Phase II Study of Docetaxel and Capecitabine in Advanced Squamous Cell Carcinoma of the Head and Neck
Phase: PHASE2
Conditions: Head and Neck Squamous Cell Carcinoma
Sponsor: University of Nebraska

 
IRB#762-14 Version 6.2 dated 01Jul2021 
 
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Phase II Study of Docetaxel and Capecitabine in  
Advanced Squamous Cell Carcinoma of the Head and Neck 
 
Principal Investigator:  
Apar Kishor Ganti, MD 
 
 
 
 
Professor, University of Nebraska Medical Center  
 
 
 
 
986840 Nebraska Medical Center 
 
 
 
 
 
Omaha, NE 68198-6840 
 
Secondary Investigators:  
 
Rabih C Fahed, MD -  
Faith Regional Carson Cancer Center, Norfolk; rabih1977@hotmail.com 
Irina E. Popa, MD -  
Faith Regional Carson Cancer Center, Norfolk; ipopa@frhs.org 
 
 
Participating Sites:  
 
        University of Nebraska Medical Center 
        Faith Regional Carson Cancer Center, Norfolk, NE 
       Omaha VA Medical Center, NE 
         
 
 
 
Statistician: 
 
 
Lynette Smith, PhD 
 
 
 
 
 
 
UNMC Investigator Initiated Project (No Sponsor) IND # 125689 Exempt  
 
National Library of Medicine - http://clinicaltrials.gov (NCT02524275) 
National Cancer Institute - http://www.cancer.gov (NCI-2015-00587) 
 
IRB Approved Version/Version Date V3.0 dated 03-16-2015 
 
 
 
 
V4.0 dated 09-23-2015 
 
 
 
 
V5.0 dated 09-05-2017 
 
 
 
 
V6.0 dated 06-28-2018 
 
 
 
 
V6.1 dated 10-16-2019 
 
 
 
 
V6.2 dated 07-01-2021 
 
 
 

 
IRB#762-14 Version 6.2 dated 01Jul2021 
 
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Index 
 
Page  2 
Abstract 
 
Page  3 
Schema 
 
Page  4 
Section  1.0 
Objectives 
Page  4 
Section  2.0 
Introduction 
Page  4 
Section  3.0 
Eligibility Criteria 
Page  7 
Section  4.0 
Registration Procedures 
Page  9 
Section  5.0 
Research Design 
Page  11 
Section  6.0 
Measurement of Effect 
Page 20 
Section  7.0 
Study Parameters 
Page 23 
Section  8.0 
Drug Formulation and Procurement 
Page 24 
Section  9.0 
Toxicity Reporting Guidelines 
Page 25 
Section 10.0 
Statistical Considerations 
Page 30 
Section 11.0 
Records to Be Kept 
Page 33 
Section 12.0 
Subject Consent Form Statement 
Page 35 
Section 13.0 
References 
Page 36 
Section 14.0 
Data Forms 
Page 38 
APPENDIX A 
Performance status: Karnofsky score & ECOG 
Page 39 
APPENDIX B 
Eligibility Checklist 
Page 40 
APPENDIX C 
Body Surface Area Calculation 
Page 42 
APPENDIX D 
Oral Medication Adherence 
Page 43 
APPENDIX E 
NCI Common Toxicity Criteria V 4.0 
Page 46 
APPENDIX F 
Medwatch Form 
Page 46 
APPENDIX G 
EORTC QLQ-C30 (version 3) 
Page 47 
APPENDIX H 
QLQ-HN35 
Page 49 
APPENDIX I 
Schedule of HBM Sample Assessments 
Page 51 
 
 

 
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ABSTRACT  
 
Title: Phase II Study of Docetaxel and Capecitabine in Advanced Squamous Cell 
Carcinoma of the Head and Neck 
 
Objectives: To assess the safety and efficacy of the combination of docetaxel and capecitabine 
in subjects with advanced squamous cell carcinoma of the head and neck who are not 
candidates for surgery or radiation therapy. 
 
Eligibility: Subjects with histologically proven squamous cell carcinoma of the head and neck 
with measurable disease that is either recurrent after attempted cure with surgery and/or 
radiation therapy or newly diagnosed disease with distant metastases or incurable at diagnosis 
are eligible. Subjects must not have received prior cytotoxic chemotherapy for metastatic 
squamous cell carcinoma of the head and neck. Subjects who have received chemotherapy as 
part of a multi-modality curative approach for head and neck cancer will be eligible as long as 
they have not received either medication (or 5-FU) as part of that regimen.  Subjects who have 
received single agent immune checkpoint inhibitors for metastatic head and neck squamous 
cell cancer will be eligible. 
 
Intervention: Subjects will receive study treatment with docetaxel 75 mg/m2 IV on day 1 in 
combination with oral capecitabine 800mg/m2 twice daily, from days 1-14 of a 3-week cycle. 
If there is no evidence of grade 2 or greater toxicity with capecitabine and if the doses of 
capecitabine are not held due to adverse effects after the first cycle, then the dose of 
capecitabine will be increased to 1000 mg/m2 twice daily for the remaining cycles. Treatment 
will be continued till progression or toxicity.   
 
Evaluation: Subjects will be evaluated every two cycles with imaging studies and clinical 
evaluation. Subjects with progressive disease will come off study. Subjects with stable or 
responding disease will continue on study with another evaluation at the end of every two 
cycles till progression.   
 
