Weekly Docetaxel, Cisplatin, and Cetuximab (TPC) in Palliative Treatment of Patients With SCCHN
Phase: PHASE2
Conditions: Head and Neck Cancer
Sponsor: Stanford University

 
 
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Weekly Docetaxel, Cisplatin, and Cetuximab (TPC) in Palliative Treatment of Patients with SCCHN 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NCT01437449 
 
Coordinating Institution 
Stanford Cancer Institute 
875 Blake Wilbur Drive 
Stanford, CA 94305 
 
Protocol Director 
 A. Dimitrios Colevas, M.D., 
      Division of Medical Oncology 
 Stanford University Medical Center 
875 Blake Wilbur Drive 
Stanford, CA  94305-5826 
 
Participating Institution Investigator 
Jonathan Riess, M.D., M.S. 
UC Davis Comprehensive Cancer Center 
4501 X Street,  
Sacramento, CA 95817 
 
Co- Investigators 
 
Harlan A. Pinto, M.D., Stanford Cancer Institute 
 
Heather Wakelee, M.D., Stanford Cancer Institute 
 
Joel Neal, M.D., PhD, Stanford Cancer Institute 
 
Biostatistician 
Alex McMillan, PhD  
Sr Res Scientist-Basic Ls in  
Health Research and Policy – Biostatistics 
Redwood Bldg,  
Stanford, California 94305 
 
Study Coordinator 
Ruth Lira  
Stanford University Medical Center 
800 Welch Road,  
Palo Alto, CA 94304 

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TABLE OF CONTENTS 
 
PROTOCOL SYNOPSIS ............................................................................................................. 4 
SCHEMA ....................................................................................................................................... 5 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .............................................. 6 
1. OBJECTIVES ........................................................................................................................ 7 
1.1. PRIMARY OBJECTIVE ......................................................................................................... 7 
1.2. SECONDARY OBJECTIVES ................................................................................................... 7 
2. BACKGROUND .................................................................................................................... 7 
2.1 STUDY AGENTS ................................................................................................................... 7 
2.3 RATIONALE ......................................................................................................................... 7 
2.4 STUDY DESIGN ................................................................................................................... 8 
3. PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES ......................... 9 
3.1 INCLUSION CRITERIA .......................................................................................................... 9 
3.2 EXCLUSION CRITERIA ......................................................................................................... 9 
3.3 INFORMED CONSENT PROCESS .......................................................................................... 10 
3.4 STUDY TIMELINE .............................................................................................................. 10 
4. TREATMENT PLAN .......................................................................................................... 10 
4.1 PREMEDICATIONS AND SUPPORTIVE CARE GUIDELINES ................................................... 11 
4.2 CRITERIA FOR REMOVAL FROM STUDY ............................................................................. 12 
4.3 ALTERNATIVES ................................................................................................................. 12 
5. AGENTS INFORMATION ................................................................................................ 12 
5.1 AGENTS ............................................................................................................................ 12 
5.2 AVAILABILITY .................................................................................................................. 12 
5.3 AGENT ORDERING ............................................................................................................ 12 
5.4 AGENT ACCOUNTABILITY ................................................................................................. 12 
6. DOSE MODIFICATIONS .................................................................................................. 12 
7. ADVERSE EVENTS AND REPORTING PROCEDURES ............................................ 15 
7.1 POTENTIAL ADVERSE EVENTS .......................................................................................... 15 
7.2 ADVERSE EVENT REPORTING............................................................................................ 17 
9. STUDY CALENDAR .......................................................................................................... 18 
10. MEASUREMENT.............................................................................................................. 19 
11. REGULATORY CONSIDERATIONS ........................................................................... 24 
11.1 INSTITUTIONAL REVIEW OF PROTOCOL ........................................................................... 24 
11.2 DATA AND SAFETY MONITORING PLAN .......................................................................... 24 
11.3 DATA MANAGEMENT PLAN ............................................................................................ 25 
12. STATISTICAL CONSIDERATIONS ............................................................................. 25 
12.1 STATISTICAL DESIGN AND TRIAL SIZE ............................................................................. 25 
12.2 DESCRIPTIVE STATISTICS AND EXPLORATORY DATA ANALYSIS OF SECONDARY ENDPOINTS: 
26 
13. REFERENCES ................................................................................................................... 27 
APPENDICES ............................................................................................................................. 29 
APPENDIX A: PARTICIPANT ELIGIBILITY CHECKLIST AND REGISTRATION PROCESS ............... 29 

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    SUPPORTING DOCUMENTATION* ................. ERROR! BOOKMARK NOT DEFINED. 
    APPENDIX B: PERFORMACE STATUS CRITERIA……………………………………………… 
    APPENDIX C: ADVERSE EVENT LOG-separate file 
    APPENDIX D: TUMOR MEASUREMENT LOG-separate file 
    APPENDIX E: CLINIC ASSESSMENT FORM-separate file 
    APPENDIX F: SAE COVER SHEET & REPORT FORM-separate file 
    APPENDIX G: HOW TO REPORT SAE- separate file 
      

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PROTOCOL SYNOPSIS 
 
TITLE 
Weekly Cisplatin and Docetaxel with 
Cetuximab  in palliative treatment of 
patients with SCCHN 
 
STUDY PHASE 
Phase 2 
INDICATION 
Squamous Cell Carcinoma of the Head and 
Neck (SCCHN) 
TREATMENT AGENTS 
Cisplatin, Docetaxel, Cetuximab Carboplatin 
PRIMARY OBJECTIVE(S) 
Response Rate 
SECONDARY OBJECTIVE(S) 
Progression Free and Overall Survival, 
Safety 
TREATMENT SUMMARY 
Docetaxel 30mg/m2/week IV over 30 
minutes.  
Cisplatin 30 mg/m2/week IV over 30 
minutes(For  certain AEs, Carboplatin to be 
substituted). 
CETUXIMAB 400 mg/m2 IV over 2 hours 
load, then 250 mg/m2 IV over 1 hour 
weekly. 
Repeated 3 of every 4 weeks: Patients to 
receive treatment during scheduled week 1 
(Day 1), 2 (Day 8), and 3 (Day 15). Taking a 
break to recover during the 4th week (Day 21 
- 28) of the 28 day cycle. If a dose is held 
during weeks 1-3, the dose may be given 
during the 4th week.   
Continue treatment until evidence of disease 
progression or unacceptable AE profile. 
 
SAMPLE SIZE  
Up to 27 patients in a Simon 2 stage design: 
10 patients will be treated in the first stage 
and up to 17 patients may be treated in the 
second stage.   
STATISTICAL CONSIDERATIONS 
To distinguish 25% RR from 50% rr with 
alpha and beta = 0.1 
 
 

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SCHEMA 
 
Patients with metastatic or recurrent 
Squamous Cell Ca of the Head and neck 
Confirm eligibility by pathology, 
RECIST evaluable lesions, organ 
function studies 
Weekly cisplatin, docetaxel, cetuximab 
days 1, 8, 15 of 28 day cycle 
Assess response by RECIST every 8 weeks 
(Primary endpoint) +/- 1 week 
Off study 
Continue treatment with cisplatin, 
docetaxel, cetuximab up to 12 cycles 
Continue treatment with 
cisplatin, docetaxel, cetuximab 
2 cycles beyond CR 
Continue cetuximab until 
progression of disease 
Continue cetuximab until 
progression of disease 
Progression 
SD or PR 
CR 
Follow for 2 years for  
OS and PFS 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
 
ADL 
Activities of daily living 
AE 
Adverse event 
BID 
Twice daily 
BSA 
Body surface area 
CBC 
Complete blood count 
CI 
Confidence interval 
CMAX 
Maximum concentration of drug 
CNS 
Central nervous system 
CRF 
Case report/Record form 
CR 
Complete response 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
GI 
Gastrointestinal 
Hgb 
Hemoglobin 
HIV 
Human Immunodeficiency Virus 
HPF 
High-power field  
HTN 
Hypertensions 
IRB 
Institutional Review Board 
IV 
Intravenous 
LLN 
Lower limit of normal  
OS 
Overall survival  
PLT 
Platelet 
PD 
Progressive diseased 
PFS 
Progression free survival  
PR 
Partial response 
QD 
Once daily 
RECIST 
Response evaluation criteria in solid tumors 
RR 
Response rate 
SAE 
Serious adverse event 
SD 
Stable disease 
TTP 
Time to progression 
ULN 
Upper limit of normal 
UNK 
Unknown 
WBC 
White blood cell 
WHO 
World Health Organization 
 

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1. 
OBJECTIVES 
 
1.1. 
Primary Objective  
To establish the response rate using RECIST 1 criteria to weekly TPC in patients with metastatic or 
relapsed squamous cell carcinoma of the head and neck. 
 
