Conditions: Carcinoma, Squamous Cell of Head and Neck
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 96
Healthy volunteers: no

Brief summary:
The purpose of this Phase I/II study is to define the maximum tolerated dose of PD 0332991 given with cetuximab and evaluated the side effects of the combination.

Detailed description:

Arms:
arm 1: PD 0332991 will be administered on Days 1 through 21 of each 28 day cycle.

Cetuximab will be administered intravenously on a weekly schedule. The first dose will be 400 mg/m2. The remaining weekly dose will be 250 mg/m2. Participants will continue to receive weekly cetuximab at 250 mg/m2 for the duration of their participation on study. arm 2: PD 0332991 will be administered on Days 1 through 21 of each 28 day cycle.

Cetuximab will be administered intravenously on a weekly schedule. The first dose will be 400 mg/m2. The remaining weekly dose will be 250 mg/m2. Participants will continue to receive weekly cetuximab at 250 mg/m2 for the duration of their participation on study. arm 3: PD 0332991 will be administered on Days 1 through 21 of each 28 day cycle.

Cetuximab will be administered intravenously on a weekly schedule. The first dose will be 400 mg/m2. The remaining weekly dose will be 250 mg/m2. Participants will continue to receive weekly cetuximab at 250 mg/m2 for the duration of their participation on study. arm 4: PD 0332991 will be administered on Days 1 through 21 of each 28 day cycle.

Cetuximab will be administered intravenously on a weekly schedule. The first dose will be 400 mg/m2. The remaining weekly dose will be 250 mg/m2. Participants will continue to receive weekly cetuximab at 250 mg/m2 for the duration of their participation on study. arm 5: PD 0332991 will be administered on Days 1 through 21 of each 28 day cycle.

Cetuximab will be administered intravenously on a weekly schedule. The first dose will be 400 mg/m2. The remaining weekly dose will be 250 mg/m2. Participants will continue to receive weekly cetuximab at 250 mg/m2 for the duration of their participation on study.

Interventions: intervention 1: Cetuximab intervention 2: PD 0332991
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_SAP_000.pdf: 
Protocol Version: Amendment 6; 10/24/17 
 
Page 1 of 73 
 
 
 
 
Phase I/II Trial of the Addition of PD 0332991 to Cetuximab in Patients with Incurable 
SCCHN 
 
Washington University School of Medicine 
Division of Oncology 
660 South Euclid Avenue, Campus Box 8056 
St. Louis, MO  63110 
 
Protocol#: 201404139  
Version Date: 10/24/17  
 
Coordinating Center: 
Washington University School of Medicine 
 
Principal Investigator: 
Douglas Adkins, M.D. 
Phone: (314) 362-4471 
E-mail: dadkins@wustl.edu  
 
Sub-Investigators 
 
 
Institution 
 
 
 
Modality 
Kathryn Trinkaus, Ph.D. 
 
Washington University  
 
Biostatistics 
Tanya Wildes, M.D. 
 
 
Washington University  
 
Medical Oncology 
Peter Oppelt, M.D. 
 
 
Washington University  
 
Medical Oncology 
Assuntina Sacco, M.D.  
 
University of California – San Diego 
Medical Oncology 
Konstantinos Arnaoutakis, M.D. 
University of Arkansas  
 
Medical Oncology 
Yifan Tu, M.D., Ph.D.  
 
St. Louis University 
 
 
Medical Oncology 
Prakash Neupane, M.D.  
 
Kansas University 
 
 
Medical Oncology 
Nabil Saba, M.D. 
 
 
Emory University 
 
 
Medical Oncology 
Conor Steuer, M.D. 
 
 
Emory University 
 
 
Medical Oncology 
Frank Worden, M.D. 
 
 
University of Michigan  
 
Medical Oncology 
Juneko Grilley-Olson, M.D. 
 
University of North Carolina 
 
Medical Oncology 
Ronald Maggiore, M.D.  
 
University of Rochester  
 
Medical Oncology 
Katharine Price, M.D.                          
Mayo Clinic                                         
Medical Oncology 
 
Study Drug: PD 0332991 (palbociclib) 
 
 
 
 
IND #:   
122402 
Clinical Trials.gov #:   
NCT02101034 
 
 
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 
 
 


Protocol Version: Amendment 6; 10/24/17 
 
Page 2 of 73 
 
Phase I/II Trial of the Addition of PD 0332991 to Cetuximab in Patients with Incurable 
SCCHN 
 
Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
05/06/2014 
Amendment #1 Version 
 
 
 
 
 
 
07/07/2014 
Amendment #2 Version 
 
 
 
 
 
 
12/22/2014 
Amendment #3 Version 
 
 
 
 
 
 
12/16/2015 
Amendment #4 Version 
 
 
 
 
 
 
06/07/2016 
Amendment #5 Version 
 
 
 
 
 
 
09/06/2017 
Amendment #6 Version 
 
 
 
 
 
 
10/24/2017 
 
 


Protocol Version: Amendment 6; 10/24/17 
 
Page 3 of 73 
 
Phase I/II Trial of the Addition of PD 0332991 to Cetuximab in Patients with Incurable 
SCCHN 
 
Principal Investigator Signature Page 
 
 
Principal Investigator: 
 
Douglas R. Adkins, M.D. 
 
 
 
 
 
Signature of Investigator 
 
Date 
 
 
 
Printed Name of Investigator 
 
 
 
By my signature, I agree to personally supervise the 
conduct of this study and to ensure its conduct in 
compliance with the protocol, informed consent, 
IRB/HRPO procedures, the Declaration of Helsinki, ICH 
Good Clinical Practices guidelines, and the applicable 
parts of the United States Code of Federal Regulations or 
local regulations governing the conduct of clinical 
studies. 
 
 
 
 


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Phase I/II Trial of the Addition of PD 0332991 to Cetuximab in Patients with Incurable 
SCCHN 
 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose Escalation Schedule (for the Phase I portion) 
Dose Level 
PD 0332991 Dose* 
Cetuximab Dose 
Level -1 
75 mg 
Loading dose: 400 mg/m2 
Weekly thereafter: 250 mg/m2 for 
the duration of study participation 
Level 1 (Starting Dose) 
100 mg 
Level 2 
125 mg 
 
* PD 0332991 is administered on Days 1 through 21 of each 28-day cycle. 
 
Treatment Plan 
PD 0332991 PO Days 1-21 of each 28 day cycle 
Cetuximab weekly 
Dosing of PD 0332991 for phase II is 125 mg (based 
on Phase I results) 
 
CT scans every 2 cycles 
Eligible Patients 
 Incurable SCCHN 
 Any (or no) prior therapy acceptable for phase I; prior treatment with a 
platin agent for Arm 1 of phase II; prior treatment with cetuximab for Arms 
2 and 3 of phase II 
 Prior treatment with cetuximab acceptable for phase I and for Arms 2 and 3 
of phase II only 
 HPV-related or -unrelated for phase I; only HPV-unrelated for Arms 1 and 
2 of phase II; only HPV-related for Arm 3 of phase II 


Protocol Version: Amendment 6; 10/24/17 
 
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Glossary of Abbreviations 
 
AE 
Adverse event 
ALT (SGPT) 
Alanine transaminase (serum glutamate pyruvic transaminase) 
ANC 
Absolute neutrophil count 
AST (SGOT) 
Aspartate transaminase (serum glutamic oxaloacetic transaminase) 
AUC 
Area under the curve 
B-HCG 
Beta human chorionic gonadotropin  
CBC 
Complete blood count 
CDK 
Cyclin dependent kinase 
CR 
Complete response 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
DLTs 
Dose Limiting Toxicities 
DNA 
deoxyribonucleic acid 
DSM 
Data and Safety Monitoring  
ECG (or EKG) 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EGFR 
Epidermal growth factor receptor 
ER 
Estrogen receptor 
FDA 
Food and Drug Administration 
FFPE 
Formalin-fixed paraffin-embedded 
FISH 
fluorescent in situ hybridization 
FWA 
Federal wide assurance 
GI 
Gastrointestinal 
HIV 
Human Immunodeficiency Virus 
HPV 
Human papilloma virus 
HRPO 
Human Research Protection Office (IRB) 
HSR 
Hypersensitivity reaction 
IHC 
Immunohistochemistry 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IULN 
Institutional upper limit of normal 
IV 
Intravenous (i.v.) 
IVPB 
IV push bolus 
LFT 
Liver function test 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 


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NIH 
National Institutes of Health 
OHRP 
Office of Human Research Protections  
OPSCC 
Oropharyngeal squamous cell carcinoma 
OS 
Overall survival 
PD 
Progressive disease 
PDX 
Patient derived xenograft 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PI 
Principal investigator 
PK 
Pharmacokinetic 
PR 
Partial response 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QASMC 
Quality Assurance and Safety Monitoring Committee 
QD 
Quaque die (once a day) 
QTc 
Corrected QT interval 
RECIST 
Response Evaluation Criteria in Solid Tumors (Committee) 
SAE 
Serious adverse event 
SCC 
Siteman Cancer Center 
SCCHN 
Squamous cell carcinoma of the head and neck 
SD 
Stable disease 
TTP 
Time to progression 
UPN 
Unique patient number 
US 
Ultrasound 
WHO 
World Health Organization 
 
 


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Table of Contents 
SCHEMA ........................................................................................................................................ 4 
1.0 
BACKGROUND AND RATIONALE ................................................................................ 9 
1.1 
Squamous Cell Carcinoma of the Head and Neck ........................................................... 9 
1.2 
EGFR ................................................................................................................................ 9 
1.3 
CCND1 and p16 in SCCHN............................................................................................. 9 
1.4 
CDK4/6 .......................................................................................................................... 10 
1.5 
Investigational Agent(s) ................................................................................................. 10 
1.6 
CDK4/6 Inhibition in HNSCC: Pre-Clinical Evidence of Tumor Response ................. 12 
1.7 
Study Rationale .............................................................................................................. 13 
1.8 
Amendment 6: Addition of Arm 3 to Phase II ............................................................... 14 
1.9 
Correlative Studies Background..................................................................................... 15 
2.0 
OBJECTIVES .................................................................................................................... 15 
2.1 
Primary Objectives ......................................................................................................... 15 
2.2 
Secondary Objectives ..................................................................................................... 16 
2.3 
Exploratory Objectives ................................................................................................... 16 
3.0 
PATIENT SELECTION .................................................................................................... 16 
3.1 
Inclusion Criteria ............................................................................................................ 16 
3.2 
Exclusion Criteria ........................................................................................................... 18 
3.3 
Inclusion of Women and Minorities............................................................................... 19 
4.0 
REGISTRATION PROCEDURES ................................................................................... 19 
4.1 
Confirmation of Patient Eligibility ................................................................................. 19 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database ........................... 20 
4.3 
Assignment of UPN ....................................................................................................... 20 
5.0 
TREATMENT PLAN ........................................................................................................ 20 
5.1 
Premedication for Cetuximab......................................................................................... 20 
5.2 
Agent Administration ..................................................................................................... 20 
5.3 
Re-Treatment Criteria .................................................................................................... 21 
5.4 
Dose Escalation Schema for Phase I .............................................................................. 22 
5.5 
Definition of MTD, DLT, Dose Escalation Criteria, and Toxicity, Response, and DLT 
Evaluations for Phase I .............................................................................................................. 22 
5.6 
Dosing for Phase II ......................................................................................................... 23 
5.7 
General Concomitant Medication and Supportive Care Guidelines .............................. 24 
5.8 
Women of Childbearing Potential .................................................................................. 24 
5.9 
Duration of Therapy ....................................................................................................... 24 
5.10 Duration of Follow-up .................................................................................................... 25 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS .................................................................... 25 
6.1 
Dose Modifications for PD 0332991 ............................................................................. 25 
6.2 
Dose Modifications or Delays for Cetuximab................................................................ 26 
7.0 
REGULATORY AND REPORTING REQUIREMENTS ............................................... 29 
7.1 
Definitions ...................................................................................................................... 29 
7.2 
Reporting to the Human Research Protection Office (HRPO) at Washington University
 