 

 
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SCHEMA: 
 
 
and  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.0  Objectives 
 
1. 
To evaluate in a Phase II study the efficacy (the radiographic assessment of disease 
status after 2 cycles of therapy) of a combination of docetaxel and capecitabine in 
subjects with advanced squamous cell carcinoma of the head and neck who are not 
candidates for surgery or radiation therapy. 
2. 
To evaluate the safety and toxicities of docetaxel and capecitabine in subjects with 
advanced squamous cell carcinoma of the head and neck. 
3. 
To descriptively examine the effects of the combination of docetaxel and capecitabine 
on the quality of life of subjects with advanced squamous cell carcinoma of the head 
and neck.  
  
2.0  Introduction 
 
Cancer of the head and neck refers to a collection of cancers, predominantly squamous cell 
carcinoma, arising from a variety of sites namely, the oral cavity, (lips, buccal mucosa, anterior 
tongue, floor of the mouth, hard palate, upper gingiva, and lower gingival), pharynx, larynx, 
nasal cavity and the paranasal sinuses (maxillary, ethmoid, sphenoid, and frontal sinuses) and 
major (paired parotids, submandibular, and sublingual) and minor salivary glands. There are 
approximately 600,000 cases of squamous cell carcinoma of the head and neck (SCCHN) 
diagnosed annually worldwide, of which approximately 52,000 cases are in the United States. 
It is estimated that in 2012 there will be 52,610 new cases of squamous cell carcinoma of the 
Screening for 
Eligibility 
Enrollment 
Cycle 1 
Docetaxel 75 
mg/m2 IV D1  
 
Capecitabine 
800mg/m2 
twice daily PO 
D1-14 
 
Pre-therapy 
blood, urine, 
and tissue 
Samples (Res) 
1week rest no 
evidence of 
grade >2 
capecitabine 
toxicity & no 
doses held due 
to adverse 
effects then 
increase 
capecitabine
Cycle 2 
Docetaxel 75 
mg/m2  IV D1  
 
Capecitabine 
1000mg/m2 
twice daily PO 
D1-14 
(remaining 
cycles) 
1 week rest 
CT scan 
Response/ 
Stable Disease 
Continue 
Docetaxel 75 
mg/m2  IV D1 
and established 
Capecitabine  
dose___mg/m2 
twice daily PO 
D1-14 every 2 
cycles 
 
After Cycle 2 
blood and urine 
Samples (Res) 
Progressive 
Disease  
Off Study 
 
End of study 
blood and urine 
Samples (Res) 
1 week rest 
evidence of 
grade >2 
capecitabine 
toxicity & 
doses held due 
to adverse 
effects then  
Doses that 
have been 
reduced may 
not be 
Cycle 2 
Docetaxel 75 
mg/m2 IV D1  
 
Capecitabine 
800mg/m2 or 
less twice daily 
PO D1-14 
(remaining 
cycles) 

 
IRB#762-14 Version 6.2 dated 01Jul2021 
 
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head and neck and 11,500 deaths from the disease1. Despite advances in diagnosis and 
treatment, there have been only small improvements 5-year survival rate for these cancers2.  
 
Patients who present with advanced stage, unresectable disease have a 5-year survival rate of 
30% as compared to 60-98% 5-year survival rates in patients who present with early stage 
disease3. With the recent advances in the management of locally advanced SCCHN, due to 
better loco-regional control, the proportion of patients with distant metastases appears to be 
increasing as compared to those with loco-regional relapse, i.e. reverse-failure pattern4,5. The 
risk of distant metastases appears to be in patients with a large primary (T4) and more 
advanced lymph node disease (N2-3)5. Also, while standard therapy for early stage head and 
neck cancer has been surgery or radiation therapy with curative intent, the prognosis with this 
approach is quite poor in patients with unresectable primary disease, with <30% patients being 
cured. The majority of patients will die of local or regionally persistent or recurrent disease6 
and re-resection and/or re-irradiation may not be suitable options. Also, nearly two thirds of 
patients present with advanced (stage III and IV) disease7, and therefore are at a higher risk of 
developing metastatic disease.  
 
The goal of treatment of metastatic or recurrent SCCHN is mainly palliative. Therapy usually 
involves a platinum based regimen. Cisplatin or carboplatin have been combined with 5-FU 
to achieve response rates of 20-30% with overall survival of about 5-7 months8. Addition of 
the epidermal growth factor receptor antibody, cetuximab appears to improve the survival to 
about 10 months9. While these data appear promising in the context of metastatic disease, the 
main problems with platinum based therapy are related to their toxicity. The major toxicities 
associated with cisplatin include neurotoxicity, nephrotoxicity, and nausea and vomiting, 
while carboplatin causes myelosuppression. Hence, studies evaluating newer, safer, 
therapeutic strategies are needed to improve outcomes in this group of patients.  
 