1.2. 
Secondary Objectives 
 
To establish the safety profile, progression free and overall survival of weekly TPC in this patient 
population. 
 
2. 
BACKGROUND 
2.1 
Study Agents 
Docetaxel and cetuximab are FDA approved for the treatment of squamous cell carcinoma of the head 
and neck (SCCHN).  Cisplatin and carboplatin, while not FDA approved for SCCHN, have been for 
several decades used as a standard of care in patients with SCCHN in combination with taxanes and 
more recently in combination with cetuximab. 2 Please refer to their respective package interests for 
details concerning pharmacology and expected adverse events. 
 
2.3 
Rationale 
Rationale/Hypothesis: 
Squamous cell carcinoma of the head and neck (SCCHN) region is one of the more chemotherapy 
sensitive human neoplasms. Response rates approaching 70% have been reported with single agent 
treatment, and recent reports demonstrate that overall response rates and complete response rates 
approaching 90% and 60%, respectively are achievable. 3-5  Despite the advances made in the treatment 
of patients with SCCHN confined to the primary and neck region, many of these patients still relapse 
and are not candidates for salvage surgery or radiation treatment. Most of these patients die as a result of 
complications of their cancer. 6-9 Additionally, up to one third of  patients present with metastatic disease 
and are therefore not eligible for multimodality potentially curative treatment. Because patients with 
recurrent or metastatic disease are generally incurable, the goals of treatment are more limited, and 
include prolongation of overall survival (OS) or progression-free survival (PFS), palliation of existing 
symptoms, and prevention of new cancer-related symptoms. Improvement in survival has been the holy 
grail of treatment in this setting.  Platinum- based chemotherapy has been the standard treatment in this 
setting, based in the fact that platinum based combinations have demonstrated the highest response rates. 
10 If overall survival is the benchmark standard, there have been only two trials to date demonstrating 
superiority of one regimen versus others.  Morton et al. compared cisplatin and bleomycin in a 2x2 
design, and only the cisplatin arms in aggregate demonstrated a statistically significant survival 
advantage of 4.3 versus 1.8 months to the CDDP containing arms. 11 
 
More recently, Vermorken and colleagues demonstrated in a landmark study that the addition of 
cetuximab to a platinum and 5-FU (PF) backbone was associated with an approximately 3 month 
improvement in median survival. 2  Unfortunately, because the design of the trial was such that patients 
in the cetuximab arm received the agent not only with PF but as a maintenance in non-progressors, it is 
theoretically possible that the survival benefit may be obtained by sequential rather than concurrent 
dosing. The higher response rate in the cetuximab arm would argue that the concurrent treatment was at 
least a contributor to the OS advantage; however, it is also worth noting that this trial, dubbed 
“EXTREME”, was notable for significant clinically relevant toxicity in both arms. Over 30% of the 
patients experienced grade 4 AEs.  It is also noteworthy that there were no grade 3 or higher diarrhea or 
mucositis toxicities reported in this trial, when in ECOG 1395, a 31% high grade stomatiitis rate was 

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reported for an identical PF regimen, leading one to wonder why so few AEs were reported on the 
EXTREME study. 12 Additionally, the standard of practice in Belgium is to hospitalize all patients for 
the administration of PF, whereas in the US, patients are typically treated in outpatient infusion centers. 
(Jan Vermorken, personal communication ASCO annual meeting 2009) 
 
To further put the EXTREME trial into context, note that Burtness and ECOG colleagues studied 
cisplatin +/- cetuximab in SCCHN patients in a smaller RCT. 13  Because the trial was much smaller 
than the Vermorken study, they were not able to demonstrate a statistically significant survival 
advantage to the addition of cetuximab, but  the survival  hazard rates in the Burtness and Vermorken 
trials were similar, suggesting that the benefit from the cetuximab was not largely due to a combination 
effect with 5-FU.  Vermorken and colleagues have also  performed a global phase 3 trial of PF +/- 
panitumumab in patients with recurrent or metastatic SCCHN with a similar design to the EXTREME 
trial which will answer whether this anti- EGFR MOAB from another IGG class will also improve 
survival.14 In this trial, AEs, including stomatitis and mucosal inflammation were substantial as well. 
Initial reports of this trial, not yet available in the peer reviewed literature, claim that the survival benefit 
associated with the EXTREME trial using cetuximab were not reproduced using panitumumab. 
 
PF’s use as the backbone regimen used for the addition of new agents in the palliative setting is largely 
driven by the large amount of data of PF in the induction setting, combined with the fact that in some 
European countries, taxanes remain unapproved for use on patients with head and neck cancer, 
precluding its use as part of an acceptable backbone regimen in the EORTC trials (Vermorken, personal 
communication ASCO 2009). 
 
Therefore, the use of PF as the backbone for the addition of cetuximab is largely due to historical and 
drug availability issues rather than what has been defined as the best therapeutic combination.  Another 
combination shown to be of equal efficacy as PF in this setting is the combination of paclitaxel and 
cisplatin (PC). A RCT comparing PF versus cisplatin 75 mg/m2 plus paclitaxel 175 mg/m2 q 21 days 
demonstrated no significant difference in RR or OS, but the high grade AEs in the PF arm were more 
common than in the PC arm. 12 Granulocytopenia rates were similar but anemia. Infection, vomiting, 
diarrhea, stomatitis, metabolic disturbances and fatigue were more prominent in the PF arm.  Therefore, 
if access to paclitaxel is not at issue, PC could be considered, based upon therapeutic index, a  superior 
doublet to use in  this setting. Similar regimens of docetaxel and cisplatin (TC) have also been studied in 
this setting, yielding high response rates and similar duration of response as PC. 15 16 17 
 
A major difficulty with the PC and TC regimens administered on a q 21 day schedule is the 
unpredictability of the hematological AE profile.  In many other oncological diseases, the use of weekly 
treatment regimens has been used to circumvent this problem without the loss of efficacy, and there are 
data specific to SCCHN which suggest that weekly taxane and cisplatin combinations are very well 
tolerated and are associated with similar response rates and OS as the q 21d regimens. 18  In the initial 
treatment  setting, platinum plus taxane plus cetuximab regiments have been shown to be highly active, 
feasible and well tolerated in SCCHN patients but when the platinum and taxanes are given on the q 21 
day schedule, toxicity is substantial. 19,20,21 While docetaxel, cisplatin, and cetuximab have been given in 
the recurrent or metastatic setting, on a q 21 day schedule toxicity has been substantial but response rates 
as high as 49% in this setting are very high relative to other combinations whose response rates are 
usually in the 30-40% range in this setting. 22 
 
2.4 
Study Design 
 
This treatment trial is a single arm, unblinded, two staged Simon 23 design to evaluate the RECIST 

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response rate to weekly TPC in patients with recurrent or metastatic  SCCHN. 
 
