Conditions: Head and Neck Cancer
Keywords: Larynx Lip Oral Cavity and Pharynx
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 70
Healthy volunteers: no

Brief summary:
The purpose of this study is to explore the activity of ZD1839 added to concurrent chemoradiotherapy and as adjuvant monotherapy in patients with locally advanced head and neck cancer. Activity is described in terms of response rate (complete responses only).

Detailed description:

Arms:
arm 1: Single arm, two-stage, phase II trial of induction therapy with carboplatin and paclitaxel, followed by ZD1839, 5-FU, hydroxyurea, and hyperfractionated radiotherapy, followed by adjuvant ZD1839 alone.

Interventions: intervention 1: ZD 1839 500mg
Intervention descriptions: intervention 1: Optional Induction chemotherapy:

Carboplatin and paclitaxel combination will be administered for 2 cycles of 4 weeks duration each. Paclitaxel: 100 mg/m2 in 500 ml of dextrose 5% in water over 3hrs. Carboplatin: Start after completion of paclitaxel on Day 1 AUC 6 (creatinine clearance \[CC\] + 25). Administered in 100 ml of normal saline over 30min after completion of paclitaxel.

Resume chemotherapy C2 on D29. ZD1839: 500mg PO QD from D1 of C1 of chemoradiotherapy, uninterrupted until disease progression. Chemotherapy should be administered during all 5 weeks of radiotherapy. P.M.:Start hydroxyurea at 500 mg PO q 12hrs × 6 days. The first daily dose of hydroxyurea on Days 1 through 5 is given 2 hours prior to the first fraction of daily radiotherapy. P.M.:Start continuous infusion of 5-FU at 600 mg/m2/day × 5D. Days 1 through 5: Radiation therapy is administered twice daily at 150 cGy ZD1839 will be administered from day 1 to 14 of every chemoradiotherapy cycle.

Protocol document:
Prot_SAP_000.pdf: 
 
 
AZ1839US/0212 
11/20/2013 
i 
A Phase II Trial of Induction Chemotherapy with Carboplatin and Paclitaxel, Followed by 
Concurrent Chemoradiation with ZD1839 (IRESSA®), 5-Fluorouracil, Hydroxyurea, and 
Twice-daily Radiation, Followed by Adjuvant ZD1839 Monotherapy in Patients with 
Locally Advanced Head and Neck Cancer 
Chicago Oral Cancer Center and Affiliated Institutions 
 
IRB Number 
12019A 
 
Principal Investigator: 
Everett Vokes, M.D. 
(773) 702-4137 
 
Co-Investigators: 
Ezra Cohen, M.D. 
5841 S. Maryland Ave., MC 2115 
Ann Mauer, M.D. 
Chicago, IL 60637 
Daniel J. Haraf, M.D. 
 
Ralph R. Weichselbaum, M.D. 
 
 
Kerstin Stenson, M.D. 
 
Marcy List, PhD  
 
Elizabeth Blair, M.D. 
 
Louis G. Portugal, M.D. 
 
Tanguy Seiwert, M.D. 
 
University of Chicago Research Nurse/ 
Allison Dekker 
     Data Management 
Shane Small  
 
Laboratory Correlatives 
Mark Lingen, DDS, PhD 
 
M. Eileen Dolan, PhD 
 
 
Statisticians 
Dezheng Huo 
 
Theodore Karrison, PhD 
 
 
 
IRESSA is a trademark of the AstraZeneca Group of companies. 
Versions: 1/16/03, 2/19/03 (Cover Page, Tables 1,2,3, Sections 6.5, 7.11, 11.1.3,  consent), 7/15/03 (Cover Page, iii, 
Sections 2, 4, 6.1.1, 6.1.2, 6.1.3, 7.1, consent), 9/2/03 (Cover Page, Tables 1,2,3, Sections 6.5, 7.11, 11.1.3), 1/20/04 
(vi, Table 3, 1.4, 2, consent), 2/16/04 (Cover Page; Sections 1, 1.2, 1.2.1, 1.2.5.3, 1.2.5.4, 1.2.5.5, 4, 5, 7.1.1, 7.3, 
7.8, 7.10, 7.11, 7.12, 7.13, 13.1, 13.2, 13.3, 13.3.1, 13.4, 13.4.1, 13.9, 13.9.1, 15.1, 15.6; Appendix B), 4/20/04 
(Section 9.5), 8/6/04 (Cover page, Sections 7.1, 13.9.1), 6/6/05 (Cover page, Sections), May 4, 2006 (Cover Page, 
iii, iv, Sections 2, 3, 4, 6.1.2), 11/20/2013( Change PI-ship )  


 
 
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ii 
 
 
A Phase II trial of Induction Chemotherapy with Carboplatin and Paclitaxel, 
Followed by Concurrent Chemoradiation with ZD1839 (IRESSA®), 5-Fluorouracil, 
Hydroxyurea, and Twice-daily Radiation, Followed by Adjuvant ZD1839 
Monotherapy in Patients with Locally Advanced Head and Neck Cancer 
 
Investigator 
Ezra Cohen, M.D. 
5841 S Maryland Ave 
Chicago, IL  60637 
Trial center(s) and number of patients planned 
4 centers, 85 patients planned  
Trial period 
 
Phase of development 
Estimated date first patient enrolled 
December 2002 
II 
Estimated date last patient enrolled 
May 2006 
 
Objectives 
Primary 
x To explore the activity of ZD1839 added to concurrent chemoradiotherapy and as adjuvant 
monotherapy in patients with locally advanced head and neck cancer.  Activity is described in 
terms of response rate (complete responses only). 
Secondary 
x 
To explore the tolerability and feasibility of ZD1839 added to concurrent chemoradiotherapy.  
x To assess quality of life (QoL) 
x To define any toxcities of ZD1839 used in concurrent chemoradiotherapy and as adjuvant 
therapy 
Exploratory 
x To assess pharmacodynamics of ZD1839 in vivo and correlate clinical outcome with 
inhibition of tyrosine kinase activity 
x To assess in vivo effects of week on/week off hyperfractionated radiotherapy 


 
 
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Trial design 
Single arm, two-stage, phase II trial of induction therapy with carboplatin and paclitaxel, 
followed by ZD1839, 5-FU, hydroxyurea, and hyperfractionated radiotherapy, followed by 
adjuvant ZD1839 alone. 
Background and rationale 
Concurrent chemoradiotherapy has proven efficacy in locally advanced head and neck cancer 
with overall survival and local control improved compared to radiotherapy alone.  Induction 
chemotherapy can reduce distant failure rate.  Despite this, there is still a 40% failure rate in 
patients with locally advanced head and neck cancer. 
Head and neck cancer has a rate of epidermal growth factor receptor (EGFR) expression of 90%.  
ZD1839 inhibits EGFR activation through interference with its tyrosine kinase intracellular 
domain.  ZD1839 has demonstrable single agent activity in head and neck cancer.  By adding 
ZD1839 to our current institutional standard of induction chemotherapy followed by concurrent 
chemoradiotherapy, we hope to improve local and distant control and overall survival.  
Furthermore, adding adjuvant ZD1839 could prevent recurrence or second primary malignancies. 
Patient population 
x Patients with stage III or IV carcinoma of the head and neck  
x Patients with squamous cell carcinoma of unknown primary originating in the neck. 
Measurable disease is not required, but all disease will be carefully evaluated using Response 
Evaluation Criteria in Solid tumors (RECIST) criteria. 
Inclusion criteria 
x Histologically or cytologically confirmed diagnosis of squamous cell or poorly differentiated 
carcinomas, or lymphoepithelioma 
x No prior or radiotherapy 
x Prior surgical therapy will consist only of incisional or excisional biopsy, and organ sparing 
procedures such as debulking of airway compromising tumors or neck dissection in a patient 
with an existing or unknown (Tx) primary tumor  
x Performance status of t 60% 
x Intact organ and bone marrow function 
 
Investigational product, dosage and mode of administration 
ZD1839 (IRESSA) 500 mg by mouth (PO) daily  


 
 
AZ1839US/0212 
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iv 
Chemotherapy agents, doses, mode of administration 
Optional Induction chemotherapy: 
Carboplatin 
and 
paclitaxel 
combination 
will 
be 
administered for 2 cycles of 4 weeks duration each.  
Chemoradiotherapy will begin 1-2 weeks after the last dose. 
Paclitaxel: 
100 mg/m2 in 500 ml of dextrose 5% in water (D5W) over 
3 hours (on days 1, 8, and 15) 
Carboplatin: 
Start after completion of paclitaxel on Day 1 
 
AUC 6 (creatinine clearance [CC] + 25).  Administer in 
100 ml of normal saline (NS) over 30 minutes after 
completion of paclitaxel.   
No therapy on Day 22.  Resume chemotherapy for cycle 2 on Day 29. 
Concomitant chemoradiotherapy: 
 
ZD1839: 
500mg PO QD from day 1 of cycle 1 of chemoradiotherapy, 
uninterrupted until disease progression, patient intolerance, 
patient withdrawal or study closure 
 
Chemotherapy should be administered during all 5 weeks 
of radiotherapy. 
Day 0 (Sunday):  
   P.M.: 
Start hydroxyurea at 500 mg PO q 12 hours u 6 days (11 
doses).  The first daily dose of hydroxyurea on Days 1 
through 5 is given 2 hours prior to the first fraction of daily 
radiotherapy.   
   6:00 P.M.:  
Start 
continuous 
infusion 
of 
5-fluorouracil 
at 
600 mg/m2/day u 5 days (120 hours). 
Days 1 through 5:  
Radiation therapy is administered twice daily at 150 cGy 
per fraction. 
Days 6 through 14 of each cycle:  
No chemoradiotherapy. 
Chemoradiotherapy cycles are repeated every 14 days until the completion of radiotherapy. 
ZD1839 will be administered from day 1 to 14 of every chemoradiotherapy cycle. 
Duration of treatment 
8 weeks induction chemotherapy 
10 weeks chemoradiation 


 
 
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v 
Number of patients expected per year 
40 (85 total) 
Number of patients expected to be enrolled each month 
3-4 
Statistical analysis  
This study wishes to explore the frequency of complete and partial clinical response rates of the 
whole regimen among advanced stage patients, to estimate the impact of concurrent 
chemoradiotherapy with ZD1839 and adjuvant ZD1839 monotherapy on pattern of failure, and to 
estimate the survival curve for these patients following treatment.  Accordingly, the primary 
endpoint will be complete response (complete response [CR]).  Secondary endpoints will be time 
to progression (TTP), incidence of second primary tumors, and survival.  Pattern of failure will 
be described as locoregional, distant, or both.  In addition to summarizing response rates, 
investigators will calculate time to progression and survival time using Kaplan-Meier product 
limit curves.  A retrospective comparison at similar time points will be made to the prior patients 
treated on Protocol 9502. 
 


 
AZ1839US/0212 
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Table 1: 
Pre-therapy and induction checklist 
Item 
Pre-
therapy 
Week 1 
induction 
Week 2 
induction 
Week 3 
induction 
Week 4 
induction 
Week 5 
induction 
Week 6 
induction 
Week 7 
induction 
Week 8 
induction 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
History and physical 
X 
X 
X 
X 
X (optional 
week 4) 
X 
X 
X 
X 
Informed consent 
X 
 
 
 
 
 
 
 
 
Panendoscopy1 
X 
 
 
 
 
 
 
 
 
Tumor map 
X 
 
 
 
 
 
 
 
 
Dental assessment 
X 
 
 
 
 
 
 
 
 
Swallowing assessment 
X 
 
 
 
 
 
 
 
 
Performance status 
X 
 
 
 
 
 
 
 
 
Concomitant medication2  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event 
 
X 
X 
X 
X 
X 
X 
X 
X 
Head and neck CT/MRI3 
X 
 
 
 
 
 
 
 
 
Chest CT 
X 
 
 
 
 
 
 
 
 
Bone scan4 
X 
 
 
 
 
 
 
 
 


 
AZ1839US/0212 
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vii
Table 1: 
Pre-therapy and induction checklist (cont.) 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
Hematology5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biochemistry6 
X7 
X 
X 
X 
X 
X 
X 
X 
X 
Creatinine Clearance8 
X 
 
 
 
 
 
 
 
 
Paclitaxel 
 
X 
X 
X 
 
X 
X 
X 
 
Carboplatin 
 
X 
 
 
 
X 
 
 
 
Research Blood Samples 
X9 
 
 
 
 
 
 
 
 
1 
Biopsy will be done within 6 weeks of starting therapy. 
2 
Document use of concomitant medication. 
3 
The same procedure should be done throughout therapy and follow-up. 
4 
If clinically indicated. 
5 
CBC, differential, and platelet count twice weekly. 
6 
Comprehensive metabolic profile (magnesium if clinically indicated). 
7 
Should include TSH. 
8 
Obtain 24-hour urine for calculation.  Alternately, can be calculated using formula (see section 6.1.2).  Recalculate if serum creatine or 
weight change > 30%. 
9 
1-7cc lavender top tube. 
CBC = complete blood count; CT = computed tomography; MRI = magnetic resonance imaging; EGFR = epidermal growth factor receptor;  
TSH = thyroid stimulating hormone. 
                                                 
 


 
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Table 2: 
Concomitant chemoradiotherapy 
Item 
Pre-CRT 
Cycle 11 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 52 
30-day 
follow-up 
History and 
physical 
X 
X 
X 
X 
X 
X 
X 
Adverse event 
X 
X 
X 
X 
X 
X 
X 
Head and neck 
CT/MRI3 
X 
 
 
 
 
 
X 
Chest CT 
X 
 
 
 
 
 
X 
Hematology4 
X 
X 
X 
X 
X 
X 
X 
Biochemistry5 
X 
X 
X 
X 
X 
X 
X 
ZD18398 
 
X 
X 
X 
X 
X 
 
5 FU 
 
X 
X 
X 
X 
X 
 
Hydroxyurea 
 
X 
X 
X 
X 
X 
 
Radiotherapy6 
 
X 
X 
X 
X 
X 
 
Dental 
assessment 
 
 
 
 
 
 
X 
Swallowing 
assessment 
X 
 
 
 
 
 
X 
Biopsy 
 
 
 
 
 
 
X7 
1  Each cycle is 2 weeks long.  See section 6.1.3. 
2  Some patients may have only 4 cycles total. 
3  The same procedure should be done throughout therapy and follow-up 
4  CBC, differential, and platelet count twice weekly 
5  Comprehensive metabolic profile (with magnesium if indicated) twice weekly. 
6  Radiotherapy is given twice daily. 
7  Within 8 weeks of completing chemoradiotherapy 
8 
Start on day 1 of cycle 1 and continue, uninterrupted, until completion of radiotherapy. Given PO, once 
daily, 500mg. 
 
Table 3: 
Follow-up  
Item 
2-month 
visit 
3-month 
visit 
4-month 
visit 
5-month 
visit 
6-month 
visit 
9-month 
visit 
12-month 
visit/Follow
-Up4 
History and 
physical 
X 
X 
X 
X 
X 
X 
X 


 
AZ1839US/0212 
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ix 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
Quality of life 
 
 
 
 
X 
 
X5 
Hematology 
X 
X 
X 
X 
X 
X 
X 
Biochemistry1 
X 
X 
X 
X 
X2 
X2 
X2 
Head and neck 
CT/MRI3 
 
X 
 
 
X 
X 
(optional) 
X 
Chest CT 
 
X 
 
 
X 
X 
(optional) 
X 
1  Comprehensive profile 
2  Should include TSH. 
3  The same procedure should be done throughout therapy and follow-up (will be repeated every 3-4 months for 
2 years, then yearly). 
4 
Frequency of follow-up beyond 12 months is left to the investigator although patients must be evaluated 
clinically and radiographically at a minimum of every 6 months until 3 years post-therapy. 
5 
And annually for 5 years. 
CT = computed tomography; MRI = magnetic resonance imaging; TSH = thyroid stimulating hormone 


 
 
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TABLE OF CONTENTS 
1 
INTRODUCTION.................................................................................................... 1 
1.1 
Background ................................................................................................................ 1 
1.1.1 Head and Neck Cancer ................................................................................... 1 
1.1.2 Locoregionally Advanced Disease (AJCC Stages III and IV) ....................... 1 
1.1.3 Chemotherapy for Locoregionally Advanced Disease ................................... 2 
1.1.4 Concomitant Chemotherapy with Fluorouracil, Hydroxyurea and Once-daily 
Radiotherapy (FHX)....................................................................................... 2 
1.1.5 &XUUHQW³3ODWIRUP´5HJLPHQ,QGXFWLRQ&DUERSODWLQDQG3DFOLWD[el Followed by 
intensive chemoradiotherapy ......................................................................... 4 
1.2 
ZD1839 ...................................................................................................................... 4 
(IILFDF\««««««««««««««««««««««««««« 
1.2.2   Signal Transduction and ZD1839 ................................................................... 5 
1.2.3 ZD1839 Pre-clinical Experience .................................................................... 6 
1.2.4 Animal Data ................................................................................................... 6 
1.2.5 Clinical Data .................................................................................................. 6 
1.3 
Quality of Life .......................................................................................................... 10 
1.3.1 Background .................................................................................................. 10 
1.3.2 Previous Work/Preliminary Data ................................................................. 10 
1.3.3 Quality of Life Objectives ............................................................................ 12 
1.4 
Study Proposal and Rationale .................................................................................. 12 
2 
TRIAL SCHEMA .................................................................................................. 14 
3 
INCLUSION CRITERIA ...................................................................................... 15 
4 
EXCLUSION CRITERIA ..................................................................................... 16 
5 
CRITERIA FOR DISCONTINUATION/WITHDRAWAL OF INFORMED 
CONSENT .............................................................................................................. 17 
6 
TREATMENT PLAN ............................................................................................ 18 
6.1 
Agent Administration ............................................................................................... 18 
6.1.1 Pre-therapy Checklist ................ ERROR! BOOKMARK NOT DEFINED. 
6.1.2 Induction Therapy ........................................................................................ 18 
6.1.3 Concomitant Chemoradiotherapy ................................................................ 20 
6.1.4 Maintenance Therapy ................................................................................... 20 
6.2 
Radiotherapy Guidelines .......................................................................................... 21 
6.3 
Supportive Care ....................................................................................................... 22 
6.4 
Surgical Guidelines .................................................................................................. 22 
6.5 
Quality of Life Measurements ................................................................................. 23 


 
 
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6.6 
Duration of Therapy ................................................................................................. 24 
7 
IDENTIFICATION OF INVESTIGATIONAL PRODUCT ............................. 24 
7.1 
ZD1839 .................................................................................................................... 24 
7.1.1 Management of Interstitial Lung Disease .................................................... 24 
7.2 
Storage ..................................................................................................................... 25 
7.3 
Accountability .......................................................................................................... 25 
7.3.1 Treatment Schedule ..................................................................................... 25 
7.3.2 ZD1839 Dose Interruption ........................................................................... 26 
7.4 
Non-hematopoietic Toxicity .................................................................................... 26 
7.5 
Skin Toxicity ............................................................................................................ 26 
7.6 
Gastrointestinal (GI) Toxicity .................................................................................. 27 
7.7 
Nausea and/or Vomiting .......................................................................................... 27 
7.8 
Diarrhea .................................................................................................................... 27 
7.9 
Hypersensitivity to ZD1839 ..................................................................................... 27 
7.10 
Management of Interstitial Lung Disease ................................................................ 27 
7.11 
Duration of ZD1839 Therapy ................................................................................... 27 
7.12 
Guideline for Dispersing Whole ZD1839 Tablets ................................................... 28 
7.13 
Other Concomitant Treatment ................................................................................. 28 
8 
EXPECTED TOXICITIES ................................................................................... 29 
8.1 
ZD1839 .................................................................................................................... 29 
8.2 
Paclitaxel .................................................................................................................. 29 
8.3 
Carboplatin ............................................................................................................... 30 
8.4 
5-Fluorouracil .......................................................................................................... 30 
8.5 
Hydroxyurea ............................................................................................................. 30 
8.6 
Radiation .................................................................................................................. 31 
9 
DOSE AND SCHEDULE MODIFICATIONS ................................................... 31 
9.1 
During Induction Chemotherapy .............................................................................. 31 
9.1.1 Dose Modification ....................................................................................... 31 
9.1.2 Hematologic Toxicity .................................................................................. 31 
9.1.3 Non-hematologic Toxicities ......................................................................... 32 
9.1.4 Motor and/or Sensory Neuropathy ............................................................... 32 
9.1.5 Fatigue, Arthralgia, Myalgias....................................................................... 32 
9.1.6 Hepatic Dysfunction .................................................................................... 33 


