyed, 
expiration date and lot number.  The pharmacist must document that the study 
drug was destroyed in accordance with their institution’s drug destruction policy 
or SOP.  A drug destruction memo and the site’s drug destruction SOP/policy 
should be sent to Celgene Medical Operations Dept.  A copy of the drug 
destruction memo should be retained at the clinical site.  In the event of study 
completion or termination, a copy of all pharmacy records (drug dispensing log, 
drug accountability log and any destruction memos) must be mailed to Celgene 
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7.2 
Carboplatin 
 Carboplatin: supplied commercially as a sterile lyophilized powder available in single-
dose vials containing 50 mg, 150 mg and 450 mg of carboplatin. Each vial contains equal 
parts by weight of carboplatin and mannitol. Please refer to package insert for information 
on preparation. 
Side effects: listed in section 9.3. Please refer to the package insert for full prescribing 
information. 
Preparation: Immediately before use, the content of each vial must be reconstituted with 
either sterile water for injection, USP, 5% dextrose in water, or 0.9% sodium chloride 
injection, USP to produce a carboplatin concentration of 10 mg/ml. When prepared as 
directed, carboplatin solutions are stable for 8 hours at room temperature. Since no 
antibacterial preservative is contained n the formulation, it is recommended that 
carboplatin solutions be discarded 8 hours after dilution. 
Storage and Stability: Unopened vials of carboplatin are stable for the life indicated on 
the package when stored at controlled room temperature and protected from light. 
Administration: Administer over 30-60 minutes after completing the nab-paclitaxel 
infusion. The Calvert Equation (Dose=AUC (CC+25) will be used to achieve the desired 
dose where CC = Wt*(140-age)/72/creatinine (if female use 85%). 
 
7.3 
Fluorouracil 
5-Fluorouracil (Adria, OH): commercially available as 10 ml ampules containing 
500 mg/10 ml.  No dilution is necessary for administration, but it may be further diluted in 
D5W or normal saline.  It is stored at room temperature and is stable for 24 hours.  It will 
be administered by intravenous continuous infusion as described in section 5.6.4.  Please 
refer to the package insert for full prescribing information.   
 
7.4 
Hydroxyurea 
Hydroxyurea (Bristol-Myers Squibb, Princeton, NY): commercially available as 500 mg 
capsules.  It is stored at room temperature and will be administered orally as described 
in section 5.6.4.  Please refer to the package insert for solution preparation and expected 
AE.  Please refer to the package insert for full prescribing information. 
 
7.5 
Paclitaxel 
Chemistry: Paclitaxel is a natural product with antitumor activity. The chemical name for 
paclitaxelis 5,20‐Epoxy‐1,2 hexahydroxytax‐11‐en 9‐one 4, 10 diacetate 2‐
benzoate 13‐ester with (2R,3S)‐N‐benzoyl‐3‐phenylisoserine. Paclitaxel is a white 


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to off‐white crystalline powder with the empirical formula C47H51NO14 and a molecular 
weight of 853.9. It is extremely lipophilic and melts at around 216‐217°C. Paclitaxel is 
highly insoluble in water. 
 
Mechanisms of Action: Microtubules have been demonstrated to be very strategic targets 
for antineoplastic agents; however, few antimicrotubule agents have been discovered and 
encompassed into standard chemotherapeutic regimens. Paclitaxel, a diterpenoid plant 
product extracted from the bark of the western yew (Taxus brevifolia), has a unique 
mechanism of action. Unlike other antimicrotubule agents in clinical use (e.g. colchicine, 
vincristine, and vinblastine) that shift the equilibrium between microtubules and tubulin 
subunits toward microtubule disassembly, paclitaxel promotes assembly of microtubules 
from tubulin dimers and stabilizes microtubules by preventing depolymerization. These 
microtubules are stable even when treated with low temperatures or calcium, conditions 
that usually promote disassembly. This unusual stability results in the inhibition of the 
normal dynamic reorganization of the microtubule network that is essential for vital 
interphase and mitotic cellular functions. In addition, paclitaxel induces abnormal arrays 
or "bundles" of microtubules during mitosis. 
 
Human Toxicology: The dose limiting toxicities and MTD of paclitaxel administered on a 
variety of schedules to subjects with solid neoplasms were previously evaluated in phase 
I trials. In these studies, paclitaxel was infused over 1, 3, 6, and 24 h, but severe acute 
reactions, characterized by bronchospasm, hypotension, stridor, tachy‐ and 
bradyarrhythmias, and death, resulted in the temporary discontinuation of all trials. These 
reactions were attributed to paclitaxel's Cremophor vehicle, since identical reactions were 
observed with other drugs formulated with it and when the vehicle alone was administered 
to animals. Since a higher incidence of these acute reactions was observed with shorter 
durations of infusion, studies that used shorter infusions were permanently discontinued, 
and trials that evaluated longer infusion durations (24 h) were resumed using antiallergic 
pre‐medications consisting of corticosteroids, H1‐ and H2‐ histamine antagonists. 
These modifications were associated with a marked reduction in the incidence of acute 
reactions. Neutropenia was the major dose‐limiting toxicity for paclitaxel in phase I solid 
tumor trials. In addition, a sensory neuropathy, characterized by a glove‐and‐sock 
distribution of numbness and paresthesias, was observed at higher doses. Nausea and 
vomiting, myalgias, mucositis, total‐body alopecia, diarrhea, and phlebitis were also 
observed.  
 
Pharmaceutical Data:  
Formulation: Paclitaxel (TAXOL®) for Injection Concentrate is a clear colorless to slightly 
yellow viscous solution. It is supplied as a solution in a nonaqueous medium. It is intended 
for dilution with a suitable parenteral fluid prior to intravenous infusion. Paclitaxel is 
available in 30 mg (5mL) vials. Each mL of sterile non‐pyrogenic solution contains 6 mg 
paclitaxel, 527 mg of Cremophor®EL (polyoxyethylated castor oil) and 49.7% (v/v) 
dehydrated alcohol, USP. 
 


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Storage and Stability: Unopened vials of Paclitaxel for Injection Concentrate are stable 
until the date indicated on the package when stored under refrigeration, 2°‐ 8°C (36°47° 
F). Refrigeration is not required for shipping. Freezing does not adversely affect the 
concentrate. Solutions for infusion which are prepared as recommended are stable at 
ambient temperature and lighting for up to 27 hours. 
 
Administration: Paclitaxel should be given after the subject has received the appropriate 
premedication as per institutional standards. Paclitaxel: supplied in 5 ml vials containing 
30 mg of drug (6mg/ml). Please refer to the package insert for information on preparation 
and for full prescribing information. 
Drug interactions: There is a potential for interaction with Ketoconazole, which might 
interfere with paclitaxel metabolism. 
Contraindications: Known hypersensitivity to either paclitaxel or Cremaphor EL. 
 
7.6 
Cisplatin 
Formulation: Cisplatin is a sterile aqueous solution, each mL containing 1 mg cisplatin 
and 9 mg sodium chloride. Cisplatin is supplied in multidose vials of 50 mg and 100 mg 
cisplatin. Please refer to package insert for information on preparation. 
NOTE: Aluminum reacts with cisplatin causing precipitate formation and loss of potency; 
therefore, needles or intravenous sets containing aluminum parts that may come in 
contact with the drug must not be used for the preparation or administration of cisplatin. 
Storage: Store at 15° to 20°C. Do not refrigerate. Protect unopened container from light. 
The cisplatin remaining in the amber vial following initial entry is stable for 28 days 
protected from light or for 7 days under fluorescent room light. 
Side effects are listed in section 6.1.6. Please refer to the package insert for full 
prescribing information. 
Availability: Cisplatin is commercially available from Bristol Laboratories Oncology 
Products. 
Administration should follow institutional guidelines and may depend on renal function, 
and ability to give pre- and post-hydration as appropriate. Typically a bolus injection will 
be given over 2-3 hours, but injection time may be extended to minimize adverse events. 
Pre- and post-hydration is required. 
 
 
 


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7.7 
Filgrastim (Neupogen) Drug Information 
Packaging and Formulation 
 
G-CSF (Filgrastim) is commercially available. Filgrastim is a sterile, clear, colorless, 
preservative-free liquid for parenteral administration, containing Filgrastim at a specific 
activity of 1.0 ± 0.6 x 108 U/mg (as measured by a cell mitogenesis assay).  The product 
is available in single use vial form and prefilled syringe.  The single use vial contains 480 
mcg Filgrastim at a fill volume of 1.6 mL.  The formulation is: 480 mcg of Filgrastim (r-
methHuG-CSF), containing acetate (0.94 mg), sorbitol (80.0 mg), Tween® 80 (0.004%), 
sodium (0.056 mg) in water for injection, USP q.s. ad (1.6 mL).  The single use prefilled 
syringe contains 0.6 mg Filgrastim at a fill volume of 0.8 mL.  The formulation is: 480 mcg 
of Filgrastim (r-methHuG-CSF), containing acetate (0.472 mg), sorbitol (40.0 mg), 
Tween® 80 (0.004%), sodium (0.028 mg) in water for injection, USP q.s. ad (0.8 mL).   
 