 
3. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
 Refer to the Participant Eligibility Checklist in Appendix A for enrollment procedures.  
 
3.1 
Inclusion Criteria 
 
3.1.1 Squamous cell carcinoma of head and neck sites, including all pharynx, larynx, oral cavity, 
skin and para-nasal sinus sites.  Patients with a diagnosis of Nasopharyngeal Carcinoma, or 
SCC of unknown primary presenting in the neck clinically compatible with head and neck 
mucosal primary sites, are eligible.  
 
3.1.2 Patients who have received prior chemoradiation, radiation, and/ or surgery in the potentially 
curative setting are eligible as long as 3 months has elapsed since the end of the potentially 
curative treatment ended. 
  
3.1.4 Patients must be greater than 16 years old. 
 
 
3.1.5 ECOG Performance Status < 3 at enrollment is required.  
 
3.1.6 Laboratory value requirements at enrollment: 
Absolute neutrophil count > 1500/mm3 
Platelet count >100K/mm3 
 
AST and ALT < 2.5 x ULN unless liver metastases documented. In this latter case, AST and ALT < 
5 x ULN required. 
Total Bilirubin < 1.5 x ULN unless the patient has Gilbert’s syndrome, in which case T. Bilirubin < 
2.5 x ULN required 
Serum Creatinine < 1.5 mg/dL OR an estimated creatinine clearance from 24 hour urine collection > 
50 ml/min 
 
3.1.7 Clinical requirements at enrollment: 
Peripheral neuropathy < grade 2 
 
Ability to understand and the willingness to sign a written informed consent document. 
 
3.2 
Exclusion Criteria 
 
3.2.1 No prior palliative chemotherapy  
 
3.2.2 Patients with active infections including known HIV are not eligible.  HIV positive patients 
on HAART with undetectable  blood HIV levels are eligible. Patients with a history or 
serological evidence of exposure to Hepatitis B without active infection are eligible for this 
study. 
 

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3.2.3 Patients with prior grade 3 allergic or infusion reactions to docetaxel, cisplatin or cetuximab 
are not eligible.  A history of well tolerated infusion reactions is NOT an exclusion. 
 
3.2.4 Pregnant women and/or nursing patients will be excluded from the study because of potential 
harm to the fetus or nursing infant.  
 
3.2.5 Because the primary endpoint of this study is response rate and not survival, patients with a 
history of other malignancies treated curatively greater than one year prior to enrollment and 
without evidence of relapse at the time of enrollment are eligible. 
 
3.2.6 Patients with known brain metastasis are eligible only if by CNS imaging there is no 
evidence of CNS progression at least 30 days following definitive CNS treatment (resection 
or radiation). 
 
      3.3 Informed Consent Process 
All participants must be provided a consent form describing the study with sufficient information for 
participants to make an informed decision regarding their participation.  Participants must sign the IRB 
approved informed consent prior to participation in any study treatment. The participant must receive a 
copy of the signed and dated consent document. A signed and dated copy must be placed into the 
patient’s medical record. The original signed copy of the consent document must be retained in the 
research file.  
 
 
3.4 
Study Timeline 
 
 
Primary Completion: 
It is estimated that accrual will take 1 year for each of the two stages and another year after each stage 
has been completed to have the complete response assessment analyzed. 
 
Study Completion: 
From first accrual to final response evaluation, 3 years. 
 
4. 
TREATMENT PLAN 
 
Patients will be treated weekly with cisplatin, docetaxel, and cetuximab according to the specifics designed 
below.  If a dose is held during weeks 1-3, the dose may be given during the 4th week. The next cycle should 
then begin with Triplet 1 the following week.  
 
STANFORD- NOTE THAT USE OF EPIC BEACON TEMPLATE #2161, ITA HEAD AND NECK 
DOCETAXEL / CISPLATIN / CETUXIMAB QWEEK(ONC)  IS STRONGLY ENCOURAGED. 
 
UC DAVIS- NOTE THAT A UC DAVIS SPECIFIC WRITTEN CHEMOTHERAPY ORDER SET WILL BE 
CREATED. 
 
AGENT 
DOSE 
SCHEDULE 
CYCLE 
duration 
Docetaxel 
30 mg/m2 over 30 minutes IV 
Days 1, 8, 15 
28 days 
Cisplatin 
30 mg/m2 over 30 minutes  IV 
Days 1, 8, 15 
Cetuximab 
Loading dose for cycle 1, day 1 will be 
administered as 400 mg/m2 ONLY IV 
Days 1, 8, 15* 

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over 120 minutes 
Then for all subsequent and/or 
maintenance doses (starting at cycle 1, 
day 8) will be given as 250 mg/m2 IV 
over 60 minutes 
Carboplatin  (only if 
substituting for cisplatin) 
AUC** = 2,  
IV over 30 minutes 
Days 1, 8, 15 
*In order to facilitate timely infusion of agents, cetuximab may be administered +/- 8 day of the cisplatin and 
docetaxel infusions since in some cases the duration of infusion on day 1 cycle 1 may be prohibitively long. In 
cases where the loading dose of cetuximab was given alone and it has been more than 5 days since the 
cetuximab was given, cetuximab may be given at the weekly dosing per protocol during the next treatment day, 
unless treatment must be held due to AE.  
In cases where cetuximab treatment has been held for more than 2 scheduled treatment visits [14 days] the 
patient may be given an additional loading dose of cetuximab. In addition, if the last treatment is >2 weeks (14 
days) from last dose, then the cycle shall begin again starting at Triplet 1 to match the loading dose of 
Cetuximab.    
 
Cycle ONE Clarification: 
 Cycle one is to include the loading dose of Cetuximab (alone) and three doses of the triplet 
(Platinum/Docetaxel/Cetuximab) when the loading dose of cetuximab was given more than 5 days from 
scheduled triplet #1 dose. [Day 1: Cetuximab Alone … Day 8: Triplet dose # 1] 
OR  
 Cycle one is to include the loading dose of Cetuximab (alone) and two doses of the triplet 
(Platinum/Docetaxel/Cetuximab) when the loading dose of cetuximab was given < 5 days from 
scheduled Platinum/Docetaxel dose. [Day 1: Cetuximab Alone … Day 5: Platinum/Docetaxel only (dose 
#1)]   
 
**Calculated using Cockcroft-Gault GFR = (140-age) * (Wt in kg) * (0.85 if female) / (72 * Cr). Therefore by 
Calvert formula, Carboplatin dose (mg) = AUC x (GFR +25) 
 
Duration of treatment: Patients may receive up to 12 cycles of cisplatin and docetaxel treatment. All confirmed 
complete responders will be treated with cisplatin and/or docetaxel for an additional 2 cycles beyond 
confirmation of CR. Cetuximab will be continued until progression of disease. 
 
4.1 
Premedications and Supportive Care Guidelines 
CETUXIMAB 
Patients shall receive prior to the first dose of cetuximab: 
 50 mg of diphenhydramine, PO or IV. 
Prior to all doses of subsequent cetuximab, patents shall receive: 
 
25-50 mg of diphenhydramine PO or IV per physician discretion. 
 
CISPLATIN 
Patients shall receive prior to each dose of cisplatin: 
Ondansetron 24 mg oral or 16 mg IV, or therapeutic equivalent 
Dexamethasone 8 mg BID orally or IV x 6 doses beginning approximately 12 hours prior to cisplatin. 
Note this also is premedication for docetaxel. Per physician discretion, following the first dose of 
cisplatin and docetaxel, dexamethasone may be reduced to 8 mg BID x 2 doses. 
Use of other antiemetics such as aprepitant, metochlopramide, prochlorperazine and lorazepan per 
physician preference are permitted. 

