Los Tres Paso Trial: Step One - Neoadjuvant Palbociclib Monotherapy, Step Two - Concurrent Chemoradiation Therapy, and Step Three - Adjuvant Palbociclib Monotherapy in Patients With p16INK4a Negative, HPV-Unrelated Head and Neck Squamous Cell Carcinoma
Phase: PHASE2
Conditions: Head and Neck Squamous Cell Carcinoma
Sponsor: Washington University School of Medicine

Protocol Version: 11/13/20 
 
Page 1 of 76 
 
 
Los Tres Paso Trial: 
Step One – Neoadjuvant Palbociclib Monotherapy, 
Step Two – Concurrent Chemoradiation Therapy, and 
Step Three – Adjuvant Palbociclib Monotherapy 
in Patients with p16INK4a Negative, HPV-Unrelated Head and Neck Squamous Cell 
Carcinoma 
 
Washington University School of Medicine, Division of Oncology 
660 South Euclid Avenue, Campus Box 8056 
St. Louis, MO  63110 
 
Protocol #: 201802162 
Version Date: 11/13/2020 
 
Principal Investigator: 
Douglas R. Adkins, M.D. 
Phone: (314) 362-4471 
E-mail: dadkins@wustl.edu  
 
Sub-Investigators 
 
 
 
Modality 
Mackenzie Daly, M.D. 
 
 
Radiation Oncology 
Hiram Gay, M.D. 
 
 
 
Radiation Oncology 
Ryan Jackson, M.D.  
 
 
Otolaryngology 
Esther Lu, Ph.D. 
 
 
 
Biostatistics 
Peter Oppelt, M.D. 
 
 
 
Medical Oncology 
Randal Paniello, M.D. 
 
 
Otolaryngology 
Patrik Pipkorn, M.D.  
 
 
Otolaryngology 
Jason Rich, M.D. 
 
 
 
Otolaryngology 
Wade Thorstad, M.D.  
 
 
Radiation Oncology 
Jose Zevallos, M.D., MPH 
 
 
Otolaryngology 
Todd Fehniger, M.D.  
 
 
Medical Oncology 
Kevin Palka, M.D. 
 
 
 
Medical Oncology 
 
Study Drug(s): 
 
Palbociclib (Ibrance) 
IND #: 
138259 
ClinicalTrials.gov #: 
NCT03389477 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to 
obtain informed consent, may not be disclosed to another party unless law or regulations require such 
disclosure.  Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them 
Los Tres Paso Trial: 

Protocol Version: 11/13/20 
 
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Step One – Neoadjuvant Palbociclib Monotherapy, 
Step Two – Concurrent Chemoradiation Therapy, and 
Step Three – Adjuvant Palbociclib Monotherapy 
in Patients with p16INK4a Negative, HPV-Unrelated Head and Neck Squamous Cell 
Carcinoma 
 
Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
02/23/2018 
Amendment #1 Version 
 
 
 
 
 
 
08/28/2018 
Amendment #2 Version 
 
 
 
 
 
 
01/14/2019 
………………………………………………………………………………PRMC Only 
Amendment #2 Version 
 
 
 
 
 
 
01/24/2019 
Amendment #3 Version 
 
 
 
 
 
 
08/26/2019 
Amendment #4 Version 
 
 
 
 
 
 
01/15/2020 
Amendment #5 Version 
 
 
 
 
 
 
03/31/2020 
Amendment #6 Version 
 
 
 
 
 
 
11/13/2020 

Protocol Version: 11/13/20 
 
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Glossary of Abbreviations 
 
AE 
Adverse event 
ALT (SGPT) 
Alanine transaminase (serum glutamate pyruvic transaminase) 
AST (SGOT) 
Aspartate transaminase (serum glutamic oxaloacetic transaminase) 
AUC 
Area under the curve 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CMP 
Comprehensive metabolic panel 
CR 
Complete response 
CRF 
Case report form 
CRT 
Chemoradiation 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
DAI 
Dosage and administration instructions 
DC 
Disease control 
DFS 
Disease-free survival 
DLT 
Dose limiting toxicity 
DNA 
deoxyribonucleic acid 
DSM 
Data and Safety Monitoring  
ECG (or EKG) 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDTA 
ethylenediaminetetraacetic acid 
FDA 
Food and Drug Administration 
FDG 
Fluorodeoxyglucose 
FOE 
Fiberoptic endoscopy 
HDPE 
High-density polyethylene 
HIV 
Human Immunodeficiency Virus 
HNSCC 
Head and neck squamous cell carcinoma 
HPV 
Human papilloma virus 
HRPO 
Human Research Protection Office (IRB) 
HSR 
Hypersensitivity reaction 
IHC 
Immunohistochemistry 
IMRT 
Intensity-modulated radiation therapy 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IPM 
Investigational Product Manual 
IRB 
Institutional Review Board 
ISH 
In situ hybridization 
IULN 
Institutional upper limit of normal 
IV 
Intravenous 

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IVPB 
IV piggyback 
mDLx 
Microlaryngoscopy 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCCN 
National Cancer Center Network 
NCI 
National Cancer Institute 
NEJM 
New England Journal of Medicine 
NIH 
National Institutes of Health 
NS 
Normal saline 
OHRP 
Office of Human Research Protections  
OPSCC 
Oropharyngeal squamous cell carcinoma 
OR 
Overall response 
OS 
Overall survival 
PD 
Progressive disease 
PEG 
Percutaneous endoscopic gastrostomy 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PI 
Principal investigator 
POACRT 
Post-operative adjuvant CRT 
PR 
Partial response 
PS 
Performance status 
PT 
Prothrombin time 
PTS 
Primary tumor site 
PTT 
Partial thromboplastin time 
QASMC 
Quality Assurance and Safety Monitoring Committee 
QOL 
Quality of life 
RECIST 
Response Evaluation Criteria in Solid Tumors (Committee) 
RM 
Recurrent/metastatic 
RNA 
Ribonucleic acid 
RPPA 
Reverse phase protein array 
RT 
Radiation therapy 
RTOG 
Radiation Therapy Oncology Group 
SAE 
Serious adverse event 
SCC 
Siteman Cancer Center 
SD 
Stable disease 
TTP 
Time to progression 
UPN 
Unique patient number 
 
 

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Table of Contents 
1.0 
BACKGROUND AND RATIONALE ................................................................................ 7 
1.1 
Head and Neck Squamous Cell Carcinoma (HNSCC) .................................................... 7 
1.2 
Definitive CRT Options and Efficacy Outcomes ............................................................. 7 
1.3 
Biology of p16 INK4a negative (HPV-unrelated) HNSCC ................................................. 8 
1.4 
Selective CDK4/6 Inhibition with Palbociclib ................................................................. 9 
1.5 
Palbociclib and Cetuximab in Recurrent/Metastatic HNSCC .......................................... 9 
2.0 
OBJECTIVES .................................................................................................................... 12 
2.1 
Primary Objective .......................................................................................................... 12 
2.2 
Secondary Objectives ..................................................................................................... 13 
2.3 
Exploratory Objectives ................................................................................................... 13 
3.0 
PATIENT SELECTION .................................................................................................... 13 
3.1 
Inclusion Criteria ............................................................................................................ 13 
3.2 
Exclusion Criteria ........................................................................................................... 14 
3.3 
Inclusion of Women and Minorities ............................................................................... 15 
4.0 
REGISTRATION PROCEDURES ................................................................................... 15 
4.1 
Confirmation of Patient Eligibility ................................................................................. 16 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database ........................... 16 
4.3 
Assignment of UPN ....................................................................................................... 16 
5.0 
TREATMENT PLAN ........................................................................................................ 16 
5.1 
Premedication Administration ........................................................................................ 17 
5.2 
Agent Administration ..................................................................................................... 17 
5.3 
Study Procedures ............................................................................................................ 18 
5.4 
Toxicity and Response Evaluations ............................................................................... 20 
5.5 
General Concomitant Medication and Supportive Care Guidelines .............................. 21 
5.6 
Women of Childbearing Potential .................................................................................. 21 
5.7 
Duration of Therapy ....................................................................................................... 21 
5.8 
Duration of Follow-up .................................................................................................... 22 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS .................................................................... 22 
6.1 
Dose Modifications for Palbociclib (Steps One and Three) .......................................... 22 
6.2 
Step Two, Cohort 1: Dose Modifications for Cisplatin ................................................. 24 
6.3 
Step Two, Cohort 2: Dose Modifications or Delays for Cetuximab .............................. 25 
7.0 
REGULATORY AND REPORTING REQUIREMENTS ............................................... 27 
7.1 
Sponsor-Investigator Reporting Requirements .............................................................. 28 
7.2 
Exceptions to Expedited Reporting ................................................................................ 30 
8.0 
PHARMACEUTICAL INFORMATION .......................................................................... 30 
8.1 
PD 0332991 (Palbociclib) .............................................................................................. 30 
8.2 
Cisplatin (CDDP, Platinol-AQ®) .................................................................................. 38 
8.3 
Cetuximab (Erbitux) ....................................................................................................... 39 
9.0 
CORRELATIVE STUDIES .............................................................................................. 42 
9.1 
Tumor Biopsy ................................................................................................................. 42 
9.2 
Peripheral Blood ............................................................................................................. 43 
9.3 
QOLs .............................................................................................................................. 43 
10.0 STUDY CALENDAR ....................................................................................................... 45 
10.1 Induction Palbociclib Monotherapy – Step One ............................................................ 45 
10.2 Definitive Chemoradiation (CRT) and Adjuvant Palbociclib - Steps Two and Three .. 46 

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11.0 DATA AND SAFETY MONITORING ............................................................................ 48 
12.0 DATA SUBMISSION SCHEDULE ................................................................................. 48 
12.1 Adverse Event Collection in the Case Report Forms ..................................................... 49 
13.0 MEASUREMENT OF EFFECT........................................................................................ 50 
13.1 Antitumor Effect – Solid Tumors ................................................................................... 50 
13.2 Disease Parameters ......................................................................................................... 50 
13.3 Methods for Evaluation of Measurable Disease ............................................................ 51 
13.4 Response Criteria ........................................................................................................... 53 
14.0 STATISTICAL CONSIDERATIONS............................................................................... 56 
14.1 Study Design .................................................................................................................. 56 
14.2 Primary Endpoint ........................................................................................................... 56 
14.3 Secondary Endpoints ...................................................................................................... 56 
14.4 Study Population ............................................................................................................ 57 
14.5 Power Analysis and Sample Size ................................................................................... 57 
14.6 Data Analysis ................................................................................................................. 57 
14.7 Interim Efficacy Assessment and Interim Analyses ...................................................... 58 
15.0 REFERENCES .................................................................................................................. 60 
APPENDIX A: ECOG Performance Status Scale ........................................................................ 63 
APPENDIX B: Medication Diary ................................................................................................. 64 
APPENDIX C: Pfizer Reportable Event Cover Sheet .................................................................. 65 
APPENDIX D: EORTC QLQ-C30 .............................................................................................. 66 
APPENDIX E: FACT-H&N ......................................................................................................... 68 
APPENDIX F: Definitions for Adverse Event Reporting ............................................................ 71 
APPENDIX G: Reporting Timelines ............................................................................................ 73 
 
 

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1.0 
BACKGROUND AND RATIONALE 
 
1.1 
Head and Neck Squamous Cell Carcinoma (HNSCC) 
 
HNSCC is the sixth most common cancer with over 50,000 new cases diagnosed each year 
in the USA and 600,000 new cases each year worldwide7. Most patients present with stage 
III-IV, non-metastatic disease that is due to smoking and unrelated to the human 
papillomavirus (HPV). Compared to HPV-related oropharyngeal squamous cell carcinoma 
(OPSCC), patients with HPV-unrelated HNSCC are older, smoke more, and have a less 
favorable prognosis8.  
 
Acceptable treatment options for these patients include definitive chemoradiation therapy 
(CRT), surgery followed by post-operative adjuvant CRT (POA[C]RT), or induction 
chemotherapy followed by CRT. Although there is general agreement that all three 
approaches result in similar outcomes, in actual practice, most patients are treated with 
definitive CRT. This pattern reflects the fact that most of these patients are treated in the 
community setting where definitive CRT is widely practiced, but surgery and induction 
chemotherapy are not. 
 
1.2 
Definitive CRT Options and Efficacy Outcomes 
 
Cisplatin or cetuximab are the two most common agents given concurrently with definitive 
radiation therapy (RT). Cisplatin is the gold standard systemic therapy recommended to be 
given concurrently with RT. Either high-dose bolus (100 mg/m2 cisplatin on Days 1, 22, 
and 43 of once daily RT or 100 mg/m2 cisplatin on Days 1 and 22 of accelerated RT) or 
weekly (40 mg/m2) cisplatin regimens are recommended in the NCCN practice guidelines9. 
Cetuximab, a taxane, or 5-FU added to cisplatin and RT are no better than cisplatin 
monotherapy and RT10,11. However, cisplatin results in substantial acute toxicity 
(mucositis, renal dysfunction, vomiting) and can only be administered safely to patients 
with normal renal function, good performance status, and low comorbidity index. 
 
Cetuximab and RT has emerged over the last decade as an alternative to cisplatin and RT, 
based on the results of the Bonner Trial (NEJM) which found that cetuximab and RT was 
more efficacious than RT alone6. Also, cetuximab did not increase the risk of mucositis 
compared with RT alone and was not associated with renal dysfunction or vomiting.  
 
Although there have been no published head-to-head comparisons of cetuximab and RT vs 
cisplatin and RT, the absolute magnitude of the improvement in overall survival (OS) 
(10%) with cetuximab and RT was comparable to historical data with cisplatin and RT. 
However, controversy exists as to whether the efficacy of cetuximab and RT is as good as 
cisplatin and RT. Several retrospective reports showed better efficacy outcomes with 
cisplatin and RT.12,13 The ongoing RTOG 1016 trial is comparing the efficacy and tolerance 
of these two CRT regimens in patients with HPV-related OPSCC. Similar studies are not 
planned or ongoing in patients with HPV-unrelated HNSCC.  
 

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Based on the controversy surrounding the comparability of these two CRT regimens, 
current practice at most programs is to route HNSCC patients with excellent performance 
status and adequate vital organ function to receive CRT with high dose bolus cisplatin. 
However, it is feasible to administer cetuximab but not cisplatin to a broader mix of 
patients, particularly those with reduced renal function, poor performance status, and a high 
comorbidity index. As such, cetuximab has been widely selected over cisplatin to be 
combined with RT for HNSCC patients with reduced performance status and/or vital organ 
function. 
 
The efficacy of CRT in patients with locally advanced p16INK4a negative/HPV-unrelated 
HNSCC1-3 is surprisingly modest with a substantial risk of disease recurrence and death. 
RTOG 0129 and RTOG 91-11 provide reference points for efficacy of CRT using 
cisplatin1-3. In patients with p16 INK4a negative OPSCC, RTOG 0129 found that CRT with 
cisplatin resulted in three-year OS of 57%, progression-free survival (PFS) 43%, local-
regional failure rate 52%, and distant metastasis rate of 16%3. In patients with larynx SCC, 
RTOG 91-11 found that CRT with cisplatin resulted in two-year OS of 74%, DFS 61%, 
local-regional failure rate 20%, and distant metastases rate of 8%.  The poorest outcomes 
occur in the infrequent subset of patients with hypopharynx SCC where the 5-year OS was 
38% and the local-regional and distant failure rate was 60%4-5. The Bonner trial provides 
reference points for the efficacy of CRT using cetuximab6. The two-year local-regional 
failure rate was 50%, the distant metastases rate was 16%, and the median OS varied based 
on sub-site: 32 months for larynx SCC, 24 months for p16INK4a negative OPSCC, and 13 
months for hypopharynx SCC.  
 
In the pool of patients with p16INK4a negative/HPV-unrelated HNSCC, larynx SCC, and 
hypopharynx SCC, the majority (> 90%) of relapse events occur within 18 months of 
completion of CRT using either cisplatin or cetuximab.  
 