Storage Conditions and Stability 
 
Filgrastim should be stored in the refrigerator at 2o to 8oC (36o to 46oF).  Avoid shaking.  
Prior to injection, Filgrastim may be allowed to reach room temperature for a maximum 
of 24 hours.  Any vial or pre-filled syringe left at room temperature for greater than 24 
hours should be discarded.  Parenteral drug products should be inspected visually for 
particulate matter and discoloration prior to administration, whenever solution and 
container permit; if particulate or discoloration are observed, the container should not be 
used.  At a concentration of 5 mcg/ml or greater in D5W, filgrastim is stable for 7 days at 
room or refrigerator temperatures.  At dilutions from 5 to 15 mcg/ml, albumin in a final 
concentration if 2mg/ml should be added to protect against adsorption to plastic materials.  
Addition of albumin is unnecessary when the drug is diluted to a concentration greater 
than 15 mcg/ml in D5W.  Dilutions in D5W are stable in glass bottles, polyvinyl chloride, 
polyolefin or polypropylene bags and IV sets, and Travenol Infusors. 
 
Dilution of Neupogen® to a final concentration of less than 5 mcg/mL is not recommended 
at any time.  Do not dilute with saline at any time because the product may precipitate. 
 
Preparation and Administration 
 
If using the vial, draw the appropriate dose into a syringe for subcutaneous injection.  If 
using the pre-filled syringe, select the appropriate pre-filled syringe for subcutaneous 
injection.  Inject only the appropriate dose, discard the unused drug.  Incompatibilities: 
Normal saline. 
 
Adverse Reactions 
 
The following events are associated with Filgrastim and meet the regulatory definition of 
“expected”.  The only consistently observed clinical toxicity described with Filgrastim is 
medullary bone pain.  Other clinical adverse events that have been described include skin 
rash, and cutaneous vasculitis.  Since commercial introduction of Neupogen®, there have 


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been rare reports of allergic-type reactions.  Biochemical abnormalities that may occur 
include increases in alkaline phosphatase, uric acid, and lactate dehydrogenase. 
 
Overdosage 
 
The maximum amount of Filgrastim that can be safely administered has not been 
determined.  Efficacy was demonstrated at doses of 4 to 8 mcg/kg/day in the phase 3 
study of nonmyeloablative chemotherapy.  Subjects in  bone marrow transplant studies 
received up to 138 mcg/kg/day without toxic effects, although there was a flattening of the 
dose response curve above daily doses of greater than 10 mcg/kg/day.   
 
In Fligrastim clinical trials of cancer subjects receiving myelosuppressive chemotherapy, 
WBC > 100,000/mm3 have been reported in less than 5% of subjects, but were not 
associated with any reported adverse clinical effects.  
 
In cancer subjects receiving myelosuppressive chemotherapy, discontinuation of 
Filgrastim therapy usually results in a 50% decrease in circulating neutrophils within 1 to 
2 days, with a return to pretreatment levels in 1 to 7 days. 
 
Toxicity/Warnings 
 
Filgrastim is contraindicated inpatients with known hypersensitivity to E coli-derived 
proteins, pegfilgrastim, Neupogen®, or any other component of the product. 
 
Rare cases of splenic rupture have been reported following the administration of colony-
stimulating factors, including Filgrastim, for peripheral blood progenitor cell (PBPC) 
mobilization in both healthy donors and subjects with cancer.  Some of these cases were 
fatal.  Individuals receiving Filgrastim who report abdominal or shoulder tip pain, 
particularly healthy donors receiving Filgrastim for PBPC mobilization, should be 
evaluated for an enlarged spleen or splenic rupture.     
 
Adult respiratory distress syndrome (ARDS) has been reported in neutropenic subjects 
with sepsis receiving Filgrastim, and is postulated to be secondary to an influx of 
neutrophils to sites of inflammation in the lungs.  Neutropenic subjects receiving 
Filgrastim who develop fever, lung infiltrates, or respiratory distress should be evaluated 
for the possibility of ARDS.  In the event that ARDS occurs, Filgrastim should be 
discontinued until resolution of ARDS and subjects should receive appropriate medical 
management for this condition. 
 
Allergic-type reactions occurring on initial or subsequent treatment have been reported in 
< 1 in 4000 subjects treated with Filgrastim.  These have generally been characterized 
by systemic symptoms involving at least 2 body systems, most often skin (rash, urticaria, 
facial edema), respiratory (wheezing, dyspnea), and cardiovascular (hypotension,  
tachycardia).  Some reactions occurred on initial exposure.  Reactions tended to occur 
within the first 30 minutes after administration and appeared to occur more frequently in 
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after administration of anti-histamines, steroids, bronchodilators, and/or epinephrine.  
Symptoms recurred in more than half the subjects who were rechallenged. 
 
Severe sickle cell crisis have been reported in subjects with sickle cell disease 
(specifically homozygous sickle cell anemia, sickle/hemoglobin C disease, and sickle/+ 
thalassemia) who received Filgrastim for PBPC mobilization or following chemotherapy. 
One of these cases was fatal.   
 
PREGNANCY AND LACTATION 
Since there are no adequate and well-controlled studies in pregnant women, the effect, if 
any, of Filgrastim on the developing fetus or the reproductive capacity of the mother is 
unknown.     
 
It is not known whether Filgrastim is excreted in human milk.  Because many drugs are 
excreted in human milk, caution should be exercised when Filgrastim is administered to 
a nursing woman. 
 
DRUG INTERACTIONS 
 
No formal drug interaction studies between pegfilgrastim and other drugs have been 
performed.  Drugs which may potentiate the release of neutrophils, such as lithium, 
should be used with caution.  Subjects receiving lithium and Filgrastim should have more 
frequent monitoring of neutrophil counts. 
 
Nursing Guidelines 
 
Filgrastim should be kept in the refrigerator until needed and the vials or Pre-filled Syringe 
should not be shaken.  The drug should be administered at the same time each day.  Vials 
and Pre-filled Syringes of filgrastim are single-dose and the remaining drug should be 
discarded.  Refer to protocol text for information regarding requirements for 
documentation of doses administered, temperatures, side effects, etc. Acetaminophen is 
the recommended analgesic for mild bone pain. Duration of therapy will be determined 
by the return of blood counts (WBC/ANC) to specific values. 
 
7.8 
Nivolumab 
Nivolumab is supplied by BMS. 
Nivolumab Storage Conditions and Handling 
Nivolumab should be stored at between 2-8 degrees Celsius (36-46 degrees Fahrenheit), and 
protected from light and freezing.  If any temperature excursions are encountered during storage, 
they should be reported to BMS.  As with all injectable drugs, care should be taken when handling 
and preparing Nivolumab.  Whenever possible, Nivolumab should be prepared in a laminar flow 
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applying aseptic technique.  Partially used vials should be disposed at the time following 
procedures for the disposal of anticancer drugs. 
Nivolumab Use Time/Stability 
Once transferred to IV bags, the solution may be stored for up to 20 hrs in a refrigerator at 2-8 
degrees Celsius and used within 8 hours at room temperature and under room light inclusive of 
administration time.  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. 
Pharmacy supplies required 
• 
Empty IV bags-50mg, 100mL, 200 mL 
• 
0.9% NaCl bags 
• 
0.2 or 1.2 micron in line filter and infusion tubing 
• 
Volumetric infusion pumps. 
Nivolumab Preparation and Administration: 
• 
Nivolumab injection is to be administered using a volumetric pump with a 0.2/1.2 micron 
pore size, low protein binding polyethersulfone membrane in-line filter at the protocol-
specific doses and infusion times. 
• 
The line should be flushed at the end of the infusion with sufficient quantity of normal 
saline per institution SOC. 
• 
Nivolumab is not to be administered as an IV push or bolus injection. 
• 
At the dose of 360 or 480mg, the total dose needed will be diluted to a minimum total 
volume of 100 ml in 0.9% Sodium Chloride injection solution. 
• 
Care must be taken to assure sterility of the prepared solution as the produce not contain 
any anti-microbial preservative or bacteriostatic agent. 
• 
Nivolumab should be administered over a 1-hour period; infusions will be controlled by a 
volumetric pump. 
• 
Nivolumab infusins are compatible with polyolefin containers and infusion sets, and glass 
bottles .  I 
• 
Allow the appropriate number of vials of Nivolumab to stand at room temperature for 
approximately 5 minutes before preparation. 
• 
Ensure that Nivolumab solution is clear, colorless, and essentially free from particulate 
matter. 
• 
Aseptically withdraw the require volume of Nivolumab into a syringe and dispense into an 
IV bag.   
o Add the appropriate volume of 0.9% Sodium Chloride injection solution. 
o Mix by gently inverting several times. DO NOT shake. 
o Record the time the Nivolumab was prepared on the IV bag label. 
o Attach the IV bag containing the Nivolumab solution to the infusion set, in-line filter, 
and infusion pump. 


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o The infusion rate of the infusion pump should be adjusted to allow for a total 
infusion time of 30 minutes. 
o At the end of the infusion period, flush the line with a sufficient quantity of 0.9% 
Sodium Chloride injection solution. 
 


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8 
CORRELATIVE/SPECIAL STUDIES 
8.1 
Objectives 
Correlative studies will be explorative in nature and will focus on tissue (serial samples) 
as well as blood based markers. The overreaching goal is in a descriptive manner to 
identify changes to the tumor / microenvironment with treatment with nivolumab + 
chemotherapy using serial samples, and also evaluate potential predictive candidate 
biomarkers. 
 
We will collect plasma samples to monitor treatment progress using cell free circulating 
tumor DNA (ctDNA). This will be done by measuring the HPV DNA titer and/or somatic 
mutations. In addition to providing a marker of treatment efficacy e.g. during induction 
with nivolumab + chemotherapy, it will also be used to assess subjects after treatment 
serially to assess any evidence of early recurrence but will not be used for clinical 
decision making at this point. 
 