 
 
AZ1839US/0212 
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9.2 
ZD1839 Dose Modifications During Chemoradiotherapy Therapy ......................... 33 
9.2.1 Diarrhea and Skin Rash ............................................................................... 33 
9.2.2 Other Toxicities ........................................................................................... 34 
9.3 
Dose Modifications during Concomitant Chemoradiotherapy ................................ 34 
9.3.1 Myelosuppression ........................................................................................ 34 
9.3.2 Mucositis, Dermatitis, Diarrhea ................................................................... 34 
9.3.3 Other Non-hematological Toxicity .............................................................. 35 
9.4 
For Other Toxicities on Day 0 of Chemoradiotherapy ............................................ 35 
9.4.1 Hepatotoxicity .............................................................................................. 35 
9.4.2 Nephrotoxicity ............................................................................................. 35 
9.5 
ZD1839 Dose Modifications During Maintenance Therapy .................................... 35 
10 
AGENT FORMULATION AND PROCUREMENT ......................................... 35 
10.1 
Paclitaxel .................................................................................................................. 35 
10.2 
Carboplatin ............................................................................................................... 36 
10.3 
Fluorouracil .............................................................................................................. 36 
10.4 
Hydroxyurea ............................................................................................................. 36 
11 
TRIAL MEASUREMENTS .................................................................................. 37 
11.1 
EGFR Expression from Samples ............................................................................. 37 
11.1.1 Rationale and Reporting of Results ............................................................. 37 
11.1.2 Sample Management .................................................................................... 39 
11.1.3 Sample Preparation and Shipment Instructions ........................................... 40 
11.1.4 Immunohistochemistry ................................................................................. 41 
11.1.5 ELISA .......................................................................................................... 42 
12 
MEASUREMENT OF EFFECT .......................................................................... 42 
12.1 
Definitions................................................................................................................ 42 
12.1.1 Measurable Disease...................................................................................... 42 
12.1.2 Non-measurable Disease .............................................................................. 42 
12.1.3 Target Lesions .............................................................................................. 42 
12.1.4 Non-target Lesions ....................................................................................... 43 
12.2 
Guidelines for Evaluation of Measurable Disease ................................................... 43 
12.3 
Response Criteria ..................................................................................................... 44 
12.3.1 Evaluation of Target Lesions ....................................................................... 44 
12.3.2 Evaluation of Non-target Lesions ................................................................ 45 
12.3.3 Evaluation of Best Overall Response........................................................... 45 
12.4 
Confirmatory Measurement/Duration of Response ................................................. 46 
12.4.1 Confirmation ................................................................................................ 46 


 
 
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12.5 
Progression-Free and Overall Survival .................................................................... 46 
12.6 
Response Review ..................................................................................................... 47 
13 
ADVERSE EVENTS ............................................................................................. 47 
13.1 
Definitions................................................................................................................ 47 
13.2 
Adverse Events ........................................................................................................ 47 
13.3 
Serious Adverse Events ........................................................................................... 48 
13.3.1 Other Significant Adverse Events ................................................................ 48 
13.4 
Recording of Adverse Events .................................................................................. 49 
13.4.1 Abnormal Laboratory Values/Vital Signs .................................................... 49 
13.5 
Lack of Efficacy ....................................................................................................... 49 
13.6 
Skin Adverse Events ................................................................................................ 49 
13.7 
Gastrointestinal Adverse Events .............................................................................. 49 
13.8 
Pregnancy ................................................................................................................. 50 
13.9 
Reporting of Serious Adverse Events ...................................................................... 51 
13.9.1 University of Chicago Reporting Guidelines ............................................... 51 
13.10 Handling Unresolved SAEs and AEs at Completion or Withdrawal....................... 52 
13.11 Data Safety and Monitoring ..................................................................................... 52 
14 
STATISTICAL CONSIDERATIONS ................................................................. 52 
14.1 
Study Design and Primary Endpoints ...................................................................... 52 
14.2 
Sample Size Determination...................................................................................... 53 
14.3 
Accrual Rate and Study Duration ............................................................................ 53 
14.4 
Evaluation of Response and Cohorts to be Analyzed .............................................. 53 
14.5 
Analytic Methods ..................................................................................................... 53 
14.5.1 Primary Analyses ......................................................................................... 53 
14.5.2 Secondary Endpoints and Analyses ............................................................. 54 
14.5.3 Analysis of Exploratory endpoints ............................................................... 54 
15 
TRIAL MANAGEMENT ...................................................................................... 55 
15.1 
Procedures in Case of Medical Emergency.............................................................. 55 
15.2 
Audits and Inspections ........................................................................................... 556 
15.3 
Changes to the Protocol ........................................................................................... 55 
15.4 
Ethics........................................................................................................................ 55 
15.5 
Ethical Conduct of the Trial ..................................................................................... 55 


 
 
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15.6 
Procedures in Case of Overdose .............................................................................. 55 
16 
REFERENCES ....................................................................................................... 57 
 
APPENDIX A«««««««««««««««« ..................................................... 61 
 
APPENDIX B «««««««««««««««««««««««««««««73 
 


 
AZ1839US/0212 
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1 
1 INTRODUCTION 
Investigators should be familiar with the Investigator Brochure (IB). 
1.1 Background 
1.1.1 Head and Neck Cancer 
Approximately 40,000 new cases of head and neck cancer are diagnosed annually in the 
United States (1).  Of these patients, two-thirds present with locoregionally advanced 
disease (American Joint Committee on Caner [AJCC] stage III or IV) and one-third 
with early stage disease (AJCC stage I or II).  At presentation, 10% of patients may be 
found to have involvement of distant organs, most commonly the lung.  In addition, 
20% of patients will develop clinically detected distant metastases over the course of 
their disease. In autopsy series up to 50% of patients with head and neck cancer are 
found to have metastases (2, 3).  It is likely that with improvements in the rate of 
locoregional control, the risk of distant failure will become predominant, and that 
systemic therapy, if efficacious, will have a major impact on outcome.  Approximately 
95% of all head and neck malignancies are squamous cell carcinomas and this 
histological type is the focus of this review and study protocol.  Also, it should be noted 
that even though head and neck malignancies are usually examined in one group, they 
represent a heterogeneous group of diseases, with variability in biologic behavior and 
natural history, prognosis, and considerations in management.  Disease sites such as the 
hypopharynx and the base of tongue have a worse prognosis compared to the larynx or 
nasopharynx (4), and may require more aggressive treatment strategies.  The vast 
majority of head and neck malignancies can be attributed to the use of tobacco and 
alcohol.  These carcinogens are synergistic, and may damage the entire aerodigestive 
epithelium.  Due to their frequent history of exposure to tobacco and alcohol, patients 
with head and neck cancer are in high risk for other comorbidities associated with 
tobacco and alcohol, such as coronary artery disease, chronic obstructive pulmonary 
disease, and liver disease (5).  In addition, they are at high risk for the development of 
second primary tumors, synchronous or metachronous, that may involve the head and 
neck region as well as other organs, predominantly the lung (6). 
1.1.2 Locoregionally Advanced Disease (AJCC Stages III and IV) 
For patients with resectable locally advanced head and neck cancer (AJCC stage III or 
IV), surgery and postoperative radiation have been traditionally considered the mainstay 
of treatment, whereas radiation therapy alone has been offered to patients with 
unresectable tumors.  It is important to recognize that the distinction between resectable 
and unresectable disease lacks clear definition.  With the exception of a few widely 
accepted signs of unresectability, such as involvement of the carotid artery, in most 
cases the assessment is subjective and relates to the experience of the surgeon and the 


 
AZ1839US/0212 
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2 
availability of reconstructive strategies.  Despite aggressive locoregional treatment with 
surgical resection and postoperative radiotherapy, locoregionally advanced disease has a 
poor prognosis with 5-year survival of less than 30% (5). The most common site of 
failure remains locoregional, whereas distant failure occurs in 20-30% of patients (7).   
1.1.3 Chemotherapy for Locoregionally Advanced Disease 
The addition of chemotherapy to the overall treatment plan in patients with 
locoregionally advanced head and neck cancer has been studied intensively.  Research 
strategies, generally, have included the use of induction (neoadjuvant) or adjuvant 
chemotherapy, as well as concomitant chemotherapy and radiation.  The primary goal 
of such research is to improve local control and survival.  Given the anatomic location 
of the disease and the frequently aggressive surgical approaches used, the use of less 
extensive surgery (and the preservation of organ function) is an important secondary 
treatment goal. Concomitant chemoradiotherapy has led to improved disease-free and 
overall survival in randomized clinical trials and also allows for organ preservation. 
1.1.4 Concomitant Chemotherapy with Fluorouracil, Hydroxyurea and Once-daily 
Radiotherapy (FHX)  
In 1986, we initiated the clinical investigation of the interaction of 5-FU, hydroxyurea 
and radiotherapy (FHX).  Both chemotherapy agents have known systemic activity and 
thus can be postulated to contribute to systemic and locoregional control of head and 
neck cancer (5).  In addition, hydroxyurea modulates the activity of 5-FU by depleting 
cellular pools of deoxyuridine monophosphate (dUMP) and facilitating binding of the 
5-FU metabolite 5-FdUMP to its target enzyme thymidylate synthase (8).  Finally, both 
agents have been shown to act as radiation enhancers in vitro and in vivo (9, 10).   
An intermittent schedule of chemoradiotherapy was used (one week on, one week off) 
based on the previous experience of Byfield et al. with single-agent 5-FU (11).  The 
recommended dose of 5-FU 800 mg/m2/day was administered as a 5-day continuous 
infusion.  The maximal tolerated dose of hydroxyurea was 1000 mg administered orally 
every 12 hours for a total of 11 doses beginning 6 to 12 hours prior to the 5-FU infusion 
with one daily dose preceding radiotherapy by 2 hours (12).  These doses resulted in 
moderate to severe mucositis and mild to moderate myelosuppression.  Radiotherapy 
was administered once daily at 180 to 200 cGy.  Five days of treatment were followed 
by a 9-day rest period to allow for recovery from toxicities (week on/week off).  
Response rates exceeded 90%.  Only 3 of 19 patients without prior local therapy 
developed locoregional recurrence.  This high locoregional activity of the FHX 
combination has been confirmed by other investigators (13-15).  
More recently, the FHX regimen was one of the arms of a 3-arm phase II randomized 
trial conducted by the RTOG (9703) in patients with stage III and IV head and neck 
cancer (13).  Regimens compared included cisplatin (10mg/m2) and 5-FU (400mg/m2) 
with 70 Gy/7 weeks of consecutive daily radiation (XCF), cisplatin (20mg/m2) and 


 
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3 
paclitaxel (30mg/m2) with 70 Gy/7 weeks consecutive daily therapy (XCT), or daily 
hydroxyurea (1 g PO twice daily [BID]) and 5-FU (800 mg/m2) with 70 Gy/13 weeks 
radiation (alternating week schedule) (FHX).  Toxicity and survival were not 
statistically different among the 3 arms.  Estimated 1- and 2-year survival rates were 
72% and 60% for XCF, 87% and 65% for FHX, and 80% and 67% for XCT, 
respectively.  The survival rates on all three arms were superior to a historic control of 
radiotherapy and cisplatin (two year survival rate 46%).  The pattern of failure showed 
predominant locoregional failure pattern for all three arms.  Therefore, conventional 
radiotherapy with concomitant chemotherapy given in consecutive weeks or a 
protracted course yielded acceptable patient toxicity and response rates.  Thus, FHX is a 
feasible regimen in a national cooperative group setting with encouraging tumor control 
results.  In the past decade, the FHX regimen has been the basis for the development of 
combined modality strategies by our group in an attempt to improve locoregional 
control and survival of previously untreated patients with locoregionally advanced head 
and neck cancer (Table 4). 
Table 4 
Summarized results with Phase II trials with C-FHX and T-FHX 
 
CFHX 
{KIES, 2001 #9} 
TFHX 
(120H){VOKES, 
2000 #574) 
TFHX 
(1H) {ROSEN, 2001 
#439} 
UNIVERSITY OF CHICAGO PROTOCOL 
NUMBER 
6950 
7929 
8626 
N 
76 
64 
90 
STAGE IV 
93% 
97% 
96% 
*PROGRESSION-FREE SURVIVAL 
72% 
63% 
62% 
*LOCAL CONTROL 
92% 
86% 
84% 
*SYSTEMIC CONTROL 
83% 
79% 
79% 
*OVERALL SURVIVAL 
55% 
64% 
59% 
GR 3/4 NEUTROPENIA 
41/39 
30/5 
28/7 
GR 3/4 THROMBOCYTOPENIA 
25/53 
1/0 
1/1 
GR 3/4 MUCOSITIS 
48/12 
56/28 
69/12 
REFERENCE 
17 
18 
19 
*3 YEAR DATA 




 
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5 
patients who received 250 and 500 mg/day ZD1839, respectively.  Symptom 
improvement, measured by the LCS component of the FACT-L and lasting at least four 
or more weeks occurred in 40.3% for the 250-mg/day group and 37.0% for the 500-
mg/day group. Median survival for the IDEAL-1 population receiving ZD1839 as 
second or third-line therapy was not calculable with the 4-month minimum follow-up at 
the time of trial closure. 
 
In IDEAL 2, the RR was 11.8 and 8.8%, and DCR was 42.2 and 36.0%, in patients who 
received 250 and 500 mg/day, respectively.  Symptom improvement, as measured by 
the LCS component of the FACT-L and lasting at least 4 or more weeks occurred in 
43.1% for the 250 mg/day group and 35.1% for the 500 mg/day group. Median survival 
for the IDEAL-2 population receiving ZD1839 as third-line or greater therapy was 6 
months. 
 
Symptom-Improvement was associated with objective tumor response and survival in 
the IDEAL 1 and 2 trials. Tumor responses occurred in patients predominantly with 
adenocarcinoma histology but responses have been observed in all histologies and 
irrespective of the number of previous chemotherapy regimens. 
 
In addition to the efficacy findings, quality of life (QOL) improvement was seen in a 
significant proportion of patients and was consistent with disease-related symptom 
improvement, which reflects the lack of significant therapy-related toxicity observed. 
 
1.2.2 Signal Transduction and ZD1839 
ZD1839 is a signal transduction inhibitor of EGFR tyrosine kinase, and it has been 
developed as an oral antitumor agent.  
Epidermal growth factor receptor is characteristic of a large family of growth factor 
receptor tyrosine kinases that share a common structure composed of an extracellular 
ligand binding domain, a short transmembrane domain, and an intracellular domain that 
has tyrosine kinase activity.  Binding of the cognate ligand, for example, epidermal 
growth factor (EGF) or transforming growth factor a (TGFa) to the extracellular domain 
of EGFR initiates a signal transduction cascade that can influence many aspects of 
tumor cell biology, including growth, survival, metastasis, and angiogenesis, as well as 
tumor cell sensitivity to chemotherapeutic and radiotherapeutic drugs.  Tyrosine 
phosphorylation provides docking sites on the EGFR for recruitment of proteins that are 
either direct substrates for EGFR-mediated phosphorylation or adaptor proteins that link 
WKHUHFHSWRUWRDFDVFDGHRI³GRZQVWUHDP´ELRFKHPLFDOUHDctions, for example, the ras-
raf-MAPK-fos pathway, which drives tumor cell proliferation (16). 


 
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6 
1.2.3 ZD1839 Pre-clinical Experience 
Key preclinical features of ZD1839 include high tolerability and the ability to delay 
growth and at higher doses to cause regression in human non-small cell lung cancer 
(NSCLC) and a wide range of other tumor xenografts (see the ZD8139 Investigator's 
Brochure [IB] for details). 
1.2.4 Animal Data 
In preclinical toxicity studies the no-effect dose level after administration of ZD1839 
for up to 1 month is 2 mg/kg per day; over a 6-month period it is 1 mg/kg per day.  In 
the 1-month studies, a dose of 40 mg/kg per day produced pathological changes in the 
ovaries of rats and in the eyes, kidneys, and skin of both rats and dogs.  Similar changes 
were detected in the 6-month studies, and, in addition, minimal/mild hepatocellular 
necrosis was also detected with increased levels of circulating plasma liver enzymes.  
These effects showed signs of partial or full reversibility after drug withdrawal.  There 
was evidence of reduced fertility in the female rat at the 20-mg/kg per day dosage as 
well as slight maternal and fetotoxicity in the rabbit.  These changes were all attributed 
to the pharmacological effects of ZD1839 on EGF-dependent tissues.  Reversible 
abnormalities of atrioventricular conduction were also seen in the dog at the 40-mg/kg 
per day dosage in the 1-month study and at the 15-mg/kg per day dosage in the 6-month 
study.  Data for dog Purkinje fibers indicate that ZD1839 has a modest potential to 
affect repolarization and hence prolong QT at high plasma concentrations.  There is 
some evidence for in vivo effects; however, these were not clear even at the highest 
dose tested. 
1.2.5 Clinical Data 
1.2.5.1 
Clinical Pharmacokinetics 
ZD1839 is extensively distributed (volume of distribution approximately 1400l), rapidly 
cleared (514 ml/minute), and has a mean elimination half-life of 48 hours in cancer 
patients.  Plasma protein binding is approximately 90%.  Following oral administration, 
absorption is moderately slow (maximum plasma concentrations typically occur 
between 3 and 7 hours after administration of the dose), and the mean terminal half-life 
is 41 hours.  The absolute bioavailability of the 250-mg tablet is approximately 60%.  
The effect of food on the absorption of ZD1839 (35% increase in area under the 
concentration-time curve [AUC]) is not considered clinically relevant, but sustained 
elevation of gastric pH above 5 results in a 47% reduction in relative bioavailability.  
Administration once daily results in 2- to 8-fold accumulation, with steady state plasma 
concentrations achieved by Days 7 to 10.  At steady state, circulating plasma 
concentrations are typically maintained within a 2- to 3-fold range across the dosing 
interval.  Population pharmacokinetic data from two phase II studies in patients with 
advanced NSCLC showed the mean steady state trough concentration following a 250-
mg dose was 261 ng/ml (95% continuous infusion [CI]: 88.0 to 774 ng/ml), with 


 
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7 
interpatient variability of 56% and intrapatient variability of 21% to 30%.  No clinically 
relevant demographic or pathophysiological covariates were identified, but there was a 
correlation between trough concentration and the incidence of diarrhea and rash. 
The majority of a radiolabeled ZD1839 dose was excreted in the feces as parent 
compound plus metabolites, while less than 4% of the dose was recovered in the urine.  
At least three sites of biotransformation were identified; resulting in the production of 
five identified circulating metabolites, one of which is present at concentrations similar 
to those of parent compound.  None of the identified metabolites is thought to 
contribute significantly to the overall pharmacological activity of ZD1839.  ZD1839 
does not induce any major cytochrome P450 enzymes, and is itself metabolized by 
CYP3A4.  Interaction studies in healthy subjects demonstrated that ZD1839 AUC (250-
mg dose) was increased by approximately 80% in the presence of itraconazole, a potent 
CYP3A4 inhibitor, an increase that may be clinically relevant because adverse 
experiences are related to dose and exposure.   
Coadministration with rifampicin, a potent CYP3A4 inducer, resulted in an 83% 
reduction in ZD1839 AUC.  Thus, coadministration with other CYP3A4 inducers (e.g., 
SKHQ\WRLQ FDUEDPD]HSLQH EDUELWXUDWHV RU 6W -RKQ¶V :RUW PD\ SRWHQWLDOO\ UHGXFH
efficacy.   
In vitro data showed that ZD1839 has inhibitory potential against CYP2D6, but an 
interaction study with metoprolol, a CYP2D6 substrate, demonstrated only a small 
effect on ZD1839 with metoprolol exposure.  The change is not considered clinically 
relevant and suggests little potential for interactions with drugs metabolized by this 
P450. 
1.2.5.2 Phase II Efficacy in Squamous Cell Carcinoma of the Head and Neck 
A recently completed trial in patients with recurrent or metastatic squamous cell 
carcinoma of the head and neck confirmed single agent activity of ZD1839 in this 
population. This trial, performed through the University of Chicago Phase II 
Consortium demonstrated an 11% response rate with an 8.1 month median overall 
survival (17). 
A second trial at the University of Chicago evaluated the efficacy of ZD1839 at a dose 
of 250m PO daily in patients with recurrent and metastatic disease. At this dose the 
observed response rate was only 1.4% with a 1.8 month progression-free survival. 
These data suggest that, at least in the setting of recurrent/metastatic SCCHN, the 
appropriate dose should be 500mg daily. 
1.2.5.3 
Phase I-II Tolerability 
Patients given ZD1839 250 mg/day or similar doses frequently had drug-related 
gastrointestinal disturbances (mainly diarrhea; sometimes associated with dehydration) 


 
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8 
and skin reactions (rash, acne, dry skin, and pruritus).  The majority of drug-related 
adverse events were mild (Common Toxicity Criteria [CTC] grade 1) and 
noncumulative, and rarely led to withdrawal of ZD1839 therapy. 
No additional safety concerns were raised for subpopulations of men or women, the 
elderly, ethnic groups, patients with renal impairment, or patients with mild-to-
moderate hepatic impairment.  Few specific drug-drug interactions were identified that 
could impact on the safety of ZD1839. 
Recent data suggest an incidence of interstitial lung disease (ILD) in lung cancer 
patients taking ZD1839 with an incidence of approximately 0.27%.  This is less than 
that reported to occur with other cancer treatments.  However, these events are 
medically significant and up to 40% of cases have possibly had an associated fatal 
outcome.  It is suggested that NSCLC may in itself predispose patients to ILD, however 
supportive epidemiological data of this type is not readily available.  The data from the 
placebo-controlled combination trials is also supportive of the hypothesis that there is 
not a significant association between Iressa and ILD events or symptoms.  However, 
there is the possibility that a causal relationship could exist. 
To date, gefitinib or ZD1839, has been administered to over 42,000 people worldwide. 
Interstitial lung disease in patients treated with ZD1839 is uncommon, with a 
worldwide incidence of less than 1%, which is comparable to that reported with other 
lung cancer therapies. Interstitial lung disease had a fatal outcome, whether deemed 
ZD1839-related or not, in approximately 0.1% in this medically complex group of the 
over 42,000 patients receiving ZD1839. 
 