The Keynote-048 study compared survival and disease progression in patients on 
pembrolizumab monotherapy or pembrolizumab with chemotherapy [EXTREME regimen - 
platinum and 5-fluorouracil (5-FU)] in previously untreated recurrent or metastatic HNSCC 
patients [29]. Data presented recently showed pembrolizumab monotherapy improved overall 
survival (OS) by 39% (p=0.0007) in patients whose tumors expressed PD-L1 (combined 
proportion score ≥1) compared to chemotherapy. The median OS was 12.3 months vs. 10.3 
months with chemotherapy. However response rates with single agent pembrolizumab was 
less than 20%. When the combination of pembrolizumab with chemotherapy was studied the 
response rates were only 42% compared to 38% with chemotherapy. Hence, despite the 
approval of pembrolizumab in the first-line setting, newer regimens need to be investigated. 
(Ref: 29. 
Rischin D, Harrington KJ, Greil R, Soulieres D, Tahara M, de Castro G, Psyrri 
A, Baste N, Neupane PC, Bratland A, Fuereder T, Hughes BGM, Mesia R, Ngamphaiboon N, 
Rordorf T, Ishak WZW, Zhang Y, Jin F, Gumuscu B, Burtness B. Protocol-specified final 
analysis of the phase 3 KEYNOTE-048 trial of pembrolizumab (pembro) as first-line therapy 
for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). J Clin Oncol 
2019;37:15_suppl, 6000.) 
 
Docetaxel: Docetaxel is a taxane that is approved for a variety of solid tumors including lung, 
breast and head and neck cancer either alone or in combination with platinum agents. As a 
single agent, it has been shown to be effective against squamous cell carcinoma of the head 
and neck xenografts10,11. It was also active in cell lines relatively resistant to cisplatin, thereby 

 
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indicating an absence of cross-resistance10. Docetaxel appears to be more cytotoxic in the 
majority of human primary tumor specimens than paclitaxel12. 
 
Docetaxel has been studied in various phase II clinical trials in patients with squamous cell 
cancer of the head and neck and has shown single agent activity ranging from 27-45%13-16. 
Three of these studies used docetaxel 100 mg/m2 as a one-hour infusion repeated every three 
weeks13-15. In these studies, the main toxicity was neutropenia, but neutropenic fever was not 
common. In addition, patients developed alopecia, fatigue, anorexia, stomatitis, diarrhea, 
peripheral neuropathy, and fluid retention. A fourth study used docetaxel at a lower dose of 
60 mg/m2 every three weeks, but the response rate obtained was similar to the above studies 
with acceptable toxicity16.  
 
5-Fluorouracil (5-FU) in head and neck cancer: 5-FU is routinely used as a radiation 
sensitizer in the management of head and neck cancer. There have been a few studies 
evaluating its efficacy as a single agent in the treatment of advanced head and neck cancer. In 
a randomized phase III study conducted 249 patients with recurrent head and neck cancer were 
randomized to one of three treatments: cisplatin 100 mg/m2 on day 1, 5-FU 1gm/m2 daily from 
days 1-4, or a combination of cisplatin and 5-FU in the same doses every 3 weeks. They found 
that when given as a single agent 5-FU had a response rate of 13%. The median survival with 
5-FU was similar to that obtained with either cisplatin alone or the combination17.  
 
Capecitabine: Capecitabine is an orally active cytotoxic prodrug of 5-fluorouracil (5-FU). 
After oral administration, capecitabine crosses the gastrointestinal barrier intact and is rapidly 
and almost completely absorbed18,19. It is subsequently converted into 5-FU in a three-stage 
mechanism involving several enzymes. In the first step, it is metabolized into 5'-deoxy-5-
fluorocytidine (dFCR) by hepatic carboxylesterase. 5'dFCR is then deaminated into 5'dFUrd 
by cytidine deaminase mainly localized in liver and tumor tissues. Finally, 5'dFUrd is 
transformed into 5-FU under the action of thymidine phosphorylase, an enzyme with higher 
activity in tumor than in normal tissues. Higher levels 5-FU are thus produced within tumors 
with minimal exposure of healthy tissue to 5-FU20,21.  
 
This suggests that at least theoretically capecitabine would have a greater activity and lesser 
systemic toxicity by being concentrated more in the tumor tissues as compared to healthy 
tissues22. In a pharmacokinetic study on 19 patients with colorectal cancers who were 
undergoing elective resection of either a primary lesion or liver metastases Schuller et al. 
found a higher concentration of 5-FU in the tumors (both primary and metastatic) than in 
adjacent healthy tissues23.  
 
Capecitabine has been studied as a single agent in patients with metastatic head and neck 
cancer. In a phase II trial of 40 patients who had failed platinum based therapy, capecitabine 
had a response rate of approximately 24% and the median survival was 7.3 months24. 
Capecitabine appears to be effective in combination with cisplatin as well. In a phase I study 
Pivot et al treated 21 patients with locally recurrent or metastatic head and neck carcinoma 
with cisplatin and capecitabine. They had a 14% CR rate and a response rate of 33%25.  
 
Combination of docetaxel and capecitabine: Preclinical studies in human cancer xenograft 
models have shown that docetaxel or paclitaxel further up-regulate thymidine phosphorylase 
in tumor tissues26. Co-administration of docetaxel or paclitaxel with capecitabine resulted in 
synergistic tumor cell killing in a xenograft model26. In a trial in women with metastatic breast 

 
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cancer, O’Shaughnessy et al., combined docetaxel every three weeks with capecitabine days 
1 -14, and reported significantly improved time to progression and survival when compared 
to treatment with docetaxel alone27; however the synergistic effect between docetaxel and 
capecitabine does not seem to be entirely related to the enhancement of thymidine 
phosphorylase activity.  
 