8.2 
Correlative analysis 
8.2.1 
Tissue: 
Baseline archival (or if not available alternatively fresh) tissue will be collected on all 
subjects as well as a biopsy at week 2-3 to assess synergistic/immunotherapy relevant 
changes in the tumor micro-environment. In the curative intent setting biopsy is readily 
doable in virtually all head and neck cancer subjects with stage IV HNC as enrolled in this 
trial. 
8.2.1.1 
Multicolor IF based assessment of immune microenvironment 
Using both archival or fresh tumor samples (tissue digest or fresh frozen/OTC tissue) and 
then the on-treatment paired biopsy during induction (nivolumab+chemotherapy), we will 
analyze dynamic changes in the immune microenvironment.  
 
The analyses may include determination of CD8, PD-L1, FOXP3, IDO, CD168, and other 
immune related markers that will be determined by immunofluorescence. Results will be 
digitally assessed, and results descriptively compared with results from flow cytometry 
(cell digest) and mRNA analysis (see below). 
 
8.2.1.2 
mRNA analysis / Immune Signatures (Nanostring or similar) 
Analysis will be performed using the Nanostring nCounter (or similar approach) using the 
Nanostring immune panel. Briefly from 3-5 FFPE slides RNA will be extracted using the 
Qiagen RNA/DNA FFPE kit and protocol.  


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8.2.1.3 
Tumor DNA Analysis 
Exome sequencing from tumor and normal blood white cells will be performed on the 
tumor samples for an exploratory analysis of correlation of genetic aberrations, immune 
phenotype and tumor response. In addition tumor RNAseq analysis will be performed 
from tumor tissue. Specific processing information will be made available in a 
continually updated SOP for tissue collection and processing.  
 
8.2.1.4 
Germline DNA analysis 
Blood will be obtained from all subjects for exome sequencing of normal DNA (see 
above). Specific processing information will be made available in a continually updated 
SOP for tissue collection and processing.  
 
8.2.1.5 
Analysis of Tumor Digests 
Fresh tumor samples will be digested using a protocol for tumor digestion employing the 
Miltenyi GentleMACS system available in the HIM Core facility. Single cell suspension 
will be stored for subsequent FACS or similar analysis.  Specific processing information 
will be made available in a continually updated SOP for tissue collection and 
processing.  
 
8.2.2 
Blood:  
8.2.2.1 
ctDNA analysis  
Using cell free circulating DNA (ctDNA) we measure HPV DNA titers and somatic 
mutations. This will be assessed as a candidate marker of treatment efficacy e.g. during 
induction with nivolumab + chemotherapy (baseline versus 2-3 weeks into treatment).  
 
Furthermore, it will also be used to assess subjects after treatment serially to assess 
any evidence of early recurrence (early detection) but will not be used for clinical 
decision making at this point. Especially as part of a de-escalation protocol early 
detection in the future may prove invaluable in order to identify subjects at risk for 
recurrence, who may benefit from additional therapy. 
 
8.2.2.2 
RNA analysis from blood 
Blood samples will be obtained at baseline and after 3 weeks (administration of cycle 2 
nivolumab dose). Samples will be processed for RNA extraction (e.g. using the PAXgene 
RNA kit/tubes). RNA will be analyses by Nanostring (see above) or RNAseq in an 
exploratory fashion comparing baseline with on-treatment inflammatory markers. Specific 
processing information will be made available in a continually updated SOP for tissue 
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8.3 
Sample and Tissue Procurement  
8.3.1 
Archival tumor collection 
 
All subjects at the time of enrollment need to provide ≥10 5-micron un-stained slides for 
correlative analysis. Subjects who cannot fulfill this requirement will need to undergo a 
new biopsy prior to enrollment on study. 
 
8.3.2 
Tissue Biopsy  
Tumor biopsy will be performed prior to starting therapy or archival tissue will be obtained 
for all subjects. At the time of surgical resection or biopsy, tissue in excess of what is 
necessary for diagnostic purposes will be obtained <15 min after removal from the 
subject. Furthermore, an on-treatment biopsy during nivolumab induction chemotherapy 
will be performed at 2-3 weeks post start of treatment as clinically feasible and subject 
consents to the procedure.  
 
Tissues will be instantaneously frozen and stored anonymously with a unique barcode at 
-80C in a locked freezer in Biospecimen Shared Resource (Tissue Bank) at The 
University of Chicago. Additional alternative processing (e.g. tissue digestion, and cell 
suspension generation for flow analyses is also acceptable).  
 
 
• Write study number, subject initials and date on plastic cryomold. 
• Weigh or estimate sample weight and slice sample into less than 0.5 cm 
thick fragments. 
• Place tissue into cryotube labeled with study number, subject initials and 
date filled with RNAlater reagent from Qiagen. 
• Freeze over liquid nitrogen vapors or in -80 C freezer. 
 
8.3.3 
Blood Isolation 
Blood will be obtained from all subjects enrolled in the study for pharmacogenomics and 
biomarker evaluation. Investigation of the relevant polymorphisms will take place in 
germline DNA extracted from peripheral whole blood (10 ml) collected in EDTA (purple 
top) plastic vacutainer tubes (i.e. BD catalog #366643). Investigation of cytokine markers 
will be from peripheral blood (10 ml) collected in a red top vacutainer tubes. Blood should 
be stored at -80 C and sent to Biospecimen Shared Resource (Tissue Bank) at The 
University of Chicago for DNA extraction and plasma isolation following standard HTRC 
protocols 
 
Isolated DNA will be store anonymously with a unique barcode at -80 C at the University 
at Chicago for future genotype analysis. 


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Subjects will have blood samples for genotyping and plasma analysis collected prior to 
induction chemotherapy. Samples for serum analysis will be collected prior to 
radiotherapy initiation, and then after the first week and at the completion of radiotherapy 
and will be collected at 2 months after radiotherapy.  
 
Plasma will be used for identification of cell free circulating tumor DNA, e.g. for HPV titer 
and somatic mutations to be assessed as a candidate biomarker for monitoring during 
treatment for efficacy and surveillance after completion of treatment for detection of early 
recurrence. 
 


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9 
STUDY CALENDAR / FLOWCHART 


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Subgroup A1: TORS 
 
 
 


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Subgroup A2: RT Only 
 
 
 
 
 


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Subgroup B: CRT 3 Cyles 
 
  
 
 


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Subgroup C: CRT 5 Cycles 
 
 


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10 
MEASUREMENT OF EFFECT 
For the purposes of this study, subjects should have both pre- and post-induction 
chemotherapy imaging of the head and neck with either CT or MRI for determination of 
response. 
 
Measurement of target lesions will be evaluated in this study using the international 
criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST v1.1) 
Committee.90  
 
10.1 
Measurement of Target Lesions 
 Tumor lesions: Must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size of 10 mm by CT scan 
(CT scan slice thickness no greater than 5 mm). 
In cases where based on discussion in tumor board the target lesions cannot be 
accurately measured by RECIST a volumetric measurement may be used IF agree upon 
by the tumor board and PI. 
 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be ⩾15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
10.2 
Measurement of Response 
Target lesion measurements will be summated on pre- and post-induction chemotherapy 
imaging. The percentage change will be calculated and the response used for treatment 
stratification as previously described. 
 
10.2.1 
Details about diagnostic imaging 
Diagnostic imaging plays an important role in the assessment of head and neck 
squamous cell carcinomas before and after treatment. Currently, computed tomography 
(CT) with contrast, fluorodeoxyglucose positron emission tomography (FDG-PET), and 
magnetic resonance imaging (MRI) are routinely used to evaluate subjects with this type 
of cancer. However, CT and FDG-PET often yield false positive or false negative 
findings for early assessment of treatment response. In particular, increased FDG 
uptake by activated inflammatory cells occurs in irradiated tissue and can result in false 
positive results during the early post-treatment period, which limits the utility of 18FDG-
PET for the detection of residual tumor prior to 12 weeks (Meng et al). This is beyond 
the “safe window” for performing surgery in cases of residual tumor that has been 
described at 4 to 12 weeks following chemoradiation, which is between the period of 
resolution of acute tissue injury and the onset of chronic tissue injury induced by 
chemoradiation that results in relatively normal wound healing, and is associated with a 
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On the other hand, measurements derived from diffusion weighted imaging perfusion 
MRI are promising techniques that can serve as potentially accurate imaging 
biomarkers of early treatment response for head and neck tumors. In particular, ADC, 
which is a measure of the magnitude of diffusion of water molecules within tissue, and is 
commonly clinically calculated using MRI with DWI, and K-trans, which is a measure of 
capillary permeability obtained using dynamic contrast enhanced (DSC) MRI, a 
perfusion weighted imaging MRI sequence, are potentially useful biomarkers for 
predicting treatment response.  
 