The occurrence of pulmonary toxicity and interstitial lung disease was similar across all 
treatment arms in the first-line NSCLC combination chemotherapy (INTACT) trials, 
which were placebo-controlled first-line trials in over 2000 patients with non-small cell 
lung cancer who received either gemcitabine and cisplatin +/- ZD1839 or carboplatin 
and paclitaxel +/- ZD1839. 
 
1.2.5.4 
ZD1839 in Combination with Chemotherapy 
A pilot phase I trial using a standard dose of paclitaxel and carboplatin in newly 
diagnosed patients with advanced NSCLC has completed recruitment.  This trial 
examined the safety and pharmacokinetics of two dose levels of ZD1839 (250 mg and 
500 mg) given concurrently with chemotherapy.  Twenty-two patients have been 
included.  No dose-limiting toxicities (DLTs) were reported in either the 250- or 500-
mg dose levels of ZD1839.  Another pilot Phase I trial is also underway involving two 
doses of ZD1839 given concurrently with gemcitabine and cisplatin, and an additional 
trial involving ZD1839 with Navelbine and Navelbine and cisplatin is scheduled to start 
recruitment. 
 


 
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9 
A pilot Phase I trial (Miller) to demonstrate the safety of ZD1839 in combination with 
carboplatin and paclitaxel in previously untreated advanced NSCLC has completed 
recruitment.  The trial examined the tolerability of ZD1839 given intermittently or 
continuously in combination with carboplatin and paclitaxel.  Twenty-five patients were 
included in the trial.  The trial showed that ZD1839 given either intermittently or 
continuously combined with carboplatin and paclitaxel was well tolerated, and no novel 
increased or cumulative toxicity had been observed.  The data showed no evidence of 
clinically significant drug-drug interactions; they also showed the concurrent 
administration of ZD1839 does not affect the systemic exposure of either carboplatin or 
paclitaxel. 
A pilot phase I trial (18) to determine the feasibility of combining ZD1839 with 5-FU 
and leucovorin (LV) and to determine the pharmacokinetics of the combination in 
patients with advanced colorectal cancer (aCRC) has completed recruitment.  The trial 
examined the tolerability of ZD1839 administered on either an intermittent or a 
continuous schedule with 5-FU and LV.   Twenty-six patients entered the study.  
Results showed that a dose-limiting toxicity (DLT) of diarrhea occurred in patients 
given the 500-mg dose of ZD1839 using the intermittent schedule; however, DLT was 
not seen in patients given the 500-mg dose of ZD1839 using the continuous schedule.  
Continuous oral administration of ZD1839 at doses up to 500 mg daily in combination 
with the dose and schedule of 5-FU/LV used in this study is generally well tolerated in 
patients with aCRC.  No significant increase or severity of diarrhea or skin toxicity 
beyond that seen with 5-FU/LV was observed. 
Two large trials have been completed in chemo-naïve patients with stage III and IV 
non-small cell lung cancer.  Patients were randomized to receive ZD1839 250 mg daily, 
ZD1839 500 mg daily, or placebo in combination with platinum-based chemotherapy 
regimens.  The chemotherapies given in these first-line trials were gemcitabine and cis-
platinum (N=1093) or carboplatin and paclitaxel (N=1037).  The addition of ZD1839, 
did not demonstrate any increase in tumor response rates, time to progression, or overall 
survival beyond that of chemotherapy alone. 
1.2.5.5 
ZD1839 in Combination with Radiotherapy 
Several preclinical studies have demonstrated the efficacy and radiosensitizing ability 
of ZD1839 (19-22) in cell lines and xenograft models. Phase I studies of ZD1839 in 
combination with radiation therapy are underway in human subjects and have thus far 
not encountered significant interactive toxicities. Furthermore, a published phase I trial 
of a monoclonal antibody directed against EGFR, cetuximab, in combination with 
radiotherapy in head and neck cancer patients concluded that administering the two 
modalities simultaneously was safe and did not require dose reduction of either the 
agent or radiotherapy (23). 
ZD1839 in combination with radiation and in combination with chemoradiation is 
currently being investigated in clinical trials. There is one trial with sufficient numbers 


 
AZ1839US/0212 
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10 
of patients enrolled to discuss safety data, a CALG-B trial led by Dr. Neal Ready. 
CALG-B trial number 30106 is a phase I/II trial of ZD1839 with induction paclitaxel 
and carboplatin followed by either radiation (stratum one) or concomitant radiation 
(stratum two) with weekly paclitaxel and carboplatin in stage III NSCLC. The total dose 
of radiation is 66 Gray given over 5-ZHHNV*UD\ZLWKF*\³ERRVW´GRVHWR
the primary tumor. The CALG-B trial enrolls two strata of stage III NSCLC patients, 
stratum one consists of performance status 2 patients and the stratum two consists of 
performance 0-1 patients. Stratum one has not yet completed recruitment to the phase I 
portion of the trial. Stratum two has completed enrollment in the phase I portion of the 
trial with 6 patients, who have been followed through completion of their induction 
chemotherapy with ZD1839 and carboplatin, paclitaxel, ZD 1839 and radiation therapy. 
The phase I safety portion of this trial, for good performance status patients, has been 
completed concluding that addition of ZD1839 to carboplatin, paclitaxel, and radiation 
is feasible. There is no change in the toxicities observed with chemo-radiation and the 
phase II portion of the trial has been opened. (Personal communication with Dr. Ready). 
1.3 Quality of Life 
1.3.1 Background 
Oral cancer affects cosmesis and critical areas of functioning including eating, speaking 
and socializing, all of which have profound effect on quality of life (24-29).  The impact 
occurs as a function of both disease and treatment.  The consequences are both 
immediate and long term, and have psychosocial as well as functional implications.   
Psychosocial and QoL issues related to surgery are obvious (both disfigurement and 
changes in levels of functioning) and were the first issues to be studied in head and neck 
cancer QoL (30-32).  New treatment protocols involving less surgery and highly toxic 
therapies pose new questions.  These regimens are specifically designed to minimize 
surgery and accompanying impairment.  However, they rely on intensive radiotherapy 
and concomitant chemoradiotherapy, which have significant immediate, delayed, and 
potentially long-term side effects, which also may profoundly influence QoL.  While 
traditional endpoints (e.g., response, time to failure, overall survival) are undeniably 
critical considerations, assessment of the patient's QoL including, patient satisfaction, 
the ability to function in key areas, and carry on daily activities, is an important 
component in the determination of the success of treatment. 
1.3.2 Previous Work/Preliminary Data 
Quality of life is comprised of multiple components, one of which is functional status.  
The measurement of functional status in oral cancer patients demands attention to the 
unique issues presented by this disease and its treatment.  In an effort to meet the need 
for a simple, practical performance scale for this patient group, investigators developed 
a new Performance Status Scale for Head and Neck Cancer Patients (PSS-HN) (33-35).  
The scale is simple and practical.  It is composed of three sub-scales measuring the 


 
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11 
areas of eating, speaking and eating in public.  These are the primary areas of disability 
in this population, yet are not addressed by standard measures of global functioning.  
The scale has been employed in a number of studies and selected, relevant data are 
presented here.   
After initial validation of the PSS-HN, investigators at University of Chicago have 
employed this performance measure in combination with multi-dimensional QoL 
measures to assess outcome in head and neck cancer patients undergoing organ 
preserving, concomitant chemoradiotherapy protocols.  The first study examined 
performance and QoL outcomes in patients at least 1 year post-completion of an organ-
preserving concomitant chemoradiotherapy protocol.  Assessment included a semi-
structured interview and standardized measures of performance status (PSS-HN), 
residual side effects (McMaster Radiotherapy Questionnaire) (36), quality of life 
(FACT-H&N) (37), mood (Profile of Mood States) (38) and depression (CESD) (39).  
Forty-seven stage II-IV patients, with no evidence of disease were entered.  The greatest 
functional impairment was inability to eat a normal diet: only 14% of the sample were 
eating normal solid foods; an additional 18% were eating a normal diet with increased 
liquid intake, and 50% were eating soft foods at best.  By logistic regression, inability to 
eat solid foods was best predicted by disease site, with patients with oropharyngeal 
cancer (versus all other sites) being four times more likely to be unable to eat solid 
foods.  No additional predictive information was provided by: stage of disease, organ 
preservation surgery, radiation dose, time since treatment, size of tumor, use of feeding 
tube or side effect severity during treatment.  Decreased QoL and clinically significant 
depression were found in approximately one quarter of the group, and were not related 
to problems eating or eating in public.  Very few patients had any speech disturbance.  
While other contributing factors were suggested (e.g., past problems with alcohol, 
residual side effects, disease site), no clear set of predictor variables has yet emerged 
(40).   
Quality of life has been included, prospectively, in recent phase II studies of intensive 
chemoradiotherapy.  Data from our stage IV cisplatin, BID radiation protocol (6950), 
the first to include comprehensive QOL assessment, highlight the toxicities of these 
therapy regimens and the need for inclusion of targeted QoL assessment. 
Data are available on the 64 patients enrolled at University of Chicago and 
Northwestern with follow-up on surviving patients through 4 years.  As presented 
below, pre-treatment problem with eating, swallowing, and pain were seen in over one 
third of patients.  Functional impairment increased during treatment, persisted through 6 
months with gradual recovery over the next few years with patients returning to 
baseline levels in many areas.  Dry mouth remained the most persistent symptom.  
Table 5 Performance outcome 
Performance Outcome 
Pre-Rx 
On-Rx 
6 Mos. 
12 Mos. 
2-4 Yrs. 


 
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12 
Diet (d 50: soft food or liquids only) 
42% 
98% 
90% 
82% 
41% 
Eating in Public (d 50: discomfort) 
26% 
N/A 
72% 
64% 
44% 
Moderate-Severe Sequelae  
 
 
 
 
 
Dry mouth 
17% 
51% 
63% 
58% 
52% 
Sticky saliva 
25% 
75% 
49% 
34% 
24% 
Swallowing 
33% 
57% 
37% 
26% 
27% 
Pain 
30% 
49% 
29% 
24% 
18% 
Tasting 
8% 
40% 
32% 
32% 
21% 
Rx = treatment. 
We are currently compiling comparable data from a recently closed, similar protocol in 
which paclitaxel replaced cisplatin during chemoradiotherapy.  We expect to see 
slightly less acute toxicity with the paclitaxel regimen.  Again patients continue to be 
followed to evaluate long- term effects.  Inclusion of QoL assessment in the current 
study will enable us to assess the impact on QoL, performance, and functional outcome, 
of adding induction chemotherapy to our established chemoradiotherapy regimen. 
1.3.3 Quality of Life Objectives 
The proposed regimen aims to improve survival and minimize distant metastases while 
minimizing performance and QoL deficits.  Thus, QoL and performance are important 
treatment endpoints.  The objective is to describe these dimensions prospectively, 
pretreatment, through treatment, to long-term follow-up.  Specific aims are to 
x GRFXPHQWSDWLHQW¶VH[SHULHQFHRIWUHDWPHQWHIIHFWV 
x evaluate changes in QoL and performance as a function of induction chemotherapy 
alone  
x determine extensiveness and persistence of QoL and function-related treatment 
effects 
x describe the pattern, timing and extent of recovery of function and QoL 
1.4 Study Proposal and Rationale 
Investigations at the Chicago Oral Cancer Center have demonstrated that patients with 
locally advanced head and neck cancer can have high survival, time to progression, and 
organ preservation rates following therapy with carboplatin/paclitaxel and T-FHX 
chemoradiotherapy.  ZD1839 is an exciting novel agent; it has single agent activity and mild 
toxicities. Recently released phase III data in non-small cell lung cancer suggest that 


 
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13 
addition of ZD1839 to chemotherapy may not increase activity of chemotherapy alone. 
However, conflicting data exist for a monoclonal EGFR antibody (cetuximab) added to 
cisplatin in head and neck cancer demonstrating a non-statistically significant advantage to 
EGFR blockade (41). This discrepancy may be agent or disease site dependent. 
Nevertheless, use of ZD1839 with radiotherapy is well supported by preclinical experience, 
the cetuximab/radiotherapy experience, and as a targeted agent may be more a more 
selective and less toxic radiation enhancer than paclitaxel. Furthermore, use of ZD1839, as a 
maintenance agent is likely to be tolerable with the potential to decrease failure rates and 
appearance of second malignancies. 
We therefore propose to incorporate into our standard program an agent from a promising 
new class of cancer therapy that targets an important pathway required for tumor growth: 
ZD1839, an inhibitor of EGFR-tyrosine kinase.  ZD1839 will be given after induction 
therapy, with concurrent chemoradiotherapy replacing a previously used cytotoxic 
(paclitaxel) and then will be continued as maintenance therapy following completion of 
FHX chemoradiotherapy for 2 years or until disease progression, unacceptable toxicity, or 
withdrawal from study since its systemic activity may prevent the regrowth of 
micrometastatic disease. 
In light of data supporting the use of 500mg of ZD1839 in SCCHN, the current protocol will 
administer this dose concurrently with chemoradiotherapy. In addition, as preliminary results 
administering maintenance therapy in locally advanced non-small cell lung cancer have not 
proven efficacious with respect to survival, the 500mg dose will not be continued beyond 
chemoradiotherapy.  
 


 
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14 
2 TRIAL SCHEMA 
OVERVIEW 
 
 
 
 
 
 
Paclitaxel 100mg/ m2 in 500 ml D5W over 3 hours IV (Days 1, 8, and 15) 
+ Carboplatin (start after completion of paclitaxel on Day 1) 
AUC 6 (CC +25) administered in 100 ml NS over 30 min IV after completion of paclitaxel 
No paclitaxel or carboplatin on Day 22.   
Resume chemotherapy for cycle 2 on Day 29 (two cycles of 4 weeks duration). 
Chemoradiotherapy will begin 1 ± 2 weeks after the last dose. 
 
 
 
 
 
Chemotherapy should be administered during all 5 weeks of radiotherapy. 
ZD1839 500mg QD PO continuous administration begins on day 1 cycle 1 of chemoradiotherapy 
and continues into maintenance. 
 
EACH CYCLE: 
Day 0 (Sunday): 
P.M.: Start hydroxyurea at 500 mg PO q 12 hours x 6 days (11 doses).   
The first daily dose of hydroxyurea on Days 1 ± 5 is given 2 hours 
prior to the first fraction of daily radiotherapy. 
6:00 P.M.: Start continuous IV infusion of 5-fluorouracil 600 mg/m2/day u 5 days (120 Hours). 
Days 1 ± 5: RT 150 Gy (twice daily) 
Days 6 ± 12: No chemoradiotherapy 
Chemoradiotherapy cycles are repeated every 14 days until completion of radiotherapy. 
 
Node dissection and surgery as necessary 
 
 
SCREENING/BIOPSY 
OPTIONAL INDUCTION CHEMOTHERAPY 
(DURATION 8 WEEKS) 
CONCOMITANT CHEMORADIATION 
(DURATION 10 WEEKS)  
FOLLOW-UP 


 
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15 
3 INCLUSION CRITERIA 
1. Histologically or cytologically confirmed diagnosis of squamous cell or poorly differentiated 
carcinomas, or lymphoepithelioma of the nasopharynx 
2. Age 18 years or older  
3. Patients with AJCC (6th edition, 2002) stage III or IV head and neck cancer  
4. Patients with AJCC (6th edition, 2002) stage IV head and neck cancer presenting with 
cervical lymph node metastasis of an unknown primary (i.e., TxN2 or TxN3) are also 
eligible. 
5. Prior to entry in the study, the resectability and alternative treatment options for each patient 
will be determined by a team composed of a head and neck surgeon, a radiation oncologist, 
and a medical oncologist.  Stage determination, optimal local treatment, and its timing 
according to this protocol will be determined at this evaluation.  Each patient will be 
classified as having resectable or unresectable disease.  The unequivocal demonstration of 
distant metastasis (M1) confers ineligibility.  
6. Unidimensionally measurable disease (based on RECIST) is desirable but not strictly 
required.  Individuals who are disease free at baseline after excisional biopsy or node 
dissection will be considered not evaluable for response assessment but are eligible. 
7. No prior or radiotherapy 
8. Prior surgical therapy will consist only of incisional or excisional biopsy and organ-sparing 
procedures such as debulking of airway-compromising tumors or neck dissection in a patient 
with an unknown primary tumor.   
9. Eastern Cooperative Oncology Group (ECOG) performance status d 2 (Karnofsky t 60%) 


 
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16 
10. Patients must have normal organ and marrow function as defined below 
absolute neutrophil count (ANC)  
 
t 1,500/Pl 
platelets  
 
 
t 100,000/Pl  
total bilirubin  
 
 
within normal institutional limits 
aspartate aminotransferase (AST, SGOT)/ 
alanine aminotransferase (ALT, SGPT)   
d 2.5 u institutional upper limit of  
 
 
 
normal 
alkaline phosphatase  
 
 
d 2 u upper limit of normal 
creatinine  
 
 
within normal institutional limits 
11. Informed consent must be obtained from all patients prior to beginning therapy.  Patients 
should have the ability to understand and the willingness to sign a written informed consent 
document. 
4 EXCLUSION CRITERIA 
1. Unequivocal demonstration of metastatic disease (i.e. M1 disease). 
2. Known severe hypersensitivity to ZD1839 or any of the excipients of this product 
3. Any coexisting malignancy that would increase risk of toxicity, interfere with interpretation 
of toxicity, or is associated with a median survival of less than 24 months.   
4. Concomitant use of phenytoin, carbamazepine, barbiturates, rifampin, phenobarbital, or St. 
John's Wort. 
5. Treatment with an investigational drug within 30 days before Day 1 of trial treatment 
6. Incomplete healing from previous surgery 
7. Pregnancy or breast feeding (women of child-bearing potential). Patients should be advised to 
use effective contraception as appropriate. 
8. History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to paclitaxel, Cremaphor EL, carboplatin, 5 FU, or hydroxyurea 
9. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure (CHF), unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements  
10. Patients with clinically significant pulmonary dysfunction, cardiomyopathy, or any history of 
clinically significant CHF are excluded.  The exclusion of patients with active coronary artery 
disease will be at the discretion of the attending physician. 