31 
7.3 
Reporting to the Quality Assurance and Safety Monitoring Committee (QASMC) at 
Washington University .............................................................................................................. 32 
7.4 
Reporting Requirements for Secondary Sites ................................................................ 32 


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7.5 
Reporting to Secondary Sites ......................................................................................... 32 
7.6 
Reporting to the FDA ..................................................................................................... 33 
7.7 
Reporting to Pfizer ......................................................................................................... 33 
7.8 
Timeframe for Reporting Required Events .................................................................... 34 
8.0 
PHARMACEUTICAL INFORMATION .......................................................................... 34 
8.1 
PD 0332991 (Palbociclib) .............................................................................................. 34 
8.2 
Cetuximab (Erbitux) ....................................................................................................... 41 
9.0 
CORRELATIVE STUDIES .............................................................................................. 44 
9.1 
Optional Tumor Biopsy .................................................................................................. 44 
9.2 
Archival Tumor Tissue................................................................................................... 45 
9.3 
Blood for Pharmacokinetic Analysis.............................................................................. 45 
9.4 
Quality of Life ................................................................................................................ 46 
10.0 STUDY CALENDAR ....................................................................................................... 47 
11.0 DATA SUBMISSION SCHEDULE ................................................................................. 47 
12.0 MEASUREMENT OF EFFECT........................................................................................ 48 
12.1 Antitumor Effect – Solid Tumors................................................................................... 48 
12.2 Disease Parameters ......................................................................................................... 49 
12.3 Methods for Evaluation of Measurable Disease ............................................................ 50 
12.4 Response Criteria ........................................................................................................... 52 
13.0 DATA AND SAFETY MONITORING ............................................................................ 55 
14.0 AUDITING ........................................................................................................................ 56 
15.0 STATISTICAL CONSIDERATIONS............................................................................... 57 
15.1 Correlative Studies ......................................................................................................... 59 
16.0 MULTICENTER REGULATORY REQUIREMENTS ................................................... 59 
17.0 REFERENCES .................................................................................................................. 61 
APPENDIX A: ECOG Performance Status Scale ........................................................................ 64 
APPENDIX B: Medication Diary ................................................................................................. 65 
APPENDIX C: Pfizer Reportable Event Cover Sheet .................................................................. 66 
APPENDIX D: CYP3A4 Inhibitors, Inducers, and Substrates..................................................... 67 
APPENDIX E: EORTC QLQ-C30 ............................................................................................... 69 
APPENDIX F: FACT-H&N ......................................................................................................... 71 
 
 


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1.0 
BACKGROUND AND RATIONALE 
 
1.1 
Squamous Cell Carcinoma of the Head and Neck 
 
Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most common cancer.  
Approximately 600,000 new cases occur yearly, and most patients present with locally 
advanced disease.  Current multimodality therapy results in 5-year overall survival (OS) of 
only 40-50%. 
 
SCCHN is a heterogeneous disease which is not completely defined by clinical variables 
such as primary tumor stage, nodal stage, and sub-site. Smoking is the most common 
etiologic agent.  More recently, human papillomavirus (HPV) was shown to be an 
important causative agent in oropharyngeal SCC (OPSCC).  Assessment of p16 by 
immunohistochemistry (IHC) is an excellent surrogate marker of transcriptionally active 
HPV in OPSCC since nearly all cases of HPV-related OPSCC will demonstrate strong and 
diffuse staining for p16.  OPSCC due to HPV carries a much better prognosis compared to 
OPSCC due to smoking, establishing the importance of HPV as a stratification variable in 
OPSCC.1 
 
Gene expression profiling has highlighted the heterogeneity of SCCHN.  Chung, et al 
identified four subtypes of SCCHN using expression profiling: 1) EGFR enriched, 2) 
mesenchymal-like, 3) normal tonsil-like, and 4) anti-oxidant enriched.2-3 Prognosis varied 
amongst these subgroups.  Importantly, the unique gene expression profile of each 
subgroup shed light on potential molecular drivers which can define tumors likely to be 
sensitive or resistant to selected targeted therapies. 
 
1.2 
EGFR 
 
EGFR is overexpressed in many cases of SCCHN and is clearly important in this disease.  
Cetuximab, a monoclonal antibody against EGFR, is the only molecularly targeted therapy 
to date that has been shown to improve OS in SCCHN.4-5 These data are proof-of-principle 
that defining the molecular drivers of the various subsets of SCCHN can lead to further 
improvements in treatment outcomes.  However, the relative benefit of cetuximab in the 
treatment of SCCHN has been modest, suggesting that most cases of SCCHN are primarily 
dependent on non-EGFR molecular drivers. 
 
1.3 
CCND1 and p16 in SCCHN 
 
CCND1, which encodes cyclin D1, is amplified in 80% or more cases of HPV-unrelated 
SCCHN6 and is a marker of poor prognosis.7-15  Internal data from this institution (J. Lewis, 
unpublished observations) showed that 116 of 121 (96%) cases of HPV-unrelated SCCHN 
had expression of cyclin D1 as assessed by IHC, and in the majority of cases, ≥ 20% of 
nuclei stained positive (range, 1-95%).  These observations did not vary across subsites as 
nearly all cases of larynx, hypopharynx, oral cavity and HPV-unrelated oropharynx 
SCCHN had expression of cyclin D1 by IHC.  In contrast, CCND1 is overexpressed in 


Protocol Version: Amendment 6; 10/24/17 
 
Page 10 of 73 
 
only 14% of cases of HPV-related OPSCC.16 CDKN2A, which encodes p16INK4a, is 
inactivated in most cases of HPV-unrelated SCCHN by mutation, methylation in 
combination with chromosome loss or by homozygous deletion.17 Over expression of 
cyclin D1 along with decreased expression of p16 and abrogation of p53 function cause 
cellular immortalization of oral keratinocytes.18 Thus, cyclin D1 over expression in the 
context of decreased expression of p16 is likely to be an important driver of HPV-
unrelated SCCHN.   
 
The consequences of cyclin D1 amplification for response to therapy are not well 
characterized; however, emerging data suggests that cyclin D1 amplification may 
adversely affect response of SCCHN tumors to the two most effective drugs used in the 
treatment of this disease: EGFR inhibitors and cisplatin.  CCND1 is one of the many genes 
induced by intranuclear EGFR, linking cell cycle progression to EGFR stimulation.19  Data 
from SCCHN cell lines suggest an association between resistance to EGFR inhibitors and 
cyclin D1 amplification and/or overexpression.20  In EGFR-mutant lung cancer cells, cyclin 
D1 expression was higher in comparison to EGFR-wild type cells.21  EGFR-mutant 
gefitinib-resistant lung cancer cells were sensitive to the CDK inhibitor flavopiridol, 
confirming the importance of the cycle D axis as a key downstream effector of mutant 
EGFR signaling.  Cyclin D1 overexpression in SCCHN was associated with cisplatin 
resistance in vitro and in vivo 22, 23 and data from patients with SCCHN has emerged that 
supports a similar relationship of cyclin D1 expression as a predictive biomarker of 
cisplatin resistance.24   
 
1.4 
CDK4/6 
 
Cyclin-dependent kinases (CDKs), play a key role in regulating cell cycle progression and 
manage cellular transitions from growth phase (G1 and G2) into phases associated with 
DNA replication (S) and mitosis (M).25,26 Interaction between CDKs and cyclin proteins, 
such as cyclin D, has been shown to be crucial in the progression of G1 to S in the cell 
cycle.27  Deregulation of aspects of the cell-cycle, including CDKs, have been shown to 
contribute to the development of cancer.25,27 CDK4 and CDK6 are two closely related 
kinases that enable tumor cell progression during phase G1 to phase S in the cell cycle.26  
CDK 4 and 6 stimulate cell cycle progression, necessary for DNA replication and for cell 
division, in combination with cyclin D.26  In preclinical studies, increased levels of cyclin 
D and decreased levels of p16, a naturally occurring inhibitor of CDK4, have been 
associated with increased sensitivity to CDK 4 and 6 inhibition.27  Preclinical studies 
suggest that inhibition of cyclin D-dependent kinase activity may prevent tumor growth.26  
Inhibition of CDK 4 and 6 has been shown to prevent the deactivation of retinoblastoma 
(Rb), a tumor suppressor protein, and interfere with tumor cell progression.28 
 
 
1.5 
Investigational Agent(s) 
 
PD 0332991 is an investigational, orally active and highly selective inhibitor of the CDK4 
and CDK6 kinases26 with low activity against a panel of 36 other protein kinases.  PD 
0332991 showed antiproliferative effects on Rb-positive cells in vitro and inhibition of 
tumor growth in several Rb-positive human breast and colon xenografts.26 In these models, 


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PD 0332991 resulted in decreased Rb phosphorylation and decreased Ki-67 expression.26 
PD 0332991 showed no activity in Rb-negative tumor xenografts.26  
 
Pfizer is evaluating PD 0332991 in multiple phase I, phase II, and phase III studies.  Two 
phase I trials evaluated single agent administration of PD 0332991 to patients with Rb-
positive cancers.29,30 One of these trials determined that the dose-limiting toxicity (DLT) 
of PD 0332991 was neutropenia and the maximum tolerated dose (MTD) was 125 mg once 
daily when administered for 21 of 28 days (3/1 schedule).29 The most common non-
hematologic adverse events included fatigue, nausea, and diarrhea.  The mean half-life of 
PD 0332991 was 25.9 hours.  Patients were selected for Rb-positive cancers, based on IHC 
stain, defined as positive if staining intensity was 1+ or greater above background.  Stable 
disease for ≥ 4 cycles (16 weeks) occurred in 27% of evaluable patients and in a number 
of tumor types (liposarcoma, testicular, renal, ovarian, breast, appendiceal, peritoneal, 
melanoma, thymoma and lung).  Another phase I trial of PD 0332991 using an alternative 
dosing plan (21 day cycles; 2/1 schedule) observed a similar likelihood of disease control 
in a variety of tumor types.30 These studies demonstrate that PD 0332991 has substantial 
activity in Rb-positive tumors.  
  
Results of a phase I study in estrogen-receptor positive, HER2-negative advanced breast 
cancer not selected for cyclin D1 amplification and/or p16 loss showed that the 
combination of PD 0332991 and letrozole was generally well tolerated, with the 
recommended dose of PD 0332991 to be 125 mg once daily.31  A second study was a 
randomized phase II trial initiated to determine the overall safety and efficacy of PD 
0332991 (125 mg) and letrozole (2.5 mg) versus letrozole alone in post-menopausal 
women with ER+ HER2- advanced breast cancer.32,33  Patients’ tumors were either 
unselected (Part 1) or selected (Part 2) for presence of biomarkers: cyclin D1 amplification 
by FISH and/or p16 loss.  In Part 1 of the trial, the objective response rate was 27% versus 
23% with PD 0332991 plus letrozole versus letrozole alone and the clinical benefit rate 
was 59% versus 44%, respectively.32 When Parts 1 and 2 of the trial were combined, the 
objective response rate was 45% for those women who received PD 0332991 plus letrozole 
versus 31% for those who received letrozole alone.  The clinical benefit rate (defined as 
complete response plus partial response plus stable disease for ≥24 weeks) was 70% versus 
44%, respectively.  The differences observed in the objective response rate and clinical 
benefit rate were statistically significant.  Importantly, the median progression-free 
survival (PFS) was significantly different (26.2 versus 7.5 months) favoring the 
combination arm.  The most frequently reported treatment-related Grade 3/4 adverse events 
(AEs) in patients who received the combination therapy were neutropenia, leukopenia, 
anemia and fatigue. 
  