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Patients shall receive at least two liters of intravenous saline hydration on days of cisplatin, one liter 
immediately prior to the cisplatin administration.  Use of magnesium supplementation, mannitol for 
diuresis and additional hydration is per physician preference. 
 
DOCETAXEL 
Dexamethasone 8 mg BID orally or IV x 6 doses beginning approximately 12 hours prior to docetaxel. 
Note this also is premedication for cisplatin.  Per physician discretion, following the first dose of 
cisplatin and docetaxel, dexamethasone may be reduced to 8 mg BID x 2 doses. 
 
CARBOPLATIN 
Ondansetron 16 mg oral or 8 mg IV, or therapeutic equivalent. 
 
 
4.2 
Criteria for Removal from Study 
Treatment will be stopped and patients will be removed from study for clinical and/or radiological 
disease progression, unacceptable adverse events, and patients who have withdrawn their consent.  
 
4.3 
Alternatives 
Standard chemotherapy regimens are available for SCCHN. All procedures noted in Section 9- Study 
Calendar for this trial are considered Standard of Care, and part of routine ordering at the discretion of 
the physician. 
 
5. 
AGENTs INFORMATION 
5.1 
Agents   
Docetaxel, cisplatin, carboplatin and cetuximab are all commercially available agents for use in patients 
with cancer and are routinely used for the palliative treatment of patients with SCCHN. Please refer to 
their respective package interests for details concerning pharmacology, preparation, compatibility, 
administration and expected adverse events. 
 
5.2 
Availability 
Docetaxel, cisplatin, carboplatin and cetuximab are all commercially available.  
 
5.3 
Agent Ordering 
N/A.  Commercial supplies to be used.  
 
5.4 
Agent Accountability 
N/A.  Commercial supplies to be used and administered according to physician orders.  
 
6. 
DOSE MODIFICATIONS 
All chemotherapy related toxicities should be graded according to the Common Terminology Criteria 
for Adverse Events Version 4.0. All dose reductions will be based on the most recent lab values and 
worst overall  clinical AE since previous evaluation interval for clinical assessments on the day of 
treatment. 
 

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Dose modification guidelines for chemotherapy and cetuximab are independent. Cetuximab can be 
continued while docetaxel and cisplatin are held (if criteria for retreatment with cetuximab are met). 
Similarly, chemotherapy can be continued while cetuximab is held (if criteria for retreatment with 
chemotherapy are met). If holding of one chemotherapy agent is required, the other chemo-agent can 
still be administered. 
 
NOTE: No dose re-escalations will be allowed once the reduction has occurred. 
Starting dose 
Dose level minus one 
Dose level minus two 
Cisplatin 30 mg/m2 
25 mg/m2 
20 mg/m2 
Docetaxel 30 mg/m2 
25 mg/m2 
20 mg/m2 
Cetuximab 250 mg/m2 
200 mg/m2 
150 mg/m2 
Carboplatin AUC 2 
AUC 1.5 
AUC 1 
 
Cetuximab dose reduction guidelines: 
 
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 
acneiform rash. Treatment with topical and/or oral antibiotics 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. NO dose reductions below 
dose level minus two. 
 
 
Cetuximab Dose modification for rash: 
 
Severe (Grade 4) 
Cetuximab dose 
change 
Outcome 
Subsequent dosing 
1st occurrence 
Hold infusion for up 
to 2 doses (2 weeks) 
improvement 
No dose change 
No improvement 
Discontinue 
cetuximab 
2nd occurrence 
Hold infusion for up 
to 2 doses (2 weeks) 
improvement 
Reduce one dose level 
No improvement 
Discontinue 
cetuximab 
3rd occurrence 
Hold infusion for up 
to 2 doses (2 weeks) 
improvement 
Reduce one dose level 
No improvement 
Discontinue 
cetuximab 
4th occurrence 
Discontinue cetuximab 
 
Cetuximab infusion reactions 
 
In clinical trials, severe, potentially fatal infusion reactions were reported.  These events include the 
rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), urticaria, and/or hypotension. 
Severe infusion reactions occurred with the administration of Cetuximab in approximately 3% of 
patients, rarely with fatal outcome (<1 in 1000). Approximately 90% of severe infusion reactions were 
associated with the first infusion of cetuximab despite the use of prophylactic antihistamines. These 
reactions were characterized by the rapid onset of airway obstruction (bronchospasm, stridor, 
hoarseness), urticaria, and/or hypotension. Caution must be exercised with every cetuximab infusion, as 
there were patients who experienced their first severe infusion reaction during later infusions. 

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Management of cetuximab infusion reactions 
 
Severe infusion reactions 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. Mild to moderate infusion reactions should be managed by slowing the infusion 
rate of cetuximab and by continued use of antihistamine medications (e.g., diphenhydramine) in 
subsequent infusions.  If the patient experiences a mild or moderate (Grade 1 or 2) infusion reaction, the 
infusion rate should be permanently reduced by 50%. Cetuximab should be immediately and 
permanently discontinued in patients who experience severe (grade 3 or 4) infusion reactions. 
 
GRADE OF Cetuximab infusion reaction 
Response 
Grade 1 or 2, flushing, rash, feverm dyspnea, 
urticaria 
Stop infusion, administer appropriate therapy, 
restart at 50% of prior infusion rate. 
Grade 3 or 4, brochospasm requiring parenteral 
medications, angioedema, hypotension, 
anaphylaxis, stridor 
Stop infusion. Permanently discontinue 
cetuximab. 
Administer epinephrine, bronchodilators, 
antihistamines, glucocorticoids, intravenous 
fluids, vasopressor agents, oxygen, etc, as 
medically indicated 
 
Docetaxel, Cisplatin, and Carboplatin dose reduction guidelines: Dose reductions are ONLY to be 
considered for chemotherapy related toxicities. 
(NO dose reductions below dose level minus two permitted) 
Toxicity and Grade 
Docetaxel modification 
Cisplatin and/or Carboplatin 
modification 
ANC Grade 2 (<1500 - 
1000/mm3) 
Reduce one level 
Reduce one level 
ANC Grade 3 or 4 (< 
1000/mm3) 
Hold for up to 2 weeks then 
reduce one level 
Hold for up to 2 weeks then 
reduce one level 
PLT Grade 2-4  (<75K/mm3) 
Hold for up to 2 weeks then 
reduce one level 
Hold for up to 2 weeks then 
reduce one level 
T Bili* Grade 2 ( > 1.5-3x 
ULN) 
Reduce one level 
No Change 
T Bili Grade 3-4 ( >3 x ULN) 
Hold for up to 2 weeks 
No Change 
Neuropathy or Hearing Loss 
Grade 2 
Hold until < Grade 1 then 
dose reduce one level for 
neuropathy, no change for  
hearing loss 
Hold until < Grade 1 then dose 
reduce one level 
Neuropathy or Hearing Loss 
Grade 3 
Hold until < Grade 1 then 
dose reduce one level for 
neuropathy, no change for 
hearing loss 
Substitute with carboplatin 
Neuropathy or Hearing Loss 
Grade 4 
Discontinue for neuropathy, 
no change for hearing loss 
Substitute with carboplatin 

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Creatinine: CALCUALTE 
CREATININE CLEARANCE 
FOR SERUM Creatinine > 
1.3** 
No dose modification 
Cr Cl > 50 ml/min, no change 
in cisplatin. CrCl < 50 ml. 
min, substitute carboplatin. 
Other non-hematological AEs 
Grade 3-4 
Hold for up to two weeks 
until < Grade 1 then dose 
reduce one dose level 
Hold  for up to two weeks 
until < Grade 1 then dose 
reduce one dose level 
* Unless Gilbert’s syndrome at baseline 
** Creatinine clearance estimate by Cockroft-Gault = [(140- age (yrs)) x  
(actual weight (kg)) / (72 x serum creatinine (mg/dl))] x (0.85 if female). 
 