Indeed, DWI has been one of the most investigated biologic imaging modalities in head 
and neck cancer, primarily due to its ability to acquire reproducible images in a short 
sequence that can be incorporated into any head and neck MRI protocol. Studies have 
demonstrated that changes in ADC and percentage change in tumor volumes between 
baseline DWI and 3-weeks mid-therapy DWI showed correlation with outcomes, as 
opposed to percentage change in mean ADC, which did not correlate with tumor control 
at 6 months. Results from these studies imply that ADC values may be more accurate in 
detecting changes in tumor architecture, possibly at an earlier stage, compared with 
conventional measures such as alterations in tumor volume or enhancement. Both 
baseline ADC and change in ADC during therapy have proved useful as predictors of 
response in a recent study in which the authors showed that tumors that responded 
completely to chemoradiation had decreased baseline ADC values compared with 
tumors that responded only partially; in this study, change in the ADC during therapy 
served as a better predictor than baseline ADC alone. Ultimately, the true value of ADC 
in prediction and monitoring of response likely lies in a combination of pre-, intra-, and 
post-therapy ADC values, which needs to be evaluated in larger samples to establish its 
utility. 
 
Diffusion-weighted MR imaging (DWI) and dynamic contrast-enhanced perfusion-
weighted imaging parameters can potentially serve as biomarkers for predicting 
treatment response in subjects with head and neck squamous cell carcinomas (Kuang 
et al, Imanishi et al, Sumi et al, Srinivasan et al, Trojanowska et al, Padhani et al, 
Surlan-Popovic et al, Galban et al, Cao et al). DWI allows quantification of the diffusion 
of water molecules in tissues using the apparent diffusion coefficient (ADC), which can 
reflect tumor cellularity. Previous studies demonstrated that tumors with high ADC 
values are less likely to respond to chemoradiation, possibly because a high ADC value 
may reflect the presence of micronecrosis and, consequently, increased resistance to 
the delivery of cytotoxic drugs as well as oxygen during chemoradiation. DWI has also 
been used in the prediction of response to chemoradiation in head and neck squamous 
cell carcinomas.  
 
The subjects in this study will undergo a standardized 3T MRI protocol at baseline 
before induction chemotherapy and approximately 1 month after immunotherapy. The 
MRI sequences included in the protocol consist of multiplanar T1, T2, post-contrast T1, 
diffusion-weighted imaging, and perfusion-weighted imaging, with the same slice 
thickness, matrix sizes, and echo and repetition times implemented for each subject. 
The detailed protocol available to the performing technologists is provided in the 
Appendix. 
 


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ADC maps are automatically generated from the DWI sequences and measurement of 
the ADC values of the tumors will be made by drawing regions of interest at the PACS 
viewing station in the University of Chicago radiology computers. Post-processing 
software (Olea) available in the radiology reading room workstations is necessary to 
derive Ktrans measurement of the tumors from the raw perfusion images. 
 
10.3 
Progression-Free and Overall Survival 
 
 
Progression-Free Survival: From the date of registration to the date of progressive 
disease or death (whichever is first) or last follow-up if censored. 
 
 
Overall Survival: From the date of registration to the date of death or date of last 
follow-up if censored. 
 
Assessment of Local/Distant Failure: If disease progression is documented, 
subjects should have full assessment of sites of failure (i.e. local and distant). Local 
failure should be assessed by radiographic imaging and physical examination. 
Distant failure should be assessed by radiographic imaging. Further assessment 
of local and distant failure can be performed if warranted by subject symptoms. 
 
Patients should be followed for a minimum of 3 years post completion, but optional 
follow-up as aligned with clinical care is acceptable. 
 


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11 
REGULATORY AND REPORTING REQUIREMENTS 
11.1 
Regulatory Guidelines 
11.1.1 
Food and Drug Administration (FDA) Approval 
This study will be conducted under an IND held by Dr. Tanguy Seiwert at the University 
of Chicago.  The University of Chicago CCTO will be responsible for facilitating all 
communications with the FDA on behalf of the IND holder.    
 
11.2 
Expedited Adverse Event Reporting 
Adverse events (AEs) will use the descriptions and grading scales found in the revised 
NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4. All appropriate 
treating areas will have access to a copy of the CTCAE version 4. A copy of the CTCAE 
version 4. A copy of the CTCAE version 4 can be downloaded from the CTEP web site 
(https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf). 
 
11.3 
Adverse Event Definitions 
11.3.1 
Adverse Event 
 
An adverse event is any untoward medical occurrence in a subject or clinical 
investigation subject administered a pharmaceutical product that does not necessarily 
have a causal relationship with the treatment. An adverse event can be any 
unfavorable and unintended sign (including a laboratory finding), symptom or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. 
 
At each evaluation subjects should be interviewed in a non-directed manner to elicit 
potential adverse reactions from the subject. The occurrence of an adverse event will 
be based on changes in the subject’s physical examination, laboratory results, and/or 
signs and symptoms, and review of the subject’s own record of adverse events. 
 
Adverse events will be followed until resolution while the subject remains on-study. 
Once the subject is removed from study, events thought to be related to the study 
medication will be followed until resolution or stabilization of the adverse event, or until 
the subject starts a new treatment regimen, or death, whichever comes first.  Subjects 
will be followed for AEs/SAEs for 100 days after their last dose of study drug(s). 
 
11.3.2 
Serious Adverse Event (SAE)  
An adverse event is considered serious if it results in ANY of the following outcomes:  
 


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1) Death 
2) Life-threatening (e.g. places subject at immediate risk of death, this does 
not include events that might have caused death if they occurred a greater 
severity) 
3) Results in inpatient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions  
5) A congenital anomaly/birth defect.  
 
Adverse events must be reported to regulatory authorities according to the definitions 
and timelines specified in the local laws and regulations. 
 
Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical judgment, 
they may jeopardize the subject or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  Examples of such 
events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse.  
 
In addition to those events meeting the definitions above, the following will be 
considered an SAE for the purposes of this study: 
 
• Potential drug induced liver injury (DILI) 
• Suspected transmission of an infectious agent (e.g. pathogenic or 
nonpathogenic) via the study drug 
• Pregnancy occurring within the period defined in section 4.1 
• Overdose 
• Death due to Disease Progression occurring within 100 days of last dose of 
study drug 
 
11.3.3 
Relatedness  
The definition of “related” being that there is a reasonable possibility that the drug caused 
the adverse experience. 
 
11.3.4 
Adverse Reactions 
An adverse event is considered to be an adverse reaction if there evidence to suggest a 
causal relationship to the study agent.  This may include a single occurrence of an 
event strongly associated with drug exposure (e.g. Stevens-Johnson Syndrome), one or 
more occurrence of an event otherwise uncommon is the study population, or an 
aggregate analysis of specific events occurring at greater than expected frequency. 
 


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11.4 
Adverse Event Reporting 
11.4.1 
Routine Adverse Event Reporting  
 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
using the Serious Event Reporting Form and/or MedWatch Form discussed below 
must also be reported in routine study data submissions.   
 
All adverse events (except grade 1 and 2 laboratory abnormalities that do not require an 
intervention), regardless of causal relationship, are to be recorded in the case report 
form and source documentation. The Investigator must determine the intensity of any 
adverse events according to the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.0 and their causal relationship.  
 
11.4.2 
Serious Adverse Event Reporting 
All serious adverse events (as defined in section 11.1.2) occurring on this study require 
expedited reporting to the University of Chicago Comprehensive Cancer Center (UC 
CCC).  The responsible Research Nurse or Clinical Research Coordinator should report 
the SAE to the Principal Investigator,CCTO and enter into Velos by the end of the 
business day when team becomes aware of the event.  Events occurring after business 
hours should be reported to the CCTO by 12pm (noon) the next business day  via email 
to qaccto@bsd.uchicago.edu. Reports in Velos should be made using the ‘Serious 
Event Report’ Form.   
 
All unexpected adverse reactions must be reported to the University of Chicago CCTO 
for FDA reporting.  The responsible Research Nurse or Clinical Research Coordinator 
should provide a complete written report using the FDA MedWatch 3500A form.  The 
completed form should be sent to the CCTO within the specified timelines below 
regardless of whether all information regarding the event is available.  If applicable, a 
follow-up report should be provided to the CCTO if additional information on the event 
becomes available.   
 
Clinical staff should not forward any adverse event reports directly to the FDA.  
The CCTO will report all events to the FDA as per the current FDA guidelines.   
 
All serious adverse events should also be reported to the local IRB of record according 
to their policies and procedures. 
   
 
11.4.3 
Serious Adverse Event Reporting to BMS 
SAEs, whether related or not related to study drug, and pregnancies must be reported 
to BMS within 24 hours of investigator knowledge of the event. SAEs must be recorded 
on BMS or an approved form; pregnancies on a Pregnancy Surveillance Form. 
 


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SAE Email Address:  Worldwide.Safety@BMS.com 
 
SAE Facsimile Number:  609-818-3804 
 
If only limited information is initially available, follow-up reports are required. (Note: 
Follow-up SAE reports should include the same investigator term(s) initially reported.)  
 
If an ongoing SAE changes in its intensity or relationship to study drug or if new 
information becomes available, a follow-up SAE report should be sent within 24 hours to 
the BMS (or designee) using the same procedure used for transmitting the initial SAE 
report.  
 
All SAEs should be followed to resolution or stabilization. 
 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
Email: Worldwide.safety@bms.com 
 
If the investigator believes that an SAE is not related to study drug, but is potentially 
related to the conditions of the study (such as withdrawal of previous therapy or a 
complication of a study procedure), the relationship should be specified in the narrative 
section of the SAE Report Form. 
 