PD 0332991 is also active in relapsed mantle cell lymphoma selected for cyclin D1 
overexpression.34 The objective response (CR or PR) rate was 18% and the stable disease 
rate was 41%.  Significant reductions in phospho-Rb (89%) and Ki-67 (74%) occurred in 
paired biopsy samples after treatment with PD 0332991. 
   
Taken together, these data provide sound evidence that inhibition of CDK4 and CDK6 
kinases can be effective treatment for cancer that is selected for cyclin D1 amplification 


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and/or p16 loss.  
 
1.6 
CDK4/6 Inhibition in HNSCC: Pre-Clinical Evidence of Tumor Response 
 
Dr. Loren Michel in our group generated cisplatin-resistant derivative SCC1 cell lines from 
cisplatin-sensitive SCC1 by continuous exposure to cisplatin. The IC50 of cisplatin-
resistant derivative SCC1 was three-fold higher than that of cisplatin-sensitive SCC1 (31.3 
uM and 11.8 uM, respectively).  
Generation of Cisplatin Resistant Derivative Cell Lines from Human Head and Neck 
Squamous Cell Cancer Lines
 
Cisplatin-resistant and cisplatin-sensitive SCC1 cell lines were then exposed to varying 
concentrations of PD 0332991, and the IC50 of the two cell lines to PD 0332991 were 
compared. As seen, the IC50 of cisplatin-resistant derivative SCC1 was 2.5 fold lower than 
that of cisplatin-sensitive SCC1 (293.1 nM and 722.2 nM, respectively) showing that 
cisplatin-resistant SCC1 is hypersensitive to PD 0332991 compared to cisplatin-sensitive 
SCC1. 
Cisplatin-Resistant Cells are Hypersensitive to PD0332991 
 
These data were replicated in another cell line (SCC25), in which the IC50 of cisplatin-


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resistant derivative SCC25 was 4.0 fold lower than that of cisplatin-sensitive SCC25. 
 
The effects of CDK 4/6 inhibition on cetuximab activity was then investigated in the SCC1 
cell line. The data shown supports that: 1) co-exposure of PD 0332991 and cetuximab adds 
to the anti-proliferative effects of cetuximab alone, and 2) PD 0332991 alone has anti-
proliferative effects on the SCC1 cell line.   
How Does Cyclin D Inhibition Influence Cetuximab Activity? 
Control
PD0332991
Cell Number
Dr. Van Tine’s laboratory is interested in: 1) validating the efficacy of PD 0332991 in 
patient-derived xenograft (PDX) models in the clinical context of cisplatin resistance and 
cetuximab synergy, and 2) identifying the mechanisms and hence the biomarkers that 
predict hypersensitivity to CDK 4/6 inhibition using the cisplatin-resistant cell lines his 
laboratory has generated as tools for this undertaking. 
 
1.7 
Study Rationale 
 
Most patients with locally advanced HPV-unrelated SCCHN develop recurrent cancer and 
all patients with metastatic SCCHN ultimately die due to the disease.  The EGFR inhibitor 
cetuximab is an important recent addition to the standard treatment options for SCCHN but 
has resulted in only modest improvements in clinical outcomes.  New treatments are 
needed.   
 
Over expression of cyclin D1 and inactivation of p16 occur in the vast majority of cases of 
HPV-unrelated SCCHN.  Genomic characterization of oral SCCHN identified 
amplification of CCND1 and/or loss of CDKN2A (p16) were found in 94% of tumors, 
supporting that cell cycle alterations were a nearly universal feature.35 Resistance to EGFR 
inhibitors and to cisplatin, the two most effective systemic agents in SCCHN, may be in 
part mediated by cyclin D1 overexpression which can be targeted with inhibitors of the 
cyclin D axis.  PD 0332991 is a selective inhibitor of CDK4 and CDK6 kinases, which 
enhanced tumor response to letrozole in women with metastatic breast cancer selected for 


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the presence of cyclin D1 amplification and/or p16 loss.  PD 0332991 also has efficacy in 
cyclin D1 overexpressing mantle cell lymphoma and has activity in a broad range of other 
solid tumors.  
 
Our laboratory investigation of PD 0332991 in the SSC1 cell line demonstrated: 1) the 
IC50 of  cisplatin-resistant derivative SCC1 to PD 0332991 was 2.5 fold lower than that of 
cisplatin-sensitive SCC1 (293.1 nM and 722.2 nM, respectively) showing that cisplatin-
resistant SCC1 is hypersensitive to PD 0332991 compared to cisplatin-sensitive SCC1, 2) 
co-exposure of PD 0332991 and cetuximab adds to the anti-proliferative effects of 
cetuximab alone, and 3) PD 0332991 alone has anti-proliferative effects on the SCC1 cell 
line. These preclinical data support the conclusions that PD 0332991 has single agent 
activity in HNSCC, PD 0332991 is more effective against cisplatin-resistant than cisplatin-
sensitive HNSCC, and PD 0332991 and cetuximab are synergistic against HNSCC.     
 
Based on the evidence presented, we propose a phase I/II trial to test our hypotheses that 
the addition of PD 0332991 to cetuximab will be feasible and will improve tumor response 
rate and time-to-progression (TTP) in patients with platin-resistant incurable SCCHN in 
comparison to historical controls.  In the phase II portion of the trial, patients will be 
required to have HPV-unrelated SCCHN tumors (which as a group are known to have 
nearly universal cyclin D1 overexpression or amplification and/or p16 loss) to enrich the 
likelihood of clinical benefit of PD 0332991. Cetuximab will be used as the platform to 
add PD 0332991 to since cetuximab is the current standard FDA-approved treatment 
indicated for patients with platin-resistant incurable SCCHN.  
 
1.8 
Amendment 6: Addition of Arm 3 to Phase II 
 
The genomics of HPV-related SCCHN has been characterized predominantly in primary 
(untreated) tumor specimens. In primary HPV-related SCCHN, overexpression of p16 is 
a physiologic response to binding of the E7 viral oncoprotein to Rb. The normal function 
of p16 to inhibit the complex of CDK 4/6 and cyclin D is inconsequential due to the 
downstream alteration of Rb function by E7. Since palbociclib inhibits at a step upstream 
of pRb, palbociclib would not be expected to benefit patients with untreated HPV-related 
SCCHN.  
 
However, recent work found that the genomics of recurrent/metastatic (RM) HPV-related 
SCCHN more closely resembles that of HPV-unrelated SCCHN.36 In particular, the 
frequencies of TP53 mutations (15%), whole genome duplication (25%), and 3p deletion 
(55%) were significantly higher in RM tumors compared to primary tumors. Mutations in 
CDKN2A and amplification of 11q13 were observed in RM HPV-related SCCHN.  
 
These data suggest that RM HPV-related SCCHN may respond to a CDK 4/6 inhibitor 
like palbociclib. Based on these observations, and the potential of palbociclib to inhibit 
one mechanism of resistance to EGFR inhibitors, we hypothesize palbociclib and 
cetuximab will result in tumor responses in patients with cetuximab-resistant RM HPV-
related SCCHN. Arm 3 will enroll only patients with cetuximab-resistant disease, for 
which there are few, if any, standard treatment options. 


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1.9 
Correlative Studies Background 
 
The purpose of the correlative studies is to correlate overall response and TTP to cyclin D1 
expression and p16 loss, both assessed by IHC, in Phase II patients with HPV-unrelated 
SCCHN treated with PD 0332991 and cetuximab.  The methodology for assessment of 
cyclin D1 and p16 by IHC has been previously described.16 At this time, a review of the 
literature does not clearly define the optimal methodology or cut thresholds for a positive 
and a negative result for cyclin D1 expression as it relates to clinical effect of PD 0332991 
or other cell cycle inhibitors.  IHC was chosen as the method to assess cyclin D1 expression 
in this study since it is a widely available methodology for assessing protein expression 
that is familiar to most investigators and clinical laboratories.  For similar reasons, p16 will 
also be assessed by IHC although a generally agreed upon definition for positive p16 
(>50%; 3+ or 4+) and negative p16 (Negative or <50%; 1+ or 2+) results are available.16 
However, these definitions are geared toward HPV-related OPSCC which are nearly 
always strongly and diffusely positive for p16 by IHC.  In our experience, HPV-unrelated 
OPSCC and SCCHN from other subsites are nearly always p16 negative (that is, truly no 
staining).  Thus, for the purposes of the correlative studies in this trial, we will define 
negative p16 to mean no staining and positive p16 to mean any staining. 
    
 
Patients who participate on the Phase II portion of the trial (Arms 1 and 2 only) will be 
asked to consent to optional pre-Cycle 1 and post-Cycle 2 (to be collected anytime between 
Days 15 and 21 inclusive and at disease progression) tumor biopsies (core or 
excisional/incisional) to perform p16 expression, Ki-67 by IHC, total and phospho-Rb by 
IHC, Cyclin D1 by IHC, and TUNEL assay, and to analyze other potential biomarkers as 
they emerge from the scientific understanding of PD0332991 activity on formalin-fixed 
paraffin-embedded (FFPE) tissue.  The major function of cyclin D-CDK4/6 complexes is 
to promote S phase entry.  This can best be assayed by examining the effects of PD 0332991 
on the proliferation marker Ki-67.  Suppression of the activity of cyclin-CDK4/6 activity 
is predicted to decrease proliferation, the readout of which will be reduced percentage of 
cells staining positive for Ki-67 post-treatment.  In addition, PD 0332991 should only be 
active in tumors that are Rb positive.  Moreover, Rb is a substrate of cyclin D-CDK4/6. 
Therefore, measurement of total and phospho-Rb, which have served as pharmacodynamic 
markers for PD 0332991 in other clinical trials, will be evaluated.  This agent should not 
affect total Rb, but suppress phospho-Rb.  Lastly, to determine whether changes in 
proliferation and Rb phosphorylation are associated with an increase in apoptosis, TUNEL 
assay will be performed.  All of these assays can be completed on FFPE tissue.   
 
 
2.0 
OBJECTIVES 
 
2.1 
Primary Objectives 
 
1. Phase I: To determine the maximum tolerated dose of PD 0332991 when administered 
in combination with cetuximab to patients with incurable SCCHN 


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2. Phase II, Arm 1: To determine the efficacy of PD 0332991 in combination with 
cetuximab in incurable platin-resistant HPV-unrelated SCCHN. Efficacy will be 
measured by the overall response rate (ORR=CR+PR) defined by RECIST criteria. 
3. Phase II, Arm 2: To determine the efficacy of PD 0332991 in combination with 
cetuximab in incurable cetuximab-resistant HPV-unrelated SCCHN.  Efficacy will be 
measured by the overall response rate (ORR=CR+PR) defined by RECIST criteria. 
4. Phase II, Arm 3: To determine the efficacy of PD 0332991 in combination with 
cetuximab in incurable cetuximab-resistant HPV-related SCCHN.  Efficacy will be 
measured by the overall response rate (ORR=CR+PR) defined by RECIST criteria. 
 