 
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17 
11. Patients must have no uncontrolled active infection other than that not curable without 
treatment of their cancer. 
12. No patients with severe baseline neurologic deficits (> grade II neuropathy) will be treated 
with induction chemotherapy.  
13. Any evidence of clinically active interstitial lung disease (patients with chronic stable 
radiographic changes who are asymptomatic need not be excluded) 
5 CRITERIA FOR DISCONTINUATION/WITHDRAWAL OF 
INFORMED CONSENT 
Patients may be discontinued from trial treatment and assessments at any time, at the discretion 
of the investigator(s).  Specific reasons for discontinuing a patient from this trial are 
x objective progression of disease  
x patient lost to follow-up (i.e., dropouts) 
x adverse events 
x protocol non-compliance 
x withdrawal of consent 
If the reason for withdrawal from the trial is the death of the patient, the two options for 
categorizing withdrawal are either progressive disease or an adverse event (AE; more than one 
AE may be documented as a reason for withdrawal).  Only one event will be captured as the 
cause of death.  Note that death is an outcome and not an AE.  
All deaths that occur within the trial period or within 30 days after administration of the last dose 
of trial drug must be reported to AstraZeneca primarily for the purposes of serious adverse event 
(SAE) reporting; however, deaths due unequivocally to progression are not SAEs. 
 
All subjects who have new or worsening CTC grade 3 or 4 laboratory values at the time of 
withdrawal must have further tests performed and the results recorded appropriately until the lab 
values have returned to CTC grade 1 or 2, unless these values are not likely to improve because 
of the underlying disease.  In these cases, the investigators must record their opinions in the 
VXEMHFW¶VPHGLFDOUHFRUGV/DERUDWRU\DEQRUPDOLWLHVVKRXOGnot be reported as adverse events 
unless any criterion for a SAE is fulfilled, the laboratory abnormality causes the subject to 
discontinue from the study, or the investigator insists the abnormality should be reported as an 
AE. 
 
At withdrawal all on-going study-related toxicities and SAEs must be followed until resolution, 
XQOHVV LQ WKH LQYHVWLJDWRU¶V RSLQLRQ WKH FRQGLWLRQ LV XQOLNHO\ WR UHVROYH GXH WR WKH VXEMHFW¶V
underlying disease. 
 
 


 
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18 
After withdrawal from treatment, subjects must be followed up for all existing and new AEs for 
30 calendar days after the last dose of trial drug. All new AEs occurring during that period must 
be reported to AstraZeneca and all study-related toxicities and SAEs must be followed up for 
resolution where possible.    
6 TREATMENT PLAN 
6.1 Agent Administration 
Induction chemotherapy and maintenance therapy will be administered on an outpatient 
basis and chemoradiotherapy will be administered on an inpatient basis.  Expected AEs and 
appropriate dose modifications for ZD1839, carboplatin, paclitaxel, 5-FU, hydroxyurea, 
and radiation are described in sections 8 and 9.  No investigational or commercial agents or 
therapies other than those described below may be administered with the intent to treat the 
patient's malignancy. 
6.1.1 Pre-therapy Checklist (all pre-therapy evaluations should be conducted 
within 4 weeks of starting therapy unless otherwise indicated) 
x Inclusion/exclusion criteria 
x Informed consent 
x Dental consultation (within 8 weeks of starting radiotherapy) 
x Speech and swallow consultation 
x Panendoscopy with biopsy and tumor map (within 6 weeks of starting therapy) 
x Radiographic studies (CT or MRI of the head and neck, CT chest, bone scan [if 
indicated], within four weeks of starting therapy) N.B.: a bone scan is not required 
prior to therapy unless the investigator feels there is a clinical indication or 
suspicion of bone metastases. 
 
x Complete blood count (CBC), complete metabolic profile (within 2 weeks of 
starting therapy).  
 
6.1.2 Induction Therapy  
The administration of induction chemotherapy in this trial is at the discretion of the 
investigator. Patients who have not received prior chemotherapy should be offered 
induction chemotherapy as specified below. 


 
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19 
Carboplatin and paclitaxel combination will be administered IV for two cycles of 
4 weeks duration each.  Chemoradiation will begin 1 ± 2 weeks after the last dose.  
Dose delays and dose modifications should take place as in section 9.  In no case 
should the six doses of induction paclitaxel be given over a period exceeding nine 
(9) weeks. 
Paclitaxel: 
100 mg/m2 in 500 ml of D5W IV over 3 hours (on Days 1, 8, 15) 
Carboplatin: Start after completion of paclitaxel on Day 1, AUC 6 (CC + 25).  
Administer in 100 ml of NS IV over 30 minutes after completion of 
paclitaxel.  No therapy on Day 22.  Resume chemotherapy for cycle 2 
on Day 29. 
A 24-hour urine collection for measurement of CC is recommended, but is not 
mandatory.  A baseline on creatinine level should be drawn within 1 week prior to 
starting chemotherapy.  The carboplatin dose will remain unchanged on the second 
cycle unless the serum creatinine increases by > 25%.  In this event, a CC should be 
recalculated for the second cycle.  No changes will be made for decreases in serum 
creatinine. 
When necessary, calculated CC should be determined as follows: 
(140  age) u weight (in kg) (u 0.85 in females) (u 1.0 in males) 
    72 u creatinine (mg/dL) 
Note: The body weight should be ideal body weight for patients whose actual body 
weight is greater than their ideal body weight (IBW), based on the following formula: 
 
 
 
Males IBW = 50 kg + 2.3 u height in inches over 5 feet 
 
 
 
Female IBW = 45.5 kg + 2.3 u height in inches over 5 feet 
Antiemetics: 
ondansetron 
hydrochloride 
(Zofran), 
dolasetron 
mesylate 
(Anzemet), or granisetron hydrochloride (Kytril) prior to 
paclitaxel on Day 1.  The use of antiemetics when paclitaxel is 
administered alone is not routinely required and is at the discretion 
of the investigator.  
Pre-medications:  dexamethasone sodium phosphate injection (Decadron) 20 mg 
IV 1 hour prior to paclitaxel 
 
diphenhydramine hydrochloride injection (Benadryl) 25 mg IV 
push to be given 1/2 hour prior to paclitaxel 
Hydration: 
At the discretion of the investigator.  


 
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20 
6.1.3 Concomitant Chemoradiotherapy 
Chemotherapy should be administered during all 5 weeks of radiotherapy.  If less than 3 
days of radiation therapy (RT) are required during Week 5, chemotherapy may be 
omitted. 
Day 0 (Sunday)  
P.M.:  
start hydroxyurea at 500 mg PO q 12 hours u 6 days 
(11 doses).  The first daily dose of hydroxyurea on Days 1 ± 
5 is given 2 hours prior to the first fraction of daily 
radiotherapy. 
6:00 P.M.:  
start continuous IV infusion of 5-FU at 600 mg/m2/day u 5 
days (120 hours). 
Day 1 ± 5 
Radiation therapy is administered twice daily at 150 cGy 
per fraction. 
Days 6 ± 12:  
No chemoradiotherapy.   
For each cycle:  
Administer 5 Pg/kg subcutaneously (SQ) of G-CSF daily, 
beginning on Day 6 through Day 12 at a minimum of 12 
hours after completion of 5-FU in patients who develop 
grade 3 neutropenia or who have neutropenia t grade 2 on 
Day 0 of any cycle.  In these patients, G-CSF will be 
utilized in all subsequent cycles.  GM-CSF can be 
substituted at the discretion of the investigator.   
Chemoradiotherapy cycles are repeated every 14 days until the completion of 
radiotherapy. 
ZD1839 will be administered continuously at 500mg QD PO (preferably in the 
morning) during radiotherapy from day 1 of cycle 1 until discontinuation criteria are 
met during maintenance therapy.  
If radiation esophagitis or pneumonitis or other radiation-related toxicities 
develop during radiation and necessitate interruption of radiation therapy, then 
ZD1839 treatment should be held and not re-started during radiation therapy.  
Every effort should be made to complete the full prescribed course of radiation 
therapy as soon as these toxicities have resolved sufficiently to proceed. 
6.1.4 Maintenance Therapy 
Adjuvant ZD1839 will not be administered at the 500mg dose level. ZD1839 will be 
discontinued upon completion of radiotherapy. 


 
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21 
6.2 Radiotherapy Guidelines 
1. All patients will have a complete dental evaluation prior to the start of radiation therapy, 
ideally prior to the start of chemotherapy. 
2. All patients will be simulated prior to the start of treatment with an appropriate 
immobilization device. 
3. Appropriate field sizes will be determined at the time of simulation to treat gross disease 
and areas of potential microscopic disease.   
4. Ideally all patients should undergo CT based treatment planning.  Initial field size and 
arrangement will be at the discretion of the attending radiation oncologist.  The optimal 
field arrangement will be determined based on the treatment planning employed.  Either 
3-D CT based treatment planning or Intensity Modulated Radiation Treatment (IMRT) 
techniques will be acceptable.  In both instances the physician will attempt to deliver an 
even dose to the target tissue and minimize doses to normal structures.  
5. Initial fields will encompass all known areas of gross tumor as defined by physical exam 
or diagnostic studies (CT or MRI).  The exact field arrangement will depend on whether 
3-D conformal or IMRT techniques are used.   
6. Blocking will be individualized for each patient.  Either custom Cerrobend blocks or 
multileaf collimator will be acceptable. 
7. Each cycle of treatment will consist of 5 consecutive days of radiation with 150 cGy 
given bid (300 cGy per day and 1500 cGy per week) in conjunction with chemotherapy.  
There should be a minimum of 6 hours between fractions.  All fields will be treated each 
day.  The exceptions will be the supraclavicular and posterior neck fields. 
8. The total radiation dose to patients will be determined based on the responses to 
induction chemotherapy and risk of disease.  The disease risk sites will be 1) gross 
disease, 2) high risk microscopic disease, and 3) low risk microscopic disease.  Gross 
disease is all demonstrated disease based on physical exam and radiographic studies.  
Low risk microscopic disease is the second echelon of clinically uninvolved nodes. 
9. Radiation doses: The dose to gross disease will be 70 to 72 Gy.  High-risk microscopic 
disease will receive 48 to 51 Gy.  Low risk microscopic disease will receive 36 to 39 Gy. 
10. The dose limit to the spinal cord will vary depending upon the technique used.  Attempts 
should be made to limit the spinal cord dose to < 40 Gy with conventional 3D radiation 
treatment.  Doses should be limited to 46 Gy with IMRT techniques and reduced fraction 
size to the spinal cord. 


 
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22 
6.3 Supportive Care 
x Antiemetics will be ordered at the discretion of the attending physician. 
x Administration of sucralfate (Carafate) suspension (1 gm QD swish and swallow on an 
empty 
stomach) 
is 
recommended 
during 
chemoradiation 
to 
ameliorate 
mucositis/esophagitis. 
x A double lumen venous access device (e.g., Port-a-Cath) will be recommended prior to 
initiation of therapy.  Use of a feeding device is recommended for high-risk patients.   
x Prior to discharge of the patients after a cycle of chemoradiation, a CBC and platelet 
count, and determination of serum electrolytes, including blood urea nitrogen (BUN) and 
creatinine will be performed.   
x Patients will be discharged with instructions for oral hygiene (e.g., oral nystatin and 
viscous lidocaine HCl (Xylocaine) solution) and replacement drugs for electrolyte 
imbalances when applicable.   
x Use of intravenous home hydration is recommended in patients with inadequate oral 
intake.  
x If Hgb < 10, patients should generally be transfused an amount sufficient to increase Hgb 
to t 10.  The use of erythropoietin is at the discretion of the investigator. 
x Treatment-related diarrhea will be managed with high-dose loperamide.  The 
recommended dose of loperamide is 4 mg initially (two capsules) then 2 mg after each 
loose stool, not to exceed 16 mg daily. 
x The use of amifostine during IFHX chemoradiotherapy is not permitted  
6.4 Surgical Guidelines 
The timing and extent of the surgical procedure remains an individualized decision between 
the patient and his or her surgeon.  Generally, it is expected that patients will undergo 
concomitant chemoradiotherapy prior to extensive surgery.  Simple excision (e.g., transoral 
laser excision) of the primary lesion may be performed initially if it can be accomplished 
while preserving organ function.  A tumor biopsy will be performed prior to therapy, on day 
1 of cycle 2 of chemoradiotherapy, and after completion of chemoradiotherapy (see Tables 1 
and 2). Modified or selective neck dissection may also be performed.  When these 
procedures are not performed initially, neck dissection should be performed following 
concomitant chemoradiotherapy for any residual nodal disease.  This may also be performed 
in patients initially staged N2b, N2c or N3, even in the absence of macroscopic residual 
disease (elective node dissection).  Surgery at the primary site should be omitted in patients 
who have achieved biopsy-proven complete response.  In patients with pathologically 


 
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23 
proven residual disease at the primary site, complete excision of disease should be 
accomplished.  Patients demonstrating progression of disease at any time or disease 
recurrence should be considered for conventional surgical management. 
6.5 Quality of Life Measurements 
N.B.: QUALITY OF LIFE MEASURMENTS WILL NOT BE CONDUCTED AT THE 500MG 
DOSE LEVEL OF ZD1839 
Quality of life and performance measures to be used in this protocol include: 
1) 
Performance Status Scale for Head and Neck Cancer Patients (PSS-HN) 
2) 
Functional Assessment of Cancer Therapy - Head and Neck Version 3 (FACT-H&N) 
3) 
Center for Epidemiological Studies ± Depression (CES-D) 
4) 
Selected questions from the McMaster University Head and Neck Radiotherapy 
Questionnaire 
Performance Status Scale for Head and Neck Cancer (PSS-HN) (34).  The PSS-HN is a 
clinician rated instrument consisting of three subscales:  Normalcy of Diet, Eating in Public, 
and Understandability of Speech.  It has been demonstrated to be reliable and valid in head 
and neck cancer patients (described in detail in section 1.3.1).   
Functional Assessment of Cancer Therapy-Head and Neck Version 3 (FACT-H&N) (37, 42).  
The FACT-H&N is a multidimensional, self-report QoL instrument specifically designed for 
use with head and neck cancer patients.  The core scale (FACT-G) consists of 27 core items 
assessing patient well being in four areas: Physical, Social/Family, Emotional, and 
Functional.  The Core scale is supplemented with site-specific modules, of which the head 
and neck version (12 items) will be employed here.   
Center for Epidemiological Studies ± Depression (CES ± D).  The CES ± D is a short, 20-
item self-report scale measuring depressive symptomatology.  It has demonstrated reliability 
and validity with scores equal to or above 16 considered suggestive of depression (39). 
McMaster Radiotherapy Questionnaire (36).  This patient self-report instrument (can be 
clinician administered) quantifies patients' perception of the frequency and severity 
(troublesomeness) of radiation related side effects. 
These will be administered prior to therapy, after induction therapy, during 
chemoradiotherapy, and at 1, 6, and 12 months after completing the study drugs and then 
annually for five years. 


 
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24 
6.6 Duration of Therapy 
In the absence of treatment delays due to adverse events, chemoradiotherapy may continue 
for 5 cycles or until one of the following criteria applies 
x Disease progression, 
x Intercurrent illness that prevents further administration of treatment 
x Unacceptable adverse event(s) 
x Patient decides to withdraw from the study, or general or specific changes in the 
SDWLHQW¶VFRQGLWLRQUHQGHUWKHSDWLHQWXQDFFHSWDEOHIRUIXUWKHUWUHDWPHQWLQWKHMXGJPHQW
of the investigator. 
7 IDENTIFICATION OF INVESTIGATIONAL PRODUCT 
7.1 ZD1839 
Other names: Gefitinib, Iressa. 
Mode of action: inhibitor of EGFR tyrosine kinase. 
ZD1839 will be supplied to the investigator by AstraZeneca as brown film-coated tablets for 
use as follows: 
Table 6 ZD1839 trial treatment 
Treatment 
Strength 
Description 
Daily dose 
Tablets per dose 
ZD1839a 
250-mg tablet 
Brown, 11mm 
250 mg 
2 
a Descriptive information for ZD1839 can be found in the Investigator's Brochure. 
 
Tablets will be packed in high-density polyethylene (HDPE) bottles with child-resistant 
closures.  Each bottle will contain 30 tablets of a single formulation.  The tablets will be 
dispensed to the patient as a 1-month supply in the bottle provided by AstraZeneca. 
7.1.1 Management of Interstitial Lung Disease   
 
If the patient develops new pulmonary infiltrates while receiving ZD1839 therapy, 
consideration of consultation with a pulmonologist is advised.  All infectious 
etiologies and tumor progressions should be excluded as the underlying cause of the 


 
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25 
infiltrates.  If these infiltrates are thought to be ZD1839 treatment related, the patient 
should permanently discontinue ZD1839.   
7.2 Storage 
All investigational products must be kept in a secure place under appropriate storage 
conditions.  All ZD1839 trial treatment will be stored in a lockable storage area, between 20-
25qC (68 ± 77qF). 
7.3 Accountability 
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VLQVWLWXWLRQ¶V UHVSRQVLELOLW\ WR HVWDEOLVK D V\VWHP IRU KDQGOLQJ WULDO
treatments, including investigational medicinal products, so as to ensure that 
x Deliveries of such products from AstraZeneca Pharmaceuticals or distribution site are 
correctly received by a responsible person (e.g., a pharmacist) 
x Deliveries are recorded 
x Certificates of delivery and return are signed, preferably by the investigator or a 
pharmacist, and copies are retained 
x Trial treatments are handled and stored safely and properly 
x Trial treatments are prescribed only by the investigator or subinvestigators named in 
Form FDA-1572 
x ZD1839 supplied for this trial is dispensed to trial patients only in accordance with the 
protocol 
x Subjects must return all unused medication and empty containers to the investigator 
x All unused ZD1839 trial treatment and empty bottles at the site or distribution center are 
destroyed  
At the end of the study, it must be possible to reconcile delivery records with records of 
usage and destroyed/returned stock. Records of usage should include the identification of 
the person to whom the trial treatment was dispensed, the quantity and date of 
dispensing, and unused study treatment returned to the investigator. Any discrepancies 
must be documented.   
7.3.1 Treatment Schedule 
ZD1839 treatment will be taken once a day, every day about the same time.  It can be 
taken with or without food. 


 
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26 
If a patient forgets to take a dose, the last missed dose should be taken as soon as the 
patient remembers, as long as it is at least 12 hours before the next dose is due to be 
taken.  The daily treatment schedule will be resumed the next day.  
This protocol will be closed 28 months after the last patient is enrolled.  At that time, 
patients will continue to be followed for survival.  AstraZeneca reserves the right to 
suspend drug supply for new patients if recruitment does not meet the protocoled target.  
In this event, drug supply for patients already receiving ZD1839 will be continued for 
28 months after the suspension date, as long as they are eligible to remain on-study.  
Once the protocol is completed (or suspended), ZD1839 has been approved, and is 
available commercially; patients who are continuing to receive clinical benefit from 
ZD1839 therapy will obtain ZD1839 via insurance or through the AstraZeneca 
Assistance program (if required criteria are met). 
 