1.3 
Biology of p16 INK4a negative (HPV-unrelated) HNSCC 
 
HNSCC is a heterogeneous disease14,15. Based on unique gene expression signatures, at 
least four subgroups have been defined, each with distinct signaling pathways14-21.  Despite 
this heterogeneity, aberrant cell cycle regulation is a ubiquitous event.  The mechanism 
underlying unrestrained proliferation varies depending on the tumor’s transcriptionally-
active HPV status. In HPV-related HNSCC, E7 viral protein drives unrestrained 
proliferation by promoting Rb degradation22. In HPV-unrelated HNSCC, Rb inactivation 
occurs through hyper-activation of the Rb inhibitory complex CDK4/cyclin D. CCND1 
(encoding cyclin D1, the regulatory subunit of the complex) is amplified and/or the 
CDK4/6 inhibitor p16INK4a is inactivated in nearly all of these cancers23-25. Alterations of 
CCND1 and p16INK4a are rare in HPV-related HNSCC. As a result, p16INK4a is 
overexpressed in HPV-related HNSCC and under expressed in HPV-unrelated HNSCC. 
 
The genetics of HPV-unrelated HNSCC influences the clinical course. CCND1 
amplification and p16INK4a inactivation are poor prognostic factors in HNSCC3,24, in part 
because cyclin D1 overexpression adversely affects tumor response to EGFR inhibitors 
and cisplatin. In HNSCC cell lines, cyclin D1 amplification and/or overexpression 

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correlated with resistance to these drugs26-28.  Studies in HNSCC reveal that cyclin D1 
overexpression is predictive of resistance to cisplatin29.   
 
1.4 
Selective CDK4/6 Inhibition with Palbociclib 
 
The essential roles of CDK4/6 and cyclin D1 in driving cell cycle progression from G1 
into S phase motivated intense investigation into blocking this regulatory complex30-32.  In 
pre-clinical models, CDK4/6 inhibition inhibits both Rb hyperphosphorylation and cell 
cycle progression33, and the efficacy of inhibition in some models correlated with increased 
cyclin D1 and decreased p16INK4a expression32. Palbociclib is the first approved selective 
inhibitor of the CDK4/6 kinases. Palbociclib exerts potent anti-proliferative effects on Rb-
positive cell lines and human breast and colon xenografts31. Palbociclib results in decreased 
Rb phosphorylation and Ki-67 expression in Rb-positive models but has no activity in Rb-
negative tumor xenografts31. As such, phase I trials restricted the evaluation of palbociclib 
to patients with Rb-positive cancers32,33. These studies determined that the dose-limiting 
toxicity (DLT) of palbociclib was neutropenia and the maximum tolerated dose (MTD) 
was 125 mg once daily, administered for 21 days of each 28 day cycle34,35.  The efficacy 
of palbociclib was demonstrated in estrogen receptor positive breast cancer36 and in mantle 
cell lymphoma37, tumors in which cyclin D contributes to their pathogenesis.    
 
1.5 
Palbociclib and Cetuximab in Recurrent/Metastatic HNSCC 
 
Because the genetics of HNSCC suggest a crucial role for CDK4/cyclin D in this disease, 
we performed a phase I trial to determine the DLT and MTD of palbociclib combined with 
standard weekly doses of cetuximab in patients with recurrent/metastatic (RM) HNSCC. 
We built upon the cetuximab platform because palbociclib targets a pathway associated 
with resistance to EGFR inhibitors26. 
 
A phase I trial using 3+3 design was performed to determine the DLT and MTD of 
palbociclib with standard dose weekly cetuximab.38 Palbociclib was administered orally 
Days 1-21 every 28 days at dose level 1 (100 mg/d) and 2 (125 mg/d, the approved 
monotherapy dose). Pharmacokinetic assessments were performed on Cycle 2 Day 15. 
Cyclin D1, p16INK4a, and Rb protein expression were measured on pre-treatment tumor. 
Tumor response was assessed using RECIST 1.1. 
 
Nine patients (five p16INK4a negative; four positive) were enrolled across dose levels 1 
(n=3) and 2 (n=6) and none experienced a DLT. A MTD of palbociclib was not reached. 
Myelosuppression was the most common adverse event. Six of nine patients had 
cetuximab-resistant and four of nine had platin-resistant disease. Disease control (DC) 
occurred in 89%, including partial response (PR) in two (22%) and stable disease in six 
(67%) patients. PRs occurred in p16INK4a negative HNSCC. Five patients (56%) had 
measurable decreases in tumor target lesions. In cetuximab-resistant HNSCC, best tumor 
response was PR in 1 and DC in 5 and median time to progression (TTP) was 112 days 
(range: 28-168). In platin-resistant HNSCC, best tumor response was PR in 1, DC in 3 and 
median TTP was 112 days (range: 28-112). The tumor response of two patients and the 
waterfall plot of best overall change in tumor target lesions are shown: 

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CT images of partial tumor response after two cycles of palbociclib and cetuximab in 
patient 4 (Dose Level 2) with p16INK4a negative hypopharynx SCC and… 
 
 
 
 
 
 
 
…patient 8 (Dose Level 2) with p16INK4a negative oral cavity SCC 
 
 
                 
 
 
 
 
 
 
Target Lesion: 4.0 cm 
Baseline 
After Cycle 2 
Target Lesion: 2.7 cm 
Target Lesion: 4.6 cm 
Target Lesion: 2.8 cm 
Baseline 
After Cycle 2 

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Waterfall plot of tumor response (% change in target lesions) achieved after Cycle 2. 
 
Time-to-best tumor response occurred by Day 56 (end of Cycle 2) in all cases. 
Upon completion of the enrollment on the phase I trial, patients are currently being enrolled 
on the phase II component of the protocol, in which patients with platin-refractory HNSCC 
(Cohort 1) or cetuximab-refractory HNSCC (Cohort 2) are treated with palbociclib and 
cetuximab. Preliminary results of the phase II trial along with the phase I trial results are 
shown in the Swimmer’s Plot below. As can be seen, the median TTP with palbociclib and 
cetuximab is longer than that of a historical cohort treated with cetuximab monotherapy.39  
-40
-30
-20
-10
0
10
20
30
            = Dose Level 1 
            = Dose Level 2 
 
   +      = p16 positive 
   -       = p16 negative 
           2            7           1         6          9         5             3           4           8         
Patient Number 
% Change in Target Lesions 
+ 
+ 
- 
- 
+ 
+ 
- 
- 
- 

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Swimmer’s plot showing the TTP for each patient treated with palbociclib and cetuximab.  
Patients treated on phase I are colored in blue.  Patients treated on phase II are divided by 
cohort: platin-resistant in green and cetuximab-resistant in lavender. Partial tumor 
responses are noted with a red triangle.  The vertical black line is the historical median TTP 
to cetuximab monotherapy and the vertical red line is the median TTP with palbociclib and 
cetuximab based on the phase I data. 
 
This trial, the first to evaluate a CDK4/6 inhibitor in HNSCC, determined that 
palbociclib 125 mg/day on days 1-21 every 28 days with cetuximab was safe. Tumor 
responses were observed, even in cetuximab- or platin-resistant disease. 
 
 
2.0 
OBJECTIVES 
 
2.1 
Primary Objective 
 
Determine the tumor response rate of newly diagnosed p16INK4a negative, HPV-unrelated 
Patients 

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HNSCC to neoadjuvant palbociclib monotherapy given over two cycles. 
 
2.2 
Secondary Objectives 
 
1. Determine the combined local-regional disease relapse risk and distant metastases risk 
at 18 months following completion of CRT.  
2. Determine the median and two-year PFS and OS (stratified by cohort) of patients 
treated with the three step sequence of palbociclib monotherapy, CRT, and adjuvant 
palbociclib monotherapy.   
 
2.3 
Exploratory Objectives 
 
1. Explore potential pharmacodynamic determinants of tumor response to palbociclib 
monotherapy using genomic, RNA, and protein expression methods. 
2. Explore potential pharmacodynamic determinants of locoregional disease relapse risk 
and distant metastases risk to palbociclib-based therapy using genomic, RNA, and 
protein expression methods. 
 
 
3.0 
PATIENT SELECTION 
 
3.1 
Inclusion Criteria 
 
1. Larynx SCC, hypopharynx SCC, or oral cavity SCC.  HPV-unrelated OPSCC [defined 
as p16INK4a negative by IHC (staining in < 70% of cells) or HPV High Risk (Type 16 
or 18) negative by ISH].  P16INK4a positive larynx SCC, hypopharynx SCC, and oral 
cavity SCC are eligible given the unknown effect of this on the biology of SCC of these 
subsites. 
2.  
Overall Stage III, IVA, or IVB disease per AJCC version 7.0. 
3. Measurable disease defined as lesions that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as ≥ 10 mm with CT scan, as ≥ 20 mm by 
chest x-ray, or ≥ 10 mm with calipers by clinical exam. 
 
4. At least 18 years of age. 
 
5. Normal bone marrow function as defined below: 
a. Absolute neutrophil count ≥ 1,000/mcL 
b. Platelets ≥ 100,000/mcL 
c. Hemoglobin ≥ 9.0 g/dL 
 
6. QTc < 500 msec by Fridericia 
 
7. Women of childbearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control, abstinence) prior to study entry, for the 
duration of study participation, and for 90 days after completion of treatment.  Should 

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a woman become pregnant or suspect she is pregnant while participating in this study, 
she must inform her treating physician immediately. 
 
8. Ability to understand and willingness to sign an IRB approved written informed 
consent document (or that of legally authorized representative, if applicable). 
 
3.1.1 Additional Cohort 1 Eligibility Criteria 
 
Patients enrolling to Cohort 1 must meet all of the following criteria: 
 
1. ECOG performance status 0-1 (see Appendix A). 
 
2. Adequate organ function defined as: 
a. Serum creatinine ≤ 1.5 x IULN and creatinine clearance ≥ 75 mL/min 
b. Bilirubin ≤ 1.5 x IULN 
c. ALT and AST ≤ 2.5 x IULN 
 
3.1.2 Additional Cohort 2 Eligibility Criteria 
 
Patients enrolling to Cohort 2 must meet at least one of the following criteria: 
 
1. ECOG performance status of 2 (see Appendix A) 
 
2. Reduced organ function defined as: 
a. Creatinine clearance 30-75 mL/min; or 
b. Bilirubin 1.5-2 x IULN; or 
c. ALT and AST 2.5-5 x IULN 
 
3.2 
Exclusion Criteria 
 
1. Diagnosis of cutaneous, paranasal sinus, salivary, or nasopharynx SCC, or diagnosis of 
neck nodes with unknown primary. 
 
2. Diagnosis of P16/HPV-ISH positive OPSCC. 
 
3. Presence of distant metastatic disease. 
 
4. Prior systemic therapy for current diagnosis of HNSCC. 
 
5. A history of other malignancy ≤ 2 years previous with the exception of basal cell or 
squamous cell carcinoma of the skin which were treated with local resection only or 
low risk/curatively treated prostate, thyroid, and cervical cancers. 
 
6. Currently receiving any other investigational agents. 
 
7. Treated within the last 7 days prior to Day 1 of protocol therapy with: 

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a. Food or drugs that are known to be STRONG CYP3A4 inhibitors (e.g. grapefruit 
juice, 
verapamil, 
ketoconazole, 
miconazole, 
itraconazole, 
erythromycin, 
clarithromycin, telithromycin, indinavir, ritonavir, nelfinavir, atazanavir, 
amprenavir, nefazodone, diltiazem, and delavirdine) or inducers (e.g. 
glucocorticoids, progesterone, rifampin, phenobarbital, St. John’s wort) [moderate 
CYP3A4 inhibitors/inducers are okay] 
b. Drugs that are known to prolong the QT interval 
c. Drugs that are proton pump inhibitors 
 
8. A history of allergic reactions attributed to compounds of similar chemical or biologic 
composition to palbociclib, cisplatin (for Cohort 1), or cetuximab (for Cohort 2). 
 
9. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or uncontrolled electrolyte disorders that can compound the effects of a 
QTc-prolonging drug (e.g. hypocalcemia, hypokalemia, hypomagnesemia). 
 
10. History of cirrhosis. 
 
11. History of renal or liver transplant. 
 
12. Pregnant and/or breastfeeding.  Women of childbearing potential must have a negative 
serum pregnancy test within 28 days of study entry.  Female patients must be surgically 
sterile or be postmenopausal, or must agree to use effective contraception during the 
period of the trial and for at least 90 days after completion of treatment. 
 
13. Known HIV-positivity and on combination antiretroviral therapy because of the 
potential for pharmacokinetic interactions with palbociclib.  In addition, these patients 
are at increased risk of lethal infections when treated with marrow-suppressive therapy.   
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial.   
 
 
4.0 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center. 
 
The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility 
2. Registration of patient in the Siteman Cancer Center database 
3. Assignment of unique patient number (UPN)  
 
 

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4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below: 
 
1. Registering MD’s name 
2. Patient’s race, sex, and DOB 
3. Three letters (or two letters and a dash) for the patient’s initials 
4. Copy of signed consent form 
5. Completed eligibility checklist, signed and dated by a member of the study team 
6. Copy of appropriate source documentation confirming patient eligibility 
 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database 
 
All patients must be registered through the Siteman Cancer Center OnCore database. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  All data 
will be recorded with this identification number on the appropriate CRFs. 
 
 
5.0 
TREATMENT PLAN 
 
“The three step” trial is a two cohort, non-randomized phase II trial in which palbociclib will be 
integrated into the standard CRT regimen with either cisplatin (cohort 1) or cetuximab (cohort 2). 
Patients with stage III-IV (non-metastatic) p16INK4a negative, HPV-unrelated HNSCC will be 
enrolled, to enrich the fraction of patients most likely to benefit from a CDK4/6 inhibitor.  
 
During step one, patients in both cohorts will be treated with neoadjuvant palbociclib monotherapy 
(125 mg/day, Days 1-21 of a 28-day cycle for two cycles). A CT scan of the neck to assess tumor 
response and a tumor biopsy for pharmacodynamics assessment will be performed before and after 
palbociclib (CT scan – Cycle 2 post-treatment Day 21 through Day 25; Tumor biopsy Cycle 2 Day 
21). Data will be pooled from the two cohorts to address the primary aim. The primary aim of the 
trial is to determine the tumor response rate (using RECIST 1.1) of newly diagnosed p16INK4a 
negative, HPV-unrelated HNSCC to palbociclib monotherapy given over two cycles, and to 
explore potential pharmacodynamic determinants of tumor response to palbociclib monotherapy 
using data derived from genomic, RNA, and protein expression methods performed on pre- and 
post-treatment tumor tissue. 
 
During step two (CRT), Cohort 1 patients will be treated with cisplatin 100 mg/m2 given on Days 
1 and 22 with RT. Cohort 2 patients will be treated with cetuximab given one week before RT and 
then weekly during RT.  Cohorts 1 and 2 will receive accelerated IMRT 70 Gy to be administered 
over 6 weeks in once daily fractions Monday through Friday, with one additional fraction of RT 
administered on (preferably) Fridays. The two fractions administered on one day will be at least 6 
hours apart. Palbociclib, an oral agent, will not be given during step two due to the severe difficulty 
with swallowing that occurs in all patients treated with CRT and due to the lack of feasibility 

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studies for this combination therapy. To assess overall tumor response (stratified by cohort), a CT 
scan of the neck will be performed 8-10 weeks following completion of CRT, and FDG-PET/CT 
will be performed 14-18 weeks following completion of CRT.  
 
During step three, patients in both cohorts will be treated with adjuvant palbociclib 125 mg/day, 
days 1-21 of each 28-day cycle for six cycles. Adjuvant palbociclib will begin 16 to 22 weeks 
following completion of CRT. 
 
5.1 
Premedication Administration 
 
No premedications are required for palbociclib. 
 
Recommended premedications for cisplatin are: palonosetron 0.25 mg IVPB, 
dexamethasone 20 mg IVPB, and fosaprepitant 150 mg IVPB.  In addition, hydration 
consisting of 1L IVF NS (also recommended: 10 meq KCl/L + 8 meq MgSO4/L) over 60 
minutes before and after cisplatin on the day of dosing is recommended, and 2L IVF NS 
over 60 minutes on the 2 days following cisplatin dosing is recommended. 
 
Recommended premedications for cetuximab are: diphenhydramine hydrochloride 50 mg 
(or an equivalent antihistamine) IVPB given at least 30 minutes prior to cetuximab, 1L IVF 
NS, hydrocortisone 100 mg IVPB, and/or albuterol inhalation (by nebulizer or inhaler) 
according to standard of care procedures. 
 
5.2 
Agent Administration 
 
5.2.1 Steps One and Three (Both Cohorts) 
 
Neoadjuvant palbociclib monotherapy will be given at a dose of 125 mg/day on 
Days 1-21 of two 28-day cycles during Step One.  Adjuvant palbociclib 
monotherapy will be given at a dose of 125 mg/day on Days 1-21 of six 28-day 
cycles during Step Three. 
 