11.4.4 
Serious Adverse Event Reporting to Celgene 
Serious adverse events (SAE) are defined above.  The investigator must inform Celgene 
in writing using a Celgene SAE form or MEDWATCH 3500A form of any SAE within 24 
hours of being aware of the event.  The written report must be completed and supplied to 
Celgene by facsimile or email within 24 hours/1 business day.  The initial report must be 
as complete as possible, including an assessment of the causal relationship between the 
event and the investigational product(s), if available.  Information not available at the time 
of the initial report (e.g., an end date for the adverse event or laboratory values received 
after the report) must be documented on a follow-up report.  A final report to document 
resolution of the SAE is required.  The Celgene tracking number (AX-CL-HN-PI-004235) 
and the institutional protocol number should be included on SAE reports (or on the fax 
cover letter) sent to Celgene.  A copy of the fax transmission confirmation or email of the 
SAE report to Celgene should be attached to the SAE and retained with the subject 
records. 
 
Celgene Drug Safety Contact Information: 
Celgene Corporation      
Global Drug Safety and Risk Management    
Connell Corporate Park      


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300 Connell Dr.  Suite 6000     
Berkeley Heights, NJ  07922        
Fax:(908) 673-9115 
E-mail: drugsafety@celgene.com 
 
11.5 
Subject registration and data submission 
11.5.1 
Registration 
All patients must be registered with the University of Chicago Head and Neck Clinical 
Research Coordinator (CRC) prior to the commencement of treatment. PI, Research 
nurse and CRC will confirm all selection criteria listed in Section 4. Confirmation is 
documented with signatures and date.  
 
11.5.2 
Data management 
The investigator or qualified designee is responsible for recording and verifying 
the accuracy of subject data. 
 
All required data must be recorded at the completion of each cycle as stated above in 
section 11.4.2.  
 
11.6 
Data and safety monitoring 
Data Safety and Monitoring will occur at the weekly University of Chicago Head and 
Neck Research Program meetings, which are led by senior level medical oncologists. At  
each meeting, the study will be reviewed for safety and progress toward completion. 
Toxicities and adverse events will be reviewed at each meeting. 
 
11.7 
Auditing 
The University of Chicago Comprehensive Cancer Center will perform routine Quality 
Assurance Audits of investigator-initiated clinical trials as described in the NCI-approved 
UC CCC DSM Plan. Audits provide assurance that trials are conducted and study data 
are collected, documented and reported in compliance with the protocol. Further, quality 
assurance audits ensure that study data are collected, documented and reported in 
compliance with Good Clinical Practices (GCP) Guidelines and regulatory requirements. 
The audit will review subjects enrolled at the University of Chicago in accordance with 
audit procedures specified in the UC CCC Data and Safety Monitoring plan. 
   
A regulatory authority (e.g. FDA) may also wish to conduct an inspection of the study, 
during its conduct or even after its completion. If an inspection has been requested by a 
regulatory authority, the site investigator must immediately inform the University of 
Chicago Cancer Clinical Trials Office and Regulatory Manager that such a request has 


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been made. 
 
11.8 
Record Retention 
Study documentation includes all CRFs, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory 
documents (e.g., protocol and amendments, IRB correspondence and approval, signed 
subject consent forms). 
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. 
Government agency regulations and directives require that all study documentation 
pertaining to the conduct of a clinical trial must be retained by the study investigator.  In 
the case of a study with a drug seeking regulatory approval and marketing, these 
documents shall be retained for at least two years after the last approval of marketing 
application in an International Conference on Harmonization (ICH) region.  In all other 
cases, study documents should be kept on file until three years after the completion and 
final study report of this investigational study. 
 
11.9 
Obligations of Study Site Investigations 
The Study Principal Investigator is responsible for the conduct of the clinical trial in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki.  The Principal Investigator is responsible for personally overseeing the 
treatment of all study subjects.  He/she must assure that all study personnel, including 
sub-investigators and other study staff members, adhere to the study protocol and all 
FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and after 
study completion.  
 
The Study Principal Investigator will be responsible for assuring that all the required 
data will be collected and entered into the CRFs. Periodically, monitoring visits or audits 
will be conducted and he/she must provide access to original records to permit 
verification of proper entry of data. 
 


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12 
STATISTICAL CONSIDERATIONS 
12.1 
Statistical methods 
12.1.1 
Primary Endpoint: Deep Response Rate (DRR) 
Overall Primary Objective: To demonstrate an increased rate of deep responses (deep 
response rate=DRR) to induction chemotherapy with the addition of nivolumab to the 
carboplatin/nab-paclitaxel backbone used in the Optima I trial. 
• In the predecessor Optima 1 study, deep responses were defined as ≥50% tumor 
shrinkage by RECIST 1.1 and this is believed to be equivalent to a clinical complete 
response (CR) as utilized in the ECOG 1308 study (which was the primary 
outcome for E1308). Hence in this study, deep responses are also defined as 
≥50% tumor shrinkage by RECIST 1.1. 
• 
We will employ a superiority test in which the objective is to establish that the 
response rate to carboplatin/nab-paclitaxel/nivolumab induction chemotherapy is 
15% higher than the response rate of 60% in Optima I which utilized a 
carboplatin/nab-paclitaxel induction regimen. 
• We will test: H0: DRR=60% (based on data from Optima 1 trial) vs HA: DRR=75% 
with addition of nivolumab to the carboplatin/nab-paclitaxel induction regimen. 
• Using Power Analysis and Sample Size (PASS v11) software, a sample of  
subjects will provide 87% power to test this hypothesis using a (one-sided) type I 
error rate of 0.10. Essentially, H0 will be rejected and nivolumab/carboplatin/nab-
paclitaxel based induction regimen declared superior if the lower, one-sided 90% 
confidence limit for the response rate exceeds 75%. No interim analysis will be 
conducted. 
 
NB: A minimum of 10 patients will be enrolled on the RT only and also TORS arm to allow 
for descriptive interpretation of the pathology results in tabular form. The overall trial may 
overenroll up to 18 patients (N=74) to fulfill this enrollment goal for the RT-only and TORS 
arms. 
 
12.1.2 
Secondary Endpoints  
Secondary objectives, respective endpoints, and analyses: 
• 
To determine the tolerability of the nivolumab/carboplatin/nab-paclitaxel induction 
chemotherapy regimen and its impact on subsequent receipt of definitive 
chemoradiotherapy. 
o Endpoint will be CTCAE v4.0 adverse events 
o The safety analysis will be performed in all treated subjects. Descriptive 
statistics of safety will be presented using the National Cancer Institute (NCI) 


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Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 by 
treatment arm. All AEs, drug-related AEs, SAEs and drug-related SAEs will 
be tabulated using the worst grade per NCI CTCAE v 4.0 criteria by system 
organ class and preferred term. On-study lab parameters including 
hematology, coagulation, chemistry, liver function and renal function will be 
summarized using worse grade per NCI CCAE v 4.0 criteria. 
o All recorded adverse events will be listed and tabulated by system organ 
class, preferred term and treatment. Vital signs and clinical laboratory test 
results will be listed and summarized by treatment. Any significant physical 
examination findings, and clinical laboratory results will be listed. ECG 
readings will be evaluated by the investigator and abnormalities, if present, 
will be listed.  
• 
To determine 2-year progression-free survival (PFS) for the entire cohort and all arms 
and compare them to the entire cohort and corresponding arms in Optima I. 
o PFS is defined as the time from registration to the date of first documented 
disease progression, as assessed by the IRC using RECIST 1.1 criteria, or 
death due to any cause, whichever occurs first. Subjects who died without a 
reported progression will be considered to have progressed on the date of their 
death. Subjects who did not progress or die will be censored on the date of 
their last evaluable tumor assessment. Subjects who did not have any on study 
tumor assessments and did not die will be censored on the date they were 
registered. Subjects who started any subsequent anti-cancer therapy, including 
tumor-directed radiotherapy and tumor-directed surgery, without a prior 
reported progression will be censored at the last evaluable tumor assessment 
prior to/on initiation of the subsequent anti-cancer therapy. 
o PFS will be estimated by Kaplan-Meier methodology and comparisons will be 
made using the log-rank test. PFS analyses will include subjects in the overall 
cohort and in each of the three arms. 
• 
To determine 2-year overall survival (OS) for the entire cohort and all arms and 
compare them to the entire cohort and corresponding arms in Optima I. 
o OS is defined as the time between the date of registration and the date of death. 
For subjects without documentation of death, OS will be censored on the last 
date the subject was known to be alive. 
o OS will be estimated by Kaplan-Meier methodology and comparisons will be 
made using the log-rank test. OS analyses will include subjects in the overall 
cohort and in each of the three arms. 
• 
To determine 2-year rates of locoregional and distant control for the entire cohort and 
all arms and compare them to the entire cohort and corresponding arms in Optima I. 
o Locoregional failure is defined as the time from registration to the date of first 
documented disease progression in the head and neck, as assessed by the 
IRC using RECIST 1.1 criteria.  


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o Distant failure is defined as the time from registration to the date of first 
documented disease progression below the clavicles, as assessed by the IRC 
using RECIST 1.1 criteria.  
o Time to locoregional and distant failure rates will be estimated by the Kaplan-
Meier methodology and comparisons will be made using the log-rank test. 
Time to LRF and DF analyses will include subjects in the overall cohort and in 
each of the three arms. 
 