7.3.2 ZD1839 Dose Interruption 
Dose interruptions should be the first approach to managing toxicity.  Repeat dose 
interruptions are allowed as required.   
7.4 Non-hematopoietic Toxicity  
In the event of CTC grade 3 or 4 non-hematopoietic AE(s) that the investigator considers 
due to suspected disease progression, re-evaluation of tumor status is indicated, irrespective 
of scheduled clinic visits. 
If any of the following conditions occur, administration of ZD1839 may be interrupted for a 
maximum of 14 days to allow the AE to resolve or decrease in severity: 
x CTC grade 3 or 4 or unacceptable toxicity, e.g., cosmetic effect of grade 2 rash 
x No consideration and/or corroborative evidence that the AE is due to progressive disease 
x The AE is consistent with previously described ZD1839 toxicity 
At a minimum, reassessment of toxicity should be done twice weekly and more frequently if 
clinically indicated.  Once the AE decreases in severity to CTC grade 1, the patient may 
continue to take the assigned dose of 250-mg daily. 
7.5 Skin Toxicity 
Patients with poorly tolerated skin toxicity may be successfully managed by providing a 
brief (up to 14 days) therapy interruption, after which the daily dose of ZD1839 should be 
reinstated.  However, the rash may improve without the need for interrupting therapy with 
ZD1839.  Of note in current trials, many patients were able to resume ZD1839 therapy at the 
same dose after resolution of rash, and they then had less extensive and/or severe rashes. 
 


 
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27 
7.6 Gastrointestinal (GI) Toxicity 
If GI toxicity is not appropriately managed, it may be associated with the development of 
dehydration. 
7.7 Nausea and/or Vomiting 
In patients who have emesis and are unable to retain ZD1839, every attempt should be made 
to obtain control of nausea and vomiting.  The dose of ZD1839 may be repeated if emesis 
occurs within 30 minutes of taking the tablet(s). 
7.8 Diarrhea 
Diarrhea has been successfully managed with anti-diarrheal agents such as loperamide.   
If a grade 4 diarrhea is associated with hemodynamic collapse, the investigator should report 
it as an SAE and remove patient from trial. 
In all cases where the subject is withdrawn due to unusual or unusually severe toxicity 
considered related to ZD1839, the investigator must report it to AstraZeneca. 
7.9 Hypersensitivity to ZD1839 
One case of hypersensitivity with hives following the first dose of ZD1839 occurred in 
phase I trials.  This was successfully managed over several months with low-dose daily oral 
antihistamines while treatment with ZD1839 continued. 
7.10 Management of Interstitial Lung Disease 
If patients present with an acute worsening or new onset of respiratory symptoms such as 
dyspnea, cough and fever, ZD1839 should be interrupted and the patient promptly 
investigated for Interstitial Lung Disease. If Interstitial Lung Disease is confirmed, and is 
believed to be ZD1839-related, ZD1839 should be permanently discontinued. 
If in-field radiation toxicities develop while the patient is receiving radiation therapy and 
interruption of radiation therapy is necessary, then ZD1839 should be held until and not re-
started during radiation therapy. Every effort should be made to complete the full course of 
radiation therapy, as soon as the acute toxicity has resolved sufficiently to proceed. ZD1839 
therapy may be restarted, if appropriate, after the patient has completed radiation therapy and 
has recovered to a CTC grade 2 or less event. 
7.11 Duration of ZD1839 Therapy 
Treatment should be discontinued only if disease progression or unacceptable/unmanageable 
drug-related adverse events occur. 


 
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28 
7.12 Guideline for Dispersing Whole ZD1839 Tablets 
ZD1839 tablets cannot be crushed.  Experimentation has shown that ZD1839 tablets will 
break up into a fine dispersion within 5 to 7 minutes when they are dropped whole into 
lukewarm water.  There are no known risks to the chemical stability of ZD1839, providing 
this process occurs immediately before administration to the patient.  There may be a risk to 
ensuring delivery of the whole dose because a certain amount of deposition of powder on the 
surfaces of the container will occur while the container is being emptied. No information 
exists concerning bioequivalence of efficacy for non-oral administration of ZD1839.  
The following procedure is recommended for administering a dispersed whole tablet to a 
patient who is unable to swallow:  
x Drop the ZD1839 tablet into an appropriate container (ideally glass to help confirm 
removal of all the dispersed material) containing approximately 1 to 2 ounces (or 50 ml) 
of lukewarm water.   
x Stir the liquid occasionally to ensure complete break-up of the tablet.  When the tablet 
has broken up into a fine dispersion (approximately 5 minutes) it can be administered to 
or by the patient. 
x Rinse the container with a similar amount of water to ensure removal of any material 
adhering to the walls of the container and administer the additional water to the patient.  
x Confirmation that the subject has received the whole dose and that it was administered in 
this fashion should be included on the subject dispensing record. 
x Because no data are available concerning the stability of the dispersed tablet, 
administration to the patient should occur immediately after dispersion is complete. 
 
7.13 Other Concomitant Treatment 
The use of investigational agents other than ZD1839 is not allowed while patients are on this 
study. 
If surgery is considered necessary for the patient, whenever possible, at least 7 days should 
elapse after the last dose of ZD1839 before surgery is performed.  ZD1839 can be resumed 
on the 7th post-operative day. 
Any patients who require ophthalmic surgery during the course of the trial will be 
temporarily withdrawn.  These patients can restart ZD1839 at the discretion of the 
investigators. 
Concomitant use of medications known to affect the conductive system, such as beta-
blockers, calcium channel blockers, or digoxin, is allowed under investigator supervision. 


 
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29 
No concomitant use of the following drugs is allowed: phenytoin, carbamazepine, 
rifampicin, phenobarbital or St. John's Wort, as these drugs induce CYP3A4 and may 
decrease levels of ZD1839. 
Coadministration of drugs that cause significant sustained elevations in gastric pH t 5 may 
reduce plasma concentrations of ZD1839, and therefore may reduce efficacy. 
International normalized ratio (INR) elevations, bleeding, or both events have been reported 
in some patients taking warfarin.  Patients taking warfarin should be monitored regularly for 
changes in prothrombin time (PT) or INR. 
Systemic retinoids should not be given because of theoretical concerns about negatively 
affecting the ZD1839 mechanism of action.  Systemic steroids are discouraged for the 
treatment of skin toxicities.  Patients who are taking steroids for reasons other than skin 
toxicity at trial entry may continue treatment.  
For subjects on steroids at the start of the study, the dose of steroids should not be changed 
without consultation with the Investigator. 
Other FDA approved medication that is considered necessary IRUWKHSDWLHQW¶VVDIHW\DQG
well-being may be given at the discretion of the investigator(s). 
No additional anti-cancer therapies, other than those specified in this protocol, should be 
given to patients while on this study. 
8 EXPECTED TOXICITIES 
8.1 ZD1839 
ZD1839 has been well tolerated in phase I and II studies.  Diarrhea and a generalized skin 
rash are the major dose limiting toxicities.  The skin rash may improve despite continuation 
of ZD1839.  Diarrhea may lead to dehydration and electrolyte disturbances.  Mucositis also 
developed as DLT in one patent.  Other non-dose limiting toxicities that were encountered in 
phase I or II trials include headache, elevated liver enzymes, skin rash, nausea, vomiting, and 
fatigue.  Symptoms are generally reversible with drug discontinuation.  Keratitis (grade 1-2) 
and dry eyes have been reported in a few subjects.  In all cases, the eye changes were 
managed with either standard treatment (artificial tears or topical corticosteroids) or the 
discontinuation of study drug.  The use of contact lenses while taking ZD1839 is 
discouraged. 
8.2 Paclitaxel 
The main toxicities associated with paclitaxel include: electrocardiogram (ECG) 
abnormalities with bradycardia, heart block, bundle branch block, and ventricular 


 
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30 
tachycardia, peripheral neuropathy, myalgias and arthralgias, nausea and vomiting (usually 
moderate), 
ischemic 
colitis, 
neutropenic 
enterocolitis, 
diarrhea, 
alopecia, 
and 
myelosuppression primarily manifesting as neutropenia.  Hypersensitivity reactions have 
occurred, with dyspnea, bronchospasm, hypotension, pancreatitis, hepatic enceph-urticaria, 
angioedema, sensation of flashing lights, and blurred vision.  Abnormalities of liver function 
tests have occurred as well but are usually mild.  The concomitant administration of 
paclitaxel and radiation to the head and neck will aggravate the local side effects of radiation 
such as dermatitis, mucositis, and others. 
8.3 Carboplatin 
Common toxicities include 
x Hematologic ± myelosuppression 
x Gastrointestinal ± nausea, vomiting, mucositis, diarrhea 
x Neurologic ± peripheral and central neuropathy and ototoxicity 
x Renal ± tubular damage 
x Dermatologic ± alopecia 
x Allergic reactions 
It is a known radiation sensitizer and may potentiate side effects of radiation. 
8.4 5-Fluorouracil 
Common toxicities include: 
x Gastrointestinal ± diarrhea, mucositis, nausea, and vomiting 
x Hematologic ± myelosuppression 
x Dermatologic ± photosensitivity, skin dryness, hand-foot syndrome, increased 
pigmentation of skin, increased pigmentation of veins used for infusion, nail changes 
Less commonly observed toxicities include 
x Cardiac ± myocardial ischemia, arrhythmias 
x Allergic reactions 
x Neurologic ± acute cerebellar syndrome, disorientation, headache 
x Eye ± lacrimal duct stenosis, lacrimation, photophobia, and visual changes 
5-FU may cause birth defects and should not be used in pregnant women.  It is a known 
radiation sensitizer and may potentiate side effects of radiation. 
8.5 Hydroxyurea 
Common side effects include: 


 
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31 
x Myelosuppression (mainly leukopenia) 
x Nausea, vomiting 
x Diarrhea or constipation 
x Stomatitis 
It may aggravate the inflammation of mucous membranes secondary to irradiation.   
Less common side effects include:   
x Dysuria or impairment of renal tubular function 
x Rare neurologic disturbances, e.g., headaches, dizziness, disorientation, hallucination 
and convulsion. 
8.6 Radiation 
Radiation to the head and neck will cause skin irritation, dry mucous membranes due to 
salivary gland dysfunction, mucositis and stomatitis.  The concomitant administration of 
chemotherapy will aggravate these side effects.  Long-term side effects include myelitis, 
osteoradionecrosis, hoarseness, hypothyroidism, and fibrosis of soft tissues. 
9 DOSE AND SCHEDULE MODIFICATIONS 
9.1 During Induction Chemotherapy 
9.1.1 Dose Modification 
Table 7 
Dose modification  
Induction Dose Level 
Carboplatin (AUC) 
Paclitaxel (mg/m2) 
  0 
6 
100 
±1 
5 
  80 
  2 
4 
  70 
 
9.1.2 Hematologic Toxicity   
Hematologic toxicity is based on any interval laboratory results within 7 days prior to 
treatment or on the day of treatment. 
Table 8 Hematologic toxicity   
ANC/Pl 
 
Platelet count/Pl 
Dose Modification 


 
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32 
> 800 
And/or 
> 50,000 
No change, give 
previous dose 
d 800 
And/or 
d 50,000 
Decrease 1 level* 
* Do not treat until ANC > 800 Pl and platelet count > 50,000 Pl.  Retreat when patient recovers at lower 
dose level.  A patient who does not recover within 2 weeks should proceed with concomitant 
chemoradiotherapy. 
ANC = absolute neutrophil count. 
9.1.3 Non-hematologic Toxicities 
Modification of carboplatin/paclitaxel dosages will occur if the toxicity is considered to 
be related to study drug.  Non-hematologic toxicities will be based on any interval 
observations between treatments or at the time of each dose. 
9.1.4 Motor and/or Sensory Neuropathy 
Table 9 
Motor and sensory neuropathy 
Neuro-sensory/Motor 
Paclitaxel 
Carboplatin 
Grade 0 ± 1 
No change 
No change 
Grade 2 
Decrease 1 dose level 
Decrease 1 dose level 
Grade 3 or greater 
Off study 
Off study 
 
 
 
9.1.5 Fatigue, Arthralgia, Myalgias 
Table 10 
Fatigue, arthralgia, myalgias 
Arthralgia, Myalgia 
Paclitaxel 
Carboplatin 
Grade 0 ± 1 (normal, mild) 
No change 
No change 
Grade 2 (decrease in ability to move) 
No change 
No change 
Grade 3 (disabled) 
Hold until d grade 2 (moderate), 
then decrease 1 dose level 
No change 
 


 
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33 
9.1.6 Hepatic Dysfunction 
Table 11 Hepatic dysfunction 
Bilirubin (mg/dL) 
Paclitaxel 
Carboplatin 
< 1.5 
No change 
No change 
1.5 ± 2.0 
Decrease 1 dose level 
No change 
> 2.0 
Hold until d 2.0, then decrease 1 dose level 
No change 
 
9.2 ZD1839 Dose Modifications During Chemoradiotherapy Therapy 
N.B.: Since experience with administration of ZD1839 with radiotherapy is limited, a 
toxicity analysis will be performed after 12 patients complete therapy. If greater than 5 
patients require dose reductions, a review of the treatment protocol will take place to 
determine if the toxicities are related to ZD1839 administration. Accrual will continue 
during this review but will be suspended if the protocol requires amendment. 
If radiation esophagitis or pneumonitis or other radiation-related toxicities develop during 
radiation and necessitate interruption of radiation therapy, then ZD1839 treatment should 
be held and not re-started during radiation therapy.  Every effort should be made to 
complete the full prescribed course of radiation therapy as soon as these toxicities have 
resolved sufficiently to proceed. 
9.2.1 Diarrhea and Skin Rash 
Grade 1 ± 2 diarrhea and skin rash do not require temporary discontinuation of 
treatment, as these toxicities may improve despite continued treatment with ZD1839.  
Diarrhea should be treated with high-dose loperamide (see section 6.3). 
For grade 3 ± 4 skin rashes felt to be secondary to ZD1839 (i.e. typical acneiform rash, 
outside of radiation field) and diarrhea or grade 2 skin rashes secondary to ZD1839 and 
diarrhea that are unacceptable to the patient for symptomatic reasons, ZD1839 should 
be temporarily held (< 2 weeks) until resolution and subsequently re-started at 250 mg.  
If symptomatic grade 2 skin rash or diarrhea recur after re-instituting treatment and 
require a second temporary discontinuation, treatment should be held until resolution to 
d grade 1 and re-instituted at 250 mg.   
For grade 3 and 4 diarrhea or skin rash felt to be secondary to ZD1839, treatment will 
be held until the patient has been reevaluated at least weekly until it resolves to d grade 
1.  Treatment will then be re-instituted at 250 mg.   


 
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34 
9.2.2 Other Toxicities 
For any other grade 2 toxicity that is medically concerning (e.g., prolonged pulmonary 
toxicity), treatment may be held until resolution.  
For any other grade 3 and 4 toxicity, or for grade 2 toxicity that may be attributed to 
ZD1839 and it is medically concerning, treatment will be discontinued and the patient 
reevaluated at least weekly until resolution to d grade 1.  Treatment will then be re-
instituted at 250 mg.    
Patients with unresolved toxicity after 3 weeks should be taken off study. 
9.3 Dose Modifications during Concomitant Chemoradiotherapy 
9.3.1 Myelosuppression 
For absolute neutrophil count (ANC) of 500/Pl to 1,000/Pl or platelet count of 
50,000/Pl to 74,000/Pl on Day 0 ± 5 of each cycle, decrease hydroxyurea to 50% of full 
dose.  On subsequent cycles, a reduced starting dose of hydroxyurea may be used. 
For ANC of d 500/Pl or platelet count d 50,000/Pl on Day 0 ± 5 of any cycle, omit 
hydroxyurea, and administer 600 mg/m2/day of 5-FU and radiotherapy only.  On 
subsequent cycles, a reduced starting dose of hydroxyurea by 50% should be used. 
In the presence of a persisting fever t 38qC or other clinically apparent infection a cycle 
can be postponed for 1 week or interrupted (if treatment cycle has already started) if this 
is necessary in the opinion of the treating medical and radiation oncologists. 
9.3.2 Mucositis, Dermatitis, Diarrhea 
For grade 4 mucositis, dysphagia, and dermatitis exceeding 7 days duration or persisting 
on Day 1 of a subsequent cycle, decrease 5-FU to 500 mg/m2/day.   
For grade 4 diarrhea exceeding 7 days duration or persisting on Day 1 of a subsequent 
cycle, decrease 5-FU to 500 mg/m2/day.  ZD1839 can be temporarily held as described 
in section 9.2.1. 
Doses will not be increased on subsequent cycles. 
TREATMENT 
CYCLES 
WILL 
NOT 
BE DELAYED FOR MUCOSITIS, 
DYSPHAGIA, DERMATITIS, OR DIARRHEA. 


 
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35 
9.3.3 Other Non-hematological Toxicity 
Radiotherapy should not be interrupted for non-hematologic toxicity except as in section 
9.1.3, or as judged necessary on a case-by-case basis by the treating radiation and 
medical oncologists. 
9.4 For Other Toxicities on Day 0 of Chemoradiotherapy 
9.4.1 Hepatotoxicity 
Grade 3, 4 ± Hold hydroxyurea 
9.4.2 Nephrotoxicity 
Grade 2 ± Give ½ dose hydroxyurea 
Grade 3, 4 ± Hold hydroxyurea 
9.5 ZD1839 Dose Modifications During Maintenance Therapy 
N.B.: ZD1839 AT THE 500MG DOSE LEVEL WILL NOT BE CONTINUED AS 
MAINTENANCE THERPAY. ZD1839 SHOULD BE DISCONTINUED UPON 
COMPLETION OF RADIOTHERAPY 
The same procedures for dose modifications will apply to maintenance therapy as for 
chemoradiotherapy with the exception that patients can be re-started on ZD1839 after any 
delay regardless of causality or length of interruption at the discretion of the treating 
physician. The physician and patient must conclude that the benefits of continuing 
maintenance therapy outweigh the risks of doing so. Regardless of dose interruptions or 
delays, maintenance therapy will not last longer than 2 years after the date of completion of 
chemoradiotherapy.  
10 AGENT FORMULATION AND PROCUREMENT 
10.1 Paclitaxel 
Paclitaxel (Taxol, Bristol-Myers Squibb, Princeton, NY): supplied in 5 ml vials containing 
30 mg of drug (6mg/ml).   Side effects are listed in section 8.2. 
Drug interactions: There is a potential for interaction with Ketoconazole, which might 
interfere with paclitaxel metabolism.   
Contraindications: Known hypersensitivity to either paclitaxel or Cremaphor EL. 


 
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36 
10.2 Carboplatin 
Carboplatin (Paraplatin ± NSC#241240): supplied commercially as a sterile lyophilized 
powder available in single-dose vials containing 50 mg, 150 mg and 450 mg of carboplatin.  
Each vial contains equal parts by weight of carboplatin and mannitol. 
Side effects: listed in section 8.3.  Please refer to the package insert for full prescribing 
information.   
Preparation: Immediately before use, the content of each vial must be reconstituted with 
either sterile water for injection, USP, 5% dextrose in water, or 0.9% sodium chloride 
injection, USP to produce a carboplatin concentration of 10 mg/ml.  When prepared as 
directed, carboplatin solutions are stable for 8 hours at room temperature.  Since no 
antibacterial preservative is contained n the formulation, it is recommended that carboplatin 
solutions be discarded 8 hours after dilution. 
Storage and Stability: Unopened vials of carboplatin are stable for the life indicated on the 
package when stored at controlled room temperature and protected from light. 
Administration: Administer over ½ hour after completing the paclitaxel infusion.  The 
Calvert Equation (Dose=AUC (CC+25) will be used to achieve the desired dose where CC = 
Wt*(140-age)/72/creatinine (if female use 85%).   
10.3 Fluorouracil 
5-Fluorouracil (Adria, OH): commercially available as 10 ml ampules containing 500 mg/10 
ml.  No dilution is necessary for administration, but it may be further diluted in D5W or 
normal saline.  It is stored at room temperature and is stable for 24 hours.  It will be 
administered by intravenous continuous infusion.  Toxicities are listed in section 8.4.  Please 
refer to the package insert for full prescribing information.   
10.4 Hydroxyurea 
Hydroxyurea (Bristol-Myers Squibb, Princeton, NY): commercially available as 500 mg 
capsules.  It is stored at room temperature and will be administered orally.  Please refer to 
the package insert for solution preparation and expected AEs (also given in section 8.5).  
Please refer to the package insert for full prescribing information. 
11 TRIAL MEASUREMENTS 
The modified RECIST criteria will be used for this trial for objective tumor response assessment; 
details are given in Appendix A.  