2.2 
Secondary Objectives 
 
1. Phases I and II, Arms 1, 2, and 3: To assess the adverse events of PD 0332991 in 
combination with cetuximab 
2. Phase II, Arms 1, 2, and 3: To assess the progression-free survival (PFS) of patients 
with incurable SCCHN treated with PD 0332991 in combination with cetuximab 
3. Phase II, Arms 1, 2, and 3: To assess the overall survival (OS) of patients with incurable 
SCCHN treated with PD 0332991 in combination with cetuximab 
4. Phase II, Arms 1, 2, and 3: To assess duration of response/stable disease of patients 
with incurable HPV-unrelated SCCHN treated with PD 0332991 in combination with 
cetuximab 
 
2.3 
Exploratory Objectives 
 
1. Phase II, Arms 1 and 2: To document changes in p16 expression, Ki-67 (IHC), 
phospho-Rb (IHC), Cyclin D1 (IHC), and apoptosis (TUNEL assay) after cetuximab 
and PD 0332991. Exploratory analysis will be performed to correlate these molecular 
changes with clinical endpoints (OR, TTP, PFS, and OS).  RNA sequencing will also 
be performed. 
2. Phase II, Arms 1, 2, and 3: To monitor quality of life as documented by QOL 
measurements from the FACT H&N and EORTC QLQ-C30. 
 
 
3.0 
PATIENT SELECTION 
 
3.1 
Inclusion Criteria 
 
1. Histologically or cytologically confirmed diagnosis of squamous cell carcinoma of the 
head and neck. 
 
2. Disease must be considered incurable.  Incurable is defined as metastatic disease or a 
local or regional recurrence in a previously irradiated site that is unresectable (or patient 
declines resection). 
 
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 


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chest x-ray, or >10 mm with calipers by clinical exam. (Phase I only: patients without 
measurable disease by RECIST 1.1 criteria but with evaluable disease by imaging or 
physical exam will be eligible as well.) 
 
4. Phase I only: any (or no) prior therapy for metastatic disease is allowed, including 
cetuximab.  If a patient has not received prior standard therapy, s/he must have been 
offered and refused prior standard therapy. 
 
5. Phase II only: 
Arm 1: disease progression after at least one cycle of prior treatment with cisplatin or 
carboplatin for incurable disease.  Prior treatment with cetuximab for incurable disease 
is not permitted. 
Arms 2 and 3: disease progression after at least one cycle of treatment with cetuximab 
for incurable disease. 
 
6. Phase II only: at least one line of prior therapy for incurable disease. 
 
7. Phase II only: 
Arms 1 and 2: disease must be determined to be HPV-unrelated.  HPV-unrelated 
SCCHN is defined as either p16-negative OPSCC or non-OPSCC (larynx, 
hypopharynx, oral cavity) or p16-negative unknown primary SCC presenting with a 
level 2 or 3 neck node.  p16 will be assessed by IHC; a specimen showing any staining 
will be considered p16-positive. 
Arm 3: disease must be HPV-related SCCHN (defined as OPSCC or unknown 
primary presenting with a neck mass that is either p16 positive or HPV ISH or PCR 
positive). 
 
8. Minimum of 14 days elapsed since the end of any prior therapy. 
 
9. At least 18 years of age. 
 
10. Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures 
to NCI CTCAE version 4.0 Grade ≤ 1 (except alopecia or other toxicities not 
considered a safety risk for the patient at investigator’s discretion) 
 
11. ECOG performance status < 2 (see Appendix A). 
 
12. Adequate bone marrow and organ function as defined below: 
a. Absolute neutrophil count > 1,500 mm3 
b. Platelets > 100,000 mm3 
c. Hemoglobin > 9 g/dL 
d. Total bilirubin < 1.5 x IULN except in the case of patients with Gilbert’s disease 
e. AST (SGOT) and ALT (SGPT) < 2.5 x IULN for patients without liver metastases 
and ≤ 5.0 x IULN for patients with liver metastases 
f. Alkaline phosphatase ≤ 2.5 x IULN for patients without bone metastases and ≤ 5.0 
x IULN for patients with bone metastases 


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g. Serum creatinine ≤ 1.5 x IULN OR calculated creatinine clearance > 50 
mL/min/1.73 m2 for patients with creatinine levels above institutional normal 
 
13. Baseline corrected QT interval (QTc) < 480 ms.  
 
14. Women of childbearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control, abstinence) prior to study entry and for 
the duration of study participation.  Should a woman become pregnant or suspect she 
is pregnant while participating in this study, she must inform her treating physician 
immediately. 
 
15. Available archival tumor tissue for the proposed correlative studies. 
 
16. Ability to understand and willingness to sign an IRB approved written informed 
consent document (or that of legally authorized representative, if applicable). 
 
3.2 
Exclusion Criteria 
 
1. Phase II, Arm 1 only: prior treatment with cetuximab. 
 
2. A history of other malignancy ≤ 1 year previous with the exception of basal cell or 
squamous cell carcinoma of the skin which were treated with local resection only, 
carcinoma in situ of the cervix, or synchronous H&N primaries. 
 
3. Currently receiving any other investigational agents. 
 
4. Patient must not have a history of or clinical evidence of central nervous system 
metastases or leptomeningeal carcinomatosis, except for individuals who have had 
previously-treated CNS metastases, are asymptomatic, and have had no requirement 
for steroids or anti-seizure medications (with the exception of Keppra) for 1 month 
prior to first dose of PD 0332991. 
 
5. A history of allergic reactions attributed to compounds of similar chemical or biologic 
composition to PD 0332991, cetuximab, or other agents used in the study. 
 
6. Treated within the last 7 days prior to Day 1 of protocol therapy with:  
a. Food or drugs that are known to be CYP3A4 inhibitors (e.g. grapefruit juice, 
verapamil, ketoconazole, miconazole, itraconazole, erythromycin, clarithromycin, 
telithromycin, indinavir, ritonavir, nelfinavir, atazanavir, amprenavir, nefazodone, 
diltiazem, and delavirdine) or inducers (i.e. dexamethasone, glucocorticoids, 
progesterone, rifampin, phenobarbital, St. John’s wort).  (See Appendix D) 
b. Drugs that are known to prolong the QT interval. 
c. Drugs that are proton pump inhibitors.  
 
7. Uncontrolled electrolyte disorders that can compound the effects of a QTc-prolonging 
drug (e.g., hypocalcemia, hypokalemia, hypomagnesemia) 


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8. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements. 
 
9. 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 contraceptive during the 
period of the trial and for at least 90 days after completion of treatment. The decision 
of effective contraception will be based on the judgment of the principal investigator 
or a designated associate. 
 
10. Phase I and Arm 1 of Phase II: Known HIV-positivity and on combination antiretroviral 
therapy because of the potential for pharmacokinetic interactions with PD 0332991.  In 
addition, these patients are at increased risk of lethal infections when treated with 
marrow-suppressive therapy.  Appropriate studies will be undertaken in patients 
receiving combination antiretroviral therapy when indicated. 
Arms 2 and 3 of Phase II: patients with HIV infection and antiretroviral therapy are not 
excluded, as there are no pharmacokinetic tests being performed. 
 
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 by Washington University 
2. Registration of patient in the Siteman Cancer Center OnCore database 
3. Assignment of unique patient number (UPN) 
 
Once the patient has been entered in the Siteman Cancer Center OnCore database, the WUSM 
coordinator will forward verification of enrollment and the UPN via email. 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below and scanning and 
emailing it to the research coordinator listed in the Siteman Cancer Center Clinical Trials 
Core Protocol Procedures for Secondary Sites packet at least one business day prior to 
registering patient: 


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1. Your name and contact information (telephone number, fax number, and email 
address) 
2. Your site’s PI’s name, the registering MD’s name, and your institution name 
3. Patient’s race, sex, and DOB 
4. Three letters (or two letters and a dash) for the patient’s initials 
5. Currently approved protocol version date 
6. Copy of signed consent form (patient name may be blacked out) 
7. Planned date of enrollment 
8. Completed eligibility checklist, signed and dated by a member of the study team 
9. Copy of appropriate source documentation confirming patient eligibility 
 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database 
 
Registrations may be submitted Monday through Friday between 8am and 5pm CT.  Urgent 
late afternoon or early morning enrollments should be planned in advance and coordinated 
with the Washington University research coordinator.  Registration will be confirmed by 
the research coordinator or his/her delegate by email within one business day.  Verification 
of eligibility and registration should be kept in the patient chart. 
 
All patients at all sites must be registered through the Siteman Cancer Center OnCore 
database at Washington University. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  Patients 
will also be identified by first, middle, and last initials.  If the patient has no middle initial, 
a dash will be used on the case report forms (CRFs).  All data will be recorded with this 
identification number on the appropriate CRFs. 
 
 
 
5.0 
TREATMENT PLAN 
 
5.1 
Premedication for Cetuximab 
 
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 cetuximab.  Premedication may also include one liter of normal saline, 
hydrocortisone 100 mg IVPB, and/or albuterol inhalation (by nebulizer or inhaler) 
according to standard of care procedures. 
 
5.2 
Agent Administration 
 
PD 0332991 should be taken by mouth on Days 1 through 21 of each 28-day cycle.  
Patients should take PD 0332991 capsules with food.  Patients will be required to keep 


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a drug diary (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. 
 
Cetuximab will be administered intravenously on a weekly schedule.  The first dose of 
cetuximab will be 400 mg/m2; every week thereafter, patients will receive a dose of 250 
mg/m2.  Patients will continue to receive weekly cetuximab at 250 mg/m2 for the duration 
of their participation on study. 
 
Upon IRB/EC approval of Amendment 5, a PD 0332991 oral solution will be available for 
patients who cannot swallow the PD 332991 capsules. 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, 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 PD 0332991 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 PD 0332991 oral solution. Patients 
can take PD 0332991 oral solution with or without food.  
 
5.3 
Re-Treatment Criteria 
 
A new cycle of treatment with PD 0332991 may begin only if: 
 ANC ≥1,000/mcL. 
 Platelets count ≥50,000/mcL. 
 Non-hematologic toxicities have returned to baseline or no greater than grade 1 (or 
no greater than grade 2 if not considered a safety risk for the patient (at the 
investigator’s discretion)). 
 
If these conditions are not met, treatment with PD 0332991 must be delayed by one week. 
If, after a one-week delay, all toxicities have recovered within the limits described above, 
treatment with PD 0332991 can be resumed. 
 
If the patient has not recovered after 2 weeks (including the scheduled 1-week off treatment 
period within a cycle), treatment with PD 0332991 will be permanently discontinued.  
 
 


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5.4 
Dose Escalation Schema for Phase I 
 
Dose Escalation Schedule (for the Phase I portion) 
Dose Level 
PD 0332991 Dose* 
Cetuximab Dose 
Level -1 
75 mg 
Loading dose: 400 mg/m2 
Weekly thereafter: 250 mg/m2 for 
the duration of study participation 
Level 1 (Starting Dose) 
100 mg 
Level 2 
125 mg 
 
* PD 0332991 is administered on Days 1 through 21 of each 28-day cycle. 
 