A study in human cancer xenograft models evaluated different schedules for the combination 
of docetaxel and capecitabine in both docetaxel sensitive and less-docetaxel sensitive 
xenografts28. The combination was evaluated in the docetaxel-sensitive MX-1 and MAXF401 
human mammary, A755 murine mammary, and the less-docetaxel-sensitive WiDr human 
colon xenograft. Although synergy was demonstrated in all xenografts, in the breast tumor 
models, docetaxel administered on day 8 in combination with capecitabine daily for 14 days 
(days 1 to 14) every 3 weeks had higher antitumor activity than when administered on days 1 
or 15. In contrast, in the colon cancer xenograft, docetaxel administered on day 1 demonstrated 
higher antitumor activity as compared with other days of administration. There was no 
significant upregulation of thymidine phosphorylase in the MAXF401 and A755 models, and 
only slight upregulation (1.9-fold) was seen in the MX-1 models, whereas there was 
significant upregulation (4.8-fold) on WiDr, the only model in which the day-1 combination 
was superior. Thus for certain tumors, modulation of docetaxel by capecitabine may be more 
important than capecitabine modulation by docetaxel29. 
 
The combination of docetaxel and capecitabine has been studied in other solid tumors with 
reasonable efficacy and toxicity. In a randomized phase III study in pre-treated metastatic 
breast cancer, the capecitabine (1250 mg/m2)-docetaxel (75 mg/m2) combination was found 
to have a response rate of 32%30. However 27% of patients discontinued treatment due to 
adverse events. In contrast in a prostate cancer study of weekly docetaxel (35 mg/m2) and a 
lower dose of capecitabine (650 mg/m2), the response rate was 68.2% and 87% of patients 
completed 4 cycles of therapy31. The combination of weekly docetaxel and capecitabine was 
found to have an overall survival that was similar to that seen with the cisplatin-5-FU 
regimen32. Current evidence suggests that if the two agents are to be used in combination, 
docetaxel should be started at a higher dose while capecitabine should be started at a dose 
lower than its maximum tolerated dose and if adverse events develop, the dose of docetaxel 
should be decreased33. 
 
Since both docetaxel and 5-FU are active agents in squamous cell carcinoma of the head and 
neck, we will evaluate the efficacy of the combination of docetaxel given every three weeks 
and capecitabine (prodrug for 5-FU) and determine if the synergy seen in other tumors is 
present in advanced squamous cell carcinoma of the head and neck.  
 
3.0  Eligibility Criteria 
Inclusion criteria: 
1. 
Histologically proven squamous cell carcinoma of the head and neck with measurable 
disease that is either recurrent after attempted cure with surgery and/or radiation 
therapy or newly diagnosed disease with distant metastases or incurable at diagnosis. 
2. 
Performance Status: Karnofsky score ≥70 or ECOG 0-2 (See Appendix A). 

 
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3. 
Age 19 years or older (the age of consent in Nebraska); Age 18 years or older 
(applicable to States where the age of majority is 18).  
4. 
No prior cytotoxic chemotherapy for metastatic squamous cell carcinoma of the head 
and neck. Subjects who have received chemotherapy as part of a multi-modality 
curative approach for head and neck cancer will be eligible as long as they have not 
received either docetaxel or capecitabine (or 5-FU) as part of that regimen.  Patients 
who have received single agent immune checkpoint inhibitors for metastatic disease 
will be eligible. 
5. 
Adequate pre-treatment bone marrow reserve (WBC count ≥3,500/mm3, platelet count 
≥100,000/mm3). 
6. 
Adequate renal function (serum creatinine less than 1.5 times the upper limits of 
normal). 
7. 
Adequate hepatic function (serum AST and ALT less than 1.5 times the upper limits 
of normal, serum alkaline phosphatase less than 2.5 times the upper limits of normal, 
serum total bilirubin is less than or equal to the upper limits of normal). 
8. 
PT or INR, and PTT ≤ 1.5 x upper limit of normal unless subject is receiving 
anticoagulants. If the subject is on anticoagulation therapy, levels should be within 
therapeutic range. 
9. 
Women of reproductive potential must be non-pregnant and non-nursing and must 
agree to employ 2 effective methods of birth control throughout the study and for up 
to 6 months following treatment.  
10. 
Women of child-bearing potential must have a negative pregnancy test within 7 days 
of initiating study. (No childbearing potential is defined as age 55 years or older and 
no menses for two years or any age with surgical removal of the uterus and/or both 
ovaries). 
11. 
The subject must be aware of the neoplastic nature of his/her disease and willingly 
provide written, informed consent after being informed of the procedure to be 
followed, the experimental nature of the therapy, alternatives, potential benefits, side-
effects, risks, and discomforts. 
Exclusion criteria: 
1. 
Prior cytotoxic chemotherapy for metastatic squamous cell carcinoma of the head and 
neck. Subjects who have received chemotherapy as part of a multi-modality curative 
approach for head and neck cancer will be eligible as long as they have not received 
either docetaxel or capecitabine (or 5-FU) as part of that regimen. 
2. 
Patients who have received chemotherapy in combination with immunotherapy for 
metastatic disease. 
3. 
Allergy to either of the study medications or 5-fluorouracil. 
4. 
Simultaneous participation in other therapeutic clinical trials will not be allowed. 
5. 
Because of potential drug interactions between allopurinol/cimetidine/antivirals and 5-
FU, if a subject is receiving any of these drugs they must be discontinued prior to 
starting this protocol. 