 
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37 
N.B.: THE ONLY CORRELATIVE STUDIES ON THE 500MG ZD1839 DOSE LEVEL WILL 
BE 
A 
PRESTUDY 
TUMOR 
BIOPSY 
AND 
BLOOD 
COLLECTION 
FOR 
PHARMACOGENOMICS (GENOTYPING).  
11.1 EGFR Expression from Samples  
11.1.1 Rationale and Reporting of Results 
The purpose of the samples is to understand the mechanism of the mode of action of 
ZD1839, and/or identify a marker to monitor or predict treatment results.  The patient 
will be informed in the patient information sheet on how the samples will be obtained 
and stored. 
11.1.1.1 EGFR signaling 
EGFR signaling is transduced via multiple pathways including PI3 kinase/AKT 
and MAP kinase.  These downstream effectors are in turn phosphorylated and are 
responsible for the intracellular effects of EGFR activation.  We plan to study 
expression of EGFR, AKT, ERK 1/2, and their phosphorylated forms before 
therapy and during chemoradiotherapy by immunohistochemistry.  Biopsies will 
be obtained in all patients (if possible) and levels of expression will be correlated 
to response.  If inadequate tissue is available for all correlative studies the order of 
priority is p-ERK, p-AKT, ERK, AKT, EGFR and p-EGFR. 
11.1.1.2 EGFR genotyping  
The level of EGFR expression is predominantly regulated by the abundance of its 
mRNA (Merlino GT-1, 2).  The transcription initiation of EGFR gene derives 
from multiple initiation sites within a GC rich promoter region (Ishii S).  The first 
intron of EGFR has been shown to regulate gene transcription, and it contains a 
CA dinucleotide repeat sequence that is highly polymorphic and is located in 
proximity to a transcriptional enhancer element (Chrysogelos SA, Maekawa T, 
Haley JD).  Repeat lengths vary from 14 to 21 in the population; with the most 
common alleles contain 16 (42%), 18 (20%), and 20 (26%) repeats (Chi DD).  
Gebhardt and colleagues have recently reported an inverse correlation between the 
number of CA repeats present and the EGFR gene transcriptional activity over a 
5-fold range (Gebhardt F).  
The role of inter-individual genetic variability on disposition, toxicity and efficacy 
of many anticancer agents is also increasingly being recognized.  Understanding 
and recognizing consequences of genetic polymorphisms of potential therapeutic 
targets and/or drug metabolizing enzymes earlier in development of new agents 
may enhance the efficacy and minimize the toxicity of these agents.  Hence, 
identifying genetic determinants responsible for inter-individual variability of 
drug response will be of paramount importance in development of such targeted 


 
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38 
therapeutic agents.  This study seeks to discover whether polymorphisms in the 
first intron of the EGFR gene are related to response or toxicity.   
11.1.1.3 Tumor Biopsies 
On-study biopsies should be collected and prepared according to section 11.1.2a.  
A total of three on-study biopsies may be performed throughout the trial if 
possible, before induction chemotherapy, during chemoradiation, and after 
chemoradiation.  Patients may refuse to undergo biopsy and still participate in the 
trial.  The first and third biopsies are for clinical, as well as research purposes and 
will help determine histology and pathologic response, respectively. 
11.1.1.4 Exploratory Serum and Plasma Markers 
Both angiogenesis and hypoxia have been linked with outcome in head and neck 
cancer.  In addition, preclinical data has revealed that ZD1839 may have 
antiangiogenic activities. Blood samples will be collected from patients before 
study entry, after induction chemotherapy, at the beginning of cycle 2 of 
chemoradiotherapy (to coincide with the biopsy), and after completion of 
chemoradiotherapy. These samples will be analyzed for quantitative determination 
of VEGF and PAI-1 levels using commercially available ELISA kits. 
Any remaining samples and test samples such as stained slides will be retained at the 
testing laboratory until completion of the trial.  Stained slides used in the development 
of diagnostics kits will be retained at the University of Chicago.  Permission for future 
research will be sought from the relevant International Ethics Committee (IEC)/ 
International Review Boards (IRB), and patients may be contacted again for informed 
consent.  
It is not proposed that the analysis of results from a specific patient are made available 
routinely to either the patient or the treating physician; however, group results from this 
trial will be published.  The patient will be informed of this in the patient information 
sheet. 
The tumor samples collected in this trial, the results of any testing, and any patents, 
diagnostic tests, drugs, and biological products developed directly or indirectly as a 
result of this trial, as well as any information derived directly or indirectly from those 
samples, are the sole property AstraZeneca (and its successors, licensees and assigns).  
The patient has no right to this property or to any share of any profits that may be 
earned directly or indirectly as a result of this trial.  The patient will be informed of this 
in the patient informed consent. 
 
11.1.2 Sample Management  


 
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39 
a) 
Collection of Tumor Slides or Tumor Blocks 
Every effort should be made to obtain biopsies that contain cells representative of the 
tumor.  The specimen should contain sufficient non-necrotic tumor tissue. Biopsies 
during study will be performed on an outpatient basis [unless the patient is undergoing 
an operative procedure (ie panendoscopy) as part of standard evaluation] under local 
anesthesia using an 18-guage core biopsy needle to obtain a total tissue length of at least 
2 cm.  These tissues should be frozen at -80qC according to protocol. 
For freezing tissues, you will need O.C.T. embedding compound (Baxter), plastic tissue 
molds (Baxter), 2-methylbutane (Sigma), dry ice, a hemostat or other clamping device, 
and a metal or plastic 1 L container.  
x Label the mold with proper tissue identification and fill partly with O.C.T.  
x If freezing unfixed tissue, dab it on a towel to remove any fluid, and immediately 
place in tissue mold with O.C.T. and continue with protocol  
x Choose the best orientation for the tissue to be frozen in, and let it settle to the 
bottom.  Note that the bottom of the mold is where cutting will begin.  
x Add more O.C.T. on top of tissue to cover it completely and fill the mold.  
x Fill the plastic or metal container half way with 2-methylbutane.  
x Add several small pieces of dry ice and wait a few moments for the temperature to 
drop to -qC.  
x Grasp the edge of the mold with the hemostat and dip into 2-methylbutane. Note 
that you should NOT submerge yet.  Dip only the most bottom part of the plastic 
mold.  
x The O.C.T. will begin to turn white as it freezes  
x When all of the O.C.T. is frozen, drop the mold into the cold 2-methylbutane to 
freeze thoroughly (~5 min)  
x Remove the mold from the freezing liquid, wrap the mold in foil, label it, and 
immediately store at -qC.   


 
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40 
b) 
Blood Collection for Correlative Studies 
 
11.1.2.b.i Genotyping 
Blood samples will be collected from patients in a 7 cc lavender top tube.  
Samples should be collected prior to therapy with ZD1839.  They will be analyzed 
for EGFR genotyping.  Note that this blood samples can be collected at any time 
as genotype is not expected to change. 
11.1.2.b.ii VEGF and PAI-1 
Blood samples will be collected from patients in 7 cc green top tubes. Samples 
will be collected prior to therapy, after induction therapy, on day 1 of cycle 2 of 
chemoradiotherapy, and after chemoradiotherapy. These will be analyzed for 
VEGF and PAI-1. 
11.1.3 Sample Preparation and Shipment Instructions 
The shipment of all human samples (blood, tissue) must comply with appropriate 
regulations as specified by the carrier.  At a minimum, all frozen tissue and blood 
samples must be packaged in dry ice within two containers with absorbent material 
between containers to control any spill or leakage.  The outer container must be 
puncture resistant (e.g., cardboard mail tube, corrugated cardboard box).  A biohazard 
sticker must be affixed to both the inner and outer containers.  All samples must be 
accompanied by a sample transmission form and shipped to: 
Dr. Mark Lingen (773-702-5548, email: MLINGEN@UCHOSPITALS.EDU) 
University of Chicago 
FMI Dock/Lab Supply 
5830 S. Ellis Ave 
Room G-02 
Chicago, IL 60637 
Attn: Rifat Hasina 
All of the participating institutions outside of the University of Chicago will be 
provided with a University of Chicago Federal Express Account assigned to this study. 
Biopsy samples that are obtained at the University of Chicago Medical Center should be 
forwarded directly to the Translational Research Laboratory in J652. 
 
 


 
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41 
Each sample must be accompanied with a list containing the following information: 
Treating Physician Information 
Patient name, ID number, date of birth, sex 
Diagnosis 
Day started on clinical protocol 
Site of biopsy 
Date and time of biopsy 
On arrival, each sample will be assigned a Study Number.  All subsequent 
handling of the tissue samples will be blinded to the investigators performing 
various tests, except for the clinical pathologists. 
Only biopsy samples determined by the pathologist to contain tumor will be subjected 
to immunohistochemical analysis.  
For all histochemical studies, samples will be marked only by an assigned study 
number.  Patient name, diagnosis and other information will be unknown to the 
laboratory/clinical investigators involved and will be revealed only after studies are 
completed for further data analysis and statistics. 
The samples collected for genotyping will be stored on ice and transported on the same 
day (labeled with patient name) to the University of Chicago (see above).  A laboratory 
accession number will be assigned to the sample and the patient name will be removed.  
Information regarding specimen identification, protocol number, and date of blood draw 
will be indicated on a requisition form.  Samples will be stored at ±80qC for no more 
than 5 days for optimal DNA isolation.  DNA extraction will be performed using 
commercial DNA isolation kits, such as Puregene (Gentra Systems, Inc., 
Minneapolis, MN).  Genotyping for EGFR will be performed according to methods 
optimized in Dr. Mark RataLQ¶VODERUDWRU\7KHWZRSULPHUVWKDWZLOOEHXVHGDUH 
V$9+)¶-Fam-GTTTGAAGAATTTGAGCCAACC-¶ 
V$9+5¶-TTCTTCTGCACATTGGCAC-¶ 
One Pl of sample will be loaded on ABI 3700 DNA sequencer, genotyped using 
GeneScan and Genotyper software. 
11.1.4 Immunohistochemistry 
Tissues will be fixed in 4% paraformaldehyde and sectioned in 4 ± VOLFHV6OLGHV
will be incubated with 1% hydrogen peroxide for endogenous peroxidase blocking.  
Slides will be incubated with 5% normal horse serum, avidin, then biotin labeling 
solutions.  The slides will be incubated with the primary antibody overnight at 4qC.  All 
primary antibodies are commercially available for use in immunohistochemistry.  The 
slides will be incubated with species-appropriate biotinylated secondary antibody in 


 
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42 
protein blocking solution for one hour at room temperature.  Avidin/biotin complex will 
be applied.  Slides will be developed with diaminobenzidine (DAB), counterstained 
with hematoxylin, dehydrated, and mounted.  Slides will be interpreted by Dr. Wendy 
Recant using a four point scoring system.  This protocol may be modified to improve 
antigen retrieval and staining. 
11.1.5 ELISA 
Samples will be analyzed for plasma VEGF (R&D systems) and serum PAI-1 (Biopool 
International) using commercially available ELISA kits. 
12  MEASUREMENT OF EFFECT 
12.1 Definitions 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the RECIST Committee (43).  Changes in only the largest diameter 
(unidimensional measurement) of the tumor lesions are used in the RECIST criteria.   
Note:  Lesions are either measurable or non-measurable using the criteria provided below.  
7KH WHUP ³HYDOXDEOH´ LQ UHIHUHQFH WR PHDVXUDELOLW\ ZLOO QRW EH XVHG EHFDXVH LW GRHV QRW
provide additional meaning or accuracy. 
12.1.1 Measurable Disease 
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as t 20 mm with conventional techniques 
(CT, MRI, x-ray) or as t 10 mm with spiral CT scan.  All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
12.1.2 12.1.2 Non-measurable Disease  
All other lesions or sites of disease, including small lesions (longest diameter < 20 mm 
with conventional techniques or < 10 mm using spiral CT scan), are considered non-
measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses 
(not followed by CT or MRI), and cystic lesions are all non-measurable. 
12.1.3 Target Lesions 
All measurable lesions up to a maximum of five lesions per organ and 10 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) and their suitability for accurate repeated 
measurements (either by imaging techniques or clinically).  A sum of the longest 


 
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43 
diameter (LD) for all target lesions will be calculated and reported as the baseline sum 
LD.  The baseline sum LD will be used as reference by which to characterize the 
objective tumor response. 
12.1.4 Non-target Lesions 
All other lesions or sites of disease should be identified as non-target lesions and should 
also be recorded at baseline.  Non-target lesions include measurable lesions that exceed 
the maximum numbers per organ or total of all involved organs as well as non-
measurable lesions.  Measurements of these lesions are not required but the presence or 
absence of each should be noted throughout follow-up.  
12.2 Guidelines 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. 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.  Given the nature of locoregional failure after prior irradiation 
characteristic of head and neck cancer, these areas are considered as progression of disease 
and will be included.  If doubt exists on appropriate scans, then biopsy will be necessary to 
measure disease. 
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 when both methods have been used to assess 
the antitumor effect of a treatment. 
Clinical lesions.  Clinical lesions will be considered measurable only when they are 
superficial (e.g., skin nodules and palpable lymph nodes).  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.  These techniques should be performed with cuts of 
10 mm or less in slice thickness contiguously.  Spiral CT should be performed 
using a 5 mm contiguous reconstruction algorithm.  This applies to tumors of the 
chest, abdomen, and pelvis.  Head and neck tumors and those of extremities 
usually require specific protocols. 
Ultrasound.  When the primary endpoint of the study is objective response 
evaluation, ultrasound should not be used to measure tumor lesions.  It is, 


 
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44 
however, a possible alternative to clinical measurements of superficial palpable 
lymph nodes, subcutaneous lesions, and thyroid nodules.  Ultrasound might also 
be useful to confirm the complete disappearance of superficial lesions usually 
assessed by clinical examination. 
Endoscopy, Laparoscopy.  The use of these techniques for objective tumor 
evaluation has not yet been fully and widely validated.  Their uses in this specific 
context require sophisticated equipment and a high level of expertise that may be 
available only at some centers.  Therefore, the use of such techniques for objective 
tumor response should be restricted to validation purposes in reference centers.  
However, such techniques can be useful to confirm complete pathological 
response when biopsies are obtained. 
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 additional criteria 
for standardized usage of prostate-specific antigen (PSA) and CA-125 response in 
support of clinical trials are being developed. 
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. 
12.3 Response Criteria 
12.3.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions 
Partial Response (PR): 
At least a 30% decrease in the sum of the longest diameter 
(LD) of target lesions, taking as reference the baseline sum 
LD 
Progressive Disease (PD): At least a 20% increase in the sum of the LD of target 
lesions, taking as reference the smallest sum LD recorded 
since the treatment started or the appearance of one or more 
new lesions 


 
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45 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
sum LD since the treatment started 
12.3.2 Evaluation of Non-target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization 
of tumor marker level 
Incomplete Response/ 
Stable Disease (SD): 
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 
$OWKRXJK D FOHDU SURJUHVVLRQ RI ³QRQ-WDUJHW´ lesions only is exceptional, in such 
circumstances the opinion of the treating physician should prevail, and the progression 
status should be confirmed at a later time by the review panel (or study chair). 
Note:  If tumor markers are initially above the upper normal limit, they must normalize 
for a patient to be considered in complete clinical response. 
12.3.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment 
until assessment 6-8 weeks after chemoradiotherapy. Pathologic response will take 
precedence over clinical or radiographic response.  If there is discordance between 
clinical and radiographic response then clinical response will take precedence.  The 
patient's best response assignment will depend on the achievement of both measurement 
and confirmation criteria (see section 12.4). 
Table 12 
Lesions 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Incomplete 
response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 


 
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46 
Any 
Any 
Yes 
PD 
CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease. 
 
Note: 
x Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
FODVVLILHGDVKDYLQJ³V\PSWRPDWLFGHWHULRUDWLRQ´(YHU\HIIRUWVKRXOGEHPDGHWR
document the objective progression, even after discontinuation of treatment. 
x In some circumstances, it may be difficult to distinguish residual disease from 
normal tissue.  When the evaluation of complete response depends on this 
determination, it is recommended that the residual lesion be investigated (fine 
needle aspirate/biopsy) before confirming the complete response status. 
12.4 Confirmatory Measurement/Duration of Response 
12.4.1 Confirmation 
To be assigned a status of PR or CR, changes in tumor measurements must be 
confirmed by repeat assessments that should be performed at least 12 weeks after the 
criteria for response are first met (this does not apply for induction therapy in this 
protocol).   
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 recurrent disease is objectively documented. 
12.5 Progression-Free and Overall Survival 
Progression-free (time to progression): From the date of registration to the date of 
progressive disease or death 
Overall survival time: From the date of registration to the date of death or date of last patient 
contact if censored 


 
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47 
12.6 Response Review 
Independent review of imaging studies will take place under the following circumstances 
x Patients felt to have a complete response 
x Patients felt to have a partial response 
x Cases of prolonged stable disease, as selected by the primary investigator. 
An experienced radiologist with no affiliation to the present study will review the films.  
Images will be free of extraneous marks whenever possible. 
13 ADVERSE EVENTS 
13.1 Definitions 
The definitions of adverse events (AEs), serious adverse events (SAEs) and other significant 
adverse events (OAEs) are given below.  It is of the utmost importance that all staff involved 
in the study is familiar with the content of this section.  The principal investigator is 
responsible for ensuring this. 
13.2 Adverse Events 
An adverse event is the development of an undesirable medical condition or the 
deterioration of a pre-existing medical condition following or during exposure to a 
pharmaceutical product, whether or not considered causally related to the product.  An 
undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., 
tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory 
findings, ECG).  In clinical trials, from the time of signing an informed consent, an AE can 
include an undesirable medical condition occurring at any time, including run-in or washout 
periods, even if no trial treatment has been administered. 
Any events that are unequivocally due to progression of disease should not be reported as an 
adverse event. 
If any of the above events occurs, information will be required as to if it is an event possibly 
due to adverse effect of the study drug or an infection possibly caused with the study drug. 
13.3 Serious Averse Events 
A serious adverse event is an AE occurring during any trial phase (i.e., run-in, treatment, 
washout, follow-up), and at any dose of the investigational product, comparator or placebo, 
that fulfills one or more of the following criteria: 
x Results in death 
x Is immediately life-threatening 


 
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48 
x Requires in-patient hospitalization or prolongation of existing hospitalization 
x Results in persistent or significant disability or incapacity 
x Is a congenital abnormality or birth defect 
x Is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above 
Any event or hospitalization unequivocally due to progression of disease should not be 
reported as a serious adverse event. 
The causality of SAEs (i.e., their relationship to study treatment) will be assessed by the 
investigator(s), who in completing the relevant case UHSRUWIRUPPXVWDQVZHU³\HV´RU³QR´
WRWKHTXHVWLRQ³'R\RXFRQVLGHUWKDWWKHUHLVDUHDVRQDEOHSRVVLELOLW\WKDWWKHHYHQWPD\
KDYHEHHQFDXVHGE\WKHGUXJ"´ 
 
13.3.1 Other significant adverse event (OAE) 
 
OAEs will be identified by the Drug Safety Physician and if applicable also by the Clinical 
Study Team Physician during the evaluation of safety data for the Clinical Study Report.  
Significant adverse events of particular clinical importance, other than SAEs and those AEs 
leading to discontinuation of the subject from study treatment, will be classified as OAEs.  
Examples of these are marked hematological and other laboratory abnormalities, and certain 
events that lead to intervention (other than those already classified as serious), dose 
reduction or significant additional treatment.  For each OAE, a narrative may be written and 
included in the Clinical Study Report. 
13.4 Recording of Adverse Events 
All AEs should be documented. A description of the event, including its date of onset and 
resolution, whether it constitutes a SAE or not, any action taken (e.g., changes to study 
treatment, other treatment given, and follow-up tests) and outcome, should be provided 
DORQJ ZLWK WKH LQYHVWLJDWRU¶V DVVHVVPHQW RI FDXVDOLW\ WKH UHODWLRQVKLS WR WKH VWXG\
treatment[s]).  AEs will also be graded according to the NCI CTC, and changes documented. 
 