Dose escalation will not occur until all patients in the cohort have completed the first cycle 
and the Principal Investigator has been able to review all toxicities. 
 
5.5 
Definition of MTD, DLT, Dose Escalation Criteria, and Toxicity, Response, 
and DLT Evaluations for Phase I 
 
5.5.1 Definition of Maximum Tolerated Dose (MTD) 
 
The maximum tolerated dose (MTD) is defined as the dose level immediately 
below the dose level at which 2 patients of a cohort (of 2 to 6 patients) experience 
dose-limiting toxicity during the first cycle.  Dose escalations will proceed until the 
MTD has been reached. 
 
5.5.2 Dose Limiting Toxicities (DLTs) 
 
Hematologic DLT is defined as any of the following that occur during the first cycle 
that are attributed as possibly, probably, or definitely related to the study treatment: 
 
 grade 4 neutropenia ≥ 7 day duration 
 grade 4 infection with grade 3 or 4 neutropenia 
 grade 4 thrombocytopenia associated with life-threatening bleeding 
 treatment held for > 14 days due to hematologic toxicity 
 febrile neutropenia of any duration with temperature > 38.5 °C 
 
Non-hematologic DLT is defined as any possibly, probably, or definitely related 
grade 3 or grade 4 non-hematologic toxicity that occurs during the first cycle with 
the following specific exceptions: 
 
 suboptimally treated grade 3 or 4 nausea, vomiting, diarrhea, anorexia, or 
lymphopenia 
 grade 3 metabolic abnormalities (specifically limited to potassium, 
magnesium and calcium) 
 any hypersensitivity / infusion reaction or acneiform rash due to cetuximab 
 treatment held for > 14 days due to non-hematologic toxicity 
 


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5.5.3 Dose Escalation Criteria 
 
Dose escalations will proceed as follows after the occurrence of dose-limiting 
toxicity (DLT): 
 
Number of Patients 
with DLT at a Given 
Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
>2 
Dose escalation will be stopped.  Three (3) additional 
patients will be entered at the next lowest dose level if 
only 3 patients were treated previously at that dose. 
1 out of 3 
Enter at least 3 more patients at this dose level. 
 
If 0 of these 3 patients experience DLT, proceed to the 
next dose level. 
 
If 1 or more of this group suffer DLT, then dose 
escalation is stopped.  Three (3) additional patients will 
be entered at the next lowest dose level if only 3 
patients were treated previously at that dose. 
<1 out of 6 at highest 
dose level below the 
maximally 
administered dose 
This is generally the recommended phase 2 dose. At 
least 6 patients must be entered at the recommended 
phase 2 dose. 
 
5.5.4 Toxicity, Response, and DLT 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 come off study due to 
treatment related adverse events(s) prior to completion of Cycle 2 and have not had 
any disease assessment. 
 
A patient is evaluable for DLT assessment only during Cycle 1 of treatment and 
only if enrolled in phase I of the trial.  If the patient is not able to be treated on Day 
1 of Cycle 2, then s/he is still considered in Cycle 1 active treatment and can 
experience a DLT.  Once the patient has been treated in Cycle 2, s/he will no longer 
be evaluated for DLTs in all subsequent cycles. 
 
5.6 
Dosing for Phase II 
 
Dosing for phase II will be administered as per Section 5.2.  Dose of PD 0332991 will be 
125 mg, which was the highest dose given in phase I (no MTD found).  Thirty patients will 


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be enrolled to Arm 1 of phase II, 30 patients will be enrolled to Arm 2 of phase II, and 24 
patients will be enrolled to Arm 3 of phase II.  Enrollment for all arms may take place 
concurrently. 
 
5.7 
General Concomitant Medication and Supportive Care Guidelines 
 
While taking PD 0332991, patients should be instructed to avoid food or drugs that are 
known strong CYP3A4 inhibitors or inducers.  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 PD 0332991 
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 PD 0332991 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. 
 
5.8 
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 study 
treatment.   
 
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 PD 0332991.  
 
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 either study drug, the investigator must be notified in 
order to facilitate outcome follow-up. 
 
5.9 
Duration of Therapy 
 
If at any time the constraints of this protocol are considered to be detrimental to the 


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patient’s health and/or the patient no longer wishes to continue protocol therapy, the 
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 
indefinitely until one of the following criteria applies: 
 
 Documented and confirmed disease progression 
 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 
unacceptable for 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. 
 
5.10 
Duration of Follow-up 
 
Patients will be followed every 2 months for 5 years or until death, whichever occurs first.  
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 PD 0332991 
 
Patients will be monitored for toxicity and the dose of PD 0332991 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 PD 0332991 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). 
 
If a patient experiences a toxicity which has not resolved to grade 2 or lower within two 
weeks (inclusive of the scheduled off-week), treatment with PD 0332991 should be 


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permanently discontinued.  
 
PD 0332991 Dose Modifications Based on Worst Treatment-Related Toxicity in the 
Previous Cycle 
Worst Toxicity During Previous Cycle 
New Dose Level 
Grade 4 neutropenia 
Decrease by one dose level 
Grade 4 thrombocytopenia 
Decrease by one dose level 
Grade 3 neutropenia associated with a documented 
infection or fever > 38.5 ºC 
Decrease by one dose level 
Grade > 3 non-hematologic toxicity (includes nausea, 
vomiting, diarrhea, and hypertension only if 
persisting despite maximal medical treatment) 
Decrease by one dose level 
Delay by > 1 week in receiving the next scheduled 
dose due to persisting treatment-related toxicities 
If recovery occurs within 2 
weeks, continue and decrease 
by one dose level 
Inability to deliver at least 80% of the planned dose of 
PD 0332991 due to adverse events possibly related to 
study treatment 
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 PD 0332991 by one dose level 
Grade 4: permanently discontinue PD 0332991 
 
6.2 
Dose Modifications or Delays for Cetuximab 
 
6.2.1 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. 


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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.   
 
6.2.2 Gastrointestinal Adverse Effects 
 
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. 
 
6.2.3 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 


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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. 
 
6.2.4 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. 
 
 


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6.2.5 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. 
 
6.2.6 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.  
 
6.2.7 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 
outlined below. 
 
The Washington University Human Research Protection Office (HRPO) requires that all events 
meeting the definition of unanticipated problem or serious noncompliance be reported as outlined 
in Section 7.2. 
 
The FDA requires that all serious and unexpected adverse events be reported as outlined in Section 
7.6. In addition, any fatal or life-threatening adverse experiences where there is a reasonable 
possibility of relationship to study intervention must be reported.  
 
Pfizer requires that adverse events be reported as outlined in Section 7.7. 
 
7.1 
Definitions 
 
7.1.1 Adverse Events (AEs) 
 
Definition: any unfavorable medical occurrence in a human subject including any 


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abnormal sign, symptom, or disease. 
 
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 
 
7.1.2 Serious Adverse Event (SAE) 
 
Definition:  any adverse drug experience occurring at any dose that results in any 
of the following outcomes: 
o Death 
o A life-threatening adverse drug experience 
o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant disability/incapacity (i.e., a substantial disruption 
of a person’s ability to conduct normal life functions) 
o A congenital anomaly/birth defect 
o Any other experience which, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical intervention 
to prevent one of the outcomes listed above 
 
All unexpected SAEs must be reported to the FDA. 
 
7.1.3 Unexpected Adverse Experience 
 
Definition: any adverse drug experience, the specificity or severity of which is not 
consistent with the current investigator brochure (or risk information, if an IB is not 
required or available). 
 
Events that are both serious AND unexpected must be reported to the FDA.  
7.1.4 Life-Threatening Adverse Experience  
 
Definition: any adverse drug experience that places the subject (in the view of the 
investigator) at immediate risk of death from the reaction as it occurred, i.e., it does 
not include a reaction that, had it occurred in a more severe form, might have caused 
death. 
 
Life-threatening adverse experiences must be reported to the FDA. 
 
 


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7.1.5 Unanticipated Problems 
 
Definition: 
 
 unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
 related or possibly related to participation in the research (“possibly related” 
means there is a reasonable possibility that the incident, experience, or outcome 
may have been caused by the procedures involved in the research); and 
 suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 
7.1.6 Noncompliance 
 
Definition: failure to follow any applicable regulation or institutional policies that 
govern human subjects research or failure to follow the determinations of the 
IRB.  Noncompliance may occur due to lack of knowledge or due to deliberate 
choice to ignore regulations, institutional policies, or determinations of the IRB. 
 
7.1.7 Serious Noncompliance 
 
Definition: noncompliance that materially increases risks, that results in substantial 
harm to subjects or others, or that materially compromises the rights or welfare of 
participants. 
 
7.1.8 Protocol Exceptions 
 
Definition: A planned deviation from the approved protocol that are under the 
research team’s control. Exceptions apply only to a single participant or a singular 
situation. 
 
Local IRB pre-approval of all protocol exceptions must be obtained prior to the 
event.  For secondary sites, the Washington University PI will issue approval of the 
exception, but it must also be submitted to the local IRB with documentation of 
approval forwarded to Washington University.  HRPO approval is not required for 
protocol exceptions occurring at secondary sites. 
 
7.2 
Reporting to the Human Research Protection Office (HRPO) at Washington 
University 
 
The PI is required to promptly notify the IRB of the following events: 
 


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 Any unanticipated problems involving risks to participants or others which occur 
at WU, any BJH or SLCH institution, or that impacts participants or the conduct of 
the study. 
 Noncompliance with federal regulations or the requirements or determinations of 
the IRB. 
 Receipt of new information that may impact the willingness of participants to 
participate or continue participation in the research study. 
 
These events must be reported to the IRB within 10 working days of the occurrence of the 
event or notification to the PI of the event.  The death of a research participant that qualifies 
as a reportable event should be reported within 1 working day of the occurrence of the 
event or notification to the PI of the event. 
 
7.3 
Reporting to the Quality Assurance and Safety Monitoring Committee 
(QASMC) at Washington University 
 
The PI is required to notify the QASMC of any unanticipated problem occurring at WU or 
any BJH or SLCH institution that has been reported to and acknowledged by HRPO as 
reportable.  (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 
a QASMC auditor. 
 
7.4 
Reporting Requirements for Secondary Sites 
 
The research team at each secondary site is required to promptly notify the Washington 
University PI and research coordinator of all reportable events (as described in Section 7.6) 
within 1 working day of the occurrence of the event or notification of the secondary site’s 
PI of the event.  This notification may take place via email if there is not yet enough 
information for a formal written report (using either an FDA MedWatch form if required 
or an institutional SAE reporting form if not).  A formal written report must be sent to the 
Washington University PI and research coordinator within 10 working days of the 
occurrence of the event or notification of the secondary site’s PI of the event.  The death 
of a research participant that qualifies as a reportable event should be reported within 1 
working day of the occurrence of the event or notification of the secondary site’s PI of the 
event. 
 
The research team at a secondary site is responsible for following its site’s guidelines for 
reporting applicable events to its site’s IRB according to its own institutional guidelines. 
The research team at Washington University is responsible for reporting all applicable 
events to the FDA.  
 
7.5 
Reporting to Secondary Sites 
 
The Washington University PI (or designee) will notify the research team at each secondary 


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site of all reportable events that have occurred at other sites within 10 working days of the 
occurrence of the event or notification of the PI of the event.  This includes events that take 
place both at Washington University and at other secondary sites, if applicable. 
 