Palbociclib is an oral drug available as capsules (or as liquid suspension).  The 
capsules should be taken with food.  Patients will be required to keep a drug diary 
(see Appendix B). 
 
If a patient misses a day’s dose entirely, s/he must be instructed not to make it up 
the next day but to just take his/her regular dose the following day. If a patient 
vomits any time after taking a dose, s/he must be instructed not to make it up but to 
resume subsequent dosing the next day as prescribed. If a patient inadvertently 
takes an extra dose during a day, s/he must be instructed to not take the next day’s 
dose. 
 
For patients who cannot swallow the palbociclib capsules, an oral solution will be 
available. Patients who begin the study receiving the oral solution will remain on 
the oral solution for the duration of their time on treatment in the study.  Patients, 

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who begin the study receiving capsules but develop difficulty swallowing the 
capsules and did not have disease progression will be allowed to switch to the 
palbociclib oral solution.  These patients will then remain on the oral solution for 
the duration of their time on treatment in the study. Each clinical site will be 
provided the oral solution Investigational Product Manual (IPM) containing the 
dosage and administration instructions (DAI) for preparation of the palbociclib oral 
solution. Patients can take palbociclib oral solution with or without food.  
 
5.2.2 Step Two, Cohort 1 
 
Cohort 1 patients will receive accelerated IMRT for a total dose of 70 Gy.  It will 
be given over 6 weeks in once daily fractions Monday through Friday, with one 
additional fraction given on (preferably) Fridays (total of 35 fractions).  The second 
fraction will be given at least 6 hours after the first.  Cohort 1 patients will receive 
cisplatin at a dose of 100 mg/m2 IVPB over 60 minutes on Days 1 and 22 of RT.  
 
5.2.3 Step Two, Cohort 2 
 
Cohort 2 patients will receive accelerated IMRT for a total dose of 70 Gy.  It will 
be given over 6 weeks in once daily fractions Monday through Friday, with one 
additional fraction given on (preferably) Fridays (total of 35 fractions).  The second 
fraction will be given at least 6 hours after the first.  Cohort 2 patients will receive 
7 weekly doses of cetuximab starting one week before RT and then weekly during 
RT.  The cetuximab loading dose is 400 mg/m2 IVPB and the remaining 6 weekly 
doses are 250 mg/m2 IVPB.  There is a +/- 2-day window for cetuximab dosing. 
 
5.3 
Study Procedures 
 
5.3.1 Baseline Assessment 
 
1. Office fiberoptic endoscopy (FOE) or operative room (OR) microlaryngoscopy 
(mDLx) to document the size and extent of the primary tumor site (PTS) along 
with research and routine biopsies of the PTS. Core or excisional biopsies of 
the involved neck nodes is an alternative approach to obtain tumor tissue.  
2. p16INK4a IHC stain on all patients. HPV-HR (16,18) ISH will be required on all 
patients with p16INK4a positive oral cavity, larynx, and hypopharynx SCC. 
3. Clinical examination with ECOG PS. 
4. Weight. 
5. Documentation of presence of PEG tube or tracheostomy tube  
6. QOL assessment 
7. CBC, CMP, Mg, PT/INR, PTT, pregnancy test (if woman of childbearing 
potential) 
8. EKG 
9. CT neck with IV contrast 
10. FDG-PET/CT 
11. Blood for genome sequencing 

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12. Primary disease site photographs 
 
5.3.2 Step One Assessments 
 
1. Between Cycle 2 post-treatment Day 21 – Day 27, tumor response assessment 
will be performed by radiologic assessment with CT neck (with IV contrast).  
2. Between Cycle 2 Days 18-22, office FOE or OR mDLx to document the size 
and extent of the PTS along with biopsy of the PTS. Core or excisional biopsies 
of the involved neck nodes is an alternative approach to obtain tumor tissue.  
3. Between Cycle 2 Days 18-22 primary disease site photographs. 
4. Clinical examination Cycle 1 Days 1, 15, and 22, and Cycle 2 Day 1 and 22. 
5. CBC Days 1, 8, 15, and 22 of each cycle. 
6. EKG Cycle 2: Day 1. 
7. AE assessments weekly for two cycles. 
8.  Study Lab collection of 3 green top tubes for PBMC at C1D22 and C2D22. 
 
5.3.3 Step Two Cohort 1 Assessments 
 
Step Two will start the day after Cycle 2 Day 28 of neoadjuvant palbociclib 
monotherapy. 
 
1. Clinical exam on Days 1, 8, 22, 29, and 36 then biweekly until adequate 
recovery from CRT toxicities per physician discretion.  
2. CBC Days 1, 8, 22, and 29. 
3. CMP, Mg Days 1 and 22. BMP, Mg on Days 8 and 29. 
4. QOL assessment Days 1 and 36. 
5. EKG Day 1. 
6. AE assessments on Days 1, 8, 22, 29, and 36 during CRT. 
7. Office FOE between 8-10 weeks after completion of CRT. 
8. CT neck with IV contrast between 8-10 weeks after completion of CRT. 
9. Primary disease site photographs between 8-10 weeks after completion of CRT. 
10. FDG-PET/CT between 14-18 weeks after completion of CRT. 
 
5.3.4 Step Two Cohort 2 Assessments 
 
Step Two will start the day after Cycle 2 Day 28 of neoadjuvant palbociclib 
monotherapy. 
 
1. Clinical exam on day of loading dose of cetuximab, then on RT Days 1, 8, 22, 
29, and 36, then biweekly until adequate recovery from CRT toxicities per 
physician discretion.  
2. CBC day of loading dose of cetuximab, then on RT Days 1, 8, 22, and 29. 
3. CMP, Mg on day of loading dose of cetuximab, then on RT Days 1 and 22. 
BMP, Mg on Days 8 and 29. 
4. QOL assessment RT Days 1 and 36. 
5. EKG on RT Day 1 (Week 2 of cetuximab). 

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6. AE assessments on day of loading dose of cetuximab, then on RT Days 1, 8, 
22, 29, and 36. 
7. Office FOE between 8-10 weeks after completion of CRT. 
8. CT neck with IV contrast between 8-10 weeks after completion of CRT. 
9. Primary disease site photographs between 8-10 weeks after completion of 
CRT. 
10. FDG-PET/CT between 14-18 weeks after completion of CRT. 
 
5.3.5 Step Three Assessments 
 
Step Three will start 16 to 22 weeks after the completion of CRT. 
 
1. Clinical examination Day 1 of each cycle. 
2. CBC Day 1 of each cycle. 
3. CMP, Mg Day 1 of each cycle. 
4. EKG Day 1 of Cycles 1 and 4, and Day 29 of Cycle 6 (EOT).  
5. QOL assessment at Cycle 1 Day 1, Cycle 4 Day 1, and Cycle 6 Day 29 
(EOT). 
6. AE assessments Day 1 of each cycle. 
7. Study Lab collection of 3 green top tubes for PBMC at C1D22. 
8. Thirty to 45 days after final cycle of adjuvant palbociclib, there will be a 
clinical examination, CBC, CMP, EKG, and AE assessment. 
 
5.3.6 Assessments after Completion of CRT 
 
1. Office FOE and CT neck (with IV contrast) and CT chest (or CXR) at 8, 12, 
18, 24, 30, 36, 42, 48, 54, and 60 months (+/- 1 month) after completion of 
CRT [FOE will be conducted as standard of care after 12 months of follow-
up, so they will occur at some, but not all, of the long-term follow-up visits] 
2. Documentation of presence of PEG tube or tracheostomy tube at the same 
monitoring intervals. 
3. Documentation of weight (Kg) at the same monitoring intervals. 
4. QOL assessments at the same monitoring intervals.  
5. Study Lab collection of 3 green top tubes for PBMC at 4 months (+/- 1 
month) after completion of adjuvant treatment (4 months post step 3). 
 
 
5.4 
Toxicity and Response Evaluations 
 
All patients who receive any study treatment are evaluable for toxicity.  Patients are 
evaluated from first receiving study treatment until a 30-day follow up after the conclusion 
of treatment or death. 
 
All patients are evaluable for disease response unless they discontinue treatment due to 
adverse event(s), patient withdrawal, or early death prior to completion of the disease 

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assessment at the end of Step 1(neoadjuvant treatment) and have not had any disease 
assessment. 
 
5.5 
General Concomitant Medication and Supportive Care Guidelines 
 
While taking palbociclib, patients should be instructed to avoid food or drugs that are 
known strong CYP3A4 inhibitors or inducers (moderate CYP3A4 inhibitors or inducers 
are okay). Patients should also refrain from the use of proton pump inhibitors; if needed, 
alternative antacid therapies may be used including H2-receptor antagonists, and locally 
acting antacids. H2-receptor antagonists should be administered with a staggered dosing 
regimen (twice daily). The dosing of palbociclib should occur at least 10 hours after the 
H2-receptor antagonist dose and 2 hours before the H2-receptor antagonist morning dose. 
Local antacid should be given at least 2 hours before or 2 hours after palbociclib 
administration.  
 
Patients should receive full supportive care during the study, including transfusion of blood 
and blood products and treatment with antibiotics, analgesics, erythropoietin, or 
bisphosphonates when appropriate.  
 
Anti-emetics (such as prochlorperazine, lorazepam, ondansetron, or other 5-HT3 
antagonists) may be administered prophylactically in the event of nausea. Anti-diarrheals, 
such as loperamide, may be administered as needed in the event of diarrhea. 
 
5.6 
Women of Childbearing Potential 
 
Women of childbearing potential (defined as women with regular menses, women with 
amenorrhea, women with irregular cycles, women using a contraceptive method that 
precludes withdrawal bleeding, and women who have had a tubal ligation) are required to 
have a negative serum pregnancy test within 28 days prior to the first dose of palbociclib.   
 
Female and male patients (along with their female partners) are required to use two forms 
of acceptable contraception, including one barrier method, during participation in the study 
and for 3 months following the last dose of palbociclib.  
 
If a patient is suspected to be pregnant, all study drugs should be immediately discontinued.  
In addition, a positive urine test must be confirmed by a serum pregnancy test.  If it is 
confirmed that the patient is not pregnant, the patient may resume dosing. 
 
If a female patient or female partner of a male patient becomes pregnant during therapy or 
within 28 days after the last dose of palbociclib, the investigator must be notified in order 
to facilitate outcome follow-up. 
 
5.7 
Duration of Therapy 
 
If at any time the constraints of this protocol are considered to be detrimental to the 
patient’s health and/or the patient no longer wishes to continue protocol therapy, the 

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protocol therapy should be discontinued and the reason(s) for discontinuation documented 
in the case report forms. 
 
In the absence of treatment delays due to adverse events, treatment may continue for 2 
cycles of neoadjuvant palbociclib, 6 weeks of CRT, and 6 cycles of adjuvant palbociclib 
or until one of the following criteria applies: 
 
• Documented and confirmed disease progression after Step 2. Patients with disease 
progression after Step 1 should proceed to Step 2. 
• Death 
• Adverse event(s) that, in the judgment of the investigator, may cause severe or 
permanent harm or which rule out continuation of study drug 
• General or specific changes in the patient’s condition render the patient unable to 
receive further treatment in the judgment of the investigator 
• Suspected pregnancy 
• Serious non-compliance with the study protocol 
• Lost to follow-up 
• Patient withdraws consent 
• Investigator removes the patient from study 
• The Siteman Cancer Center decides to close the study 
 
Patients who prematurely discontinue treatment for any reason will be followed as 
indicated in the study calendar. 
 
5.8 
Duration of Follow-up 
 
Patients will have follow-up visits after the end of treatment at 30-45 days, and will also 
have visits at 8 months after end of CRT, 12 months after end of CRT, and every 6 months 
thereafter until 5 years have elapsed since the end of treatment.  Patients removed from 
study for unacceptable adverse events will be followed until resolution or stabilization of 
the adverse event. 
 
 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS 
 
6.1 
Dose Modifications for Palbociclib (Steps One and Three) 
 
Patients will be monitored for toxicity and the dose of palbociclib may be adjusted as 
indicated in the table below.  Dose reduction by 1, and if possible, 2 dose levels will be 
allowed depending on the type and severity of toxicity encountered. Patients requiring 
more than 2 dose reductions will be discontinued from the study. 
 
Recommended dose reductions for palbociclib are to decrease the current dose by 25 mg. 
The lowest dose available is 75 mg. Doses may be held as needed for toxicity resolution 
during a cycle. Doses omitted for toxicity are not replaced or restored within the same cycle 
(meaning that the cycle remains 28 days regardless of the number of doses of taken). 

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If a patient experiences toxicity which has not resolved to grade 2 or lower within two 
weeks (inclusive of the scheduled off-week), treatment with palbociclib should be 
permanently discontinued.  
 
Palbociclib Dose Modifications Based on Worst Treatment-Related Toxicity in the 
Previous Cycle 
Worst Toxicity During Previous Cycle 
New Dose Level 
Grade 4 neutropenia 
- Withhold Palbociclib until 
recover to Grade ≤ 2. Resume 
at the next lower dose. 
Grade 4 thrombocytopenia 
- Withhold Palbociclib until 
recover to Grade ≤ 2. Resume 
at the next lower dose. 
Grade 3 neutropenia associated with a documented 
infection or fever > 38.5 ºC 
 Withhold Palbociclib until 
recover to Grade ≤ 2. Resume 
at the next lower dose. 
Grade > 3 non-hematologic toxicity (includes nausea, 
vomiting, diarrhea, and hypertension only if persisting 
despite maximal medical treatment) 
 Withhold Palbociclib until 
symptoms resolve to  
• Grade ≤ 1: 
• Grade ≤ 2 (if not 
considered a safety risk for 
the patient 
Resume at the next lower 
dose. 
Delay by > 1 week in receiving the next scheduled dose 
due to persisting treatment-related toxicities 
If recovery to Grade ≤ 2 
occurs within 2 weeks, 
continue and decrease by one 
dose level 
Inability to deliver at least 80% of the planned dose of 
palbociclib due to adverse events possibly related to 
study treatment 
Withhold Palbociclib until 
recovery to Grade ≤ 2. 
Decrease by one dose level. 
 
6.1.1 Dose Adjustments Due to QTc Prolongation 
 
Any patients who develops new grade 2 or greater ECG QT corrected interval 
prolonged at any time during the study will need to have the ECG repeated 
immediately for confirmation. 
 
Grade 2: no adjustments; continue at same dose level 
Grade 3 (reversible cause identified and corrected): withhold treatment until QTc 
< 470 msec, then resume treatment at the same dose level 
Grade 3 (no reversible cause identified): withhold treatment until QTc < 470 msec, 
then decrease palbociclib by one dose level 
Grade 4: permanently discontinue palbociclib 

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6.1.2 Dose Adjustments Due to Interstitial Lung Disease (ILD)/Pneumonitis 
 
Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis (e.g. 
hypoxia, cough, dyspnea). In patients who have new or worsening respiratory 
symptoms and are suspected to have developed ILD/pneumonitis, interrupt 
palbociclib immediately and evaluate the patient. Permanently discontinue 
palbociclib in patients with severe ILD or pneumonitis. 
 
6.2 
Step Two, Cohort 1: Dose Modifications for Cisplatin 
 
6.2.1 Peripheral Neuropathy 
 
Grade 0, 1, or 2: no dose modification. 
 
Grade 3 or 4: Hold cisplatin until the event resolves to < grade 3. 
 
6.2.2 Ototoxicity 
 
If grade 1 or 2 hearing loss occurs, the risk of additional hearing loss versus the 
potential benefit of continuing cisplatin chemotherapy should be made.  Grade 3 
and 4 hearing loss is an indication to discontinue the drug. 
 
6.2.3 Kidney Impairment 
 
Calculated Creatinine 
Clearance 
Percent Dose to Give 
≥ 60 mL/min 
100% 
< 60 mL/min 
0% (withhold treatment for this cycle and repeat serum 
creatinine weekly after additional hydration), then for 
next chemotherapy cycle: 
If CrCl was already < 60 mL/min 
and is now:  
The percent dose 
to give is:  
> 50 but < 60 
80% 
≥ 40 but ≤ 50 
50% 
< 40 
0% 
Please note that dose reduction percentage is calculated by taking off from the 
original dose and not the previous dose.  Creatinine clearance is to be calculated 
using Cockcroft-Gault. 
 