12.1.3 
Exploratory Objectives/Endpoints/Analyses 
• 
To determine rates of acute and late toxicity using CTCAE v4.0 and compare them to 
rates of acute and late toxicity on the Optima I and RAVD trials. 
o Endpoint will be CTCAE v4.0 adverse events 
o Results will be tabulated and comparisons will be made using the chi-square, 
Fisher’s exact, or t-test as appropriate. 
• 
To determine quality of life scores in subjects and compare them to quality of life 
scores on the RAVD trial. 
o Endpoints will be overall and domain subset scores on the QOL instruments 
used. 
o Results will be tabulated and comparisons will be made using the chi-square, 
Fisher’s exact, or t-test as appropriate. 
• 
To determine the comparative efficacy and toxicity profiles of TORS versus RT for 
management of low risk disease will be exploratory and dependent on number of 
subjects that are treated. 
o Endpoints for efficacy will include progression-free and overall survival, as 
calculated above. Comparisons will be made using the log-rank test. 
o Endpoint for toxicity will be CTCAE v4.0 adverse events. Results will be 
tabulated and comparisons will be made using the chi-square, Fisher’s exact, 
or t-test as appropriate. 
 
12.1.4 
Laboratory/Translational Objectives 
We will interrogate the immune micro-environment at baseline, and 2-3 weeks into 
induction therapy with nivolumab and chemotherapy with an optional on-treatment biopsy. 
This will be exploratory as previously described with descriptive statistical analyses 
summarized in tabular format. 
 
12.1.5 
Visual Aid Objectives 
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multidisciplinary consultation and prior to allocation to treatment arm. These may be 
administered during the induction therapy. We will also distribute anonymous and 
optional questionnaires to providers in surgery, medical oncology, and radiation 
oncology at Head and Neck Multidisciplinary Tumor Board once subject enrollment is 
discontinued. 


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and can they be spared by IMRT? Int J Radiat Oncol Biol Phys 60:1425-39, 2004 
 
28. 
Setton J, Caria N, Romanyshyn J, et al: Intensity-Modulated Radiotherapy 
in the Treatment of Oropharyngeal Cancer: An Update of the Memorial Sloan-Kettering 
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Physics 82:291-298 
 
29. 
Adelstein DJ, Li Y, Adams GL, et al: An intergroup phase III comparison of 
standard radiation therapy and two schedules of concurrent chemoradiotherapy in 
patients with unresectable squamous cell head and neck cancer. J Clin Oncol 21:92-8, 
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30. 
Forastiere AA, Goepfert H, Maor M, et al: Concurrent chemotherapy and 
radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 
349:2091-8, 2003 
 
31. 
Vokes 
EE, 
Haraf 
DJ, 
Mick 
R, 
et 
al: 
Intensified 
concomitant 
chemoradiotherapy with and without filgrastim for poor-prognosis head and neck cancer. 
J Clin Oncol 12:2351-9, 1994 
 
32. 
Vokes EE, Panje WR, Schilsky RL, et al: Hydroxyurea, fluorouracil, and 
concomitant radiotherapy in poor-prognosis head and neck cancer: a phase I-II study. J 
Clin Oncol 7:761-8, 1989 
 
33. 
Vokes EE, Beckett M, Karrison T, et al: The interaction of 5-fluorouracil, 
hydroxyurea, and radiation in two human head and neck cancer cell lines. Oncology 
49:454-60, 1992 
 
34. 
Vokes EE, Weichselbaum RR: Concomitant chemoradiotherapy: rationale 
and clinical experience in patients with solid tumors. J Clin Oncol 8:911-34, 1990 
 
35. 
Moran RG, Danenberg PV, Heidelberger C: Therapeutic response of 
leukemic mice treated with fluorinated pyrimidines and inhibitors of deoxyuridylate 
synthesis. Biochem Pharmacol 31:2929-35, 1982 
 
36. 
Brockstein B, Haraf DJ, Stenson K, et al: Phase I study of concomitant 
chemoradiotherapy with paclitaxel, fluorouracil, and hydroxyurea with granulocyte colony-
stimulating factor support for patients with poor-prognosis cancer of the head and neck. 
J Clin Oncol 16:735-44, 1998 
 
37. 
Brockstein B, Haraf DJ, Stenson K, et al: A phase I-II study of concomitant 
chemoradiotherapy with paclitaxel (one-hour infusion), 5-fluorouracil and hydroxyurea 
with granulocyte colony stimulating factor support for patients with poor prognosis head 
and neck cancer. Ann Oncol 11:721-8, 2000 
 
38. 
Kies MS, Haraf DJ, Rosen F, et al: Concomitant infusional paclitaxel and 
fluorouracil, oral hydroxyurea, and hyperfractionated radiation for locally advanced 
squamous head and neck cancer. J Clin Oncol 19:1961-9, 2001 
 
39. 
Vokes EE, Kies MS, Haraf DJ, et al: Concomitant chemoradiotherapy as 
primary therapy for locoregionally advanced head and neck cancer. J Clin Oncol 18:1652-
61, 2000 
 
40. 
Rosen FR, Haraf DJ, Kies MS, et al: Multicenter randomized Phase II study 
of paclitaxel (1-hour infusion), fluorouracil, hydroxyurea, and concomitant twice daily 
radiation with or without erythropoietin for advanced head and neck cancer. Clin Cancer 
Res 9:1689-97, 2003 
 
41. 
Haraf DJ, Rosen FR, Stenson K, et al: Induction chemotherapy followed by 
concomitant TFHX chemoradiotherapy with reduced dose radiation in advanced head 
and neck cancer. Clin Cancer Res 9:5936-43, 2003 
 
42. 
Vokes EE, Stenson K, Rosen FR, et al: Weekly carboplatin and paclitaxel 
followed by concomitant paclitaxel, fluorouracil, and hydroxyurea chemoradiotherapy: 
curative and organ-preserving therapy for advanced head and neck cancer. J Clin Oncol 
21:320-6, 2003 
 
43. 
Pointreau Y, Garaud P, Chapet S, et al: Randomized trial of induction 
chemotherapy with cisplatin and 5-fluorouracil with or without docetaxel for larynx 
preservation. J Natl Cancer Inst 101:498-506, 2009 
 
44. 
Posner MR, Hershock DM, Blajman CR, et al: Cisplatin and fluorouracil 
alone or with docetaxel in head and neck cancer. N Engl J Med 357:1705-15, 2007 


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45. 
Vermorken JB, Remenar E, van Herpen C, et al: Cisplatin, fluorouracil, and 
docetaxel in unresectable head and neck cancer. N Engl J Med 357:1695-704, 2007 
 
46. 
Cohen EEW KT, Kocherginsky M, et al.: DeCIDE: A phase III randomized 
trial of docetaxel (D), cisplatin (P), 5-fluorouracil (F) (TPF) induction chemotherapy (IC) in 
patients with N2/N3 locally advanced squamous cell carcinoma of the head and neck 
(SCCHN). J Clin Oncol 30, 2012 
 
47. 
Haddad R, O'Neill A, Rabinowits G, et al: Induction chemotherapy followed 
by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent 
chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a 
randomised phase 3 trial. Lancet Oncol 14:257-64, 2013 
 
48. 
Hitt R, Grau JJ, López-Pousa A, et al: A randomized phase III trial 
comparing 
induction 
chemotherapy 
followed 
by 
chemoradiotherapy 
versus 
chemoradiotherapy alone as treatment of unresectable head and neck cancer. Annals of 
Oncology, 2013 
 
49. 
Herman LC, Chen L, Garnett A, et al: Comparison of carboplatin-paclitaxel 
to docetaxel-cisplatin-5-flurouracil induction chemotherapy followed by concurrent 
chemoradiation for locally advanced head and neck cancer. Oral Oncol 50:52-8, 2014 
 
50. 
Cohen EEW, Karrison TG, Kocherginsky M, et al: Phase III Randomized 
Trial of Induction Chemotherapy in Patients With N2 or N3 Locally Advanced Head and 
Neck Cancer. Journal of Clinical Oncology, 2014 
 
51. 
Surapaneni MS, Das SK, Das NG: Designing Paclitaxel Drug Delivery 
Systems Aimed at Improved Patient Outcomes: Current Status and Challenges. ISRN 
Pharmacology 2012:623139, 2012 
 
52. 
Hansson BG, Rosenquist K, Antonsson A, et al: Strong association between 
infection with human papillomavirus and oral and oropharyngeal squamous cell 
carcinoma: a population-based case-control study in southern Sweden. Acta Otolaryngol 
125:1337-44, 2005 
 
53. 
Mork J, Lie AK, Glattre E, et al: Human papillomavirus infection as a risk 
factor for squamous-cell carcinoma of the head and neck. N Engl J Med 344:1125-31, 
2001 
 
54. 
Marur S, D'Souza G, Westra WH, et al: HPV-associated head and neck 
cancer: a virus-related cancer epidemic. Lancet Oncol 11:781-9, 2010 
 
55. 
Furniss CS, McClean MD, Smith JF, et al: Human papillomavirus 16 and 
head and neck squamous cell carcinoma. Int J Cancer 120:2386-92, 2007 
 
56. 
Hammarstedt L, Lindquist D, Dahlstrand H, et al: Human papillomavirus as 
a risk factor for the increase in incidence of tonsillar cancer. Int J Cancer 119:2620-3, 
2006 
 
57. 
Rampias T, Sasaki C, Weinberger P, et al: E6 and e7 gene silencing and 
transformed phenotype of human papillomavirus 16-positive oropharyngeal cancer cells. 
J Natl Cancer Inst 101:412-23, 2009 
 
58. 
Sturgis EM, Ang KK: The epidemic of HPV-associated oropharyngeal 
cancer is here: is it time to change our treatment paradigms? J Natl Compr Canc Netw 
9:665-73, 2011 
 