 
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6. 
Prior malignancy, except for adequately treated basal cell or squamous cell carcinoma 
of the skin, or thyroid cancer; carcinoma in situ of the cervix or breast; prostate cancer 
of Gleason Grade 6 or less with stable PSA levels (GnRH analogs or androgen receptor 
blockers acceptable); or other cancers from which the subject has been disease-free for 
at least five years. 
7. 
Uncontrolled intercurrent illnesses including, but not limited to symptomatic 
congestive heart failure, severe oxygen dependent chronic obstructive pulmonary 
disease, unstable angina or uncontrolled cardiac arrhythmia that could jeopardize the 
subject’s ability to receive the chemotherapy described in the protocol safely. 
8. 
Pregnant and nursing women are excluded from this study because the chemotherapy 
agents have the potential for teratogenic or abortifacient effects. 
9. 
Inability to co-operate with the study visit schedule and other requirements of the 
protocol. 
10. 
Any other clinically significant medical disease or condition, laboratory abnormality 
or psychiatric illness that, in the Investigator’s opinion, may interfere with protocol 
adherence or a subject’s ability to give informed consent. 
 
NOTE:  
All questions regarding eligibility for all potential subjects should be directed to the UNMC 
Fred & Pamela Buffet Cancer Center Project Coordinator.  
 
UNMC and Participating/Collaborating Sites should use the Eligibility Checklist (See 
Appendix B) as source documentation.  It should be reviewed, signed, and dated prior to 
registration by the treating physician. The eligibility checklist must be accompanied by all 
other source documents that verifies the subject’s eligibility (i.e., dictation, pathology, 
radiology, laboratory, etc.).  
  
4.0 Registration Procedures 
 
4.1 Recruitment 
Subjects, who are referred to Nebraska Medicine / UNMC; Faith Regional Carson Cancer 
Center, Norfolk, NE or other IRB approved participating/collaborating sites, with 
histologically proven squamous cell carcinoma of the head and neck with measurable 
disease that is either recurrent after attempted cure with surgery and radiation therapy or 
newly diagnosed disease with distant metastases, may be eligible for this trial.  
 
Screening eligibility, based on standard clinical care, will be performed by the treating 
physician at the time of encounter. On initial presentation, a history and physical 
examination are performed, laboratory data obtained and Performance Status is assessed. 
Imaging studies obtained include a high-resolution multi-detector computed tomography 
(CT) of the neck and chest. Additional radiologic/imaging evaluations for staging will be 
performed as clinically indicated and is at the discretion of the treating physician.  
 
The subject’s primary Oncologist will make the decision as to eligibility of the candidate 
based on the eligibility criteria listed above, prior to offering consent (See Section 3.0).  

 
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If the subject is screened as potentially eligible, he/she will then be offered the option to 
participate. An informed consent will be signed by the subject after thorough review of the 
study is completed with the physician and his/her designee.  
 
Some Insurance carrier’s may decline to cover the costs of usual medical care if the subject 
is participating in a clinical trial. The subject will be provided assistance by the research 
nurse coordinator or designated staff in determining if the insurance carrier will decline 
coverage. Insurance carriers may or may not pay for study related expenses. The subject can 
then decide if they wish to participate.  
 
4.2 Eligibility Verification/Registration  
Before subjects are registered to the study, an Eligibility Checklist (See Appendix B) must 
be completed to verify the subject meets the eligibility criteria. Informed consent must be 
obtained by following procedures defined in section 12.6 entitled Process of Informed 
Consent.  Subjects will be registered through the Sponsor Principal Investigator by 
contacting the UNMC Fred & Pamela Buffett Cancer Center Research Project Coordinator.   
 
All Study personnel from UNMC and non-UNMC IRB approved sites will contact the 
UNMC Project Coordinator if a subject appears to meet the eligibility criteria. They will 
scan/email the completed Eligibility Checklist (See Appendix B) to the UNMC Project 
Coordinator. The Eligibility Checklist will be maintained in a study file. If the UNMC 
Project Coordinator confirms that the subject meets criteria and target accrual has not been 
met, approval for the subject will be given. A confirmation of Registration will be forwarded 
by the UNMC Project Coordinator. 
 
Registration: 
Study site personnel will provide the UNMC Project Coordinator with the following 
information: 
• Demographics scan cover sheet (located in the Study Manual) 
• Copy of the signed and dated consent form  
• Signed Eligibility Checklist 
• Source documents with assigned subject I.D. (if known on each page or subject 
identification) to support eligibility (i.e., Medical/Surgical Hx, labs, pathology 
reports, scans, etc.). 
Registration Date: Eligibility verification and notification of assigned subject number (by 
UNMC) will be known as the Registration date.  
 
Date of Enrollment: This is defined as the date of the start of study treatment / first protocol 
related intervention. 
 
4.3  Instructions for Subjects Who Do Not Start Assigned Protocol Treatment  
If a subject does not receive any assigned protocol treatment after consenting, baseline and 
follow-up data will still need to be collected and must be submitted according to the 
instructions in the protocol.  The reason he/she did not receive any treatment and the date 
and type of the first non-protocol treatment that the subject receives must also be reported.  

 
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5.0  Research Design 
This is a Phase II, Open Label, Non-Randomized trial for patients with recurrent or metastatic 
squamous cell carcinoma of the head and neck.  All subjects will receive the same dose of the 
combination chemotherapy drugs docetaxel and capecitabine.  
 