7. 
ADVERSE EVENTS  
 
7.1 
Potential Adverse Events 
Docetaxel, cisplatin, carboplatin and cetuximab are all commercially available.  
Please refer to the approved package inserts for these agents to see the complete list of reported AEs. Below 
is a brief summary of common AEs with these agents: 
 
Cisplatin:  
1.Renal: A dose-related, cumulative renal tubular injury can occur; adequate 
hydration and diuresis usually minimize the risk. Salt-wasting nephropathy 
and/or orthostatic hypotension with hyporeninemic hypoaldosteronism can 
occur in up to 10% of patients. 
2. Neurologic: A dose-related ototoxicity, manifested by high-frequency hearing 
loss and tinnitus, occurs in about 30% of patients. Paresthesias, decreased 
vibratory, position, and touch sensations are less common; particularly at 
cumulative doses <400 mg/m2. 
3. Hematologic: Mild leukopenia and thrombocytopenia occur in 25-30% of 
patients, but are rarely dose-limiting; anemia is less common. A potentially 
fatal hemolytic uremic syndrome has been reported. 
4. Gastrointestinal: Severe, dose-limiting nausea and vomiting occur in almost 
100% of patients unless adequate antiemetic prophylaxis is given. Even with 
successful prophylaxis of acute nausea a delayed (72-96 hour) reaction, 
requiring additional therapy may occur. Anorexia and taste changes may also 
occur. 
5. Hypersensitivity: Allergic reactions are reported in up to 20% of patients 
Symptoms include: rash, facial edema, wheezing, hypotension, and 
tachycardia. Severe anaphylaxis is rare. 
6. Other: Electrolyte wasting (magnesium, potassium and sodium), papilledema, 
optic neuritis, retrobulbar neuritis are reported 
 
Carboplatin: 
1. Myelosuppression is the major dose-limiting toxicity. Thrombocytopenia, neutropenia, leukopenia, and 
anemia are common. 
2. Allergic Reactions: Hypersensitivity to carboplatin has been reported in 2% of 
patients receiving the drug. Symptoms include rash, urticaria, erythema, pruritus, and rarely bronchospasm 
and hypotension.  
3.  Neurologic: Peripheral neuropathies have been observed in 4% of patients receiving carboplatin with 
mild paresthesia being the most common. 

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4.  Gastrointestinal: Nausea and vomiting are the most common GI events; both usually resolve within 24 
hours and respond to antiemetics. Other GI events include diarrhea, weight loss, constipation, and 
gastrointestinal pain. 
5. Hepatic Toxicity: Elevated alkaline phosphatase, total bilirubin, and SGOT 
have been observed. 
6. Other: Pain and asthenia are the most common miscellaneous adverse events. Alopecia has been reported 
in 3% of the patients taking carboplatin. 
 
     Docetaxel: 
1. Myelosuppression (neutropenia, leukopenia, thrombocytopenia, 
anemia). 
2. Hypersensitivity: Minor symptoms include hypotension, flushing, chest pain, abdominal or extremity 
pain, skin reactions, pruritus, dyspnea, and tachycardia. More severe reactions 
include hypotension requiring treatment, dyspnea with bronchospasm, 
generalized urticaria, and angioedema. The majority (53%) of the reported 
reactions occurred within 2-3 minutes of initiation of treatment and 78% 
occurred within the first 10 minutes. Reactions usually occurred with the first 
and second doses. 
3. Cardiovascular: Atrial arrhythmia (sinus bradycardia [usually transient and 
asymptomatic], sinus tachycardia, and premature beats); significant events 
include syncope, hypotension, other rhythm abnormalities (including ventricular 
tachycardia, bigeminy, and complete heart block requiring pacemaker 
placement), and myocardial infarction. Hypertension, possibly related to 
concomitant administration of dexamethasone, may also occur. 
4. Neurologic: Sensory changes (taste changes); peripheral neuropathy; arthralgia 
and myalgia (dose-related, more common when colony-stimulating factors are 
also administered); seizures; mood alterations; neuroencephalopathy; hepatic 
encephalopathy; motor neuropathy; and autonomic neuropathy (paralytic ileus 
and symptomatic hypotension). 
6. Dermatologic: Alopecia, universal, complete, and often sudden, between days 
14-21; injection site reactions (erythema, induration, tenderness, skin 
discoloration); infiltration (phlebitis, cellulitis, ulceration, and necrosis, rare); 
radiation recall; and rash. 
6. Gastrointestinal: Nausea, vomiting, diarrhea, mucositis, pharyngitis, typhlitis 
(neutropenic enterocolitis), ischemic colitis, and pancreatitis. 
7. Hepatic: Increased SGOT (SAST), SGPT (ALT), bilirubin, alkaline 
phosphatase; hepatic failure, and hepatic necrosis. 
8. Other: Fatigue, headaches, light-headedness, myopathy, elevated serum 
creatinine, elevated serum triglycerides, and visual abnormalities (sensation of 
flashing lights, blurred vision). 
 
 
 
 
Cetuximab:  
1. Infusion reaction: Characterized by airway obstruction (e.g., bronchospasms, stridor, 
hoarseness), urticaria, hypotension; infusion reactions occur in about 3% of patients, 
rarely with fatal outcome (< 1 in 1,000) 
2. Pulmonary: Interstitial lung disease (less than 0.5% of cases, usually reported in patients 
with pre-existing fibrotic lung disease), pulmonary emboli, dyspnea, increased cough 
3. Hematologic: Leukopenia, anemia 
4. Gastrointestinal: Nausea, vomiting, diarrhea, constipation, dyspepsia, abdominal pain, 
anorexia, stomatitis, kidney failure, 

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5. Dermatologic: Rash, acne, dry skin, pruritus, ulceration, alopecia, nail disorder 
6. Circulatory: Deep vein thrombosis 
7.  Neurological: Headache, depression 
8. Allergy: Allergic reaction, anaphylactoid reaction 
9. Ocular: Conjunctivitis 
10. Other: Hypomagnesemia , asthenia, weight loss, dehydration, fatigue. 
 
  
7.2 
Adverse Event Reporting 
The Protocol Director (PD) or designee will assess each Adverse Event (AE) to determine whether it is 
unexpected according to the Informed Consent, Protocol Document, or Investigator’s Brochure, and 
related to the investigation. All Serious Adverse Events (SAEs) will be tracked until resolution or until 
30 after the last dose of the study treatment.  
 
Any Serious and Non-Serious Adverse Events experience from the following list will be clearly noted in 
source documentation during each treatment cycle and will be captured on the study specific Case 
Report Forms (CRFs): Neuropathy, Cetuximab Rash, Hearing Loss, low Absolute Neutrophil Count 
(ANC), low Platelet Count (PLT), low Hemoglobin (Hgb), and worst Creatinine levels.  
 
SAEs CTCAE v 4.0 Grade 3 and above, and all subsequent follow-up reports will be reported to the 
CCTO Safety Office regardless of the event’s relatedness to the investigation. Following review by the 
CCTO Safety Officers, any events meeting the IRB definition of ‘Unanticipated Problem’ will be 
reported to the IRB using eProtocol within 10 working days of the review, or within 5 working days for 
deaths or life-threatening experiences. 
 
 
 

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9. STUDY CALENDAR 
Schedules shown in the Study Calendar below represent the first 3 cycles. Subsequent cycles should follow 
the same pattern. All assessments are Standard of Care (SOC) and routine ordering applies at the 
physician’s discretion.  
 