59. 
Gillison ML, D'Souza G, Westra W, et al: Distinct risk factor profiles for 
human papillomavirus type 16-positive and human papillomavirus type 16-negative head 
and neck cancers. J Natl Cancer Inst 100:407-20, 2008 


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60. 
Posner MR, Lorch JH, Goloubeva O, et al: Survival and human 
papillomavirus in oropharynx cancer in TAX 324: a subset analysis from an international 
phase III trial. Ann Oncol 22:1071-7, 2011 
 
61. 
Rischin D, Young RJ, Fisher R, et al: Prognostic significance of p16INK4A 
and human papillomavirus in patients with oropharyngeal cancer treated on TROG 02.02 
phase III trial. J Clin Oncol 28:4142-8, 2010 
 
62. 
O'Sullivan B, Huang SH, Perez-Ordonez B, et al: Outcomes of HPV-related 
oropharyngeal cancer patients treated by radiotherapy alone using altered fractionation. 
Radiother Oncol 103:49-56, 2012 
 
63. 
Huang SH, Xu W, Waldron J, et al: Refining American Joint Committee on 
Cancer/Union for International Cancer Control TNM stage and prognostic groups for 
human papillomavirus-related oropharyngeal carcinomas. J Clin Oncol 33:836-45, 2015 
 
64. 
O'Sullivan B, Huang SH, Su J, et al: Development and validation of a 
staging system for HPV-related oropharyngeal cancer by the International Collaboration 
on Oropharyngeal cancer Network for Staging (ICON-S): a multicentre cohort study. 
Lancet Oncol 17:440-51, 2016 
 
65. 
Bratman SV, Bruce JP, O’Sullivan B, et al: HUman papillomavirus genotype 
association with survival in head and neck squamous cell carcinoma. JAMA Oncology 
2:823-826, 2016 
 
66. 
Dawson LA, Anzai Y, Marsh L, et al: Patterns of local-regional recurrence 
following parotid-sparing conformal and segmental intensity-modulated radiotherapy for 
head and neck cancer. Int J Radiat Oncol Biol Phys 46:1117-26, 2000 
 
67. 
O'Sullivan B, Warde P, Grice B, et al: The benefits and pitfalls of ipsilateral 
radiotherapy in carcinoma of the tonsillar region. Int J Radiat Oncol Biol Phys 51:332-43, 
2001 
 
68. 
Spencer CR, Gay HA, Haughey BH, et al: Eliminating radiotherapy to the 
contralateral retropharyngeal and high level II lymph nodes in head and neck squamous 
cell carcinoma is safe and improves quality of life. Cancer 120:3994-4002, 2014 
 
69. 
Chera BS, Amdur RJ, Tepper J, et al: Phase 2 Trial of De-intensified 
Chemoradiation 
Therapy 
for 
Favorable-Risk 
Human 
Papillomavirus-Associated 
Oropharyngeal Squamous Cell Carcinoma. Int J Radiat Oncol Biol Phys 93:976-85, 2015 
 
70. 
Holsinger FC, Ferris RL: Transoral Endoscopic Head and Neck Surgery and 
Its Role Within the Multidisciplinary Treatment Paradigm of Oropharynx Cancer: Robotics, 
Lasers, and Clinical Trials. Journal of Clinical Oncology, 2015 
 
71. 
Morisod B, Simon C: Meta-analysis on survival of patients treated with 
transoral surgery versus radiotherapy for early-stage squamous cell carcinoma of the 
oropharynx. Head & Neck 38:E2143-E2150, 2016 
 
72. 
Chen AM, Daly ME, Luu Q, et al: Comparison of functional outcomes and 
quality of life between transoral surgery and definitive chemoradiotherapy for 
oropharyngeal cancer. Head & Neck 37:381-385, 2015 
 
73. 
Nichols AC, Yoo J, Hammond JA, et al: Early-stage squamous cell 
carcinoma of the oropharynx: Radiotherapy vs. Trans-Oral Robotic Surgery (ORATOR) – 
study protocol for a randomized phase II trial. BMC Cancer 13:133-133, 2013 
 
74. 
Sadeghi N, Li NW, Taheri MR, et al: Neoadjuvant chemotherapy and 
transoral surgery as a definitive treatment for oropharyngeal cancer: A feasible novel 
approach. Head Neck, 2016 
 
75. 
Bernier J, Cooper JS, Pajak TF, et al: Defining risk levels in locally 
advanced head and neck cancers: a comparative analysis of concurrent postoperative 


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radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head 
Neck 27:843-50, 2005 
 
76. 
NCT01898494: Transoral Surgery Followed By Low-Dose or Standard-
Dose Radiation Therapy With or Without Chemotherapy in Treating Patients With HPV 
Positive Stage III-IVA Oropharyngeal Cancer.  
 
77. 
Ma DJ, Price KA, Moore EJ, et al: Abstract CT227: MC1273: Phase II 
evaluation of aggressive dose de-escalation for adjuvant chemoradiation in HPV 
associated oropharynx cancer. Cancer Research 75:CT227-CT227, 2015 
 
78. 
Stenson KM, Haraf DJ, Pelzer H, et al: The role of cervical 
lymphadenectomy after aggressive concomitant chemoradiotherapy: the feasibility of 
selective neck dissection. Arch Otolaryngol Head Neck Surg 126:950-6, 2000 
 
79. 
Liauw SL, Mancuso AA, Amdur RJ, et al: Postradiotherapy neck dissection 
for lymph node-positive head and neck cancer: the use of computed tomography to 
manage the neck. J Clin Oncol 24:1421-7, 2006 
 
80. 
Mehanna H, Wong W-L, McConkey CC, et al: PET-CT Surveillance versus 
Neck Dissection in Advanced Head and Neck Cancer. New England Journal of Medicine 
374:1444-1454, 2016 
 
81. 
Berman D, Korman A, Peck R, et al: The development of 
immunomodulatory monoclonal antibodies as a new therapeutic modality for cancer: The 
Bristol-Myers Squibb experience. Pharmacology & Therapeutics 148:132-153, 2015 
 
82. 
Pardoll 
DM: 
The 
blockade 
of 
immune 
checkpoints 
in 
cancer 
immunotherapy. Nat Rev Cancer 12:252-264, 2012 
 
83. 
NCT02764593: Chemotherapy +/- Nivolumab in Patients With Intermediate 
and High-Risk Local-Regionally Advanced Head and Neck Squamous Cell Carcinoma.  
 
84. 
George B, Kelly K, Ko A, et al: ABI-007-ST-001 A Phase I study of 
nivolumab and nab-paclitaxel regimen in solid tumors: Results from the Pancreatic 
Cnacer and Non-Small Cell Lung Cancer Cohort, ESMO 2016 abstract 2027 
 
85. 
NCT02254278: Reduced-Dose Intensity-Modulated Radiation Therapy 
With or Without Cisplatin in Treating Patients With Advanced Oropharyngeal Cancer.  
 
86. 
NCT01302834: Radiation Therapy With Cisplatin or Cetuximab in Treating 
Patients With Oropharyngeal Cancer.  
 
87. 
NCT01855451: Weekly Cetuximab/RT Versus Weekly Cisplatin/RT in HPV-
Associated Oropharyngeal Squamous Cell Carcinoma (HPVOropharynx).  
 
88. 
NCT02258659: Nab-paclitaxel and Carboplatin Followed by Response-
Based Local Therapy in Treating patients With Stage III or IV HPV-Related 
Oropharyngeal Cancer (OPTIMA).  
 
89. 
Jordan RC, Lingen MW, Perez-Ordonez B, et al: Validation of methods for 
oropharyngeal cancer HPV status determination in US cooperative group trials. Am J 
Surg Pathol 36:945-54, 2012 
 
90. 
Eisenhauer E, Therasse P, Bogaerts J, et al: New response evaluation 
criteria in solid tumours: revised RECIST guideline (version 1.1). European journal of 
cancer 45:228-247, 2009 
           91. Ali FM, Johns N, Finlay AY, Salek MS, Piguet V. Comparison of the paper-
based and electronic versions of the Dermatology Life Quality Index: evidence of 
equivalence. Br J Dermatol. 2017.   


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.    92.Campbell N, Ali F, Finlay AY, Salek SS. Equivalence of electronic and paper-based 
patient-reported outcome measures. Qual Life Res. 2015;24(8):1949-61. 
 