7.6 
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 any 
unanticipated problem to the FDA as follows: 
 
 Report any unexpected fatal or life-threatening adverse experiences (Section 7.1.4) 
associated with use of the drug (i.e., there is a reasonable possibility that the 
experience may have been caused by the drug) by telephone or fax no later than 7 
calendar days after initial receipt of the information. 
 Report any serious, unexpected adverse experiences (Section 7.1.2), as well as 
results from animal studies that suggest significant clinical risk within 15 
calendar days after initial receipt of this information.   
 
All MedWatch forms will be sent by the investigator or investigator’s team to the FDA at 
the following address or by fax: 
 
Food and Drug Administration 
Center for Drug Evaluation and Research 
Division of Oncology Drug Products 
5901-B Ammendale Rd. 
Beltsville, MD 20705-1266 
FAX: 1-800-FDA-0178 
 
Secondary sites must submit a completed MedWatch form to the Washington University 
PI and research coordinator within 4 calendar days (for fatal or life-threatening adverse 
experiences) or 11 calendar days (for serious, unexpected adverse experiences).  The 
Washington University PI will be responsible for submitting all MedWatch forms from 
secondary sites to the FDA within the timeframes specified above. 
 
7.7 
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 Section 7.7) that occurs during the SAE reporting period (as 
defined in Section 7.9) in a study subject receiving PD 0332991.  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 PD 0332991 during 
pregnancy or lactation is reportable.  In addition, occupational exposure to PD 0332991 is 
reportable, and a lack of effect of PD 0332991 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.  
 
7.8 
Timeframe for Reporting Required Events  
 
Adverse events will be tracked for 30 days following the last day of study treatment. 
 
 
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: 
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 


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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. 
 
 
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 


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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.  
 
 
 
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 


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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 
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 
 
PD 0332991 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 belowError! Reference source not found..  
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; 


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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. 
 
PD 0332991 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. 
 
 


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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 
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 
 
PD 0332991 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.  
 
PD 0332991 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. 
 
 


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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, 
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 
 


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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. 
 
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 
Cetuximab (Erbitux) 
 
8.2.1 Cetuximab Description 
 
Cetuximab is an anti-EGFR human-to-murine chimeric antibody. 
 
8.2.2 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. 


Protocol Version: Amendment 6; 10/24/17 
 
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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 
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. 
 
8.2.3 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. 
 
8.2.4 Supplier 
 
Cetuximab is commercially available and is listed in the compendia as indicated for 
the therapy of HNSCC. 
 
8.2.5 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. 
 


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8.2.6 Storage and Stability 
 
Cetuximab should be stored in a secure area according to local regulations. Store 
vials under refrigeration at 2 C to 8 C (36 F to 46 F). DO NOT FREEZE. 
Increased particulate formation may occur at temperatures at or below 0C.  This 
product contains no preservatives.  Preparations of cetuximab in infusion containers 
are chemically and physically stable for up to 12 hours at 2 C to 8 C (36 F to 46 
F) or up to 8 hours at controlled room temperature (20 C to 25 C; 68 F to 77 F).  
Discard any remaining solution in the infusion container after 8 hours at controlled 
room temperature or after 12 hours at 2 to 8 C.  Discard any unused portion of the 
vial. 
 
8.2.7 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. 
 
8.2.8 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.  
 
8.2.9 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 


Protocol Version: Amendment 6; 10/24/17 
 
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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). 
 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. 
 
8.2.10 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 
Optional Tumor Biopsy 
 
9.1.1 Collection of Specimens 
 
Phase II patients (Arms 1 and 2 only) will be asked to consent to three optional 
tumor biopsies, the first at pre-treatment and the second at the end of Cycle 2 
(between Days 15 and 21 inclusive) and the third at disease progression (from 
cetuximab and PD0332991). 
 
Tumor tissue biopsy site will be chosen by the PI.  Readily accessible sites for 
biopsy such as subcutaneous or dermal soft tissue masses or neck nodal masses will 
not likely require image guidance.  In those tumor sites that are not readily 
accessible for biopsy such as deep neck masses or visceral organ metastases, image 
guidance (ultrasound or CT) will be used.  The biopsy will consist of a minimum 
of 4 needle cores (14 gauge is preferred) or 2 small (each 4 x 4 x 4 mm) pieces of 
tumor.  Tissue should be delivered on saline within 30 minutes of collection.  Tissue 


Protocol Version: Amendment 6; 10/24/17 
 
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is to be stored at the Siteman Cancer Center Tissue Procurement Core Facility until 
analysis in the lab of Dr. Van Tine. The optional pre-treatment and Cycle 2 Day 
15-21 and disease progression tumor biopsies (core or excisional/incisional) will 
be used to perform RNAseq, p16 expression, Ki-67 by IHC, total and phospho-Rb 
by IHC, Cyclin D1 by IHC, and TUNEL assay, and to analyze other potential 
biomarkers as they emerge from the scientific understanding of PD0332991 activity 
on formalin-fixed paraffin-embedded (FFPE) tissue. 
 
9.1.2 Handling of Specimens 
 
Tissue should be sent to the Tissue Procurement Core Facility for processing and 
storage until analysis. 
 
9.2 
Archival Tumor Tissue 
 
Fifteen slides are needed (minimum of 4 accepted). 
 
9.2.1 Phase I 
 
Eight additional slides will be collected for each patient. 
 
p16 by IHC will be performed on all patients if not already available for review. 
 
Analysis of cyclin D1 expression as well as total and phospho-Rb by IHC will be 
performed on all archived specimens. 
 
9.2.2 Phase II 
 
p16 by IHC will be performed on all patients to determine eligibility and arm 
assignment. 
 
Analysis of cyclin D1 expression as well as total and phospho-Rb by IHC will be 
performed on all archived specimens. 
 
9.3 
Blood for Pharmacokinetic Analysis 
 
Blood for pharmacokinetic analysis will be drawn from all Phase I and Phase II Arm 1 
patients only.  Blood will be drawn at the following time points: 
 Cycle 1 Day 15 pre-cetuximab 
 Cycle 1 Day 15 post-cetuximab 
 Cycle 1 Day 22 pre-cetuximab 
 Cycle 1 Day 22 post-cetuximab 
 Cycle 2 Day 15 pre-PD 0332991 
 Cycle 2 Day 15 immediately post-PD 0332991 
 Cycle 2 Day 15 pre-cetuximab 
 Cycle 2 Day 15 immediately post-cetuximab 


Protocol Version: Amendment 6; 10/24/17 
 
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 Cycle 2 Day 15 1 hour post-PD 0332991 
 Cycle 2 Day 15 2 hours post-PD 0332991 
 Cycle 2 Day 15 4 hours post-PD 0332991 
 Cycle 2 Day 15 8 hours post-PD 0332991 
 Cycle 2 Day 22 pre-cetuximab 
 Cycle 2 Day 22 post-cetuximab 
 
9.3.1 PD 0332991 PK Collection and Processing 
 
For each time point, collect 3 mL of venous blood into K2EDTA tubes.  Upon 
collection of the blood PK samples, keep them on wet ice at all times prior to 
processing the plasma.  Samples will be centrifuged at approximately 1700 x g for 
about 10 minutes at 4°C.  The plasma will be stored in an appropriately labeled 
amber screw-capped polypropylene tube at approximately -70°C within 1 hour of 
collection.  Specimens will be batch shipped to a lab designated by Pfizer at a later 
date. 
 
9.3.2 Cetuximab PK Collection and Processing 
 
For each time point, collect 3 mL of venous blood into a red top glass tube 
containing no additive. Upon collection of the blood PK samples, keep them on wet 
ice to allow blood to clot prior to processing to serum.  Samples will be centrifuged 
at approximately 1700 x g for about 10 minutes in a refrigerated centrifuge at 4°C 
to harvest serum.  Rapidly transfer a minimum of 1 mL serum into the pre-labeled 
2 mL clear polypropylene storage cryovial. The samples will be stored in a freezer 
at approximately -20°C within 1 hour of collection.  Ship frozen samples to CRO 
on dry ice. 
 
9.4 
Quality of Life 
 
The EORTC QLQ-C30 (Appendix E) and FACT H&N (Appendix F) will be given at 
baseline and on Day 1 of Cycles 2, 3, 4, and 6 for patients in Phase II (all 3 arms) only. 
 
 
 


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10.0 
STUDY CALENDAR 
 
Screening evaluations are to be conducted within 28 days prior to start of protocol therapy.   
 
Screening 
Weekly 
during 
Cycle 1 
Prior to Day 1 of each 
cycle (every 4 weeks 
Cycle 2 and beyond)p 
EOT 
F/Uj 
Physical exam 
X 
X 
X 
X 
 
Vitals signs 
X 
X 
 Xa 
X 
 
Performance status 
X 
X 
X 
X 
 
Adverse event assessment  
    X ------------------------------------------------------------- Xk 
CBC 
X 
X 
Xb 
X 
 
Chemistry panel, LFTsf 
X 
X 
X 
X 
 
Pregnancy test 
X 
 
 
X 
 
EKG 
X 
Xc 
Xc 
 
 
CT neck and chest 
Xd 
 
Xd 
 
 
Archival tissue 
Xm 
 
 
 
 
Optional tumor biopsy  
Xe 
 
Xe 
X 
 
QOLs (Phase II only) 
X 
 
Xn 
 
 
Blood for PKso 
 
Refer to Section 9.3 
 
 
PD0332991g 
 
X ------------------------------------ Xg 
 
 
Cetuximabh 
 
X -------------------------------------- Xh 
 
 
aVital signs should be taken weekly, even if treatment is held for toxicity. This can occur at chemotherapy visits when 
not having physical exams. 
bCBC to be performed weekly throughout all cycles, even if treatment is held for toxicity  
cEKG: Day 22 of each cycle 
dTumor assessments with CT of neck and chest will be performed at screening and at subsequent 8 week intervals 
(every 2 cycles). 
eTumor biopsies will be encouraged at baseline and at Cycle 2 Day 15-21 and at disease progression in patients in for 
Phase II patients (Arms 1 and 2 only). Cyclin D1, p16 by IHC, Ki-67, RNAseq, total and phospho-Rb and TUNEL 
assays will be performed on all three tissue sets. 
fChemistry includes Ca, Mg, K, Na, glucose, albumin, urea, creatinine; LFTs include ALT, AST, alkaline phosphatase, 
total bilirubin; please refer to Section 7.8 for special LFT AE reporting guidance. 
gPD0332991 will be taken orally on Days 1-21 of a 28 day cycle. 
hCetuximab will be administered weekly 
jFollow-up will consist of checks every 2 months (+/- 2 weeks) for recurrence and survival for 5 years; this may be 
done over the phone or as a review of the medical record. 
kAdverse events should be collected for 30 days after the last dose of study treatment. 
mp16, cyclin D1, and total and phospho-Rb will be assessed from FFPE tissue (15 slides, minimum of 4 accepted) on 
all patients (p16 to be done at screening; other testing to be performed at a later date) 
nAdminister QOLs at C2D1, C3D1, C4D1, and C6D1. 
oPhase I and Phase II Arm 1 only 
p+/- 2 day window for visits 
 
 
11.0 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 


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Page 48 of 73 
 
 
Electronic data management systems will be used in this trial in collaboration with the Institute for 
Informatics at Washington University.   
 