 
Pre-
Studyh 
Cycle 1 
Cycle 2 
Cycle n 
Off 
Studyd 
   
 
Dose 
1f 
Dose 
2 
Dose 
3 
Breakg 
Dose 
4 
Dose 
5 
Dose 
6 
Breakg 
Dose 
n 
Dose 
n2 
Dose 
n3 
Breakg 
 
 
Cetuximab, docetaxel, and 
cisplatin (or carboplatin)a 
 
 
 
Xf 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
Informed consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
 
X 
 
X----------------------------------------------------------------------------------------------X 
 
 
 
Physical exam 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Vital signsb 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Performance status 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC w/diff, plts 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
Serum chemistryc 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
Adverse event evaluation 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Tumor measurements and 
radiological evaluation 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
Xe 
 
a: 
Investigational Agent: Dose as assigned; route/schedule. 
b: 
Blood Pressure, Heart Rate (Pulse), Temperature. 
c:      Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, SGOT[AST], 
SGPT[ALT], sodium. 
d: 
Off-study evaluation to be conducted within 30 days of last dose.   
e:     Off-study evaluation 
f:       In order to facilitate timely infusion of agents, cetuximab may be administered +/- 8 day of the cisplatin and docetaxel infusions since in some 
cases the duration of infusion on day 1 cycle 1 may be prohibitively long. In cases where the loading dose of cetuximab was given alone and it 
has been more than 5 days since the cetuximab was given, cetuximab may be given at the weekly dosing per protocol during the next treatment 
day, unless treatment must be held due to AE.  
g:      If a dose is held during weeks 1-3, the dose may be given during the 4th week. The next cycle should then begin with Triplet 1 the following 
week 
h:      Pre-study evaluations must be completed within 28 days of treatment initiation, Day 1, with the exception of labs. Labs must be repeated to 
confirm continued eligibility for day 1 within institution standards for tx initiation. 
Cycle 1 Clarification:  
          Cycle one is to include the loading dose of Cetuximab (alone) and three doses of the triplet (Platinum/Docetaxel/Cetuximab) when the loading 
dose of cetuximab was given more than 5 days from scheduled triplet #1 dose. [Day 1: Cetuximab Alone … Day 8: Triplet dose # 1] OR 
          Cycle one is to include the loading dose of Cetuximab (alone) and two doses of the triplet (Platinum/Docetaxel/Cetuximab) when the loading 
dose of cetuximab was given < 5 days from scheduled Platinum/Docetaxel dose. [Day 1: Cetuximab Alone … Day 5: Platinum/Docetaxel only 
(dose #1)]   
 
 

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10. 
MEASUREMENT  
 
Antitumor Effect:  PRIMARY ENDPOINT IS RECIST DEFINED RESPONSE RATE 
 
For the purposes of this study, patients should be re-evaluated for response every 8 weeks +/- 1 week.  
In addition to a baseline scan, confirmatory scans should also be obtained not less than 4 weeks 
following initial documentation of objective response.  
 
All measurements will be noted on a tumor measurement log and will have screenshots of relevant 
imaging or clinical findings available to support measurements.  
 
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). 
1Changes 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. 
 
Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first treatment 
with TPC. 
 
Evaluable for objective response.  Only those patients who have measurable disease present at baseline, 
have received at least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for response.  These patients will have their response classified according to the definitions 
stated below.  (Note:  Patients who exhibit objective disease progression prior to the end of cycle 1 will 
also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle of 
therapy, and have had their disease re-evaluated will be considered evaluable for non-target disease.  
The response assessment is based on the presence, absence, or unequivocal progression of the lesions.  
 
 
Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately measured in at least 
one dimension (longest diameter to be recorded) as >20 mm by chest x-ray or as >10 mm with CT scan, 
MRI, or calipers by clinical exam.  All tumor measurements must be recorded in millimeters (or decimal 
fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be considered 
measurable.   
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph node must 
be >15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no 
greater than 5 mm).  At baseline and in follow-up, only the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered non-

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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.  
 
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, 

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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.   
 
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. 
 

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Response Criteria 
 
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. 
 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): 
Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 
mm short axis). 
 
Note:  If tumor markers are initially above the upper 
normal limit, they must normalize for a patient to be 
considered in complete clinical response. 
 
 
Non-CR/Non-PD:  
 
 
Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be 
representative of overall disease status change, not a single lesion 
increase.     
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed at a 
later time by the review panel (or Principal Investigator). 
 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until disease 

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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. 
 
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 

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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 
 
Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time measurement 
criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or 
progressive disease is objectively documented (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR until the 
first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the criteria 
for progression are met, taking as reference the smallest measurements recorded since the treatment 
started, including the baseline measurements.  
 
 
Response Review 
 
All response assessments rendered by radiologists or sub-investigators must be confirmed by site PIs. 
 
SECONDARY ENDPOINTS: 
 
PFS is defined as the duration of time from start of treatment to time of progression or death, whichever 
occurs first. 
Overall survival is defined as time from start of treatment until death from any cause. Patients will be 
followed for progression on study after treatment completion quarterly with clinic visits or until another 
treatment is initiated. 
 
 
11. 
REGULATORY CONSIDERATIONS 
11.1 
Institutional Review of Protocol 
The protocol, the proposed informed consent and all forms of participant information related to the study 
(e.g. advertisements used to recruit participants) will be reviewed and approved by the Stanford IRB and 
Stanford Cancer Institute’s Scientific Review Committee (SRC).  Any changes made to the protocol will 
be submitted as a modification and will be approved by the IRB prior to implementation.  The Protocol 
Director will disseminate the protocol amendment information to all participating investigators. 
Investigators will be expected to obtain IRB approval within 90 days for all amendments.  
 
11.2 
Data and Safety Monitoring Plan 
 
The Stanford Cancer Institute’s Data and Safety Monitoring Committee (DSMC) will be the monitoring 
entity for this study. The DSMC will audit study-related activities to determine whether the study has 
been conducted in accordance with the protocol, local standard operating procedures, FDA regulations, 
and Good Clinical Practice (GCP).  In addition, the DSMC will regularly review serious adverse events 

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and protocol deviations associated with the research to ensure the protection of human subjects.  Results 
of the DSMC audit will be communicated to the IRB and the appropriate regulatory authorities at the 
time of continuing review, or in an expedited fashion, as needed. 
 
11.3 
Data Management Plan and Study Documentation 
 
Electronic case report forms for specified protocol related information on each trial patient, using the 
REDCap system, will be created.  The Protocol Director and participating site investigators must 
maintain adequate and accurate participant case histories with observations and other data pertinent to 
the study. Original source documents should be transcribed to Case Report Forms (CRFs) and used to 
communicate study data to the lead site. Source documents include hospital records, clinical charts, 
laboratory and pharmacy records, and recorded electronic data.  
 
Participating Center’s PIs will be responsible for maintaining the clinical protocol and subjects’ study 
charts, reporting adverse events, assuring that consent is obtained and documented, and reporting the 
status of the trial in continuing renewals submitted to their IRB and trials monitoring group(s) as per 
their facility protocol. A chart with all the relevant research patient information will be maintained for 
each patient at each institution by the research coordinator and/or responsible PD for that specific 
institution. Paper copies of the documentation from the medical record which support the data entered 
into REDCap will be kept in patient specific binders in a secure, locked, and HIPPA compliant 
environment. Patient charts will be reviewed by Stanford PI and/or Study Coordinator.  
 
Participating Institutions will complete all electronic CRFs in REDCap within 2 weeks of a patients’ 
visit and provide paper source documents supporting the data entered to Stanford for monitoring via 
secure email to rlira@stanford.edu. Note the subject line of the email is required to first include 
“secure:” in it. The research coordinator or participating center’s investigator will be responsible for 
database records of patient data and providing them to Stanford. Any electronic data will be kept on a 
secured server file system. 
 