5.1  Pre-treatment Evaluations- Standard of Care (SOC) 
No tests or procedures are conducted solely for the purposes of research to determine subject 
eligibility. 
WITHIN FOUR WEEKS 
• History and physical  
• CBC with differential, Platelet count   
• Comprehensive Metabolic Panel (CMET) – electrolytes (sodium, potassium, 
chloride, bicarbonate, creatinine, BUN, AST, ALT, T. protein, albumin, bilirubin, 
alkaline phosphatase, calcium, glucose) 
• PT, PTT, INR 
• Serum/urine pregnancy test (if applicable) 
• Height and weight 
• Performance Status Assessment using Karnofsky Score 
• Quality of Life (QOL) Assessment 
• Vital signs, including blood pressure 
• High-resolution multi-detector computed tomography (CT) of the neck and chest  
• The need for further radiologic evaluations for staging, as clinically indicated, is 
at the discretion of the treating physician. 
• Provide pathology report for review of confirmation of diagnosis. 
 
Research Samples will be collected at baseline, after cycle 2 and at the end of treatment. 
(See protocol section 5.6 for details).  
 
5.2  Drug Administration / Treatment Plan 
5.2.1  Body Surface Area Calculations  
Dosage calculations will be based on the subject’s body surface area, at baseline. Actual 
height and weight should be used in determining body surface area. (See Appendix C). Dose 
adjustments at the beginning of each cycle do not need to be made unless there has been a 
>10% weight gain/loss.  
 
5.2.2  Premedication  
All subjects will receive premedication for nausea and vomiting with appropriate anti-emetic 
regimens based on recommendations made by the NCCN Guidelines (SOC), pre and post 
medications 
as 
prescribed 
by 
the 
treating 
physician. 
 
(See 
http://www.nccn.org/professionals/physician_gls/PDF/antiemesis.pdf). 
 
Subjects will receive dexamethasone 4 mg twice a day orally on the day before, the day of and 
the day after docetaxel to help decrease the edema associated with docetaxel. 
 

 
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5.2.3  Systemic Therapy (Medicare Qualifying research related combination 
chemotherapy)  
• Docetaxel 75 mg/m2 IV in normal saline IV over one hour on day 1; cycled every 21 
days (3 weeks) for all cycles. 
• Capecitabine 800mg/m2 orally twice daily on days 1-14 of a 3 week cycle for the initial 
cycle (Cycle 1).  
If there is no evidence of grade 2 or greater toxicity with capecitabine and if the doses of 
capecitabine are not held due to adverse effects after the first cycle, THEN for Subsequent 
Cycles (Cycle 2 and remaining cycles) the dose of capecitabine will be increased to 1000 
mg/m2 orally twice daily on days 1-14 of a 3 week cycle for the remaining cycles.  
 
To provide a means of ensuring oral route of medication adherence to patients while 
participating in this clinical trial, standard procedure for “Oral, Sublingual, and/or Buccal 
Route Medication Adherence Standard Procedure (V 1.0 11-25-2013)” will be followed (See 
Appendix D). 
 
5.2.4  Criteria for holding and resuming treatment 
As per Section 5.4 dose modifications instruction.  
 
5.2.5 Evaluations during therapy (SOC)  
Every 3 weeks during chemotherapy:  
• Subjects will be clinically evaluated by an oncologist for toxicities 
• CBC w/ differential, platelet count  
• Comprehensive metabolic panel (CMET) – electrolytes (sodium, potassium, 
chloride, bicarbonate, creatinine, BUN, AST, ALT, T. protein, albumin, bilirubin, 
alkaline phosphatase, calcium, glucose) 
• Weight 
• Performance Status Assessment 
• QOL Assessment  
• Vital signs, including blood pressure 
Every 6 weeks during chemotherapy: 
• High-resolution multi-detector computed tomography (CT) of the neck and chest. 
• The need for further radiologic evaluations for staging, as clinically indicated, and 
is at the discretion of the treating physician. 
 
Data will be collected on dose delays/reductions, hospitalizations, treatment discontinuation, 
deaths and toxicities. 
 
5.3 Clinical Endpoint/Radiographic Assessment of disease status  
A dedicated CT Response assessment will be done after every 2 cycles per standard of care 
and at the completion of the study. Subjects with stable or responsive disease will continue on 
therapy until progression. 
 

 
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Follow-up (SOC): All patients will be clinically evaluated by an oncologist at the completion 
of the study and then followed for survival. 
 
Post Trial Assessments:  
• Subjects who go off study treatment at any time during the trial will be followed for 
30 days after the last day of treatment or until other disease-related treatment begins. 
For all subjects, drug-related Serious Adverse Events (SAEs) and Adverse Events 
(AEs) will be followed until resolution, baseline or ≤ grade 1 levels.  
 
• Subjects who responded or maintained stable disease during the study will be followed 
for date of disease progression and/or death. Subjects may refuse to participate in the 
post-trial assessments. 
 
5.4 Dose modifications 
5.4.1 General instructions for dose modifications 
• Adverse events (AEs) will be graded according to the National Cancer Institute 
Common Terminology, Criteria for Adverse Events (NCI-CTCAE), version 4.0 
(See Appendix E), which can be accessed at the following URL: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40  
• All doses should be based on the AE requiring the greatest modification. 
• Doses may be delayed, missed or reduced based on subject tolerance.  Missed 
doses will not be made up at the end of the cycle. 
• Doses that have been reduced may not be escalated.  
• Proceeding with study therapy after grade 4 events, other than 
neutropenia/granulocytopenia and thrombocytopenia is at the discretion of the 
treating physician. 
 