6.2.4 Thrombocytopenia 
 
Nadir of last course 
Platelets (Day 1 of each cycle) 
< 100,000 
> 100,000 

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between 50,000 and 100,000 
Hold cisplatin 
Cisplatin = 100% 
< 50,000 (1st occurrence) 
Hold cisplatin 
Cisplatin = 80% 
<50,000 (2nd occurrence) 
Hold cisplatin 
Cisplatin = 60% 
 
6.3 
Step Two, Cohort 2: Dose Modifications or Delays for Cetuximab 
 
6.3.1 Dermatologic Adverse Effects 
 
Patients developing dermatologic toxicities while receiving cetuximab should be 
monitored for the development of inflammatory or infectious sequelae, and 
appropriate treatment of these symptoms initiated.  Dose modifications of any 
future cetuximab infusions should be instituted in case of severe (grade 3) 
acneiform rash.  Treatment with topical and/or oral antibiotics (minocycline 100 
mg bid) should be considered; topical corticosteroids are not recommended. 
 
If a patient experiences severe acneiform rash, cetuximab treatment adjustments 
should be made according to the following table.  In patients with mild and 
moderate skin toxicity, treatment should continue without dose modification. 
 
Cetuximab Dose Modification Guidelines 
Grade 3 
Acneiform Rash 
Cetuximab 
Outcome 
Cetuximab Dose 
Modification 
1st occurrence 
Delay infusion 1-2 
weeks 
Improvement 
Continue at 250 mg/m2 
 
 
No Improvement 
Discontinue cetuximab 
2nd occurrence 
Delay infusion 1-2 
weeks  
Improvement 
Reduce Dose Level -1 
 
 
No Improvement 
Discontinue cetuximab 
3rd occurrence 
Delay infusion 1-2 
weeks 
Improvement 
Reduce to Dose Level -2 
 
 
No Improvement 
Discontinue cetuximab 
4th occurrence 
Discontinue cetuximab 
 
Cetuximab Dose Levels* 
Starting dose 
250 mg/m2 
Dose Level –1 
200 mg/m2 
Dose Level –2 
150 mg/m2 
*There will be no dose level reductions below a weekly dose of 150 mg/m2.   
 
6.3.2 Gastrointestinal Adverse Effects 

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Antiemetic agents may be administered prior to the administration of cetuximab.  
Diarrhea will be treated symptomatically with antidiarrheal agents.  Should GI 
toxicity become severe enough to require hospitalization or outpatient IV fluid 
replacement, all treatment should be discontinued temporarily until the patient’s 
condition improves. 
 
6.3.3 Management of Hypersensitivity Reactions 
 
Mild (grade 1) hypersensitivity reactions (HSRs) characterized by mild pruritus, 
flushing, rhinitis, rash, and fever are treated with symptom-directed management, 
including cessation of infusion, administration of diphenhydramine 25 mg IVP 
(may repeat x2).  Vital signs should be monitored every 15 minutes until symptoms 
resolve.  Treatment may be restarted at the same rate at resolution of symptoms. 
 
Moderate (grade 2) HSRs consist of generalized pruritus, flushing, rash, back pain, 
dyspnea, hypotension, and rigors. The infusion should be stopped, and oxygen 
should be administered if the patient is experiencing dyspnea.  Normal saline 500 
mL bolus may be given if the patient is hypotensive (may repeat as needed).  
Diphenhydramine 50 mg IVP should be administered, followed by hydrocortisone 
100 mg IVP followed by meperidine 25 mg IV (for rigors).  Vital signs should be 
monitored every 2 minutes until stable, then every 15 minutes until symptoms 
resolve.  Treatment may be restarted at resolution of symptoms as follows: 8 hour 
rate for 5 minutes, then 4 hour rate for 5 minutes, the 2 hour rate for 5 minutes until 
the original rate of infusion is reached. 
 
Severe (grade 3) HSRs are characterized by bronchospasm, generalized urticaria, 
hypotension, and angioedema.  These HSRs should be managed by stopping the 
infusion and administering: normal saline 500 mL bolus (repeat as needed), 
epinephrine (1:1000) 0.3 mg IM, diphenhydramine 50 mg IVP, hydrocortisone 100 
mg IVP, and albuterol 2.5 mg inhalation (for bronchospasms).  Vital signs should 
be monitored every 2 minutes until stable, then every 15 minutes until symptoms 
resolve.  If cetuximab is restarted, restart the infusion rate at 25% of original rate 
for 30 minutes, then increase to 50% of infusion rate for the remainder of the 
infusion.  The infusion rate should be permanently reduced by 50%. 
 
Life-threatening/disabling (grade 4) HSRs consist of anaphylaxis, airway 
obstruction, shock, cardiac arrest, or prolonged hypotension. 
 
Grade 4 HSRs require the immediate interruption of cetuximab therapy and 
permanent discontinuation from further treatment with cetuximab.  Appropriate 
medical therapy including epinephrine, corticosteroids, intravenous antihistamines, 
bronchodilators, and oxygen should be available for use in the treatment of such 
reactions.  Patients should be carefully observed until the complete resolution of all 
signs and symptoms. 
 

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6.3.4 Infusion Reaction Adverse Effects 
 
Severe infusion reactions (Grade 4) require the immediate interruption of 
cetuximab therapy and permanent discontinuation from further treatment.  
Appropriate medical therapy including epinephrine, corticosteroids, intravenous 
antihistamines, bronchodilators, and oxygen should be available for use in the 
treatment of such reactions.  Patients should be carefully observed until the 
complete resolution of all signs and symptoms. 
 
In prior clinical trials, mild to moderate infusion reactions were managed by 
slowing the infusion rate of cetuximab and by continued use of antihistamine pre-
medications (e.g., diphenhydramine) in subsequent doses.  If the patient 
experiences a moderate (Grade 3) infusion reaction, the infusion rate should be 
permanently reduced by 50%.  For grade 1 or 2 reactions, additional doses of 
diphenhydramine or corticosteroids may be administered. 
 
6.3.5 Drug Fever Adverse Effects 
 
If a patient experiences isolated drug fever, subsequent pre-treatment with 
acetaminophen or a non-steroidal anti-inflammatory agent may be considered. If a 
patient experiences recurrent isolated drug fever following premedication and post-
dosing with an appropriate antipyretic, the infusion rate for subsequent dosing 
should be 50% of previous rate. 
 
6.3.6 Pulmonary Adverse Effects 
 
In the event of acute onset (grade ≥ 2) or worsening pulmonary symptoms which 
are not thought to be related to underlying cancer, cetuximab therapy should be 
interrupted and a prompt investigation of these symptoms should occur. Cetuximab 
retreatment should not occur until these symptoms have resolved to grade 1.  If 
interstitial lung disease is confirmed, cetuximab should be discontinued and the 
patient should be treated appropriately.  
 
6.3.7 Renal Adverse Effects 
 
Hypomagnesemia has been reported with cetuximab when administered as a single 
agent and in combination with multiple different chemotherapeutic regimens. 
Patients receiving cetuximab should be monitored for hypomagnesemia. 
Magnesium repletion may be necessary based on clinical judgment. 
 
 
7.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require reporting as 
outline below. Please refer to Appendix F for definitions and Appendix G for a grid of reporting 
timelines. 

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Adverse events will be tracked from the start of treatment through 30 days following the last day 
of study treatment. All adverse events must be recorded on the toxicity tracking case report form 
(CRF). 
 
Refer to the data submission schedule in Section 12 for instructions on the collection of AEs in the 
EDC. 
 
Reporting requirements for Washington University study team may be found in Section 7.1. 
 
 
7.1 
Sponsor-Investigator Reporting Requirements 
 
 
7.1.1 Reporting to the Human Research Protection Office (HRPO) at 
Washington University 
 
Reporting will be conducted in accordance with Washington University IRB 
Polices. 
 
Pre-approval of all protocol exceptions must be obtained prior to implementing the 
change. 
 
7.1.2 Reporting to the Quality Assurance and Safety Monitoring 
Committee (QASMC) at Washington University 
 
The Sponsor investigator is required to notify the QASMC of any unanticipated 
problems involving risks to participants or others occurring at WU or any BJH or 
SLCH institution that has been reported to and acknowledged by HRPO.  
(Unanticipated problems reported to HRPO and withdrawn during the review 
process need not be reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via 
email to qasmc@wustl.edu. Submission to QASMC must include the myIRB form 
and any supporting documentation sent with the form. 
 
7.1.3 Reporting to Pfizer 
 
Within 24 hours of first awareness of the event (immediately if the event is fatal or 
life-threatening), the PI or designee will report to Pfizer by facsimile any serious 
adverse drug experience (as defined in Appendix F) that occurs during the SAE 
reporting period (as defined in Section 7.0) in a study subject receiving palbociclib.  
Such SAEs will be reported using MedWatch form and the Pfizer Reportable Event 
Fax Cover Sheet (Appendix C) should also be included.  SAEs should be reported 
as soon as they are determined to meet the definition, even if complete information 
is not yet available. 

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Even though there may not be an associated SAE, exposure to palbociclib during 
pregnancy or lactation is reportable.  In addition, occupational exposure to 
palbociclib is reportable, and a lack of effect of palbociclib may also be reportable. 
 
Hy’s Law Cases: Cases of potential drug-induced liver injury as assessed by 
laboratory test values (“Hy’s Law Cases”) are also reportable to Pfizer.  If a study 
subject develops abnormal values in aspartate transaminase (AST) or alanine 
transaminase (ALT) or both, concurrent with abnormal elevations in total bilirubin 
and no other known cause of liver injury, that event would be classified as a Hy’s 
Law Case.  
 
7.1.4 Reporting to the FDA 
 
The conduct of the study will comply with all FDA safety reporting requirements.  
PLEASE NOTE THAT REPORTING REQUIREMENTS FOR THE FDA 
DIFFER FROM REPORTING REQUIREMENTS FOR HRPO/QASMC.  It 
is the responsibility of the Washington University principal investigator to report 
to the FDA as follows: 
 
• Report any unexpected fatal or life-threatening, suspected adverse reaction 
(refer to Appendix F for definitions) no later than 7 calendar days after initial 
receipt of the information.   
• Report a suspected adverse reaction that is both serious and unexpected 
(SUSAR, refer to Appendix F) no later than 15 calendar days it is determined 
that the information qualifies for reporting. Report an adverse event (Appendix 
F) as a suspected adverse reaction only if there is evidence to suggest a causal 
relationship between the drug and the adverse event, such as: 
o A single occurrence of an event that is uncommon and known to be 
strongly associated with drug exposure 
o One or more occurrences of an event that is not commonly associated 
with drug exposure but is otherwise uncommon in the population 
exposed to the drug 
o An aggregate analysis of specific events observed in a clinical trial that 
indicates those events occur more frequently in the drug treatment group 
than in a concurrent or historical control group 
• Report any findings from epidemiological studies, pooled analysis of multiple 
studies, or clinical studies that suggest a significant risk in humans exposed to 
the drug no later than 15 calendar days after it is determined that the information 
qualifies for reporting. 
• Report any findings from animal or in vitro testing that suggest significant risk 
in humans exposed to the drug no later than 15 calendar days after it is 
determined that the information qualifies for reporting. 
• Report any clinically important increase in the rate of a serious suspected 
adverse reaction of that listed in the protocol or IB within 15 calendar days after 
it is determined that the information qualifies for reporting. 

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Submit each report as an IND safety report in a narrative format or on FDA Form 
3500A or in an electronic format that FDA can process, review, and archive.  Study 
teams must notify the Siteman Cancer Center Protocol Development team of each 
potentially reportable event within 1 business day after initial receipt of the 
information, and must bring the signed 1571 and FDA Form 3500A to the Siteman 
Cancer Center Protocol Development team no later than 1 business day prior to the 
due date for reporting to the FDA. 
 
Each notification to FDA must bear prominent identification of its contents (“IND 
Safety Report”) and must be transmitted to the review division in the Center for 
Drug Evaluation and Research (CDER) or in the Center for Biologics Evaluation 
and Research (CBER) that has responsibility for review of the IND.  Relevant 
follow-up information to an IND safety report must be submitted as soon as the 
information is available and must be identified as such (“Follow-up IND Safety 
Report”).  
 
 
7.2 
Exceptions to Expedited Reporting 
 
Events that do not require expedited reporting as described in Section 7.1 
• planned hospitalizations 
• hospitalizations < 24 hours 
• respite care 
• events related to disease progression 
 
Events that do not require expedited reporting must still be captured in the EDC. 
 
8.0 
PHARMACEUTICAL INFORMATION 
 
8.1 
PD 0332991 (Palbociclib)  
 
8.1.1 PD 0332991 Description 
 
Laboratory Code: PD 0332991-00 
Molecular Weight: 447.54 
Molecular Formula: C24H29N7O2 
 
Formulations: 
Capsule: 
PD-0332991-00 capsules will be provided as the active ingredient with precedented 
excipients filled in hard gelatin capsules composed of gelatin and precedented 
colorants.  These formulations will be packaged in appropriate packaging material 
and should be stored in line with labeled storage conditions. 
 
Oral Solution: 

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PD-0332991-00 will be provided and/or dosed as an oral solution using precedented 
excipients with appropriate packaging and storage conditions. 
 
8.1.2 Clinical Pharmacology 
 
PD 0332991 is a highly selective inhibitor of Cdk4/cyclinD1 kinase activity (IC50 = 
11 nM; Ki = 2 nM). PD 0332991 has selectivity for Cdk4/6, with little or no activity 
against a large panel of 34 other protein kinases including other Cdks and a wide 
variety of tyrosine and serine/threonine kinases. Cdk6, another enzyme that also 
complexes with cyclin-D subunits, is also commonly expressed in mammalian cells 
and tumors. Cdk6 is highly homologous to Cdk4 and can perform the same function 
by phosphorylating Rb, thus potentially creating a redundant mechanism to 
promote cell cycle progression. Consequently, inhibition of both enzymes is 
necessary to ensure complete suppression of Rb phosphorylation and the greatest 
possible spectrum of antitumor activity. Results indicate that PD 0332991 inhibits 
Cdk6 with equivalent potency to Cdk4. 
 
8.1.3 Pharmacokinetics and Drug Metabolism 
 
To date pharmacokinetic data have been reported for four studies (A5481001, 
A5481002, A5481003 and A5481004). Final PK data are available from studies 
A5481001 and A5481002.  Pharmacokinetic parameters are available from all 74 
patients enrolled in Protocol A5481001 following a single-dose (Day 1 of Cycle 1), 
and from 51 patients following multiple-dose administration (Day 8 of Cycle 1) of 
daily doses ranging from 25 to 225 mg of PD 0332991 (Table 4.). On Day 1, all 
patients had detectable plasma concentrations of PD 0332991 at the first measured 
time point (1 hour) following oral administration. The exposure (AUC(0-10) and 
Cmax) increased in a dose-proportional manner over the dose range of 25-225 mg 
QD following PD 0332991 administration on Days 1 and 8 of Cycle 1, although 
some variability (low to moderate) around these doses was observed particularly at 
the 150 mg QD dose level. 

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Steady-state PK parameters are available for nine patients on Day 14 of Cycle 1 
(receiving 200 mg SC 0332991 QD for 2 weeks) and four patients on Day 21 of 
Cycle 1 (receiving 125 mg QD for 3 weeks).  PD 0332991 was absorbed with a 
median Tmax of ~4 hours. The mean PD 0332991 Vz/F was 3103 L, which is 
significantly greater than total body water (42 L), indicating that PD 0332991 
extensively penetrates into peripheral tissues. PD 0332991 was eliminated slowly; 
the mean elimination half-life (t½) was 26.5 hours and the mean CL/F was 86.1 
L/hour. PD 0332991 accumulated following repeated dosing with a median Rac of 
2.4, which is consistent with the elimination half-life.  
 

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Renal excretion of PD 0332991 was a minor route of elimination with ~1.7% of the 
drug excreted unchanged in urine over the 10-hour collection period in the 125 mg 
and 200 mg dose group, combined. The mean renal clearance (CLR) was 6.59 
L/hour.  
 
An exploratory evaluation of the circulating metabolites for PD 0332991 was 
conducted in plasma samples obtained from patients treated with PD 0332991 200 
mg QD. Preliminary assessment of the pooled plasma samples on Day 14 of Cycle 
1 indicated that the glucuronide conjugate of PD 0332991 and the lactam of PD 
0332991 were the main metabolites present in plasma. Other metabolites observed 
were the glucuronide conjugates of hydroxylated PD 0332991 and the glucuronide 
conjugate of reduced PD 0332991. 
  