For an AE to be a suspected drug-related event, there should be at least a reasonable 
possibility of a causal relationship between the study medicinal product and the AE. 
 
13.4.1 
Abnormal laboratory values/vital signs 
The reporting of laboratory /vital signs abnormalities as both laboratory findings and adverse 
events should be avoided.  They should not be reported unless any criterion for a SAE is 
fulfilled, the laboratory /vital signs abnormalities causes the subject to discontinue from the 
study, or the investigator insists the abnormality should be reported as an AE.  If an 
abnormal laboratory value /vital sign is associated with clinical signs and symptoms, the 
sign/symptom should be reported as an AE and the associated laboratory result/vital sign 
should be considered additional information that must be collected on the relevant CRF. 
 


 
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49 
Any new conditions reported during the study will be documented as an AE.  Only those 
findings that are in addition to the condition being treated will be documented as AE.  
Conditions that are considered by the investigator to be unequivocally disease-related will 
not be documented as AEs. 
 
$Q\GHWULPHQWDOFKDQJHLQDSDWLHQW¶VFRQGLWLRQVXEVHTXHQWWRKLs or her entering the trial 
and during the 30-day follow-up period after the final treatment, should be considered an 
AE.  The development of a new cancer should be regarded as an AE.  New cancers are those 
that are not the primary reason for the administration of the trial treatment and have been 
LGHQWLILHGDIWHUWKHSDWLHQW¶VLQFOXVLRQLQWKLVFOLQLFDOWULDO 
13.5 Lack of Efficacy 
When there is deterioration in the condition for which the medicine is being used (i.e., breast 
cancer), there may be uncertainty as to whether this is lack of efficacy or an AE.  In such 
cases, unless the reporting physician considers that the medicine contributed to the 
deterioration, or local regulations state to the contrary, the deterioration should be 
considered a lack of efficacy and not an AE. 
13.6 Skin Adverse Events 
A variety of agents can be used to manage skin rashes.  These include mild-to-moderate 
strength steroid creams, topical or systemic antibiotics, topical or systemic antihistamines, 
and occasionally retinoid creams. 
There is no standard, known, or established treatment proven effective for drug-related skin 
rashes or changes due to ZD1839.  Most commonly, a pustular rash has been observed, 
which frequently improves even though the same dose of ZD1839 therapy is continued 
uninterrupted.  The need for oral or topical antibiotics is a clinical decision of the 
investigator and should be preceded by a culture of affected areas and, if indicated, a 
dermatology consultation.  Oral retinoids should not be given because of theoretical 
concerns about negatively affecting the ZD1839 mechanism of action.  Oral steroids are also 
strongly discouraged.  
13.7 Gastrointestinal Adverse Events 
Diarrhea can be debilitating and on rare occasions is potentially life threatening.  Guidelines 
developed by an American Society of Clinical Oncology (ASCO) panel for treating 
chemotherapy-induced diarrhea are abstracted below (44). 
Pharmacological approaches include the following: 
x Loperamide administered as an initial 4-mg dose followed by 2-mg doses every 4 hours.  
This dose and regimen are moderately effective. 


 
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50 
x Clonidine, nonsteroidal anti-inflammatory drugs, and the serotonin antagonist 
cryoheptadine have been shown to be effective in controlling diarrhea associated with 
inflammation of the bowel. 
The synthetic octapeptide octreotide has been shown to be effective in the control of 
diarrhea induced by fluoropyrimidine-based chemotherapy regimens when administered as 
an escalating dose by continuous infusion or subcutaneous injection.  Octreotide can be 
administered at doses ranging from 100 micrograms twice daily to 500 micrograms 3 times 
daily, with a maximum-tolerated dose of 2000 micrograms 3 times daily in a 5-day regimen. 
13.8 Pregnancy 
Should a pregnancy occur, it must be reported in accordance with the following procedures: 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the trial treatment 
under investigation may have interfered with the effectiveness of a contraceptive 
medication.  However, the outcome of all pregnancies (spontaneous miscarriage, elective 
termination, normal birth or congenital abnormality) must be followed up and documented, 
even if the patient was discontinued from the trial. 
All reports of congenital abnormalities or birth defects are SAEs.  Spontaneous miscarriages 
should also be reported and handled as SAEs.  Elective abortions without complications 
should not be handled as AEs.  All outcomes of pregnancy must be reported to AstraZeneca 
on the pregnancy outcomes report form. 
13.9 Reporting of Serious Adverse Events 
Federal and Manufacturer Reporting Guidelines 
Investigators and other site personnel must inform the FDA, via a Medwatch form, of any 
SAE that occurs during the course of the study.  The PI must also fax a copy of the 
Medwatch report to AstraZeneca at the time the event is reported to the FDA.  It is the 
responsibility of the investigator to compile all necessary information and ensure that the 
FDA receives a report according to the FDA reporting requirement timelines and to ensure 
that these reports are also submitted to AstraZeneca at the same time. 
 
Send by way of fax to: 302-886-7483 
Attention:  IRESSA£ IIT Safety Representative 
 
Follow-up information on SAEs must also be reported by the investigator to AstraZeneca 
and the FDA within the same time frames. 
 
If a non-serious AE becomes serious, this and other relevant follow-up information must 
DOVREHSURYLGHGWR$VWUD=HQHFDDQGWKH)'$ZLWKLQWKH)'$¶VUHJXODWRU\WLPHOLQHV 
 


 
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51 
All SAEs have to be reported to AstraZeneca, whether or not considered causally 
related to the investigational product.  All SAEs will be documented.  The investigator 
is responsible for informing the IRB and/or the Regulatory Authority of the SAE as 
per local requirements. 
13.9.1 University of Chicago Reporting Guidelines 
Participating institutions must report serious adverse events to their own IRBs and the 
Cancer Clinical Trials Office (CCTO) at the University of Chicago who will in turn submit 
AE reports to the protocol chair for review.  These AE reports will then be submitted to the 
University of Chicago IRB and circulated to all participating institutions.  A copy will be 
forwarded to the appropriate research nurse. 
 
Within 24 hours of knowledge of Serious Adverse Event 
If the reaction requires reporting, it should be called to the CCTO (773-834-0357) within 24 
hours (or next business day) when the investigator/research study nurse becomes aware of the 
event.   
The following information is required when calling in the event: 
x Name and Telephone Number of Reporter 
x Patient Initials 
x Patient Medical Record Number 
x IRB Protocol Number 
x PI of Study 
x Treating Physician 
x Date of Event 
x Description of Event (including grade of the event and if the event 
required hospitalization) 
 
An email will be sent to the research nurse, treating physician and PI of the study informing 
that the SAE notification has been received. 
Within 5 working days of knowledge of Serious Adverse Event 
A completed MedWatch must be sent to the CCTO (fax number (773) 702-8855) within 5 
working days of event occurrence.  If the event occurred at the University of Chicago, the 
8QLYHUVLW\ RI &KLFDJR¶V ,5% $GYHUVH (YHQW )RUP PXVW DOVR EH ILOOHG RXW  7KH 8& ,5%
Serious 
and 
Unexpected 
Adverse 
Event 
form 
is 
available 
on-line 
at: 
HTTP://ORS/IRB/AESERIOUS.PDF. The UC IRB Fatal/Life-Threatening Event form is 
available on-line at: HTTP://ORS/IRB/AEFATAL.PDF..  This form must be typed. Once the 


 
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52 
forms are completed, the PI will then UHYLHZVLJQDQGSODFHIROGHULQWKH4$FRRUGLQDWRU¶V
box. 
Once the appropriate SAE documents have been received, the CCTO will submit these to the 
IRB and a copy will be forwarded to the appropriate research nurse.  Copies will also be sent 
to participating institutions. 
 
13.10 Handling Unresolved SAEs and AEs at Completion or Withdrawal 
All trial treatment-related toxicities and SAEs must be followed until resolution, unless, in 
WKH LQYHVWLJDWRU¶V RSLQLRQ WKH FRQGLWLRQ LV XQOLNHO\ WR UHVROYH EHFDXVH RI WKH SDWLHQW¶V
underlying disease. 
13.11 Data Safety and Monitoring 
Data Safety and Monitoring will occur at the weekly University of Chicago section 
meetings, which are lead by senior level medical oncologists.  At each meeting, all active 
studies will be reviewed for safety and progress toward completion. Toxicities and adverse 
events will be reviewed at each meeting and a Data Safety and Monitoring form will be 
completed for each protocol and signed by either the principal investigator, the chairman of 
the section or by his designate if the chairman is not available. 
14 STATISTICAL CONSIDERATIONS 
14.1 Study Design and Primary Endpoints 
A comprehensive statistical analysis plan (SAP) will be produced prior to locking of the 
database.   
The primary objective of this study is to test whether the new treatment regimen with 
ZD1839 is at least as effective as previous standard regimen, which has complete response 
rate of 80%.  The study will be conducted as a single arm, two-stage, non-inferiority phase II 
trial.  The primary endpoint for this study is the complete response rate achieved 1 month 
after chemoradiotherapy.  A two-stage design will be used to explore the activity of ZD1839 
added to concurrent chemoradiotherapy.  A sample size of 59 patients will be sufficient to 
detect a 15% lower response rate than standard treatment.   
During the first stage, 25 patients will be recruited, and the study will be terminateGLI
complete responses are observed after completing chemoradiotherapy among those 
evaluable.  Otherwise an additional 34 patients will be recruited for a total of 59 patients 
overall.  If 45 or more responses are observed at the end of the study, we shall conclude the 
new treatment is not inferior to the standard treatment.  


 
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53 
14.2 Sample Size Determination 
With a total sample size of 59 in this design, the probability of falsely rejecting the null 
hypothesis is at most 0.05 (one-sided alpha=0.05) and the probability of correctly rejecting 
the null hypothesis if the alternative hypothesis is true is at least 0.80 (power = 80%).  In 
addition, the false negative rate in the first stage is less than 0.05.  
 
14.3 Accrual Rate and Study Duration 
To account for patients with non-measurable disease an inflation factor of 10% will be 
applied to the sample size, resulting in a total of 65 patients to be accrued.  It is anticipated 
that 3 ± 4 patients per month can be accrued, for a total accrual period of 18 months.  
Response assessment and correlative marker analysis will proceed upon completion of the 
regimen by all patients (approximately 4 ± 6 weeks after the last patient is enrolled). 
Subsequent to these analyses, follow-up to obtain TTP, time to site-specific failure, and total 
survival will continue.  Minimum follow-up of 12 months will be required to provide 
adequate precision for estimates of time-to-event endpoints.  Follow-up will be maintained 
for the remainder of patients' lifetimes to obtain further information on long-term disease 
course and mortality. 
14.4 Evaluation of Response and Cohorts to be Analyzed 
All patients included in the study will be assessed for response to treatment, even if there are 
major protocol treatment deviations or if they are ineligible (intent-to-treat population).  
Criteria described in Appendix A will be used to assign each patient to one of the following 
response categories: 1) complete response, 2) partial response, 3) stable disease, 
4) progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) 
early death because of other cause, or 9) unknown (not assessable, insufficient data). 
All patients who have met the eligibility criteria will be included in the main analysis of the 
response rate.  Patients in response categories 4 ± 9 will be considered as failing to respond 
to treatment (disease progression).  Thus, an incorrect treatment schedule or drug 
administration will not result in exclusion from the analysis of the response rate. 
14.5 Analytic Methods 
14.5.1 Primary Analyses 
Primary analysis of response will consist of estimation of complete response as 
described in section 12.3.  Exact confidence limits on response rate will be computed 
with the use of the binomial distribution. 


 
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54 
14.5.2 Secondary Endpoints and Analyses 
Overall survival and progression-free survival (PFS) will be calculated using the 
Kaplan-Meier estimator.  Median survival times and their associated 95% confidence 
intervals will also be calculated.  Patient and disease characteristics prior to treatment as 
well as surgical intervention will be evaluated as potential prognostic factors using Cox 
proportional hazards models.  In addition to the overall analyses we will stratify by 
whether patients received surgery or not and evaluate the extent to which the addition of 
surgery affects outcomes and quality of life (see below). 
All observed toxicities will be recorded and summarized using appropriate descriptive 
statistics including mean, standard deviation, median, range and frequency counts. 
Descriptive statistics will be compiled for assessments of QoL and performance 
outcomes at pre-therapy, after induction therapy, and several points after 
chemoradiotherapy as described in section 6.5.  Patterns of change over time in QoL 
subscale scores and performance assessments will be evaluated using paired and 
longitudinal data analysis methods. 
Performance data will be used to classify patient status at some fixed follow-up time 
(e.g., six months or one year post therapy) into binary outcome categories, such as 
ability to eat solid foods (yes/no).  Logistic regression modeling will be used to identify 
factors predictive of these outcomes. 
A certain degree of patient attrition from the QoL study, due to patient mortality and 
other factors, is assumed.  Characteristics of individuals with missing data will be 
evaluated to identify imbalance in baseline characteristics.  In the absence of apparent 
systematic loss, data will be analyzed assuming that the observations are missing at 
random.  In the case of evidence for systematic patterns of missing data ("informative" 
missingness), alternative strategies for analyzing such data, depending on the pattern 
will be investigated. 
Adverse events will be summarized using counts and proportions, in order to determine 
the tolerability of the treatment combination. 
14.5.3 Analysis of Exploratory endpoints 
Molecular correlative markers, including p-ERK, p-AKT, ERK, AKT, EGFR, p-EGFR, 
genotyping, plasma VEGF, and serum PAI-1 will be analyzed using simple paired data 
methods (paired t-test or Wilcoxon signed-rank test, as appropriate) for changes 
between pre-therapy and during chemoradiotherapy (when applicable).  Logistic 
regression will be used to determine if those patients showing marker changes 
indicative of ZD1839 activity experience superior clinical response. 


 
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55 
15 TRIAL MANAGEMENT 
15.1 Procedures In Case of Medical Emergency 
The principal investigator(s) is responsible for ensuring that procedures and expertise are 
available to handle medical emergencies during the study. 
15.2 Audits and Inspections 
Authorized representatives of AstraZeneca, a regulatory authority, or an IRB may visit the 
center to perform audits or inspections, including source data verification.  The purpose of 
an AstraZeneca audit or inspection is to examine all trial related activities and documents 
systematically and independently to determine whether these activities were conducted, and 
data were recorded, analyzed, and accurately reported according to the protocol, Good 
Clinical Practice (GCP), and any applicable regulatory requirements.  The investigator 
should contact AstraZeneca immediately if contacted by a regulatory agency about an 
inspection at his or her center. 
15.3 Changes to the Protocol 
If it is necessary for the trial protocol to be amended, the amendment or a new version of the 
trial protocol must be reported to and approved by the IRB.  If a protocol amendment 
UHTXLUHVDFKDQJHWRDSDUWLFXODUFHQWHU¶V:ULWWHQ,QIRUPHG&RQVHQW)RUPWKHQWKH,5%PXVW 
be notified.  Approval of the revised Written Informed Consent Form by the IRB is required 
before the revised form is used. 
AstraZeneca's willingness to supply study drug is predicated upon the review of the 
protocol.   The investigator agrees to provide prior written notice to AstraZeneca of any 
modifications to the protocol or informed consent form.    
15.4 Ethics 
The principal investigator(s) is also responsible for providing the IRB with reports of any 
SAEs from any other trial conducted with the investigational product.   
15.5 Ethical Conduct of the Trial 
The trial will be performed in accordance with GCP. 
15.6 Procedures in Case of Overdose 
There is currently no known antidote for ZD1839.  The treatment of AEs associated with 
overdose should be supportive and for the underlying adverse symptoms.  To date, no 
patient has experienced an overdose with ZD1839. 


 
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56 
Information on overdoses that do not result in AEs should be forwarded to AstraZeneca.  
This will then be reported to AstraZeneca Drug Safety in accordance with procedures 
defined for non-SAEs. 


 
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57 
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Appendix A 
Objective tumor response criteria (RECIST) 
 


 
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1 
INTRODUCTION  
The introduction explores the definitions, assumptions, and purposes of tumor response 
criteria.  Below, guidelines that are offered may lead to more uniform reporting of 
outcomes of clinical trials.  Note that, although single investigational agents are discussed, 
the principles are the same for drug combinations, non-investigational agents, or 
approaches that do not involve drugs.  
Tumor response associated with the administration of anticancer agents can be evaluated 
for at least three important purposes that are conceptually distinct:  
x Tumor response as a prospective end point in early clinical trials.  In this situation, 
objective tumor response is employed to determine whether the agent/regimen 
demonstrates sufficiently encouraging results to warrant further testing.  These trials 
are typically phase II trials of investigational agents/regimens (see appendix 
section 1.2), and it is for use in this precise context that these guidelines have been 
developed.  
x Tumor response as a prospective end point in more definitive clinical trials designed to 
provide an estimate of benefit for a specific cohort of patients. These trials are often 
randomized comparative trials or single-arm comparisons of combinations of agents 
with historical control subjects.  In this setting, objective tumor response is used as a 
surrogate end point for other measures of clinical benefit, including time-to-event 
(death or disease progression) and symptom control (see appendix section 1.3).  
x Tumor response as a guide for the clinician and patient or study subject in decisions 
about continuation of current therapy.  This purpose is applicable both to clinical trials 
and to routine practice (see appendix section 1.1), but use in the context of decisions 
regarding continuation of therapy is not the primary focus of this document.  
However, in day-to-day usage, the distinction among these uses of the term "tumor 
response" can easily be missed, unless an effort is made to be explicit.  When these 
differences are ignored, inappropriate methodology may be used and incorrect conclusions 
may result.  
1.1 
Response Outcomes in Daily Clinical Practice of Oncology  
The evaluation of tumor response in the daily clinical practice of oncology may not be 
performed according to predefined criteria.  It may, rather, be based on a subjective 
medical judgment that results from clinical and laboratory data that are used to assess the 
treatment benefit for the patient.  The defined criteria developed further in this document 
are not necessarily applicable or complete in such a context.  It might be appropriate to 


 
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make a distinction between "clinical improvement" and "objective tumor response" in 
routine patient management outside the context of a clinical trial.  
1.2 
Response Outcomes in Uncontrolled Trials as a Guide to Further Testing of a 
New Therapy  
"Observed response rate" is often employed in single-arm studies as a "screen" for new 
anticancer agents that warrant further testing.  Related outcomes, such as response 
duration or proportion of patients with complete responses, are sometimes employed in a 
similar fashion.  The use of a response rate in this way is not encumbered by an implied 
assumption about the therapeutic benefit of such responses but rather implies some degree 
of biologic antitumor activity of the investigated agent.  
For certain types of agents (i.e., cytotoxic drugs and hormones), experience has 
demonstrated that objective antitumor response observed at a rate higher than would have 
been expected to occur spontaneously can be useful in selecting anticancer agents for 
further study.  Some agents selected in this way have eventually proven to be clinically 
useful.  Furthermore, criteria for "screening" new agents in this way can be modified by 
accumulated experience and eventually validated in terms of the efficiency by which agents 
so screened are shown to be of clinical value by later, more definitive, trials.  
In most circumstances, however, a new agent achieving a response rate determined a 
priori to be sufficiently interesting to warrant further testing may not prove to be an 
effective treatment for the studied disease in subsequent randomized phase III trials.  
Random variables and selection biases, both known and unknown, can have an 
overwhelming effect in small, uncontrolled trials.  These trials are an efficient and 
economic step for initial evaluation of the activity of a new agent or combination in a given 
disease setting.  However, many such trials are performed, and the proportion that will 
provide false-positive results is necessarily substantial.  In many circumstances, it would be 
appropriate to perform a second small confirmatory trial before initiating large resource-
intensive phase III trials.  
Sometimes, several new therapeutic approaches are studied in a randomized phase II trial.  
The purpose of randomization in this setting, as in phase III studies, is to minimize the 
impact of random imbalances in prognostic variables.  However, randomized phase II 
studies are, by definition, not intended to provide an adequately powered comparison 
between arms (regimens).  Rather, the goal is simply to identify one or more arms for 
further testing, and the sample size is chosen so to provide reasonable confidence that a 
truly inferior arm is not likely to be selected.  Therefore, reporting the results of such 
randomized phase II trials should not imply statistical comparisons between treatment 
arms.  
 