REDCap is a web-based clinical studies data management system that will be used for capture of 
clinical data from this trial.  An electronic study calendar will drive the study’s data collection 
workflow.  Each participating center has access only to data from its own participants by creation 
of Data Access Groups.  Washington University, as the data coordinating center, has access to data 
from all sites. 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
Demographics Form 
On Study Form 
On Study Prior Therapy Form 
Treatment Assignment Form 
Prior to starting treatment 
Treatment Form 
EKG Form 
Every cycle 
Adverse Event Form 
Continuous 
Tumor Biopsy Form 
PKs Form 
Baseline and end of Cycle 2 
QOLs Form 
Baseline and at C2D1, C3D1, C4D1, and C6D1 
Treatment Summary Form 
Completion of treatment 
Follow Up Form 
Every 2 months for 5 years 
Tumor Measurement Form 
Baseline, end of every even numbered cycles, 
and end of treatment 
MedWatch Form 
See Section 7.0 for reporting requirements 
 
Any queries generated by Washington University must be responded to within 28 days of receipt 
by the participating site.  The Washington University research team will conduct a regular review 
of data status at all secondary sites, with appropriate corrective action to be requested as needed. 
 
 
12.0 
MEASUREMENT OF EFFECT 
 
12.1 
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. 


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12.2 
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 
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.  


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12.3 
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 
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.   


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Page 51 of 73 
 
 
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 
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 


Protocol Version: Amendment 6; 10/24/17 
 
Page 52 of 73 
 
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. 
 
12.4 
Response Criteria 
 
12.4.1 Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm.  (Note:  
the appearance of one or more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
12.4.2 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 


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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). 
 
12.4.3 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 
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. 
 


Protocol Version: Amendment 6; 10/24/17 
 
Page 54 of 73 
 
                                      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 
 
 
12.4.4 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 disease control (CR, PR, stable disease):  Disease control 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.  
 
12.4.5 Efficacy 
 
Efficacy will be measured by the overall response rate (CR+PR) defined by 
RECIST criteria and by time to progression. 
 
12.4.6 Progression-Free Survival 
 
Progression-free survival is defined as the duration of time from start of treatment 
to time of progression or death, whichever occurs first. 
 
12.4.7 Overall Survival 
 
Overall survival is measured from time of diagnosis to time of death. 
 
12.4.8 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 


Protocol Version: Amendment 6; 10/24/17 
 
Page 55 of 73 
 
the best approach.  
 
 
13.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, an 
independent Data and Safety Monitoring Committee (DSMC) will be specifically convened for 
this trial to review toxicity data at least every 6 months following the activation of the first 
secondary site.  A DSMC will consist of no fewer than 3 members including 2 clinical investigators 
and a biostatistician.  Like investigators, DSMC members are subject to the Washington University 
School of Medicine policies regarding standards of conduct. Individuals invited to serve on the 
DSMC will disclose any potential conflicts of interest to the trial principal investigator and/or 
appropriate university officials, in accordance with institution policies. Potential conflicts that 
develop during a trial or a member’s tenure on a DSMC must also be disclosed.  
 
The DSM report will be prepared by the study statistician with assistance from the study team, 
will be reviewed by the DSMC, and will be submitted to the Quality Assurance and Safety 
Monitoring Committee (QASMC). 
 
Note that during the phase I dose escalation, 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 QASMC.  The report provided to QASMC 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 QA 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 including numbers from 
participating sites 
 Protocol activation date at each participating site 
 Average rate of accrual observed in year 1, year 2, and subsequent years at each 
participating site 
 Expected accrual end date, accrual by cohort, and accrual by site 
 Objectives of protocol with supporting data and list the number of participants who have 
met each objective 
 Measures of efficacy 
 Early stopping rules with supporting data and list the number of participants who have met 
the early stopping rules 
 Summary of toxicities at all participating sites 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  
 


Protocol Version: Amendment 6; 10/24/17 
 
Page 56 of 73 
 
Further DSMC responsibilities are described in the DSMC charter. 
 
Until such a time as the first secondary site activates this protocol, a semi-annual DSM report to 
be prepared by the study team will be submitted to the QASMC beginning 6 months after study 
activation at Washington University. 
 
The study principal investigator and coordinator will monitor for serious toxicities on an ongoing 
basis. Once the principal investigator or coordinator becomes aware of an adverse event, the AE 
will be reported to the HRPO and QASMC according to institutional guidelines (please refer to 
Section 7.0). 
 
Refer to the Washington University Quality Assurance and Data Safety Monitoring Committee 
Policies and Procedures for full details on the responsibilities of the DSMC at 
https://siteman.wustl.edu/wp-content/uploads/2015/10/QASMC-Policies-and-Procedures-
03.31.2015.pdf  
 
14.0 
AUDITING 
 
As coordinating center of this trial, Washington University (via the Quality Assurance and Safety 
Monitoring Committee (QASMC) will monitor each participating site to ensure that all protocol 
requirements are being met; that applicable federal regulations are being followed; and that best 
practices for patient safety and data collection are being followed per protocol.  Participating sites 
will be asked to send copies of all audit materials, including source documentation.  The audit 
notification will be sent to the Washington University Research Patient Coordinator, who will 
obtain the audit materials from the participating institution. 
 
Notification of an upcoming audit will be sent to the research team one month ahead of the audit. 
Once accrual numbers are confirmed, and approximately 30 days prior to the audit, a list of the 
cases selected for review (up to 10 for each site) will be sent to the research team. However, if 
during the audit the need arises to review cases not initially selected, the research team will be 
asked to provide the additional charts within two working days. 
 
Items to be evaluated include: 
 Subject screening and enrollment 
 Reporting of adverse events 
 Maintenance of HIPAA compliance 
 Completeness of regulatory documentation 
 Completeness of participant documentation 
 Acquisition of informed consent 
 IRB documentation 
 Issues of protocol adherence 
 
Additional details regarding the auditing policies and procedures can be found at 
https://siteman.wustl.edu/wp-content/uploads/2015/QASMC-Policies-and-Procedures-
03.31.2015.pdf  
 


Protocol Version: Amendment 6; 10/24/17 
 
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15.0 
STATISTICAL CONSIDERATIONS 
 
This trial consists of an open-label phase I study, where the MTD and DLT of the combination of 
PD 0332991 will be determined, followed by a phase II study where patients with incurable HPV-
unrelated SCCHN will be treated with PD 0332991 and cetuximab.  The phase I portion of the 
study will adopt a 3 + 3 design and at most 12 patients will be needed in this group.  
 
Dose escalations and de-escalations will proceed as follows after the occurrence of dose-limiting 
toxicity (DLT): 
 
Cohort 
# DLTs 
Escalation Decision Rule 
1 
0 
Escalate to dose 2. 
 
1 
Enter 3 additional patients at dose 1. 
 
2 
De-escalate to dose -1. 
2 
0 
Conclude that the MTD has not yet been reached. 
 
1 
Enter 3 additional patients at dose 2 if 0 in cohorts 1 
and 2. Identify dose 2 as the MTD if 1 in cohorts 1 
and 2. 
 
2 
Conclude that dose 1 is the MTD. 
 
For the phase II Arm 1 portion, based upon currently available data for cetuximab alone in platin-
resistant incurable SCCHN37, an overall tumor response rate (CR + PR) of 13% or lower would 
be unacceptable and an overall tumor response rate of 26% or higher of clinical interest.  A total 
of 30 eligible and evaluable patients will be accrued to the phase II portion of the study, and if 4 
or more patients’ tumors respond, the therapy will be accepted for further investigation.  The 
design is based on Thall P and Sung H-G38. 
 
Assumes 13% response with standard treatment, response rate increase of 13% (26% response rate 
with experimental treatment), expected (grade 3 or 4) toxicity rate of 46% with standard, 0% 
allowable increase with experimental treatment. 
 
Stop for poor response if: 
Stop for excess (grade 3 or 4) toxicity if: 
# Patients is: 
# Responses is ≤: 
# cases of toxicity is 
≥: 
In 1st # patients 
3 
0 
 
 
4 
0 
4 
4 
5 
0 
5 
5 
6 
0 
5 
6 
7 
0 
6 
7 
8 
0 
7 
8 
9 
0 
7 
9 
10 
0 
8 
10 
11 
0 
8 
11 
12 
1 
9 
12 
13 
1 
10 
13 


Protocol Version: Amendment 6; 10/24/17 
 
Page 58 of 73 
 
14 
1 
10 
14 
15 
1 
11 
15 
16 
1 
11 
16 
17 
1 
12 
17 
18 
2 
13 
18 
19 
2 
13 
19 
20 
2 
14 
20 
21 
2 
14 
21 
22 
2 
15 
22 
23 
2 
15 
23 
24 
3 
16 
24 
25 
3 
17 
25 
26 
3 
17 
26 
27 
3 
18 
27 
28 
3 
18 
28 
29 
3 
19 
29 
30 
3 
19 
30 
 
 
For the phase II arm 2 portion, the tumor response rate to any agent in patients with cetuximab-
resistant incurable SCCHN is unknown but it is expected to be < 13%.  An overall tumor response 
0123456789
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
0
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 29 30
The trial will be suspended for review if the number of responses is 
on or below the lower (blue) line or the number of cases of (grade 3 or 
4) toxicity is on or above the upper (red) line:
# Responses
# Cases of Toxicity
STOP FOR EXCESS TOXICITY
CONTINUE
STOP FOR POOR RESPONSE


Protocol Version: Amendment 6; 10/24/17 
 
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rate (CR+PR) of 13% or lower would be unacceptable and an overall tumor response rate of 26% 
or higher would be of clinical interest.  A total of 30 eligible and evaluable patients will be accrued 
to the phase II arm 2 portion of the study, and if 4 or more patients’ tumors respond, the therapy 
will be accepted for further investigation.  The design is based on Thall P and Sung H-G38.  The 
table and figure above also apply to phase II Arm 2. 
 
For phase II Arm 3 portion, an overall tumor response rate (CR + PR) of 5% or lower would be 
unacceptable and an overall tumor response rate of 20% or higher of clinical interest. A total of 24 
eligible and evaluable patients will be accrued to this arm. One or more tumor responses in the first 18 
patients are required to continue enrollment. Two or more tumor responses in the first 24 patients are 
required to accept the alternative hypothesis. The design has probability = .74 of early stopping after 
the first cohort of 18 patients if the true response rate is 5% or less. The cumulative probability of 
completing the study (enrolling 24 patients) is 0.70 if the true response rate is 20% or greater. The 
design is based on Thall P and Sung H-G38. 
 
Number 
of patients 
Cumulative probability 
of early stopping if 
response rate = 5% 
(null hypothesis) 
Cumulative probability of 
early stopping if response 
rate = 20% 
(minimum alternative 
hypothesis) 
Cumulative probability of 
continuing to end of study 
if response rate = 20% 
(minimum alternative 
hypothesis) 
1 
0 
0 
0 
18 
0.7436 
0.2858 
.7142 
24 
0.8335 
0.2953 
.7047 
 
15.1 
Correlative Studies 
 
Standard statistical methods will be used to describe cyclin D1 and p16 results by IHC, 
which will then be correlated to overall tumor response and TTP in Phase II patients.  
Similarly, RNAseq, Ki-67, total and phospho-Rb, and TUNEL assay performed on paired 
pre-Cycle 1 and post-Cycle 2 FFPE tumor tissue will be described and compared using 
standard statistical methods. 
 
 
16.0 
MULTICENTER REGULATORY REQUIREMENTS 
 
Washington University requires that each participating site sends its informed consent document 
to be reviewed and approved by the Washington University Regulatory Coordinator (or designee) 
prior to IRB/IEC submission.    
 