The preliminary results from the recently performed food-effect study (“A5481021, 
a Phase 1, open-label 4 sequence 4 period crossover study of palbociclib (PD-
0332991) in healthy volunteers to estimate the effect of food on the bioavailability 
of palbociclib”) has provided evidence that when a single 125 mg dose of 
palbociclib was administered under fed conditions (including high fat or low fat 
meal given together with palbociclib, or moderate fat meal given 1 hour before and 
2 hours after palbociclib) as a freebase capsule formulation the palbociclib exposure 
levels were more uniform across the population than when taken in the fasting 
condition. 
 
Drug-drug interaction between PD 0332991 and letrozole was evaluated during the 
Phase 1 portion of a breast cancer study (A5481003 The preliminary data indicate 
a lack of a potential for drug-drug interaction between PD 0332991 and letrozole 
when administered in combination. 
 
In a study in healthy subjects (Study A5481079), a PD 0332991 oral solution 
administered under fasted conditions and fed conditions (moderate fat, standard 

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calorie meal) was bioequivalent to the commercial free base capsule formulation of 
PD 0332991 given under fed conditions.  Additionally, the PD 0332991 oral 
solution administered under fasted conditions was bioequivalent to PD 0332991 
oral solution administered under fed conditions, suggesting that the PD 0332991 
oral solution formulation can be given without regards to food intake. Additional 
information may be found in the IB for PD 0332991. 
 
8.1.4 Supplier(s) 
 
Pfizer will supply the study agent.  The study agent will be free of charge to the 
patient. 
  
8.1.5 Dosage Form and Preparation 
 
Palbociclib Capsules 
PD 0332991 will be supplied as capsules containing 75 mg, 100 mg, or 125 mg 
equivalents of PD 0332991 free base.  The sponsor will supply the oral drug 
formulation to sites in high-density polyethylene (HDPE) bottles containing 
75 mg, 100 mg, or 125 mg capsules.  The capsules can be differentiated by their 
size and color, as shown in the table below.  Labeling will occur according to local 
regulatory requirements. 
 
PD 0332991 Capsule Characteristics 
Strength 
Capsule color 
75 mg 
Sunset Yellow 
100 mg  
Caramel/Sunset Yellow 
125 mg 
Caramel 
 
The patient number and the protocol number should be recorded on the bottle 
label in the spaces provided. Site personnel must ensure that patients clearly 
understand the directions for self-medication. Patients should be given a sufficient 
supply to last until their next study visit. Unused drug and/or empty bottles should 
be returned to the site at the next study visit. Returned, unused medication 
MUST NOT be re-dispensed to the patient.  
 
PD 0332991 is an agent that must be handled and administered with care. 
Patients should be instructed to keep their medication in the bottles provided 
and not transfer it to any other container. Due to possible unknown hazards 
associated with topical and environmental exposure to experimental agents, 
capsules must not be opened and/or emptied into any vehicle for oral ingestion; 
capsules must be swallowed intact. 
 
Only one capsule strength will be dispensed to the patient at each dispensing visit.  
In the event of dose modification, request should be made of the patient to return 
all previously dispensed medication to the clinic and new capsules will be 
dispensed. 

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Palbociclib Oral Solution 
PD 0332991 oral solution (25 mg/mL) will be supplied in HDPE packaged bottles 
with a PIBA (push in bottle adapter) and a reusable oral syringe for dosing.  
Labeling will occur according to local regulatory requirements. Each clinical site 
will be provided the oral solution IPM which contains the detailed dosage and 
administration instructions for preparation of the PD 0332991 oral solution.  The 
oral solution should be prepared and dispensed by an appropriately qualified and 
experienced member of the study staff (eg, physician, nurse, physician’s assistant, 
or pharmacist) as allowed by local, state, and institutional guidance. 
 
The patient number should be recorded on the bottle label in the spaces provided 
by site personnel at the time of assignment to patient.  Site personnel must ensure 
that patients clearly understand the directions for self-medication.  Patients should 
be given a sufficient supply to last until their next study visit.  Unused drug and/or 
empty bottles should be returned to the site at the next study visit.  Returned, 
unused medication MUST NOT be re-dispensed to the patient.  
 
PD 0332991 oral solution is an agent that must be handled and administered with 
care.  Patients should be instructed to keep their medication in the bottles provided 
and not transfer it to any other container. 
 
8.1.6 Storage and Stability 
 
PD 0332991 capsules should be stored at controlled room temperature (15-25°C, 
59-77°F) in their original container. PD 0332991 oral solution should be stored in 
its original container and in accordance with the conditions described in the oral 
solution IPM.  Medication should be kept in a secured locked area at the study site 
in accordance with applicable regulatory requirements. Returned medication 
should be stored separately from medication that needs to be dispensed.  
 
To ensure adequate records, PD 0332991 capsules and oral solution will be 
accounted for as instructed by Pfizer. Unless otherwise authorized by Pfizer, at the 
end of the clinical trial all drug supplies unallocated or unused by the subjects must 
be returned to Pfizer or its designee. All containers of PD 0332991 that were sent 
to the investigator throughout the study must be returned to the sponsor or designee, 
whether they are used or unused, and whether they are empty or contain 
capsules/solution. 
 
8.1.7 Administration 
 
Patients should be encouraged to take their dose of PD 0332991 at approximately 
the same time each day.  Patients should be instructed to record daily 
administration of the study drugs in a patient diary. 
 
Patients must be instructed to withhold their daily dose of PD 0332991 on 

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pharmacokinetic sampling days until the pre-dose pharmacokinetic sample and 
safety assessments (ie, hematology, blood chemistry and ECGs) have been 
completed.  On days the patient is in the clinic, PD 0332991 will be taken when 
instructed by the investigator. 
 
Patients who miss a day’s dose must be instructed NOT to “make it up” the next 
day. Patients who vomit any time after taking a dose must be instructed NOT to 
“make it up,” and to resume treatment the next day as prescribed. Patients who 
inadvertently take 1 extra dose during a day must be instructed to skip the next 
day’s dose 
 
Palbociclib Capsules 
Patients should be instructed to swallow PD 0332991 capsules whole and not to 
chew them prior to swallowing. No capsule should be ingested if it is broken, 
cracked, or otherwise not intact. PD 0332991 capsules will be administered once a 
day, orally, for 21 days followed by 7 days off treatment in 28-day cycles.  Patients 
should take PD 0332991 with food.  
 
Palbociclib Oral Solution 
For patients who are unable to swallow capsules, a PD 0332991 oral solution is 
available as of IRB/EC approval of Amendment 5.  
 
For patients who develop inability to swallow capsules during the study, it is 
allowed to switch to the PD 0332991 oral solution.  
 
The PD 0332991 oral solution (25 mg/mL) will be administered using an oral 
syringe at volumes corresponding to the dose prescribed by the investigator (125 
mg dose = 5mL, 100 mg dose = 4 mL, and 75 gm dose = 3 mL). Detailed 
instructions for administration of the oral solution can be found in the DAI.  
 
PD 0332991 oral solution will be administered once a day, orally or via feeding 
tube, for 21 days followed by 7 days off treatment in 28-day cycles. The route of 
administration of the oral solution (oral vs via feeding tube) will be recorded in 
patient’s dosing diary and the study CRF.  
 
Patients can take PD 0332991 oral solution with or without food. 
 
8.1.8 Special Handling Instructions 
 
Females of childbearing potential should not handle or administer the study agent 
unless they are wearing gloves. 
 
8.1.9 Pregnancy 
 
The nonclinical safety profile of palbociclib has been well characterized through 
the conduct of single- and repeat-dose toxicity studies up to 39 weeks in duration, 

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and safety pharmacology, genetic toxicity, reproductive and developmental 
toxicity, and phototoxicity studies.  Consistent with the pharmacologic activity of 
palbociclib (cell cycle inhibition, CDK4/6 inhibition), the primary target organ 
findings included hematolymphopoietic (decreased cellularity of bone marrow and 
lymphoid organs) and male reproductive organ (seminiferous tubule degeneration, 
and secondary effects on the epididymis, prostate, and seminal vesicle) effects in 
rats and dogs, and altered glucose metabolism that was accompanied by effects on 
the pancreas and secondary changes in the eye, teeth, kidney, and adipose tissue in 
rats only, and effects on bone in rats only that were observed following single 
and/or repeat dosing at clinically relevant exposures.  Altered glucose metabolism 
(hyperglycemia/glucosuria) correlated with pancreatic islet cell vacuolation that 
was determined to reflect a loss of beta cells with corresponding decreases in insulin 
and C-peptide.  The reversibility of the effects on glucose homeostasis, pancreas, 
eye, kidney, and bone was not established following a 12-week non-dosing period; 
whereas partial to full reversal of effects on the hematolymphopoietic and male 
reproductive systems, teeth, and adipose tissue were observed.  Additionally, a 
potential for QTc prolongation and hemodynamic effects were identified from 
safety pharmacology studies, and developmental toxicity was identified from 
embryo-fetal development studies in the rat and rabbit.  Though gastrointestinal 
effects would be anticipated from a cell cycle inhibitor and while effects were 
observed in rats and dogs following single- and repeat-dose studies up to 3 weeks 
in duration (emesis, fecal changes, and microscopic changes in stomach and 
intestines), the effects were of limited severity at clinically relevant doses.  
Gastrointestinal effects were not prominent in longer duration studies, limited to 
effects on the glandular stomach and rodent-specific effects on the non-glandular 
stomach in rats following 27 weeks of intermittent dosing that did not reverse 
during a 12-week non-dosing period.  Additional palbociclib-related findings 
considered non-adverse at tolerated doses based on limited severity and/or absence 
of degenerative changes included cellular vacuolation in multiple tissues that was 
morphologically consistent with phospholipidosis; hepatic (increases in liver 
enzymes, hepatocellular hypertrophy/increased vacuolation), renal (increased 
CPN), adrenal (cortical cell hypertrophy), and respiratory (clinical signs, tracheal 
epithelial cell atrophy) effects; and prolonged coagulation times.  Reversibility 
(partial or full) was established for these additional toxicities.  Finally, palbociclib 
was determined to be an aneugen, for which a no effect exposure was identified 
 
8.1.10 QT Interval 
 
The patients enrolled in clinical studies should be closely monitored for potential 
cardiovascular symptoms. Appropriate monitoring should include clinical 
examinations, vital signs, routine ECGs, and AEs monitoring. In case of QTc 
prolongation, concomitant conditions such as electrolyte unbalances or use of 
medications affecting the QT interval should be ruled out or corrected. In case of 
clinically significant toxicities, PD 0332991 administration should be interrupted 
and the dose reduced as indicated in clinical protocols. 
 

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In Study A5481001 using QTcF, 46 of 73 patients had a maximum increase from 
baseline of <30 msec and no patient had a maximum on treatment value of ≥ 500 
msec. Notably, one female patient who had received PD 0332991 at 75 mg QD on 
Schedule 3/1, had a maximum QTcF increase of 67 msec from baseline to Cycle 1. 
Additionally, QTcF increases ranging from 39 to 51 msec compared to baseline 
persisted throughout her ECG collection period of 5 subsequent cycles. After 7 
cycles, the dose was increased to 100 mg QD. The patient remained on treatment 
for a total of 39 cycles with no cardiac related adverse events. QT data analysis for 
study A5481002 indicated no clinically significant mean changes with ECGs. 
Using Fridericia's correction in the A5481002 study, all 17 subjects in the analysis 
had a maximum increase from baseline of <30 msec and a maximum post-baseline 
value for QTc of <500 msec. 
 
8.2 
Cisplatin (CDDP, Platinol-AQ®) 
 
8.2.1 Cisplatin Description 
 
Molecular formula: PtCl2H6N2 
Molecular weight: 300.1. 
 
8.2.2 Clinical Pharmacology 
 
The mechanism of action of cisplatin has not been clearly elucidated. However the 
most likely mechanism of antitumor action of this drug resides in its ability to 
inhibit DNA synthesis, and to a lesser degree, RNA and protein synthesis. It has 
also been shown that Cisplatin binds to DNA and produces inter-strand cross-links. 
Also cisplatin is not phase-sensitive and its cytotoxicity is similar in all phases of 
the cell cycle. Additional information can be found in the package insert. 
 
8.2.3 Supplier 
 
Cisplatin is commercially available as 1 mg/mL in both 50 mL multiple dose vial 
and 100 mL multiple dose vial. 
 
8.2.4 Dosage Form and Preparation 
 
The stability of cisplatin in solution is dependent upon the chloride ion 
concentration present in the diluent. Cisplatin should be diluted into an IV solution 
containing NaCL at a minimum chloride ion concentration of 0.040 mol/L (0.2% 
NaCL). Needles, syringes, catheters and IV administrations sets containing 
aluminum must be avoided during preparation and administration due to cisplatin-
aluminum reaction causing precipitation and loss of potency. Mannitol 12.5 to 25 
gm may be added per institutional guidelines. 
 
 

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8.2.5 Storage and Stability 
 
The dry, unopened vials should be stored at room temperature (15° -25° C). The 
unopened container should be protected from light and stored in the carton until 
contents are used. Do not refrigerate. 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. 
 
8.2.6 Administration 
 
Patients will receive cisplatin via IV infusion over 60 minutes.  Adequate hydration 
must be maintained during and after administration as described in the treatment 
section. It is recommended that all patients should be premedicated with 
antiemetics. 
 
8.3 
Cetuximab (Erbitux) 
 
8.3.1 Cetuximab Description 
 
Cetuximab is an anti-EGFR human-to-murine chimeric antibody. 
 
8.3.2 Clinical Pharmacology 
 
The epidermal growth factor receptor (EGFR, HER1, c-ErbB-1) is a 
transmembrane glycoprotein that is a member of a subfamily of type I receptor 
tyrosine kinases including EGFR, HER2, HER3, and HER4. The EGFR is 
constitutively expressed in many normal epithelial tissues, including the skin and 
hair follicle. Expression of EGFR is also detected in many human cancers including 
those of the head and neck, colon, and rectum. 
 
Cetuximab binds specifically to the EGFR on both normal and tumor cells, and 
competitively inhibits the binding of epidermal growth factor (EGF) and other 
ligands, such as transforming growth factor-alpha. In vitro assays and in vivo 
animal studies have shown that binding of cetuximab to the EGFR blocks 
phosphorylation and activation of receptor-associated kinases, resulting in 
inhibition of cell growth, induction of apoptosis, and decreased matrix 
metalloproteinase and vascular endothelial growth factor production. Signal 
transduction through the EGFR results in activation of wild-type KRAS protein. 
However, in cells with activating KRAS somatic mutations, the mutant KRAS 
protein is continuously active and appears independent of EGFR regulation. 
 
In vitro, cetuximab can mediate antibody-dependent cellular cytotoxicity (ADCC) 
against certain human tumor types. In vitro assays and in vivo animal studies have 
shown that cetuximab inhibits the growth and survival of tumor cells that express 
the EGFR. No antitumor effects of cetuximab were observed in human tumor 
xenografts lacking EGFR expression. The addition of cetuximab to radiation 

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therapy or irinotecan in human tumor xenograft models in mice resulted in an 
increase in anti-tumor effects compared to radiation therapy or chemotherapy alone. 
 
8.3.3 Pharmacokinetics and Drug Metabolism 
 
Cetuximab administered as monotherapy or in combination with concomitant 
chemotherapy or radiation therapy exhibits nonlinear pharmacokinetics. The area 
under the concentration time curve (AUC) increased in a greater than dose 
proportional manner while clearance of cetuximab decreased from 0.08 to 0.02 
L/h/m2 as the dose increased from 20 to 200 mg/m2, and at doses >200 mg/m2, it 
appeared to plateau. The volume of the distribution for cetuximab appeared to be 
independent of dose and approximated the vascular space of 2–3 L/m2. 
 
Following the recommended dose regimen (400 mg/m2 initial dose; 250 mg/m2 
weekly dose), concentrations of cetuximab reached steady-state levels by the third 
weekly infusion with mean peak and trough concentrations across studies ranging 
from 168 to 235 and 41 to 85 μg/mL, respectively. The mean half-life of cetuximab 
was approximately 112 hours (range 63–230 hours). The pharmacokinetics of 
cetuximab were similar in patients with HNSCC and those with colorectal cancer. 
Based on a population pharmacokinetic analysis, female patients with colorectal 
cancer had a 25% lower intrinsic clearance of cetuximab than male patients. 
Qualitatively similar, but smaller gender differences in cetuximab clearance were 
observed in patients with HNSCC. The gender differences in clearance do not 
necessitate any alteration of dosing because of a similar safety profile. 
 