 
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1.3 
Response Outcomes in Clinical Trials as a Surrogate for Palliative Effect  
1.3.1 Use in Nonrandomized Clinical Trials  
The only circumstance in which objective responses in a nonrandomized trial can permit a 
tentative assumption of a palliative effect (i.e., beyond a purely clinical measure of benefit) 
is when there is an actual or implied comparison with historical series of similar patients.  
This assumption is strongest when the prospectively determined statistical analysis plan 
provides for matching of relevant prognostic variables between case subjects and a defined 
series of control subjects.  Otherwise, there must be, at the very least, prospectively 
determined statistical criteria that provide a very strong justification for assumptions about 
the response rate that would have been expected in the appropriate "control" population 
(untreated or treated with conventional therapy, as fits the clinical setting).  However, even 
under these circumstances, a high rate of observed objective response does not constitute 
proof or confirmation of clinical therapeutic benefit.  Because of unavoidable and 
nonquantifiable biases inherent in nonrandomized trials, proof of benefit still requires 
eventual confirmation in a prospectively randomized, controlled trial of adequate size.  The 
appropriate end points of therapeutic benefit for such a trial are survival, progression-free 
survival, or symptom control (including quality of life).  
1.3.2 Use in Randomized Trials  
Even in the context of prospectively randomized phase III comparative trials, "observed 
response rate" should not be the sole, or major, end point.  The trial should be large 
enough that differences in response rate can be validated by association with more 
definitive end points reflecting therapeutic benefit, such as survival, progression-free 
survival, reduction in symptoms, or improvement (or maintenance) of quality of life.  
2 
MEASURABILITY OF TUMOR LESIONS AT BASELINE  
2.1 
Definitions  
At baseline, tumor lesions will be categorized as follows: measurable (lesions that can be 
accurately measured in at least one dimension [longest diameter to be recorded] as >20 mm 
with conventional techniques or as >10 mm with spiral CT scan [see appendix section 
2.2]) or nonmeasurable (all other lesions, including small lesions [longest diameter < 20 
mm with conventional techniques or < 10 mm with spiral CT scan] and truly 
nonmeasurable lesions).  
The term "evaluable" in reference to measurability is not recommended and will not be 
used because it does not provide additional meaning or accuracy.  


 
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All measurements should be recorded in metric notation by use of 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 treatment.  
Lesions considered to be truly nonmeasurable include the following: bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast disease, 
lymphangitis cutis/pulmonis, abdominal masses that are not confirmed and followed by 
imaging techniques, and cystic lesions.  
(Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable, and the conditions under which such lesions should be considered 
must be defined in the protocol when appropriate.)  
2.2 
Specifications by Methods of Measurements  
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 when both methods have been 
used to assess the antitumor effect of a treatment.  
2.2.1 Clinical Examination  
Clinically detected lesions will be considered measurable only when they are superficial 
(e.g., skin nodules and palpable lymph nodes).  For the case of skin lesions, documentation 
by color photography ² including a ruler to estimate the size of the lesion ² is 
recommended.  
2.2.2 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.  
2.2.3 CT and MRI  
CT and MRI are the best currently available and most reproducible methods for measuring 
target lesions selected for response assessment.  Conventional CT and MRI should be 
performed with contiguous cuts of 10 mm or less in slice thickness.  Spiral CT should be 
performed by use of a 5-mm contiguous reconstruction algorithm.  This specification 
applies to the tumors of the chest, abdomen, and pelvis, while head and neck tumors and 
those of the extremities usually require specific protocols.  


 
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2.2.4 Ultrasound  
When the primary end point of the study is objective response evaluation, ultrasound 
should not be used to measure tumor lesions that are clinically not easily accessible.  It may 
be used as a possible alternative to clinical measurements for superficial palpable lymph 
nodes, subcutaneous lesions, and thyroid nodules.  Ultrasound might also be useful to 
confirm the complete disappearance of superficial lesions usually assessed by clinical 
examination.  
2.2.5 Endoscopy and Laparoscopy  
The utilization of these techniques for objective tumor evaluation has not yet been fully or 
widely validated.  Their uses in this specific context require sophisticated equipment and a 
high level of expertise that may be available only in some centers.  Therefore, utilization of 
such techniques for objective tumor response should be restricted to validation purposes in 
specialized centers.  However, such techniques can be useful in confirming complete 
histopathologic response when biopsy specimens are obtained.  
2.2.6 Tumor Markers  
Tumor markers alone cannot be used to assess response.  However, if markers are initially 
above the upper normal limit, they must return to normal levels for a patient to be 
considered in complete clinical response when all tumor lesions have disappeared.  
Specific additional criteria for standardized usage of prostate-specific antigen and CA 
(cancer antigen) 125 response in support of clinical trials are being validated.  
2.2.7 Cytology and Histology  
Cytologic and histologic techniques can be used to differentiate between partial response 
and complete response in rare cases (e.g., after treatment to differentiate between residual 
benign lesions and residual malignant lesions in tumor types such as germ cell tumors).  
Cytologic confirmation of the neoplastic nature of any effusion that appears or worsens 
during treatment is required when the measurable tumor has met criteria for response or 
stable disease.  Under such circumstances, the cytologic examination of the fluid collected 
will permit differentiation between response or stable disease (an effusion may be a side 
effect of the treatment) and progressive disease (if the neoplastic origin of the fluid is 
confirmed).  New techniques to better establish objective tumor response will be 
integrated into these criteria when they are fully validated to be used in the context of 
tumor response evaluation.  


 
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3 
TUMOR RESPONSE EVALUATION  
3.1 
Baseline Evaluation  
3.1.1 Assessment of Overall Tumor Burden and Measurable Disease  
To assess objective response, it is necessary to estimate the overall tumor burden at 
baseline to which subsequent measurements will be compared.  Only patients with 
measurable disease at baseline should be included in protocols where objective tumor 
response is the primary end point.  Measurable disease is defined by the presence of at 
least one measurable lesion (as defined in appendix section 2.1).  If the measurable disease 
is restricted to a solitary lesion, its neoplastic nature should be confirmed by 
cytology/histology.  
3.1.2 Baseline Documentation of "Target" and "Nontarget" Lesions  
All measurable lesions up to a maximum of five lesions per organ and 10 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 
(those with the longest diameter) and their suitability for accurate repeated measurements 
(either by imaging techniques or clinically).  A sum of the longest diameter for all target 
lesions will be calculated and reported as the baseline sum longest diameter.  The baseline 
sum longest diameter will be used as the reference by which to characterize the objective 
tumor response.  
All other lesions (or sites of disease) should be identified as nontarget lesions and should 
also be recorded at baseline.  Measurements of these lesions are not required, but the 
presence or absence of each should be noted throughout follow-up.  
3.2 
Response Criteria  
3.2.1 Evaluation of Target Lesions  
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions.  The criteria have been adapted from the original WHO 
Handbook, taking into account the measurement of the longest diameter only for all target 
lesions: complete response ² the disappearance of all target lesions; partial response ² 
at least a 30% decrease in the sum of the longest diameter of target lesions, taking as 
reference the baseline sum longest diameter; progressive disease ² at least a 20% increase 
in the sum of the longest diameter of target lesions, taking as reference the smallest sum 
longest diameter recorded since the treatment started or the appearance of one or more new 
lesions; stable disease ² neither sufficient shrinkage to qualify for partial response nor 


 
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sufficient increase to qualify for progressive disease, taking as reference the smallest sum 
longest diameter since the treatment started.  
3.2.2 Evaluation of Nontarget Lesions  
This section provides the definitions of the criteria used to determine the objective tumor 
response for nontarget lesions: complete response ² the disappearance of all nontarget 
lesions and normalization of tumor marker level; incomplete response/stable disease ² 
the persistence of one or more nontarget lesion(s) and/or the maintenance of tumor marker 
level above the normal limits; and progressive disease ² the appearance of one or more 
new lesions and/or unequivocal progression of existing nontarget lesions.  
(Note: Although a clear progression of "nontarget" lesions only is exceptional, in such 
circumstances, the opinion of the treating physician should prevail and the progression 
status should be confirmed later by the review panel [or study chair]).  
3.2.3 Evaluation of Best Overall Response  
The best overall response is the best response recorded from the start of treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  In general, the patient's best response 
assignment will depend on the achievement of both measurement and confirmation 
criteria (see appendix section 3.3.1).  Appendix Table 1 provides overall responses for all 
possible combinations of tumor responses in target and nontarget lesions with or without 
the appearance of new lesions.  
(Notes:  
x Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
classified as having "symptomatic deterioration."  Every effort should be made to 
document the objective disease progression, even after discontinuation of treatment.  
x Conditions that may define early progression, early death, and inevaluability are study 
specific and should be clearly defined in each protocol (depending on treatment 
duration and treatment periodicity).  
x In some circumstances, it may be difficult to distinguish residual disease from normal 
tissue.  When the evaluation of complete response depends on this determination, it is 
recommended that the residual lesion be investigated (fine-needle aspiration/biopsy) 
before confirming the complete response status.).  
 


 
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3.2.4 Frequency of Tumor Re-evaluation  
Frequency of tumor re-evaluation while on treatment should be protocol specific and 
adapted to the type and schedule of treatment.  However, in the context of phase II studies 
where the beneficial effect of therapy is not known, follow-up of every other cycle (i.e., 
6 to 8 weeks) seems a reasonable norm.  Smaller or greater time intervals than these could 
be justified in specific regimens or circumstances.  
After the end of the treatment, the need for repetitive tumor evaluations depends on 
whether the phase II trial has, as a goal, the response rate or the time-to an event (disease 
progression/death).  If time to an event is the main end point of the study, then routine re-
evaluation is warranted of those patients who went off the study for reasons other than the 
expected event at frequencies to be determined by the protocol.  Intervals between 
evaluations twice as long as on study are often used, but no strict rule can be made.  
Appendix Table 1  Overall responses for all possible combinations of tumor responses 
in target and nontarget lesions with or without the appearance of new lesions 
Target lesions 
Nontarget lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Incomplete response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease.   
See text for more details. 
 
3.3 
Confirmatory Measurement/Duration of Response  
3.3.1 Confirmation  
The main goal of confirmation of objective response in clinical trials is to avoid 
overestimating the response rate observed.  This aspect of response evaluation is 
particularly important in nonrandomized trials where response is the primary end point.  In 
this setting, to be assigned a status of partial response or complete response, changes in 


 
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tumor measurements must be confirmed by repeat assessments that should be performed 
no less than 4 weeks after the criteria for response are first met.  Longer intervals as 
determined by the study protocol may also be appropriate.  
In the case of stable disease, measurements must have met the stable disease criteria at 
least once after study entry at a minimum interval (in general, not less than 6 to 8 weeks) 
that is defined in the study protocol (see appendix section 3.3.3).  
(Note: Repeat studies to confirm changes in tumor size may not always be feasible or may 
not be part of the standard practice in protocols where progression-free survival and overall 
survival are the key end points.  In such cases, patients will not have "confirmed 
response."  This distinction should be made clear when reporting the outcome of such 
studies.)  
3.3.2 Duration of Overall Response  
The duration of overall response is measured from the time that measurement criteria are 
met for complete response or partial response (whichever status is recorded first) 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 complete response is measured from the time 
measurement criteria are first met for complete response until the first date that recurrent 
disease is objectively documented.  
3.3.3 Duration of Stable Disease  
Stable disease is measured from the start of the treatment until the criteria for disease 
progression are met (taking as reference the smallest measurements recorded since the 
treatment started).  The clinical relevance of the duration of stable disease varies for 
different tumor types and grades.  Therefore, it is highly recommended that the protocol 
specify the minimal time interval required between two measurements for determination of 
stable disease.  This time interval should take into account the expected clinical benefit that 
such a status may bring to the population under study.  
(Note: The duration of response or stable disease as well as the progression-free survival 
are influenced by the frequency of follow-up after baseline evaluation.  It is not in the 
scope of this guideline to define a standard follow-up frequency that should take into 
account many parameters, including disease types and stages, treatment periodicity, and 
standard practice.  However, these limitations to the precision of the measured end point 
should be taken into account if comparisons among trials are to be made.)  
 


 
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3.4 
Progression-free Survival/Time to Progression  
This document focuses primarily on the use of objective response end points.  In some 
circumstances (e.g., brain tumors or investigation of noncytoreductive anticancer agents), 
response evaluation may not be the optimal method to assess the potential anticancer 
activity of new agents/regimens.  In such cases, progression-free survival/time to 
progression (PFS/TTP) can be considered valuable alternatives to provide an initial 
estimate of biologic effect of new agents that may work by a noncytotoxic mechanism.  It 
is clear though that, in an uncontrolled trial proposing to utilize progression-free 
survival/time to progression, it will be necessary to document with care the basis for 
estimating what magnitude of progression-free survival/time to progression would be 
expected in the absence of a treatment effect.  It is also recommended that the analysis be 
quite conservative in recognition of the likelihood of confounding biases, e.g., with regard 
to selection and ascertainment.  Uncontrolled trials using progression-free survival or time 
to progression as a primary end point should be considered on a case-by-case basis, and the 
methodology to be applied should be thoroughly described in the protocol.  
4 
RESPONSE REVIEW  
For trials where the response rate is the primary end point, it is strongly recommended that 
all responses be reviewed by an expert or experts independent of the study at the study's 
completion.  Simultaneous review of the patients' files and radiologic images is the best 
approach.  
(Note: When a review of the radiologic images is to take place, it is also recommended that 
images be free of marks that might obscure the lesions or bias the evaluation of the 
reviewer[s]).  
5 
REPORTING OF RESULTS  
All patients included in the study must be assessed for response to treatment, even if there 
are major protocol treatment deviations or if they are ineligible.  Each patient will be 
assigned one of the following categories: 1) complete response, 2) partial response, 
3) stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early 
death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data). (Note: By arbitrary convention, category 9 usually designates the 
"unknown" status of any type of data in a clinical database.)  
All of the patients who met the eligibility criteria should be included in the main analysis 
of the response rate.  Patients in response categories 4 ± 9 should be considered as failing 
to respond to treatment (disease progression). Thus, an incorrect treatment schedule or 
drug administration does not result in exclusion from the analysis of the response rate. 
Precise definitions for categories 4 ± 9 will be protocol specific.  


 
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All conclusions should be based on all eligible patients.  
Subanalyses may then be performed on the basis of a subset of patients, excluding those 
for whom major protocol deviations have been identified (e.g., early death due to other 
reasons, early discontinuation of treatment, major protocol violations).  However, these 
subanalyses may not serve as the basis for drawing conclusions concerning treatment 
efficacy, and the reasons for excluding patients from the analysis should be clearly 
reported.  The 95% confidence intervals should be provided.  
6 
RESPONSE EVALUATION IN RANDOMIZED PHASE III TRIALS  
Response evaluation in phase III trials may be an indicator of the relative antitumor 
activity of the treatments evaluated but may usually not solely predict the real therapeutic 
benefit for the population studied.  If objective response is selected as a primary end point 
for a phase III study (only in circumstances where a direct relationship between objective 
tumor response and a real therapeutic benefit can be unambiguously demonstrated for the 
population studied), the same criteria as those applicable to phase II trials (RECIST 
guidelines) should be used.  
On the other hand, some of the guidelines presented in this special article might not be 
required in trials, such as phase III trials in which objective response is not the primary 
end point.  For example, in such trials, it might not be necessary to measure as many as 
10 target lesions or to confirm response with a follow-up assessment after 4 weeks or 
more.  Protocols should be written clearly with respect to planned response evaluation and 
whether confirmation is required so as to avoid post-hoc decisions affecting patient 
evaluability.


 
AZ1839US/0212 
March 7, 2006 
 
73 
 
Appendix B 
Forms to accompany laboratory samples 
 


 
 
 
 
The University of Chicago 
Tissue and Blood Sample Collection Form 
Clinician/Research Nurse: Please Fill Out 
Tissue Samples 
Patient Name or Initials: ____________________ UC MR # (if applicable): ____________ 
Patient Protocol ID #: 12019- ________________  Date Tissue Obtained: ______________ 
Institution: ______________________________ 
Attending Physician: _______________ 
Site of Biopsy: ___________________________ 
Site of Primary Tumor: ______________ 
Pre/Post Therapy  (Please circle) 
Did Surgical Pathology receive tissue for diagnosis?  Yes   No 
&RQWDFW3HUVRQ¶V3KRQH Number and email address at Affiliate:  
Blood Samples 
 
 
date drawn 
time 
date shipped 
  
Pre-Therapy:   
2 green top/plasma   
  
  
(batched on dry ice) 
  
1 purple top/DNA 
  
  
  
(fresh on ice pack) 
Post-Induction:  2 green top/plasma   
  
  
(batched on dry ice) 
Cycle 2 Day 1: 
2 green top/plasma   
  
  
(batched on dry ice) 
Post-Chemo: 
2 green top/plasma   
  
  
(batched on dry ice) 
Researcher: Please Fill Out 
Date Samples received: _________________ 
 
Data entered into Database: Yes 
No 
Name of Data Manager informed: _______________________ 
Date Informed:_________ 
Location in ±80C freezer UC 0   -  
Approximate size and number of tissue: ____________________________________________ 
Notes: 
 
 
Questions or Problems? Please contact: 
Dr. Rifat Hasina, University of Chicago, 5841 S Maryland, MC 3083, Chicago, IL 60637 
Phone 773-834-9814 or 773-702-0119, Pager 773-753-1880-9747 email: rhasina@bsd.uchicago.edu 
Protocol 12019  


 
 
 
SHIPPING DIRECTIONS 
 
All shipments must contain a completed Sample Identification form.  
 
Prior to shipment please email both of the following persons the FedEX bill number: 
 
Rifat Hasina: RHASINA@BSD.UCHICAGO.EDU 
Shannon Delaney: SDELANEY@MEDICINE.BSD.UCHICAGO.EDU 
 
Tissue Samples need to be shipped on dry ice; may be batched at institution and shipped with Plasma 
samples to the below address: 
 
Dr. Rifat Hasina 
c/o Dr. Mark Lingen 
University of Chicago 
FMI Dock/Lab Supply 
5830 S. Ellis Ave 
Room G-02 
Chicago, IL 60637 
Phone: 773-834-9814 
 
 
 
 
 
 
 
 
Plasma Sample need to be shipped on dry ice; may be batched at institution and shipped with Tissue 
Samples to: 
 
Dr. Rifat Hasina 
c/o Dr. Mark Lingen 
University of Chicago 
FMI Dock/Lab Supply 
5830 S. Ellis Ave 
Room G-02 
Chicago, IL 60637 
Phone: 773-834-9814 
 
*Purple Tubes for DNA need to be sent on ice packs overnight to: 
 
 
 
Dr. Rifat Hasina 
c/o Dr. Mark Lingen 
University of Chicago 
FMI Dock/Lab Supply 
5830 S. Ellis Ave 
Room G-02 
Chicago, IL 60637 
Phone: 773-834-9814 
 
* Please draw purple tubes on Monday, Tuesday or Wednesday only.