11.4 
Site Communication 
 
When all participating institutions have successfully received IRB approval and have started enrolling 
patients, teleconferences to discuss participants and study-related matters will be held once per quarter, 
although call may occur more frequently if necessary. Teleconferences will be coordinated by Research 
Staff at a participating institution (PIs, Research Coordinators, Nurses, and Co-Investigators if needed 
will participate). Any issues will patient compliance, database entry, or other items will also be 
discussed in these calls. Calls will include review by PIs of subject data to assure validity as well as the 
safety of subjects; and the progress of the trials may also be discussed. At times of study renewals or 
more frequently if needed, PIs will review safety reports and clinical trial efficacy endpoints and 
confirm that the safety outcomes favor continuation of the study. 
 
12. 
STATISTICAL CONSIDERATIONS 
 
12.1 
Statistical design and trial size 
This treatment trial is a single arm, unblinded, two staged Simon 23design to evaluate the RECIST 
response rate to weekly TPC in patients with recurrent or metastatic  SCCHN. Patients must have 
received at least one cycle of weekly TPC in order to be evaluable for response.   The assumption is that 
we wish to distinguish between a response rate of 25% which would be uninteresting and a response rate 

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Page 26 of 31
of 50% which would merit further testing, based on response rates of trials with similar agents on 
different schedules.22 Choosing an alpha type error probability of 0.1 and a beta type error probability of 
0.1 would mean that in order to proceed beyond the first stage, at least 3 of 10 patients would have to  
have responses, and at least  10 of up to 27 patients would have to respond in order declare this regimen 
of interest.  The expected sample size would be 18 patients to see at least 10 responders and the 
probability of early termination if the true response rate is 25% would be 0.52. 
 
12.2 
Descriptive Statistics and Exploratory Data Analysis of secondary endpoints: 
Overall survival (OS) (the time from registration to death or date of last 
contact) and progression free survival  (PFS) (patients alive without RECIST progression) are  
secondary endpoints of the study. Kaplan-Meier estimates of overall and progression-free survival rates 
will be calculated, along with their corresponding 95% confidence intervals. The median, 12-month and 
24-month overall and progression free survival rates will be estimated. AEs attributable to ATO will be 
collected according the study calendar and tabulated for cumulative evaluation. 

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13. 
REFERENCES 
 
1. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). European journal of cancer 2009;45:228-47. 
2. 
Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck 
cancer. New England Journal of Medicine 2008;359:1116-27. 
3. 
Colevas AD, Norris CM, Tishler RB, et al. Phase II trial of docetaxel, cisplatin, fluorouracil, and 
leucovorin as induction for squamous cell carcinoma of the head and neck.[see comment]. Journal of Clinical 
Oncology 1999;17:3503-11. 
4. 
Kies MS, Haraf DJ, Athanasiadis I, et al. Induction chemotherapy followed by concurrent 
chemoradiation for advanced head and neck cancer: improved disease control and survival. Journal of Clinical 
Oncology 1998;16:2715-21. 
5. 
Shin DM, Glisson BS, Khuri FR, et al. Phase II study of induction chemotherapy with paclitaxel, 
ifosfamide, and carboplatin (TIC) for patients with locally advanced squamous cell carcinoma of the head and 
neck.[see comment]. Cancer 2002;95:322-30. 
6. 
Ang KK, Harris J, Garden AS, et al. Concomitant boost radiation plus concurrent cisplatin for advanced 
head and neck carcinomas: radiation therapy oncology group phase II trial 99-14. J Clin Oncol 2005;23:3008-
15. 
7. 
Denis F, Garaud P, Bardet E, et al. Final results of the 94-01 French Head and Neck Oncology and 
Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in 
advanced-stage oropharynx carcinoma. J Clin Oncol 2004;22:69-76. 
8. 
Olmi P, Crispino S, Fallai C, et al. Locoregionally advanced carcinoma of the oropharynx: conventional 
radiotherapy vs. accelerated hyperfractionated radiotherapy vs. concomitant radiotherapy and chemotherapy--a 
multicenter randomized trial. Int J Radiat Oncol Biol Phys 2003;55:78-92. 
9. 
Zorat PL, Paccagnella A, Cavaniglia G, et al. Randomized phase III trial of neoadjuvant chemotherapy 
in head and neck cancer: 10-year follow-up. J Natl Cancer Inst 2004;96:1714-7. 
10. 
Colevas AD. Chemotherapy options for patients with metastatic or recurrent squamous cell carcinoma of 
the head and neck. Journal of Clinical Oncology 2006;24:2644-52. 
11. 
Morton R, Rugman F, Dorman E, al e. Cisplatinum and bleomycin for advanced or recurrent 
squamous cell carcinoma of the head and neck: 
A randomised factorial phase III controlled trial. Cancer Chemotherapy and Pharmacology 1985;15:283-9. 
12. 
Gibson MK, Li Y, Murphy B, et al. Randomized phase III evaluation of cisplatin plus fluorouracil 
versus cisplatin plus paclitaxel in advanced head and neck cancer (E1395): an intergroup trial of the Eastern 
Cooperative Oncology Group. J Clin Oncol 2005;23:3562-7. 
13. 
Burtness B. Cetuximab and cisplatin for chemotherapy-refractory squamous cell cancer of the head and 
neck. J Clin Oncol 2005;23:5440-2. 
14. 
Vermorken J, Stöhlmacher J, Davidenko I, et al. An analysis of safety in patients (pts) with recurrent 
and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) receiving chemotherapy (CT) 
with or without panitumumab (pmab) in a phase III clinical trial (SPECTRUM). Journal of Clinical Oncology 
2009;27. 
15. 
Baur M, Kienzer HR, Schweiger J, et al. Docetaxel/cisplatin as first-line chemotherapy in patients with 
head and neck carcinoma: a phase II trial. Cancer 2002;94:2953-8. 
16. 
Gedlicka C, Formanek M, Selzer E, et al. Phase II study with docetaxel and cisplatin in the treatment of 
recurrent and/or metastatic squamous cell carcinoma of the head and neck. Oncology 2002;63:145-50. 
17. 
Schoffski P, Catimel G, Planting AS, et al. Docetaxel and cisplatin: an active regimen in patients with 
locally advanced, recurrent or metastatic squamous cell carcinoma of the head and neck. Results of a phase II 
study of the EORTC Early Clinical Studies Group. Ann Oncol 1999;10:119-22. 
18. 
Guntinas-Lichius O, Appenrodt S, Veelken F, Krug B. Phase II study of weekly docetaxel and cisplatin 
in patients with advanced recurrent and metastatic head and neck cancer. Laryngoscope 2006;116:613-8. 

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19. 
Haddad RI, Tishler RB, Norris C, et al. Phase I study of C-TPF in patients with locally advanced 
squamous cell carcinoma of the head and neck. Journal of clinical oncology : official journal of the American 
Society of Clinical Oncology 2009;27:4448-53. 
20. 
Pinto C, Di Fabio F, Barone C, et al. Phase II study of cetuximab in combination with cisplatin and 
docetaxel in patients with untreated advanced gastric or gastro-oesophageal junction adenocarcinoma 
(DOCETUX study). British journal of cancer 2009;101:1261-8. 
21. 
Argiris A, Heron DE, Smith RP, et al. Induction docetaxel, cisplatin, and cetuximab followed by 
concurrent radiotherapy, cisplatin, and cetuximab and maintenance cetuximab in patients with locally advanced 
head and neck cancer. Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology 2010;28:5294-300. 
22. 
Giugay J, Fayette J, Dillies A, et al. Cetuximab, docetaxel, and cisplatin (TPEx) as first-line treatment in 
patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN): First 
results of phase II trial GORTEC 2008-03. Journal of Clinical Oncology 2011;29:SUPPL; ABSTR 5567. 
23. 
Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989;10:1-10. 
 