8.3.4 Supplier 
 
Cetuximab is commercially available and is listed in the compendia as indicated for 
the therapy of HNSCC. 
 
8.3.5 Dosage Form 
 
Each single-use, ready to use 50-mL vial contains 100 mg of cetuximab at a 
concentration of 2 mg/mL and is formulated in a preservative-free solution 
containing 8.48 mg/mL sodium chloride, 1.88 mg/mL sodium phosphate dibasic 
heptahydrate, 0.42mg/mL sodium phosphate monobasic monohydrate, and Water 
for injection, USP. 
 
8.3.6 Storage and Stability 
 
Cetuximab should be stored in a secure area according to local regulations. Store 
vials under refrigeration at 2ο C to 8ο C (36ο F to 46ο F). DO NOT FREEZE. 
Increased particulate formation may occur at temperatures at or below 0οC.  This 
product contains no preservatives.  Preparations of cetuximab in infusion containers 
are chemically and physically stable for up to 12 hours at 2ο C to 8ο C (36ο F to 46ο 
F) or up to 8 hours at controlled room temperature (20ο C to 25ο C; 68ο F to 77ο F).  

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Discard any remaining solution in the infusion container after 8 hours at controlled 
room temperature or after 12 hours at 2ο to 8ο C.  Discard any unused portion of the 
vial. 
 
8.3.7 Safety Precautions 
 
Appropriate mask, protective clothing, eye protection, gloves, and Class II vertical-
laminar-airflow safety cabinets are recommended during preparation and handling.  
Opened vials must be disposed of at the investigational center as chemotherapy or 
biohazardous waste provided documented procedures for destruction are in place.  
 
Cetuximab therapy should be used with caution in patients with known 
hypersensitivity to cetuximab, murine proteins, or any component of this product. 
It is recommended that patients wear sunscreen and hats and limit sun exposure 
while receiving cetuximab as sunlight can exacerbate any skin reactions that may 
occur. 
 
8.3.8 Premedication 
 
In an effort to prevent a hypersensitivity reaction, all patients should be 
premedicated with diphenhydramine hydrochloride 50 mg (or an equivalent 
antihistamine) IVPB given at least 30 minutes prior to the cetuximab.  
Premedication will also include 1Liter normal saline, hydrocortisone 100 mg IVPB 
and albuterol inhalation (by nebulizer or inhaler) according to standard of care 
procedures.  
 
8.3.9 Preparation and Administration 
 
Cetuximab must not be administered as an IV push or bolus. Cetuximab must be 
administered with the use of a low protein binding 0.22-micrometer in-line filter. 
Cetuximab is supplied as a 50-mL, single-use vial containing 100 mg of cetuximab 
at a concentration of 2 mg/mL in phosphate buffered saline. DO NOT SHAKE OR 
DILUTE. 
 
Cetuximab can be administered via infusion pump. 
 
Infusion Pump: 
• Draw up the volume of a vial using a sterile syringe attached to an appropriate 
needle (a vented spike or other appropriate transfer device may be used). 
• Fill cetuximab into a sterile evacuated container or bag such as glass containers, 
polyolefin bags (e.g., Baxter Intravia), ethylene vinyl acetate bags (e.g., Baxter 
Clintec), DEHP plasticized PVC bags (e.g., Abbott Lifecare), or PVC bags. 
• Repeat procedure until the calculated volume has been put in to the container.  
Use a new needle for each vial. 
• Administer through a low protein binding 0.22-micrometer in-line filter (placed 
as proximal to the patient as practical). 

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• Affix the infusion line and prime it with cetuximab before starting the infusion. 
• Maximum infusion rate should not exceed 5 mL/min. 
• Use 0.9% saline solution to flush line at the end of infusion. 
• The infusion rate of cetuximab must never exceed 10 mg/minute (5 mL/min). 
The infusion time of cetuximab should not exceed 4 hours. Patients must be 
continuously observed during the infusion for signs of anaphylaxis. 
 
8.3.10 Patient Monitoring 
 
Patients should be closely monitored for treatment-related adverse events, 
especially hypersensitivity reactions during the infusion and for one post-infusion 
observation hour. Vital signs (blood pressure, heart rate, and temperature) will be 
monitored and recorded prior to the administration of cetuximab, 1/2 hour into the 
infusion, at the completion of the infusion, and 1 hour post-infusion for the initial 
dose. During all subsequent administrations of cetuximab, vital signs will be 
monitored and recorded prior to administration of cetuximab and at the end of the 
infusion; however, it is recommended that the patient be observed for 1-hour post 
infusion. 
 
 
9.0 
CORRELATIVE STUDIES 
 
9.1 
Tumor Biopsy 
 
Tumor biopsies (core or excisional/incisional) will be used to perform whole exome 
sequencing (WES), RNAseq, p16INK4a expression, Ki-67 by IHC, total and phospho-Rb by 
IHC, Cyclin D1 by IHC, Cyclin E by IHC, Cyclin A by IHC, p53 by IHC, p21 by IHC, 
p27 by IHC, and TUNEL assay. Reverse phase protein array (RPPA) will be performed. 
RPPA is a high-throughput antibody-based technique developed for Functional Proteomics 
studies to evaluate protein activities in signaling networks.  Additional analyses of other 
potential biomarkers may be performed as they emerge from the scientific understanding 
of palbociclib activity. If a biopsy is not feasible for financial reasons or safety concerns, 
at the Primary Investigator’s discretion, the biopsy may be foregone. 
 
9.1.1 Collection of Specimens 
 
Tumor tissue will be collected at baseline and then after two cycles of neoadjuvant 
palbociclib monotherapy (conclusion of Step One).  It should be collected form the 
primary tumor site if possible, but involved neck nodal tumor tissue is an 
alternative.  If possible, the same site should be biopsied at baseline and end of C2. 
 
The biopsy should consist of a minimum of 4 needle cores (14-18 gauge is 
preferred) if neck nodal tissue or 2 small (each 4 x 4 x4 mm) pieces of tumor if 
primary tumor site tissue. 
 

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If the patient has been previously enrolled in Washington University’s TAP 
protocol (head and neck bank, HRPO #201102323), tissue that has been banked 
may be accessed in lieu of fresh biopsy at baseline. 
 
9.1.2 Handling of Specimen(s) 
 
Tissue should be delivered on saline to the Siteman Cancer Center Tissue 
Procurement Core within 30 minutes of collection. 
 
9.2 
Peripheral Blood 
 
Peripheral blood will be stored to serve as normal DNA comparisons to tumor DNA.  It 
will also be used in an exploratory fashion to look for immunologic changes. 
 
9.2.1 Collection of Specimen 
 
Thirty mL of peripheral blood will be collected into 3 green top tubes at baseline, 
Cycle 1 D22 of neoadjuvant treatment, Cycle 2 D 22 of neoadjuvant treatment, 
Cycle 1 D22 of adjuvant treatment, and four months post completion of adjuvant 
treatment. 
 
9.2.2 Handling of Specimen(s) 
 
Deliver to the SCC Tissue Procurement Core within 30 minutes of collection. 
 
9.3 
QOLs 
 
Quality of life will be assessed by administration of the EORTC QLQ-C30 (Appendix D) 
and the FACT H&N (Appendix E) at the following time points: 
• Baseline 
• Step One Cycle 2 Day 22 
• Day 1 of RT 
• Day 35 of RT 
• 8-10 weeks after completion of CRT 
• Cycle 1 Day 1 (adjuvant) 
• Cycle 4 Day 1 (adjuvant) 
• EOT (adjuvant) 
• 8 months after completion of CRT 
• 12 months after completion of CRT 
• 18 months after completion of CRT 
• 24 months after completion of CRT 
• 30 months after completion of CRT 
• 36 months after completion of CRT 
• 42 months after completion of CRT 
• 48 months after completion of CRT 

Protocol Version: 11/13/20 
 
Page 44 of 76 
• 54 months after completion of CRT 
• 60 months after completion of CRT 
 
 

Protocol Version: 11/13/20 
 
Page 45 of 76 
 
10.0 
STUDY CALENDAR 
 
10.1 
Induction Palbociclib Monotherapy – Step One  
 
 
Baseline4 
Step 1 – Cycle 1 
Step 1 – Cycle 2 
Definitive Chemotherapy/Radiation 
D1 
D8 
D15 
D22 
D1 
D8 
D15 
D22 
Between  
D18 and D22 
 
Palbociclib administration1 
 
X1 
X1 
X1 
 
X1 
X1 
X1 
 
 
 
PE w/ECOG PS 
X 
X 
 
X 
X 
X 
 
 
X 
 
 
CBC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
CMP + magnesium 
X 
 
 
 
 
 
 
 
 
 
 
PT/INR, PTT 
X 
 
 
 
 
 
 
 
 
 
 
Neck CT w/contrast 
X 
 
 
 
 
 
 
 
X5 
 
 
FDG-PET/CT 
X 
 
 
 
 
 
 
 
 
 
 
Laryngoscopy w/biopsy2 
X 
 
 
 
 
 
 
 
 
X 
 
EKG 
X 
 
 
 
 
X 
 
 
 
 
 
Pregnancy test3 
X 
 
 
 
 
 
 
 
 
 
 
FACT-H&N,  
EORTC QLQ-C30 
X 
 
 
 
 
 
 
 
X 
 
 
Blood for genomic 
sequencing 
X 
 
 
 
X 
 
 
 
X 
 
 
Rad Tx Planning 
 
 
 
 
 
X 
 
 
 
 
See Study Calendar 2 
Primary Site Photographs 
X 
 
 
 
 
 
 
 
 
X 
 
1. Palbociclib po 125 mg/day, Days 1-21 of a 28 day cycle.  
2. Tumor biopsy specimens (punch, incisional or core needle) will be obtained from PTS or neck nodes.  P16 to be tested by IHC and/or HPV-HR ISH at    
    baseline only.  Assessment of primary tumor site will be done by laryngoscopy performed in the office or operating room. If the patient has been   
    previously enrolled in Washington University’s TAP protocol (head and neck bank, HRPO #201102323), tissue that has been banked may be accessed  
    in lieu of fresh biopsy at baseline.  
3. In women of childbearing potential only.  
4. Baseline assessments must take place no more than 28 days prior to enrollment.                   
5. To occur anytime post treatment D21-D25 (for M, 26 for W and 27 for Th patients).

Protocol Version: 11/13/20 
 
Page 46 of 76 
10.2 
Definitive Chemoradiation (CRT) and Adjuvant Palbociclib - Steps Two and Three 
 
 
Step 2 
Short 
Term 
Follow-up 
(weeks)12 
Step 3 
Long-Term Follow-Up 
Definitive CRT 
(weeks) 
Adjuvant Palbociclib9 
Post 
Step 
310  
Months post-end of CRT11 
0 
1 
2 
3 
4 
5 
6 
8-
10  
14-
18  
1 
2 
3 
4 
5 
6 
8 
12 
18 
24 
30 
36 
42 
48 
54 
60 
Cohort 1: Cisplatin1 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2: Cetuximab7 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Accelerated IMRT2 
 
X------------------------X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Palbociclib5 
 
 
 
 
 
 
 
 
 
X5 
X5 
X5 
X5 
X5 
X5 
 
 
 
 
 
 
 
 
 
 
 
PE w/palpation 
X 
X 
X 
 
X 
X 
X 
X4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
CMP + magnesium 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
BMP + magnesium 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neck CT w/contrast  
 
 
 
 
 
 
 
X 
 
 
 
X6 
 
 
X6 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FDG-PET/CT 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laryngoscopy 
 
 
 
 
 
 
 
X 
 
 
 
X3 
 
 
X3 
 
X 
X 
X14 
X14 
X14 
X14 
X14 
X14 
X14 
X14 
EKG                                     
X 
 
 
 
 
 
 
 
X8 
 
 
X8 
 
X8 
X 
 
 
 
 
 
 
 
 
 
 
FACT-H&N 
 
X 
 
 
 
 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EORTC QLQ-C30 
 
X 
 
 
 
 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Primary Site Photographs 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for genomic 
sequencing 
 
 
 
 
 
 
 
 
 
X13 
 
 
 
 
 
X13 
 
 
 
 
 
 
 
 
 
 
1. Cisplatin 100mg/m2 D1, D22. IV Fluids D2-3, D23-24. Sites standard premedication(s) prior to each administration.     
2. Delivered once per day M-Th with a boost of 2 treatments at least 6 hours apart on Friday      
3. Assessment of primary tumor site will be done by laryngoscopy performed in the office or operating room. To occur 8 months post CRT.     
4. Weekly until adequate recovery from CRT toxicities (per physician discretion)  
5. Palbociclib po 125 mg/day, Days 1-21 of a 28 day cycle   
6. To occur 8 months post CRT.  CT of Neck AND Chest 
7.Cetuximab 400mg/m2 D-7, 250 mg/m2 D1, 8, 15, 22, 29, 36. Sites standard premedication(s) prior to each administration. Week 0 (D -7) applies 
to cohort 2 only. 
8. C1D1, C4D1, C6D29 
9. Starting 16-22 weeks post CRT 
10. 30-45 days after final cycle of adjuvant palbociclib 
11. +/- 1 month 
12. After completion of CRT 
13. To be collected at Step 3 Cycle 1 D22 and at 4 months post Step 3 (see protocol section 9.2) 

Protocol Version: 11/13/20 
 
Page 47 of 76 
 
14. Laryngoscopy (FOE) will be conducted as standard of care after 12 months of follow-up, so they will occur at some, but not all, of the long-
term follow-up visits

Protocol Version: 11/13/20 
 
Page 48 of 76 
 
11.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, the 
Principal Investigator will provide a Data and Safety Monitoring (DSM) report to the Washington 
University Quality Assurance and Safety Monitoring Committee (QASMC) semi-annually 
beginning six months after accrual has opened (if at least one patient has been enrolled) or one 
year after accrual has opened (if no patients have been enrolled at the six-month mark). 
 
For phase I dose escalation studies, the Principal Investigator will review all patient data at least 
monthly (or before each dose-escalation if occurring sooner than monthly), and provide a semi-
annual report to the Quality Assurance and Safety Monitoring Committee (QASMC). For phase II 
or dose expansion cohorts of a phase I study, the Principal Investigator will review all patient data 
at least every six months, and provide a semi-annual report to the QASMC. This report will 
include: 
• HRPO protocol number, protocol title, Principal Investigator name, data coordinator 
name, regulatory coordinator name, and statistician 
• Date of initial HRPO approval, date of most recent consent HRPO approval/revision, 
date of HRPO expiration, date of most recent audit, study status, and phase of study 
• History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol exceptions, 
error, or breach of confidentiality including start/stop dates and reason 
• Study-wide target accrual and study-wide actual accrual 
• Protocol activation date 
• Average rate of accrual observed in year 1, year 2, and subsequent years 
• Expected accrual end date and accrual by cohort 
• Objectives of protocol with supporting data and list the number of participants who 
have met each objective 
• Measures of efficacy (phase I studies only if efficacy is objective of the protocol) 
• Early stopping rules with supporting data and list the number of participants who have 
met the early stopping rules 
• Power analysis and/or interim analysis (if described in the protocol) 
• Summary of toxicities separated by cohorts with the number of dose-limiting toxicities 
indicated 
• Abstract submissions/publications 
• Summary of any recent literature that may affect the safety or ethics of the study  
 
The study principal investigator and Research Patient Coordinator will monitor for serious 
toxicities on an ongoing basis. Once the principal investigator or Research Patient Coordinator 
becomes aware of an adverse event, the AE will be reported to the HRPO and QASMC according 
to institutional guidelines. 
 