5.4.2 Docetaxel Dose Modifications  
5.4.2.1 Hematologic Toxicity 
Potential hematologic toxicities of docetaxel that are most common would be -Neutropenia, 
anemia.  Since severe myelosuppression is uncommon with capecitabine therapy, the dose of 
capecitabine will not be decreased for hematologic toxicity occurring in the prior cycle if full 
doses of docetaxel were given. 
 
Docetaxel will be held for an ANC <1,500/μL and/or platelet count <100,000/μL. For 
subsequent cycles, if there is a delay of more than 1 week because of low blood counts, the 
dose of docetaxel will be reduced by 25% for subsequent courses. In the event of a delay of 
more than 4 weeks, the subject will be taken off study. 
 
In the event of febrile neutropenia, the dose of docetaxel will be reduced by 25% and filgrastim 
will be administered for subsequent courses. If febrile neutropenia occurs despite filgrastim, 
the dose of docetaxel will be reduced by another 25% for subsequent courses. 
 
5.4.2.2 Non-Hematologic Toxicity 
Dose Modifications for Abnormal Liver Function 

 
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Subjects who develop abnormal liver function tests for any reason while on the study will have 
the following dose reductions (See Table 1): 
 
              Table 1:  Docetaxel Dosing based on Alk Phos and AST/ALT 
 
 
AST or ALT 
 
 
≤ ULN 
>1x but ≤1.5x  
>1.5x but ≤5x  
>5x ULN 
Alkaline 
Phosphatase 
≤ ULN 
Full Dose 
Full Dose 
Full Dose 
Hold* 
>1x but ≤ 2.5x  
Full Dose 
Full Dose 
Reduced by 25% 
Hold* 
>2.5x but ≤ 5x  
Full Dose 
Reduced by 25% 
Hold* 
Hold* 
>5x ULN 
Hold* 
Hold* 
Hold* 
Hold* 
                   *Hold until recovered (maximum 21 days) then re-treat at a reduced dose.  “Recovered” is 
                     defined as meeting the study baseline eligibility criteria. 
 
Both AST and ALT should be drawn.  The more abnormal of the two values (AST or ALT) 
should be used in determining the dose. 
 
Docetaxel should not be administered to subjects with serum total bilirubin >ULN.  If serum 
total bilirubin is >ULN on treatment day, hold docetaxel until serum total bilirubin is ≤ ULN 
(maximum 21 days), then re-treat at a 25% reduced dose. 
 
Both chemotherapy drugs will be held for grade 3 or 4 neurotoxicity and may be restarted on 
resolution to less than a grade 1 (unless recovery is >2 weeks for which subject will be 
removed from study).  The dose of docetaxel will be decreased by 25% at resumption. 
Docetaxel will be discontinued if grade 3 or 4 neurotoxicity recurs after a dose reduction and 
capecitabine will be continued as a single agent. 
 
Treatment should be discontinued for Grade 4 hypersensitivity reactions.  There are no dose 
reductions for hypersensitivity reactions. 
There are no dose reductions for fluid retention. 
 
5.4.3 Capecitabine Dose Modifications  
5.4.3.1 Hematologic Toxicity 
Since severe myelosuppression is uncommon with capecitabine therapy, the dose of 
capecitabine will not be decreased for hematologic toxicity occurring in the prior cycle if full 
doses of docetaxel were given. 
5.4.3.2 Non-Hematologic Toxicity 
Certain toxicities, such as diarrhea, abdominal pain, constipation, palmar-plantar 
erythrodysesthesia (hand-foot syndrome), etc., are typically associated with capecitabine 
therapy.  Therefore, the dose of capecitabine will be preferentially reduced for such toxicities 
(See Table 2). Again, both chemotherapy drugs will be held for grade 3 or 4 neurotoxicity and 
may be restarted on resolution to less than a grade 1 (unless recovery is >2 weeks for which 
subject will be removed from study). The dose of docetaxel will be decreased by 25% at 
resumption. Docetaxel will be discontinued if grade 3 or 4 neurotoxicity recurs after a dose 
reduction, and capecitabine will be continued as a single agent. 

 
IRB#762-14 Version 6.2 dated 01Jul2021 
 
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Treatment should be discontinued for Grade 4 hypersensitivity reactions.  There are no dose 
reductions for hypersensitivity reactions. 
 
There are no dose reductions for fluid retention. 
 
For grade 2 diarrhea, stomatitis or hand-foot syndrome, capecitabine will be held until the 
event returns to a grade 0 or 1 and then resumed at the same dose. If these symptoms persist 
until the start of the next cycle, the cycle will be delayed until it is resolved to a grade 0 or 1 
and then continued at 100% of the original dosing.  
 
For grade 3 diarrhea, stomatitis or hand-foot syndrome, capecitabine will be resumed with a 
25% dose reduction once the diarrhea/hand-foot syndrome has resolved to a grade 0 or 1. 
Docetaxel will be continued at the same dose. 
 
On any subsequent development of grade 2 or higher diarrhea, stomatitis or hand-foot 
syndrome, therapy will be held until symptoms resolved to grade 0 or 1 and then the doses of 
both agents will be reduced by 25%. In the event of a delay of more than 4 weeks, the subject 
will be taken off study. 
 