 
 

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 APPENDICES 
APPENDIX A: Participant Eligibility Checklist and Registration Process 
A Participant Eligibility Checklist must be completed in its entirety for each subject prior to registration. The completed, 
signed, and dated checklist must be retained in the patient’s study file and/or the study’s Regulatory Binder.  
Participant Eligibility Checklist 
Inclusion Criteria 
 
__Yes __No 
1. Is the patient willing and able to understand and sign the study specific Informed Consent 
Form (ICF)? 
__Yes       __No 
2. Is the patient 16 years or older? 
__Yes       __No 
3. Has the patient been diagnosed with Squamous Cell Carcinoma of Head and Neck? Sites 
include all pharynx, larynx, oral cavity, skin and para-nasal sinus sites. (Patients with a 
diagnosis of Nasopharyngeal Carcinoma, or SCC of unknown primary presenting in the neck 
clinically compatible with head and neck mucosal primary sites, are eligible.) 
__Yes       __No 
__N/A 
4. At least 3 months have elapsed since the end of a potentially curative treatment: prior 
chemoradiation, radiation, and/ or surgery? (If so, patient is eligible). 
__Yes       __No 
5. Does the patient have an ECOG Performance Status < 3 at the time of enrollment? 
__Yes       __No 
6. Does the patient meet the following screening laboratory assessments for enrollment?: 
- Absolute Neutrophil Counts ≥ 1500 cells/ mm3 
- Platelet count > 100 K/mm3 
- Serum AST and ALT < 2.5 x ULN, if liver metastasis is documented: AST & ALT < 5 
xULN 
- Total Bilirubin < 1.5x upper limit of normal (ULN), unless pt has Gilbert’s Syndrome: 
T.Bilirubin < 2.5 x ULN 
- Serum Creatinine < 1.5 mg/dL OR estimated creatinine clearance from 24 hour urine 
collection > 50 ml/min 
__Yes       __No  
7. Does the patient have peripheral neuropathy < grade 2? 
Exclusion Criteria 
 
__Yes       __No 
1. Has the patient received prior palliative chemotherapy? 
__Yes       __No 
2. Does the patient have active infections including known HIV? (HIV positive patients on 
HAART with undetectable blood HIV levels are eligible & patients with a history or 
serological evidence of exposure to Hepatitis B without active infection are eligible for this 
study.) 
__Yes       __No 
3. Has the patient had a prior grade 3 allergic or infusion reactions to docetaxel, cisplatin or 
cetuximab are not eligible.(A history of well tolerated infusion reactions is NOT an exclusion.) 
__Yes       __No 
4. Does the patient have a history of other malignancies treated curatively LESS than one 
year prior to enrollment and/or with evidence of relapse at the time of enrollment? 
__Yes       __No 
5. Is the patient female and pregnant or nursing?  
__Yes       __No 
6. Does the patient have known brain metastasis? NOTE: patient is eligible only if by CNS 
imaging there is no evidence of CNS progression at least 30 days following definitive CNS 
treatment (resection or radiation). 
 
My signature below confirms that I have reviewed the patient’s current and past medical history to confirm they are 
[Eligible or Not Eligible ] in meeting the criteria for study entry: 
 
 
Principal Investigator/Co-Investigator  
 
 
Printed Name 
 
 
 
Date 
 
 
Co-Investigator/Other Practitioner 
 
 
 
Printed Name 
 
 
 
Date 
 
 
Clinical Research Coordinator/Other Personnel 
 
 
Printed Name 
 
 
 
Date 

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Registration Process 
All participating sites must provide a copy of their IRB approved consent form to the Stanford Protocol Director 
prior to site initiation and when ICF amendments have been obtained.  
 
To register a patient, the study site will call the Study Coordinator at the Stanford Cancer Institute:  XXX-XXX-
XXXX , Monday through Friday, between 9:00 a.m. and 3:30 p.m. (Pacific Time). If the Study Coordinator is 
away, contact the PD (Dr. Colevas) at XXX-XXX-XXXX.  
 
The individual making the phone call will provide the patient’s eligibility information, including all necessary 
source documents supporting information for eligibility confirmation in advance via secure email to 
rlira@stanford.edu. Note the subject line of the email is required to first include “secure:” in it.  
 
If email submission is not available, the documents may be faxed to XXX-XXX-XXXX with a cover sheet: 
RE: Request for Registration of TPC Clinical Trial Patient.  
Attn: Dr. Colevas/Ruth Lira 
Note: Your direct contact information must be included and you are required to send an email to notify site of 
fax submission, as fax line is not a dedicated line readily checked by research staff.  
 
No subject may begin study treatment prior to registration, and assignment of a subjects’ identification number.  
 
Participating sites will have eligibility verified by two personnel at their institution and subsequently verified a 
third time by Stanford Cancer Institute. All necessary source documents to be sent to Stanford must include: 
 
 Patient Signed and Dated Informed Consent Form 
 Participant Eligibility Checklist (verified by two personnel with appropriate signatures and dates) 
 Patients’ Medical Record information: 
o Prior chemotherapy treatment  
o Prior radiation treatment  
o Prior surgery and pathology reports  
o Laboratory Results confirming eligibility within 1 week of submission 
o Demographics  
o Concurrent Medications 
o Physical Exam 
o Vital Signs (Height, Weight, Blood Pressure, Heart Rate (pulse), and Temperature) 
o Performance Status 
o AE evaluation 
o Radiological Reports completed within 28 days of anticipated Cycle 1 Triplet 1/Loading Dose 
 
At registration, Stanford will sequentially assign eligible subjects an identification number. As confirmation, 
Stanford will provide the participating investigator with written verification of the subject’s registration by 
email or fax. The maximum allowable time between registration and the first administration of study treatment 
is 14 days. The subject’s identification number will be used on all study specific Case Report Forms (CRFs) and 
serious adverse event (SAE) forms. Participant information should be entered into OnCore within 7 days by 
Stanford University and/or the participating institution.    

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APPENDIX B: 
Performance Status Criteria 
a) ECOG Performance Status Scale 
b) Karnofsky Performance Scale 
Grade 
c) Descriptions 
d) Percent 
e) Description 
0 
Normal activity 
Fully active, able to carry on all pre-
disease performance without restriction 
100 
Normal, no complaints, no evidence 
of disease 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease 
1 
Symptoms, but ambulatory 
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or sedentary 
nature (e.g., light housework, office 
work) 
80 
Normal activity with effort; some 
signs or symptoms of disease 
70 
Cares for self, unable to carry on 
normal activity or to do active work 
2 
In bed < 50% of the time 
Ambulatory and capable of all self-
care, but unable to carry out any work 
activities 
Up and about more than 50% of 
waking hours 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs 
50 
Requires considerable assistance and 
frequent medical care 
3 
In bed > 50% of the time 
Capable of only limited self-care, 
confined to bed or chair more than 
50% of waking hours 
40 
Disabled, requires special care and 
assistance 
30 
Severely disabled, hospitalization 
indicated 
Death not imminent 
4 
100% bedridden 
Completely disabled 
Cannot carry on any self-care 
Totally confined to bed or chair 
20 
Very sick, hospitalization indicated 
Death not imminent 
10 
Moribund, fatal processes 
progressing rapidly 
5 
Dead 
0 
Dead 
 
APPENDICES attached as separate files: 
APPENDIX C: ADVERSE EVENT LOG 
APPENDIX D: TUMOR MEASUREMENT LOG 
APPENDIX E: CLINIC ASSESSMENT FORM 
APPENDIX F: SAE COVER SHEET & REPORT FORM 
APPENDIX G: HOW TO REPORT SAE