12.0 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 

Protocol Version: 11/13/20 
 
Page 49 of 76 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
On-Study Form 
Cohort Assignment Form 
Research Blood Form 
Baseline 
PEG Tube Tracker 
Trach Tube Tracker 
Weight Form 
Toxicity Form 
Continuous 
Step 1 Treatment Form 
End of each cycle during Step 1 
Step 2 Treatment Form 
End of Step 2 
Step 3 Treatment Form 
End of each cycle during Step 3 
MEDWATCH Form 
Refer to Section 7.0 
Visual Response Form 
As needed 
FOE or mDLx Form 
Baseline 
Between Day 18 & 22 of Step One Cycle 2 
8-10 Week Follow-up 
8, 12, 18, 24, 30, 36, 42, 48, 54, and 60 months after 
completion of CRT 
FACT-H&N Form and 
QLQ-C30 Form 
Baseline 
Step One Cycle 2 Day 22 
Day 1 and 36 of RT 
8-10 week Follow-up 
Cycle 1 Day 1 and Cycle 4 Day 1 (adjuvant) 
EOT (adjuvant) 
8, 12, 18, 24, 30, 36, 42, 48, 54, and 60 months after 
completion of CRT 
RECIST Form 
Baseline 
Step One Cycle 2 Day 22 
8-10 Week Follow-up 
8, 12, 18, 24, 30, 36, 42, 48, 54, and 60 months after 
completion of CRT 
Follow Up Form 
8, 12, 18, 24, 30, 36, 42, 48, 54, and 60 months after 
completion of CRT 
Death Form 
Time of death 
 
 
12.1 
Adverse Event Collection in the Case Report Forms 
All adverse events that occur beginning with start of treatment must be captured in the 
Toxicity Form.  
 
Participant death due to disease progression should be reported on the Toxicity Form as 
grade 5 disease progression.  If death is due to an AE (e.g. cardiac disorders: cardiac arrest), 

Protocol Version: 11/13/20 
 
Page 50 of 76 
report as a grade 5 event under that AE.  Participant death must also be recorded on the 
Death Form. 
 
13.0 
MEASUREMENT OF EFFECT 
 
13.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 8 weeks.  
In addition to a baseline scan, confirmatory scans should also be obtained not less than 4 
weeks following initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline (version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter 
(unidimensional measurement) of the tumor lesions and the shortest diameter in the case 
of malignant lymph nodes are used in the RECIST criteria. 
 
13.2 
Disease Parameters 
 
Measurable disease:  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm by chest 
x-ray, as >10 mm with CT scan, or >10 mm with calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a 
lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable disease:  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since 
they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions:  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target lesions 

Protocol Version: 11/13/20 
 
Page 51 of 76 
and recorded and measured at baseline.  Target lesions should be selected on the basis of 
their size (lesions with the longest diameter), be representative of all involved organs, but 
in addition should be those that lend themselves to reproducible repeated measurements.  
It may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected.  A sum of the diameters (longest for non-nodal lesions, 
short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters.  If lymph nodes are to be included in the sum, then only the short 
axis is added into the sum.  The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
 
Non-target lesions:  All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should 
also be recorded at baseline.  Measurements of these lesions are not required, but the 
presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
13.3 
Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions:  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed 
using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI:  This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 

Protocol Version: 11/13/20 
 
Page 52 of 76 
type and site of disease.  Furthermore, as with CT, the modality used at follow-up should 
be the same as was used at baseline and the lesions should be measured/assessed on the 
same pulse sequence.  It is beyond the scope of the RECIST guidelines to prescribe specific 
MRI pulse sequence parameters for all scanners, body parts, and diseases.  Ideally, the 
same type of scanner should be used and the image acquisition protocol should be followed 
as closely as possible to prior scans.  Body scans should be performed with breath-hold 
scanning techniques, if possible. 
 
PET-CT:  At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a PET-
CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then 
the CT portion of the PET-CT can be used for RECIST measurements and can be used 
interchangeably with conventional CT in accurately measuring cancer lesions over time.  
Note, however, that the PET portion of the CT introduces additional data which may bias 
an investigator if it is not routinely or serially performed.   
 
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation exposure 
at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers:  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published [JNCI 
96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  
In addition, the Gynecologic Cancer Intergroup has developed CA-125 progression criteria 
which are to be integrated with objective tumor assessment for use in first-line trials in 
ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology:  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or stable 

Protocol Version: 11/13/20 
 
Page 53 of 76 
disease is mandatory to differentiate between response or stable disease (an effusion may 
be a side effect of the treatment) and progressive disease. 
 
FDG-PET:  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
 
• Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
• No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this 
is PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of 
disease on CT, additional follow-up CT  scans are needed to determine if there is 
truly progression occurring at that site (if so, the date of PD will be the date of the 
initial abnormal FDG-PET scan).  If the positive FDG-PET at follow-up 
corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD. 
• FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease-specific medical 
literature for the indication.  However, it must be acknowledged that both 
approaches may lead to false positive CR due to limitations of FDG-PET and 
biopsy resolution/sensitivity. 
  
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
13.4 
Response Criteria 
 
13.4.1 Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm.  (Note:  
the appearance of one or more new lesions is also considered progressions). 
 

Protocol Version: 11/13/20 
 
Page 54 of 76 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
13.4.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph nodes must be non-pathological 
in size (<10 mm short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and the 
progression status should be confirmed at a later time by the review panel (or 
Principal Investigator). 
 
13.4.3 Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).  The 
patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
    
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 

Protocol Version: 11/13/20 
 
Page 55 of 76 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once 
>4 wks. from baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be reported 
as “symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
 
                                      For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since 
SD is increasingly used as an endpoint for assessment of efficacy in some trials so to 
assign this category when no lesions can be measured is not advised 
 
 
13.4.4 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded 
since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first 
met for CR until the first date that progressive disease is objectively documented.  
 
Duration of stable disease:  Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started, including the baseline 
measurements.  
 
13.4.5 Progression-Free Survival 

Protocol Version: 11/13/20 
 
Page 56 of 76 
 
PFS is defined as the duration of time from start of treatment to time of progression 
or death, whichever occurs first. 
 
13.4.6 Overall Survival 
 
Overall survival is measured from time of diagnosis to time of death. 
 
13.4.7 Response Review 
 
All responses will be reviewed by an expert independent of the study at the study’s 
completion.  Simultaneous review of the patients’ files and radiological images is 
the best approach.  
 
 
14.0 
STATISTICAL CONSIDERATIONS 
 
14.1 
Study Design 
 
This three-step, non-randomized, open-label, phase II trial is designed to explore the 
efficacy effect of palbociclib in addition to the standard CRT regimen with either cisplatin 
or cetuximab in patients with p16INK4a negative, HPV-unrelated HNSCC (OP, Larynx, 
Hypopharynx, and Oral Cavity), Stage III-IV disease. In step one, all patients will be 
treated with neoadjuvant palbociclib monotherapy for two cycles (28 days per cycle). In 
step two (CRT), based upon performance status and organ function at enrollment, patients 
will be assigned to two cohorts: one will be treated with cisplatin and RT over 6 weeks, 
and the second will be treated with cetuximab and RT over 7 weeks. In step three, all 
patients in the trial (both cohorts) will be treated with adjuvant palbociclib for six cycles 
(28 days per cycle) following the completion of CRT.  
 
14.2 
Primary Endpoint 
 
Overall tumor response to neoadjuvant palbociclib monotherapy at the end of step one, a 
categorical variable (CR, PR, SD, or Progression). Overall tumor response rate is defined 
as the proportion of subjects who achieve a CR or PR based on RECIST criteria.  
 
14.3 
Secondary Endpoints 
 
 Local-regional disease relapse, a binary variable (Yes vs. No). Local-regional disease 
relapse rate is defined as the proportion of subjects alive who have local-regional 
progressed disease at 18 months following completion of CRT.  
 Distant metastases, a binary variable (Yes vs. No). Distant metastases rate is defined as 
the proportion of subjects alive who have distant metastases at 18 months following 
completion of CRT.  
 Progression-free survival (PFS), defined as the days from the start of Step 2 (CRT) to 
the first documentation of disease progression or death from any cause or the end of 
follow-up.  

Protocol Version: 11/13/20 
 
Page 57 of 76 
 Overall survival (OS), defined as the days from the time of diagnosis to death from any 
cause or the end of follow-up.  
 
14.4 
Study Population 
 
Twenty-four eligible patients with p16INK4a negative/HPV-unrelated OPSCC, larynx SCC, 
hypopharynx SCC, and oral cavity SCC will be enrolled into the trial to receive 2 months 
of neoadjuvant palbociclib monotherapy at Step One, 6-7 weeks CRT (either cisplatin or 
cetuximab) at Step Two, and 6 months of adjuvant palbociclib at Step Three. The sampling 
method is non-random. Patients with excellent performance status and adequate vital organ 
function at enrollment will be assigned to the cisplatin cohort. Patients with reduced 
performance status and/or vital organ function will be assigned to the cetuximab cohort.  
 
14.5 
Power Analysis and Sample Size 
 
Power analysis is conducted based upon the primary endpoint. The results of a small phase 
I trial of palbociclib and cetuximab in RM-HNSCC (Michel, et al., 2016) showed a tumor 
response rate of 22% (2 of 9 pts). In the phase I trial, the tumor response rate was 17% (1 
of 6 pts) in cetuximab-resistant disease, supporting an independent effect of palbociclib in 
this disease. Assuming the true tumor response rate with palbociclib monotherapy in 
patients with p16INK4a negative untreated HNSCC could be substantially higher than 17%, 
a sample size of 24 patients yields a >80% power if the true tumor response rate is at least 
38%, using a one-sided exact test at the significance level of 0.05 and null response rate of 
17%. PASS 15.0 was used for sample size calculation. The results of this exploratory study 
are considered hypothesis-generating, and will provide critical baseline information to 
develop future confirmatory trials.  
 
14.6 
Data Analysis 
 
All data will be evaluated as observed, and no imputation method for missing values will 
be used. All data will be presented in a descriptive manner. All analyses are considered as 
exploratory, even if statistical tests are used.  
 
Descriptive statistics will be used to summarize the trial results, i.e., statistics for 
continuous variables may include means, medians, ranges and appropriate measures of 
variability. Qualitative variables will be summarized by counts and percentages. The 
uncertainty of estimates will be assessed by confidence intervals. 
 
14.6.1 Primary Endpoint Analyses  
 
The tumor response rate to neoadjuvant palbociclib monotherapy at the end of step 
one and the corresponding 95% confidence interval will be calculated for the whole 
sample. Exact binomial one sample proportion test will be conducted to compare 
the estimated tumor response rate to a null response rate of 17%.  
 
14.6.2 Secondary Endpoints Analyses  

Protocol Version: 11/13/20 
 
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Local-regional disease relapse rate and distant metastases rate and their 
corresponding 95% confidence intervals will be calculated in each cohort, 
separately. PFS and OS at two-year will be presented in subject listings. PFS and 
OS will be analyzed by Kaplan-Meier method in each cohort, separately. Paired t-
test or paired-sample Wilcoxon Signed Rank test will be used to compare the 
genomic, RNA, and protein expression data derived at baseline and then after two 
cycles of neoadjuvant palbociclib monotherapy. The association between the 
genomic, RNA, and protein expression data derived after 2 cycles of palbociclib 
monotherapy and local-regional disease relapse/distant metastases will be explored 
through independent t-test, Fisher’s Exact test, or Kruskal-Wallis test as 
appropriate.  
 
14.7 
Interim Efficacy Assessment and Interim Analyses 
 
An interim efficacy assessment will be performed after the first 14 patients are enrolled 
and have completed step one. Progression events will be the primary concern for the 
interim efficacy analysis. Progression, as used for this purpose, will be defined as disease 
progression on CT scan of the neck (assessed by RECIST criteria) occurring at the 
completion of step one. The occurrence of three or more progression events during step 
one will be cause to stop trial accrual to assess if the trial should be amended, closed, or 
continued as planned. The interim analysis will be prepared for preliminary (abstract) 
presentation at cancer meeting(s). Trial accrual will not be stopped while the interim 
efficacy analysis is ongoing.  The stopping rule will not be considered in this interim 
efficacy analysis given the small sample size. 
 
A safety assessment will be performed for the first 14 patients enrolled using a continuous 
method. The safety endpoint of interest is delays in starting potentially curative 
chemoradiation therapy defined as failure to start chemoradiation within three weeks of 
cycle 2 day 28 (of Step One) due to adverse events considered to be definitely, probably, 
or possibly related to palbociclib. Trial accrual should be stopped to assess if the trial 
should be amended, closed, or continued as planned, using the following thresholds for 
continuous assessment: 
 
# of patients delayed in starting chemoradiation 
In first # of patients 
2 
4 
2 
5 
2 
6 
3 
7 
3 
8 
3 
9 
4 
10 
4 
11 
4 
12 
4 
13 
5 
14 

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Page 60 of 76 
 
15.0 
REFERENCES 
 
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Chemotherapy and Radiotherapy for Organ Preservation in Advanced Laryngeal Cancer. N Engl 
J Med. 2003; 349(22):2091-8. 
[2] Forastiere AA, Zhang Q, Weber RS, Maor MH, Goepfert H,  Pajak TF, et al. Long-Term 
Results of RTOG 91-11: A Comparison of Three Nonsurgical Treatment Strategies to Preserve 
the Larynx in Patients With Locally Advanced Larynx Cancer. J Clin Oncol. 2013;31(7):845-52. 
[3] Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tan PF, et al. Human 
Papillomavirus and Survival of Patients with Oropharyngeal Cancer. N Engl J Med. 2010;363:24-
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 [4] Newman JR, Connolly TM, Illing EA, Kilgore ML, Locher JL and Carroll WR. Survival 
Trends in Hypopharyngeal Cancer: A Population-Based Review.  Laryngoscope. 2015;125:624-
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 [5] Lefebvre JL, Andry G, Chevalier D, Luboinski B, Collette L, Traissac L, et al. Laryngeal 
preservation with induction chemotherapy for hypopharyngeal squamous cell carcinoma: 10-year 
results of EORTC trial 24891. Ann Oncol.  2012;23(10):2708-14. 
[6] Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, et al. Radiotherapy plus 
cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354:567–78. 
 [7] Howlader N, Noone AM, Krapcho M, et al (eds). SEER Cancer Statistics Review, 1975-2012, 
National Cancer Institute.  Bethesda, MD, http://seer.cancer.gov/csr/1975_2012/ posted to the 
SEER website, April 2015.  
[8] Allen CT, Lewis Jr. JS, El-Mofty SK, Haughey BH, Nussenbaum B. Human Papillomavirus 
and oropharynx cancer: Biology, detection and clinical implications. Laryngoscope. 2010; 120: 
1756-72. 
[9] National Comprehensive Cancer Network. Head and Neck Cancers (Version 1.2015). 
http://nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf. Accessed March 24, 2016. 
[10] Ang KK, Zhang Q, Rosenthal DI, Nguyen-Tan, PF, Sherman EJ, Weber RS, et al. 
Randomized Phase III Trial of Concurrent Accelerated Radiation Plus Cisplatin with or Without 
Cetuximab for Stage III to IV Head and Neck Carcinoma: RTOG 0522. J Clin Oncol. 2014;32(27): 
2940-54.  
[11] Blanchard P, Baujat B, Holostenco V, Bourredjem A, Baey C, Bourhis J, et al. Meta-analysis 
of chemotherapy in head and neck cancer (MACH-NC): A comprehensive analysis by tumour site. 
Radiother Oncol. 2011;100:33-40.  
 [12] Petrelli F, Coinu A, Riboldi V, Borgonovo K, Ghilardi M, Cabiddu M, et al. Concomitant 
platinum-based chemotherapy or cetuximab with radiotherapy for locally advanced head and neck 
cancer: A systematic review and meta-analysis of published studies. Oral Oncol. 2014;50:1041-8. 
[13] Ley J, Mehan P, Wildes TM, Thorstad W, Gay HA, Michel L, et al. Cisplatin versus 
Cetuximab Given Concurrently with Definitive Radiation Therapy for Locally Advanced Head 
and Neck Squamous Cell Carcinoma.  Oncology. 2013;85:290-6. 
 [14] Chung CH, Parker JS, Karaca G, Wu J, Funkhouser WK, Moore D, et al. Molecular 
classification of head and neck squamous cell carcinomas using patterns of gene expression. 
Cancer Cell. 2004;5:489–500. 
[15] Chung CH, Parker JS, Ely K, Carter J, Yi Y, Murphy BA, et al. Gene expression profiles 
identify epithelial-to-mesenchymal transition and activation of nuclear factor-kappaB signaling as 