 
 


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APPENDIX A: PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status 
Scale 
 
Karnofsky 
Performance Status 
scale 
 
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 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: RTOG/NRG EARLY TOXICITY GRADING 
 
Tissue 
Grade 1 
2 
3 
4 
Skin 
Follicular, faint or dull 
erythema / epilation / dry 
desquamation / decreased 
sweating 
Tender or bright 
erythema, patchy 
moist 
desquamation / 
moderate edema 
Confluent, moist 
desquamation other 
than skin folds, pitting 
edema 
Ulceration, 
hemorrhage, necrosis 
Mucous 
membrane 
Injection / may experience 
mild pain not requiring 
analgesic 
Patchy mucositis 
that may produce 
an inflammatory 
serosanguinous 
discharge / may 
experience 
moderate pain 
requiring analgesia 
Confluent fibrinous 
mucositis / may include 
severe pain requiring 
narcotic 
Ulceration, 
hemorrhage or 
necrosis 
Eye 
Mild conjunctivitis w/ or w/o 
scleral injection / increased 
tearing 
Moderate 
conjunctivitis w/ or 
w/o keratitis 
requiring steroids 
and/or antibiotics / 
dry eye requiring 
artificial tears / iritis 
with photophobia 
Severe keratitis with 
corneal ulceration / 
objective decrease in 
visual acuity or in visual 
fields / acute glaucoma / 
panophthalmitis 
Loss of vision (uni or 
bilateral) 
Ear 
Mild external otitis with 
erythema, pruritus, 
secondary to dry 
desquamation not requiring 
medication. Audiogram 
unchanged from baseline 
Moderate external 
otitis requiring 
topical medication / 
serous otitis media 
/ hypoacusis on 
testing only 
Severe external otitis 
with discharge or moist 
desquamation / 
symptomatic hypoacusis 
/ tinnitus, not drug 
related 
Deafness 
Salivary 
gland 
Mild mouth dryness / 
slightly thickened saliva / 
may have slightly altered 
taste such as metallic taste 
/ these changes not 
reflected  
in alteration in baseline 
feeding behavior, such as 
increased use of liquids 
with meals 
Moderate to 
complete dryness / 
thick, sticky saliva / 
markedly altered 
taste 
(none) 
Acute salivary gland 
necrosis 
Pharynx & 
esophagus 
Mild dysphagia or 
odynophagia / may require 
topical anesthetic or non-
narcotic analgesics / may 
require soft diet 
Moderate 
dysphagia or 
odynophagia / may 
require narcotic 
analgesics / may 
require puree or 
liquid diet 
Severe dysphagia or 
odynophagia with 
dehydration or weight 
loss > 15% from 
pretreatment baseline 
requiring NG feeding 
tube, IV fluids, or 
hyperalimentation 
Complete obstruction, 
ulceration, perforation, 
fistula 
Larynx 
Mild or intermittent 
hoarseness / cough not 
requiring antitussive / 
erythema of mucosa 
Persistent 
hoarseness but 
able to vocalize / 
referred ear pain, 
sore throat, patchy 
fibrinous exudate 
Whispered speech, 
throat pain or referred 
ear pain requiring 
narcotic / confluent 
fibrinous exudate, 
Marked dyspnea, 
stridor or hemoptysis 
with tracheostomy or 
intubation necessary 


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or mild arytenoid 
edema not 
requiring narcotic / 
cough  
requiring 
antitussive 
marked arytenoid 
edema 
HEME 
1 
2 
3 
4 
WBC 
3.0 - < 4.0 
2.0 - < 3.0 
1.0 - < 2.0 
< 1.0 
Platelets 
75 - < 100 
50 - < 75 
25 - < 50 
<25 or spontaneous 
bleeding 
Neutrophils 
1.5 - < 1.9 
1.0 - < 1.5 
0.5 - < 1.0 
< 0.5 or sepsis 
Hgb / Hct 
11 - 9.5 (28% - < 32%) 
< 9.5 - 7.5 ( < 28%) 
< 7.5 - 5.0 (Packed cell 
transfusion required) 
(none) 
 
 
 


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APPENDIX C: RTOG LATE TOXICITY GRADING 
 
Tissue 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Skin 
Slight atrophy; 
pigmentation 
change; some hair 
loss 
Patch atrophy; 
moderate 
telangiectasia; total 
hair loss 
Marked atrophy; gross 
telangiectasia 
Ulceration 
Subcutaneous tissue 
Slight induration 
(fibrosis) and loss 
of subcutaneous fat 
Moderate fibrosis but 
asymptomatic; slight 
field contracture; <10% 
linear reduction 
Severe induration and loss of 
subcutaneous tissue; field 
contracture > 10% linear 
measurement 
Necrosis 
Mucous membrane 
Slight atrophy and 
dryness 
Moderate atrophy and 
telangiectasia; little 
mucous 
Marked atrophy with complete 
dryness 
Ulceration 
Salivary glands 
Slight dryness of 
mouth; good 
response on 
stimulation 
Moderate dryness of 
mouth; poor response 
on stimulation 
Complete dryness of mouth; no 
response on stimulation 
Fibrosis 
Spinal cord 
Mild L'Hermitte's 
syndrome 
Severe L'Hermitte's 
syndrome 
Objective neurological findings 
at or below cord level treated 
Mono, para 
quadraplegia 
Brain 
Mild headache; 
slight lethargy 
Moderate headache; 
great lethargy 
Severe headache; severe CNS 
dysfunction (partial loss of 
power or dyskinesia) 
Coma 
Eye 
Asymptomatic 
cataract; minor 
corneal ulceration 
or keratitis 
Symptomatic cataract; 
moderate corneal 
ulceration; minor 
retinopathy or 
glaucoma 
Severe keratitis; severe 
retinopathy or detachment 
Panophthalmitis 
/ blindness 
Larynx 
Hoarseness; slight 
arytenoid edema 
Moderate arytenoid 
edema; chondritis 
Severe edema; severe 
chondritis 
Necrosis 
Esophagus 
Mild fibrosis; slight 
difficulty in 
swallowing solids; 
no pain on 
swallowing 
Unable to take solid 
food normally; 
swallowing semisolid 
food; dilatation may be 
indicated 
Severe fibrosis; able to swallow 
only liquids; may have pain on 
swallowing; dilatation required 
Necrosis / 
perforation 
fistula 
Bone 
Asymptomatic; no 
growth retardation; 
reduced bone 
density 
Moderate pain or 
tenderness; growth 
retardation; irregular 
bone sclerosis 
Severe pain or tenderness; 
complete arrest of bone growth; 
dense bone sclerosis 
Necrosis / 
spontaneous 
fracture 
 
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APPENDIX D: SAMPLE TRANSMISSION FORM AND INSTRUCTIONS 
Tissue and Blood Sample Collection Form 
 
Clinician/Research Nurse: Please Fill Out 
Tissue Samples 
Subject Name: ___________________ 
           UC MR # (if applicable): _______________ 
Subject Protocol ID #:______________ 
            Date Tissue Obtained: _________________ 
Date of Birth: ______________________________ Attending Physician: __________________ 
Site of Biopsy: ___________________________ 
Institution: _________________ 
Date consent was signed: ___________________      Diagnosis:__________________ 
Pre/Post Therapy  (Please circle) 
 
 
Day started on clinical protocol:__________ 
Did Surgical Pathology receive tissue for diagnosis?  Yes   No 
Contact Person’s Phone Number and email Address at Affiliate: 
Blood Samples 
 
 
date drawn 
time 
date shipped 
  
Pre-Therapy, 
during, 
and 
post-therapy   
1 Tiger Top for 
Plasma 
  
  
  
 
Pre-therapy 
and 2-3 weeks 
into induction 
1 RNA collection 
tube 
 
 
 
 
Pre-therapy 
1 lavender top/DNA  
 
 
 
 
Researcher: Please Fill Out 
Date Samples received: _________________ 
 
Data entered into Database: Yes
 
No 
Name of Data Manager informed: _______________________ 
Date Informed:_________ 
Location in –80C freezer - _________________ 
Approximate size of tissue: _____________________________________________ 
Notes:  
 


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Questions or Problems? Please contact: 
HTRC, University of Chicago, 5841 S Maryland, MC 3083, Chicago, IL 60637 
Phone  773-702-0119, Pager 773-753-1880-9747 
 
 


 
 
118 
 
APPENDIX E: ACCEPTED FORMS OF BIRTH CONTROL 
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION  
• 
Hormonal methods of contraception including combined oral contraceptive 
pills, vaginal ring, injectables, implants and intrauterine devices (IUDs) 
such as Mirena® by WOCBP subject or male subject’s WOCBP partner   
• 
IUDs, such as ParaGard®   
• 
Bilateral Tubal ligation   
• 
Vasectomized partner   
• 
Complete Abstinence*   
 
 
 
*Complete abstinence is defined as complete avoidance of heterosexual 
intercourse and is an acceptable form of contraception for all study drugs. 
Female subjects must continue to have pregnancy tests. Acceptable 
alternate methods of highly effective contraception must be discussed in 
the event that the subject chooses to forego complete abstinence.   
 
 
 
Subjects are encouraged to use two methods of contraception, with one 
method being highly effective and the other method being either highly 
effective or less effective as listed below:   
 
LESS EFFECTIVE METHODS OF CONTRACEPTION  
• 
Diaphragm with spermicide   
• 
Male condoms and spermicide   
• 
Male condom without spermicide   
• 
Female condom*         
*A male and female condom must not be used together 
 
 
UNACCEPTABLE METHODS OF CONTRACEPTION: 
o Vaginal sponge 
o Progestin only pills 
o Cervical cap with spermicide 
o Periodic abstinence (calendar, symptothermal, post-ovulation 
methods) 
o Withdrawal (coitus interruptus) 
o Spermicide only 
o Lactation amenorrhea method (LAM) 
o A male and a female condom must not be used together 
  
 
 


 
 
119 
 
APPENDIX F: QUALITY OF LIFE FORMS AND PERFORMANCE 
MEASURES 
 


 
 
120 
 
 
 
 


 
 
121 
 
 


 
 
122 
 
 
 
 
 


 
 
123 
 


 
 
124 
 


 
 
125 
 


 
 
126 
 


 
 
127 
 


 
 
128 
 


 
 
129 
 


 
 
130 
 


 
 
131 
 


 
 
132 
 


 
 
133 
 


 
 
134 
 
 


 
 
135