Site activation is defined as when the secondary site has received official written documentation 
from the coordinating center that the site has been approved to begin enrollment.  At a minimum, 
each participating institution must have the following documents on file at Washington University 
prior to study activation: 
 Documentation of IRB approval of the study in the form of a letter or other official 
document from the participating institution’s IRB.  This documentation must show 
which version of the protocol was approved by the IRB. 


Protocol Version: Amendment 6; 10/24/17 
 
Page 60 of 73 
 
 Documentation of IRB approval of an informed consent form. The consent must 
include a statement that data will be shared with Washington University, including the 
Quality Assurance and Safety Monitoring Committee (QASMC), the DSMC (if 
applicable), and the Washington University study team. 
 Documentation of FWA, signed FDA Form 1572 (if applicable), and the CVs of all 
participating investigators. 
 Protocol signature page signed and dated by the investigator at each participating site. 
 
The coordinating center Principal Investigator (or designee) is responsible for disseminating to the 
participating sites all study updates, amendments, reportable adverse events, etc.  Protocol/consent 
modifications and IB updates will be forwarded electronically to the secondary sites within 4 
weeks of obtaining Washington University IRB approval.  Activated secondary sites are expected 
to submit protocol/consent/IB modifications to their local IRBs within 4 weeks of receipt, unless 
otherwise noted.  Upon the secondary sites obtaining local IRB approval, documentation of such 
shall be sent to the Washington University study team within 2 weeks of receipt of approval. 
 
Documentation of participating sites’ IRB approval of annual continuing reviews, protocol 
amendments or revisions, all SAE reports, and all protocol violations/deviations/exceptions must 
be kept on file at Washington University. 
 
The investigator or a designee from each institution must participate in a regular conference call 
to update and inform regarding the progress of the trial. 
 
 


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17.0 
REFERENCES 
 
1 Ang K, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl 
J Med. 363, 24–35 (2010). 
2 Chung C, et al. Molecular classification of head and neck squamous cell carcinomas using 
patterns of gene expression. Cancer Cell. 5, 489–500 (2004). 
3 Chung C, et al. Gene expression profiles identify epithelial-to-mesenchymal transition and 
activation of nuclear factor-kB signaling as characteristic of a high risk squamous cell carcinoma. 
Cancer Res. 66, 8210–8218 (2006). 
4 Bonner J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. 
N Engl J Med. 354, 567–578 (2006). 
5 Vermorken J, et al. Platinum-Based Chemotherapy plus Cetuximab in Head and Neck Cancer. N 
Engl J Med. 359 1116-1127 (2008).  
6 Smeets S, et al. Genome-wide DNA copy number alterations in head and neck squamous cell 
carcinomas with or without oncogene-expressing human papillomavirus. Oncogene 25, 2558–
2564 (2006). 
7Bova R, et al. Cyclin D1 and p16INK4A expression predict reduced survival in carcinoma of the 
anterior tongue. Clin Cancer Res. 5, 2810-2819 (1999). 
8Akervall J, et al. Amplification of cyclin D1 in squamous cell carcinoma of the head and neck 
and the prognostic value of chromosomal abnormalities and cyclin D1 overexpression. Cancer. 
79, 380-389 (1997). 
9Okami K, et al. Cyclin D1 amplification is independent of p16 inactivation in head and neck 
squamous cell carcinoma. Oncogene. 18, 3541-3545 (1999). 
10Liu S, et al. Image cytometry of cyclin D1: a prognostic marker for head and neck squamous cell 
carcinomas. Cancer Epidemiol Biomark Prev. 10, 455-459 (2001). 
11Kyomoto R, et al. Cyclin-D1-gene amplification is a more potent prognostic factor than its 
protein over-expression in human head-and-neck squamous-cell carcinoma. Int J Cancer. 74, 576-
581 (1997). 
12Muller D, et al. Amplification of 11q13 DNA markers in head and neck squamous cell 
carcinomas: correlation with clinical outcome. Eur J Cancer. 33, 2203-2010 (1997). 
13Mineta H, et al. Cyclin D1 overexpression correlates with poor prognosis in patients with tongue 
squamous cell carcinoma. Oral Oncol. 36, 194-198 (2000). 
14Michalides R, et al. Overexpression of cyclin D1 indicates a poor prognosis in squamous cell 
carcinoma 
of the head and neck. Arch Otolaryngol Head Neck Surg. 123, 497-502 (1997).  
15Jares P, et al. PRAD-1/cyclin D1 gene amplification correlates with messenger RNA 
overexpression and tumor progression in human laryngeal carcinomas. Cancer Res. 54, 4813-4817 
(1994). 
16 Scantlebury J, et al. Cyclin D1—a prognostic marker in oropharyngeal squamous cell carcinoma 
that is tightly associated with high-risk human papillomavirus status. Human Pathol. 2013 Aug; 
44(8): 1672-80.  
17 Reed A, et al. High frequency of p16 (CDKN2/MTS-1/INK4A) inactivation in head and neck 
squamous cell carcinoma. Cancer Res. 56, 3630–3633 (1996). 
18 Smeets S, et al. Immortalization of oral keratinocytes by functional inactivation of the p53 and 
pRb pathways. Int J Cancer. 128, 1596-1605 (2011). 


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19 Lin S, et al. Nuclear localization of EGF receptor and its potential new role as a transcription 
factor. Nature Cell Biol. 3, 802–808 (2001). 
20 Kalish L, et al. 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. 10, 7764-7774 (2004). 
21 Kobayashi S, et al. Transcriptional Profiling Identifies Cyclin D1 as a Critical Downstream 
Effector of Mutant Epidermal Growth Factor Receptor Signaling. Cancer Res. 66, 11389-11398 
(2006). 
22 Zhang P, et al. Identification of genes associated with cisplatin resistance in human oral 
squamous cell carcinoma cell line. BMC Cancer. 6, 224 (2006). 
23 Zhou X, et al. 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. 124, 
483-489 (2009). 
24 Feng Z, et al. CCND1 as a Predictive Biomarker of Neoadjuvant Chemotherapy in Patients with 
Locally Advanced Head and Neck Squamous Cell Carcinoma. PLoS ONE. 6, e26399 (2011). 
25 Hirama T. and H. Phillip Koeffler. Role of the Cyclin-Dependent Kinase Inhibitors in the 
Development of Cancer. Blood. 86, 841-854 (1995). 
26 Fry D. et al. Specific Inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated 
antitumor activity in human tumor xenografts. Mol cancer Ther. 3, 1427-1437 (2004). 
27 Finn R, 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.  11, 1-13 (2009) 
28 Baughn L, 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. 66, 7661-7668 (2006). 
29 Flaherty K, 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. 18, 568-576 (2012). 
30 Schwartz G, et al. Phase I study of PD 0332991, a cyclin-dependent kinase inhibitor, 
administered in 3-week cycles (Schedule 2/1). Brit J Cancer. 104, 1862-1868 (2011). 
31 ASCO Accepted Poster Presentation #3060. Phase 1 study of PD 0332991, a cyclin-D kinase 
(CDK) 4/6 inhibitor in combination with letrozole for first-line treatment of patients with ER-
positive, HER2-negative breast cancer. Monday, June 7, 2010: 8:00am-12:00pm. D. Slamon – 
Presenter. 46th Annual Meeting of the American Society of Clinical Oncology (ASCO). June 4-8, 
2010.     
32 Finn R, et al. Preliminary results of a randomized phase 2 study of PD 0332991, a cyclin-
dependent kinase 4/6 inhibitor, in combination with letrozole for first-line treatments of patients 
with postmenopausal, ER-positive, HER2-negative advanced breast cancer. Presented at: SABCS 
33 Finn R, et al. Results of a randomized phase 2 study of PD 0332991, a cyclin-dependent kinase 
(CDK) 4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of 
ER+/HER2- advanced breast cancer (BC). Cancer Res. 72, 91s (2012). 
34 Leonard J, et al. Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients 
with mantle cell lymphoma. Blood. 119, 4597-4607 (2012). 
35 Pickering C, et al. Integrative genomic characterization of oral squamous cell carcinoma 
identifies frequent somatic drivers. Cancer Disc. OnlineFirst: April 25, 2013. 


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36 Morris L, et al. The molecular landscape of recurrent and metastatic head and neck cancers: 
Insights from a precision oncology sequencing platform. JAMA Oncol. 3(2), 244-255 (2017). 
37 Vermorken, J. B. 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. 25, 2171-2177 (2007). 
38 Thall P and Sung H-G. Some extensions and applications of a Bayesian strategy for 
monitoring multiple outcomes in clinical trials, Statistics in Medicine 17, 1563-1580 (1998). 
 
 
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 service. The Siteman Cancer Center is supported in part by 
an NCI Cancer Center Support Grant #P30 CA91842. 
 
 
 


Protocol Version: Amendment 6; 10/24/17 
 
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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:  PD 0332991 
Cycle:    
 
Study ID#:   
 
 
 
Formulation: ___ Liquid   ___ Capsules  
Route (if liquid): ___ By mouth   ___ Feeding tube 
 
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for each month.  Take _____mg of PD 0332991 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 to your physician or your study coordinator 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 PD 0332991 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 
 
 
 
 
 
 
 


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APPENDIX C: Pfizer Reportable Event Cover Sheet 
 
 
 


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APPENDIX D: CYP3A4 Inhibitors, Inducers, and Substrates 
 
(Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University 
School of Medicine (2007). "http://medicine.iupui.edu/clinpharm/ddis/clinical-table/" Accessed 
01/22/14.) 
 
CYP3A4 Inhibitors - Avoid 
Indinavir 
Nelfinavir 
Ritonavir 
Clarithromycin 
Itraconazole 
Ketoconazole 
Nefazodone 
Erythromycin 
Grapefruit juice 
Verapamil 
Diltiazem 
Cimetidine 
Amiodarone 
Fluvoxamine 
Mibefradil 
Toleandomycin 
 
CYP3A4 Inducers – Avoid and Consider an Alternate Medication 
Carbamazepine 
Phenobarbital 
Phenytoin 
Pioglitazone 
Rifabutin 
Rifampin 
St. John’s wort 
Troglitazone 
 
CYP3A4 Substrates – Not Recommended, Consult PI before Use 
Clarithromycin 
Erythromycin 
Telithromycin 
Quinidine  3-OH 
Alprazolam 
Diazepam  3-OH 
Midazolam 
Triazolam 
Cyclosporine 
Tacrolimus 
Indinavir 
Ritonavir 


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Saquinavir 
Cisapride 
Astemizole 
Chlorpheniramine 
Amlodipine 
Diltiazem 
Felodipine 
Nifedipine 
Nisoldipine 
Nitrendipine 
Verapamil 
Atorvastatin 
Lovastatin 
Simvastatin 
Aripiprazole 
Boceprevir 
Buspirone 
Gleevec 
Haloperidol 
Methadone 
Pimozide 
Quinine 
Sildenafil 
Tamoxifen 
Telaprevir 
Trazodone 
Vincristine 
 
 
 
 


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APPENDIX E: 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? 
 
 
 
 


Protocol Version: Amendment 6; 10/24/17 
 
Page 70 of 73 
 
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 
 
 
 


Protocol Version: Amendment 6; 10/24/17 
 
Page 71 of 73 
 
APPENDIX F: 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 
 
 


Protocol Version: Amendment 6; 10/24/17 
 
Page 72 of 73 
 
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 
 
 
 


Protocol Version: Amendment 6; 10/24/17 
 
Page 73 of 73 
 
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