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characteristic of a high risk head and neck squamous cell carcinoma. Cancer Res. 2006;66:8210–
8. 
[16] Stransky N, Egloff AM, Tward AD, Kostic AD, Cibulskis K, Sivanchenko A, et al. The 
mutational landscape of head and neck squamous cell carcinoma. Science. 2011;333(6046):1157-
60. 
[17] Agrawal N, Frederick MJ, Pickering CR, Bettegowda C, Chang K, Li RJ, et al. Exome 
sequencing of head and neck squamous cell carcinoma reveals inactiving mutations in NOTCH1. 
Science. 2011;333(6046):1154-7. 
[18] Cancer Genome Atlas Network. Comprehensive genomic characterization of head and neck 
squamous cell carcinomas. Nature. 2015;517(7536):576-82. 
[19] Mountzios G, Rampias T, Psyrri A. The mutational spectrum of squamous-cell carcinoma of 
the head and neck: targetable genetic events and clinical impact. Ann Oncol. 2014;25(10):1889-
1900. 
[20] Seiwert TY, Zuo Z, Keck MK, Khattri A, Pedamallu CS, Stricker T, et al. Integrative and 
comparative genomic analysis of HPV-positive and HPV-negative head and neck squamous cell 
carcinomas. Clin Cancer Res. 2015;21(3):632-41. 
[21] Keck MK, Zuo Z, Khattri A, Stricker TP, Brown CD, Imanguli M, et al. Integrative analysis 
of head and neck cancer identifies two biologically distinct HPV and three non-HPV subtypes. 
Clin Cancer Res. 2015;21(4):870-81. 
[22] Allen CT, Lewis JS Jr, El-Mofty SK, Haughey BH, Nussenbaum B. Human Papillomavirus 
and oropharynx cancer: Biology, detection and clinical implications. Laryngoscope. 
2010;120:1756-72. 
[23] Smeets SJ, Braakhuis BJM, Abbas S, Snijders PJ, Ylstra B, van de Wiel MA, et al. Genome-
wide DNA copy number alterations in head and neck squamous cell carcinomas with or without 
oncogene-expressing human papillomavirus. Oncogene. 2006;25:2558–64. 
[24] Scantlebury JB, Luo J, Thorstad WL, El-Mofty SK, Lewis JS Jr. Cyclin D1—a prognostic 
marker in oropharyngeal squamous cell carcinoma that is tightly associated with high-risk human 
papillomavirus status. Human Pathol. 2013;44(8):1672-80.  
[25] Reed AL, Califano J, Cairns P, Westra WH, Jones RM, Koch W, et al. High frequency of p16 
(CDKN2/MTS-1/INK4A) inactivation in head and neck squamous cell carcinoma. Cancer Res. 
1996;56: 3630–3. 
[26] Kalish LH, Kwong RA, Cole IE, Gallagher RM, Sutherland RL, Musgrove EA. Deregulated 
Cyclin D1 Expression Is Associated with Decreased Efficacy of the Selective Epidermal Growth 
Factor Receptor Tyrosine Kinase Inhibitor Gefitinib in Head and Neck Squamous Cell Carcinoma 
Cell Lines. Clin Cancer Res. 2004;10:7764-74. 
[27] Zhang P, Zhang Z, Zhou X, Qiu W, Chen F, Chen W. Identification of genes associated with 
cisplatin resistance in human oral squamous cell carcinoma cell line. BMC Cancer. 2006;6: 224. 
[28] Zhou X, Zhang Z, Yang X, Chen W, Zhang P. Inhibition of cyclin D1 expression by cyclin 
D1 shRNAs in human oral squamous cell carcinoma cells is associated with increased cisplatin 
chemosensitivity. Int J Cancer. 2009;124:483-9. 
[29] Feng Z, Guo W, Zhang C, Xu Q, Zhang P, Sun J, et al. CCND1 as a Predictive Biomarker of 
Neoadjuvant Chemotherapy in Patients with Locally Advanced Head and Neck Squamous Cell 
Carcinoma. PLoS ONE. 2011;6:e26399. 
[30] Hirama T, Koeffler HP. Role of the Cyclin-Dependent Kinase Inhibitors in the Development 
of Cancer. Blood. 1995;86:841-54. 

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[31] Fry DW, Harvey PJ, Keller PR, Elliott WL, Meade M, Trachet E, et al. Specific Inhibition of 
cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor 
xenografts. Mol Cancer Ther. 2004;3:1427-37. 
[32] Finn RS, Dering J, Conklin D, Kalous O, Cohen DJ, Desai AJ, et al. PD 0332991, a selective 
cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-
positive human breast cancer cell lines in vitro. Breast Cancer Res.  2009;11(5):1-13. 
[33] Baughn LB, Di Liberto MD, Wu K, Toogood P, Louie T, Gottschalk R, et al. A Novel Orally 
Active Small Molecule Potently Induces G1 Arrest in Primary Myeloma Cells and Prevents Tumor 
Growth by Specific Inhibition of Cyclin-Dependent Kinase 4/6. Cancer Res. 2006;66(15):7661-7. 
[34] Flaherty KT, LoRusso PM, Demichele A, Abramson VG, Courtney R, Randolph SS, et al. 
Phase I, Does-Escalation Trial of the Oral Cyclin-Dependent Kinase 4/6 Inhibitor PD 0332991, 
Administered Using a 21-Day Schedule in Patients with Advanced Cancer. Clin Cancer Res. 
2012;18:568-76. 
[35] Schwartz GK, LoRusso PM, Dickson MA, Randolph SS, Shaik MN, Wilner KD, et al. Phase 
I study of PD 0332991, a cyclin-dependent kinase inhibitor, administered in 3-week cycles 
(Schedule 2/1). Brit J Cancer. 2011;104:1862-8. 
[36] Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, et al. The cyclin-dependent 
kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line 
treatment of estrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-
1/TRIO-18): a randomized phase 2 study. Lancet Oncol. 2015;16:25-35.  
[37] Leonard JP, LaCasce AS, Smith MR, Noy A, Chirieac LR, Rodig SJ, et al. Selective CDK4/6 
inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma. Blood. 
2012;119:4597-607. 
[38] Michel L, Ley J, Wildes TM, Schaffer A, Robinson A, Chun S, et al. Phase I trial of 
Palbociclib, A Selective Cyclin Dependent Kinase 4/6 Inhibitor, in Combination with Cetuximab 
in Patients with Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma. Oral Oncol. 
2016;58:41-8. 
[39] Vermorken JB, Trigo J, Hitt R, Koralewski P, Diaz-Rubio E, Rolland F, et al. Open-label, 
Uncontrolled, Multicenter Phase II Study to Evaluate the Efficacy and Toxicity of Cetuximab as a 
Single Agent in Patients with Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head 
and Neck who Failed to Respond to Platinum-Based Therapy. J Clin Oncol. 2007;25(16):2171-7. 
 
We would like to thank the Alvin J. Siteman Cancer Center at Washington University School of 
Medicine and Barnes-Jewish Hospital in St. Louis, Missouri, for the use of the Clinical Trials 
Core which provided protocol development services. The Siteman Cancer Center is supported in 
part by an NCI Cancer Center Support Grant #P30 CA91842. 
 
 

Protocol Version: 11/13/20 
 
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APPENDIX A: ECOG Performance Status Scale 
 
 
Grade 
 
 
Description 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
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). 
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. 
3 
 
In bed >50% of the time.  Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
 
Dead. 
 
 
 
 

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APPENDIX B: Medication Diary 
 
Today’s Date:    
 
 
Agent:  Palbociclib 
Cycle:    
 
Study ID#:   
 
 
 
Formulation: ___ Liquid   ___ Capsules  
Route (if liquid): ___ By mouth   ___ Feeding tube 
 
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for each cycle.  Take _____mg of palbociclib at approximately the same time each day with 
food (if capsules) or with or without food (if liquid).  Swallow the capsules whole and do not chew them. 
2. Record the date, the number of capsules taken, and when you took them. 
3. If you forget to take your dose before 6:00PM, then do not take a dose that day.  Restart taking it the next day. 
4. If you have any questions or notice any side effects, please record them in the comments section.  Record the 
time if you should vomit. 
5. Please return the forms when you go to your next appointment.  Please bring your unused study medications 
and/or empty bottles with you to each clinic visit so that a pill count can be done. 
6. Avoid St. John’s Wort, Seville oranges, grapefruit, grapefruit juice, grapefruit hybrids, pummelos, and exotic 
citrus fruits from 7 days before you start taking palbociclib and throughout the entire study.   
Day 
Date 
What time was 
dose taken? 
# of capsules 
taken, if applicable 
Comments 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
22 
 
 
 
 
23 
 
 
 
 
24 
 
 
 
 
25 
 
 
 
 
26 
 
 
 
 
27 
 
 
 
 
28 
 
 
 
 

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APPENDIX C: Pfizer Reportable Event Cover Sheet 
 
 
 

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APPENDIX D: EORTC QLQ-C30 
 
We are interested in some things about you and your health. Please answer all of the questions 
yourself by circling the number that best applies to you. There are no "right" or "wrong" 
answers. The information that you provide will remain strictly confidential. 
 
 
Not 
at 
All 
A 
Little 
Quite a 
bit 
Very 
Much 
1. Do you have any trouble doing strenuous activities, 
like carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
2. Do you have any trouble taking a long walk? 
1 
2 
3 
4 
3. Do you have any trouble taking a short walk outside of 
the house? 
1 
2 
3 
4 
4. Do you need to stay in bed or a chair during the day? 
1 
2 
3 
4 
5. Do you need help with eating, dressing, washing 
yourself or using the toilet? 
1 
2 
3 
4 
During the past week: 
Not 
at 
All 
A 
Little 
Quite a 
Bit 
Very 
Much 
6. Were you limited in doing either your work or other 
daily activities? 
1 
2 
3 
4 
7. Were you limited in pursuing your hobbies or other 
leisure time activities? 
1 
2 
3 
4 
8. Were you short of breath? 
1 
2 
3 
4 
9. Have you had pain? 
1 
2 
3 
4 
10. Did you need to rest? 
1 
2 
3 
4 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
12. Have you felt weak? 
1 
2 
3 
4 
13. Have you lacked appetite? 
1 
2 
3 
4 
14. Have you felt nauseated? 
1 
2 
3 
4 
15. Have you vomited? 
1 
2 
3 
4 
16. Have you been constipated? 
1 
2 
3 
4 
During the past week: 
Not 
at 
All 
A 
Little 
Quite a 
Bit 
Very 
Much 
17. Have you had diarrhea? 
 
 
 
 
18. Were you tired? 
 
 
 
 
19. Did pain interfere with your daily activities? 
 
 
 
 
20. Have you had difficulty in concentrating on things, 
like reading a newspaper or watching television? 
 
 
 
 
21. Did you feel tense? 
 
 
 
 
22. Did you worry? 
 
 
 
 
23. Did you feel irritable? 
 
 
 
 
24. Did you feel depressed? 
 
 
 
 

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Page 67 of 76 
25. Have you had difficulty remembering things? 
 
 
 
 
26. Has your physical condition or medical treatment 
interfered with your family life? 
 
 
 
 
27. Has your physical condition or medical treatment 
interfered with your social activities? 
 
 
 
 
28. Has your physical condition or medical treatment 
caused you financial difficulties? 
 
 
 
 
For the following questions please circle the number between 1 and 7 that 
best applies to you 
29. How would you rate your overall health during the past week? 
1 
2 
3 
4 
5 
6 
7 
Very Poor 
 
 
 
 
 
Excellent 
30. How would you rate your overall quality of life during the past week? 
1 
2 
3 
4 
5 
6 
7 
Very Poor 
 
 
 
 
 
Excellent 
 
 
 

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

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

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

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APPENDIX F: Definitions for Adverse Event Reporting 
 
A. Adverse Events (AEs) 
 
As defined in 21 CFR 312.32: 
 
Definition: any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug-related. 
 
Grading: the descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting.  A 
copy of the CTCAE version 4.0 can be downloaded from the CTEP website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the terms 
listed that should be used are those provided by the Department of Health and Human Services’ 
Office for Human Research Protections (OHRP).  A copy of this guidance can be found on 
OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
B. Suspected Adverse Reaction (SAR) 
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse event for which there is a reasonable possibility that the drug caused 
the adverse event.  “Reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the adverse event.  “Suspected adverse reaction” implies a 
lesser degree of certainty about causality than adverse reaction, which means any adverse event 
caused by a drug. 
 
C. Life-Threatening Adverse Event / Life Threatening Suspected Adverse Reaction  
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse drug event or suspected adverse reaction is considered “life-
threatening” if, in the view of the investigator, its occurrence places the patient at immediate 
risk of death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death. 
 
D.  Serious Adverse Event (SAE) or Serious Suspected Adverse Reaction 
 
As defined in 21 CFR 312.32: 
 
Definition:  an adverse event or suspected adverse reaction is considered “serious” if, in the 
view of the investigator, it results in any of the following outcomes: 
o Death 
o A life-threatening adverse event 

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o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
o A congenital anomaly/birth defect 
o Any other important medical event that does not fit the criteria above but, based upon 
appropriate medical judgment, may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed above 
 
E. Protocol Exceptions 
 
Definition: A planned change in the conduct of the research for one participant. 
 
F. Deviation 
 
Definition: Any alteration or modification to the IRB-approved research without prospective 
IRB approval.  The term “research” encompasses all IRB-approved materials and documents 
including the detailed protocol, IRB application, consent form, recruitment materials, 
questionnaires/data collection forms, and any other information relating to the research study. 
 
A minor or administrative deviation is one that does not have the potential to negatively impact 
the rights, safety, or welfare of participants or others or the scientific validity of the study. 
 
A major deviation is one that does have the potential to negatively impact the rights, safety, or 
welfare of participants or others or the scientific validity of the study. 
 

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APPENDIX G: Reporting Timelines 
 
Expedited Reporting Timelines 
Event 
HRPO 
QASMC 
FDA 
Drug/Device 
Manufacturer 
Serious AND unexpected 
suspected adverse reaction 
 
 
Report no later than 15 
calendar days after it is 
determined that the 
information qualifies for 
reporting 
Within 24 hours of first 
awareness of the event  
Unexpected fatal or life-
threatening suspected 
adverse reaction 
 
 
Report no later than 7 
calendar days after initial 
receipt of the information 
Immediately if the event is 
fatal or life-threatening 
Unanticipated problem 
involving risk to 
participants or others 
Report within 10 working 
days.  If the event results in 
the death of a participant 
enrolled at WU/BJH/SLCH, 
report within 1 working day. 
Report via email after IRB 
acknowledgment 
 
 
Major deviation 
Report within 10 working 
days.  If the event results in 
the death of a participant 
enrolled at WU/BJH/SLCH, 
report within 1 working day. 
 
 
 
A series of minor deviations 
that are being reported as a 
continuing noncompliance 
Report within 10 working 
days.   
 
 
 
Protocol exception 
Approval must be obtained 
prior to implementing the 
change 
 
 
 
Clinically important 
increase in the rate of a 
serious suspected adverse 
 
 
Report no later than 15 
calendar days after it is 
determined that the 
 

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Event 
HRPO 
QASMC 
FDA 
Drug/Device 
Manufacturer 
reaction of that list in the 
protocol or IB 
information qualifies for 
reporting 
Complaints 
If the complaint reveals an 
unanticipated problem 
involving risks to 
participants or others OR 
noncompliance, report 
within 10 working days.  If 
the event results in the death 
of a participant enrolled at 
WU/BJH/SLCH, report 
within 1 working day.  
Otherwise, report at the time 
of continuing review. 
 
 
 
Breach of confidentiality 
Within 10 working days. 
 
 
 
Incarceration 
If withdrawing the 
participant poses a safety 
issue, report within 10 
working days.   
 
If withdrawing the 
participant does not 
represent a safety issue and 
the patient will be 
withdrawn, report at 
continuing review. 
 
 
 
 
 
 
 
 

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Routine Reporting Timelines 
Event 
HRPO 
QASMC 
FDA 
Drug/Device 
Manufacturer 
Adverse event or SAE that 
does not require expedited 
reporting 
If they do not meet the 
definition of an 
unanticipated problem 
involving risks to 
participants or others, report 
summary information at the 
time of continuing review 
Adverse events will be 
reported in the toxicity table 
in the DSM report which is 
typically due every 6 
months. 
The most current toxicity 
table from the DSM report 
is provided to the FDA with 
the IND’s annual report. 
 
Minor deviation 
Report summary 
information at the time of 
continuing review. 
 
 
 
Complaints 
If the complaint reveals an 
unanticipated problem 
involving risks to 
participants or others OR 
noncompliance, report 
within 10 working days.  If 
the event results in the death 
of a participant enrolled at 
WU/BJH/SLCH, report 
within 1 working day.  
Otherwise, report at the time 
of continuing review. 
 
 
 
Incarceration 
If withdrawing the 
participant poses a safety 
issue, report within 10 
working days.   
 
If withdrawing the 
participant does not 
represent a safety issue and 
 
 
 

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the patient will be 
withdrawn, report at 
continuing review.