 
 
Table 2:  Capecitabine Dosing for diarrhea, stomatitis or hand-foot syndrome 
*Hold until returned to grade 0 or 1. 
**Delay cycle until returned to grade 0 or 1. If delay is more than 4 weeks, the subject is taken off study. 
 
5.5  Supportive Care  
5.5.1 Requirement for venous access 
Central venous access is not required for protocol participation, but may minimize the risk of 
venous irritation associated with docetaxel therapy.  A previously placed central venous 
access device will be employed if it is functioning properly (free infusion of saline, 
unimpeded blood return, good condition of external appliance, no recent history of device 
infection or thrombosis).  Should the subject require central venous access, an implanted port 
central venous access device (i.e. a Medi-Port® or Port-a-Cath®) or a peripherally inserted 
central catheter (PICC) will be placed. Other aspects of catheter/port management will be in 
accordance with nursing clinic central venous port procedures. 
 
5.5.2 Diarrhea 
Loperamide should not be taken prophylactically. Subjects will be instructed to begin 
taking loperamide after the (1) first poorly formed or loose stool, (2) first episode of 5 or 
 
Within same cycle 
At start of next cycle 
Any subsequent development 
of Grade 2 or higher 
GRADE 2 
diarrhea/stomatitis/ha
nd-foot syndrome 
Hold* then resumed at 
100% 
Delay cycle** then 
resumed at 100% 
 
Hold* then  Reduce both 
docetaxel and capecitabine by 
25% 
GRADE 3 
diarrhea/stomatitis/ha
nd-foot syndrome 
Hold* then  Reduce by 
25% 
Delay cycle** then 
reduced by 25% 
 
Hold* then  Reduce both 
docetaxel and capecitabine by 
25% 

 
IRB#762-14 Version 6.2 dated 01Jul2021 
 
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more bowel movements, OR (3)  2 “watery” stools in one day (20).  Loperamide should be 
taken in the following manner: 4 mg at the first onset of diarrhea THEN 2 mg after each 
loose stool (do not exceed 8 tablets in 24 hours or 16 mg total). 
Subjects must notify the research team as to when they initiated loperamide therapy. If 
diarrhea persists despite loperamide therapy, then the subject should be evaluated for the 
need for IV fluid and electrolyte replacement. 
Subjects may take alternative medications as prescribed by the treating physician. 
 
5.5.3 Palmar-Plantar Erythrodysesthesia (hand-foot syndrome) 
The use of pyridoxine (vitamin B6) may ameliorate the palmar-plantar erythro-dysesthesia 
associated with certain chemotherapeutic agents including fluorouracil.  Therefore, a 
therapeutic trial of pyridoxine 50 to 150 mg po tid daily for six weeks should be tried at the 
first symptoms of hand-foot syndrome. 
 
5.5.4 Stomatitis/Mucositis 
Mild symptoms will be treated with topical antiseptic and analgesic agents. Both viscous 
lidocaine and diphenhydramine have local anesthetic properties, while the aluminum 
hydroxide component of Maalox has a beneficial drying property. Subjects with severe pain 
require systemic narcotic analgesics. Topical anti-fungal agents will be added as clinically 
indicated. More severe symptoms will require all of the above, as well as stronger 
analgesic agents and admission to hospital for IV fluid and electrolyte replacement if 
dehydrated. GELCLAIR bioadherent oral gel is a topical agent that can provide pain relief 
for 5-7 hours after administration. Subjects with ulcers on the lips may benefit from a 
topical lip balm such as Abreva (10% docosanol). 
A rinse with baking soda and salt is an inexpensive and convenient remedy: mix 2 teaspoons 
salt and 2 teaspoon baking soda in 1 cup warm water; swish and spit; repeat 4 times daily. 
 
Sample prescription mouthwash formulas: take 5 cc of the formula, swish for 30 seconds 
then spit out; repeat 4 to 6 times daily (may swallow if there is esophageal involvement) 
 
       1) Tetracycline suspension 
500 mg/20 mL 
Diphenhydramine 
50 mg/20 mL 
Nystatin  
50,000 U/5 mL 
Maalox  
30 mL 
Sterile Water, USP 
105 mL 
                                2) 2% viscous lidocaine 
30 mL 
Diphenhydramine elixir 
60 mL (12.5 mg/5 mL) 
Maalox  
90 mL 
 
5.5.5 Treatment of Fever and Neutropenia 

 
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Subjects developing a fever of 100.5 degrees F or higher will have a CBC with WBC 
differential obtained along with a history and physical examination to look for signs of 
infection. 
If the ANC is less than 1000/µL, a specific treatment plan as prescribed by the treating 
physician or the sites Institutional Guidelines will be followed.  
Fever and neutropenia occurring during a treatment cycle may require interruption of 
chemotherapy. The subject may resume chemotherapy at the start of the next scheduled 
cycle, if therapy for infection has been completed and the subject meets other criteria for 
starting a new cycle. 
 
 

 
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5.5.6 Management of Docetaxel Acute Hypersensitivity 
 
 
5.5.7   Fluid Retention 
Subjects developing new onset edema, progression of existing edema or another sign of fluid 
retention are to be treated with oral diuretics.  Regimens found to be effective in the 
management of fluid retention due to docetaxel are listed below: 
• Triamterene/hydrochlorothiazide one capsule oral daily up to three times a day. 
• Furosemide 40 mg oral daily if edema progresses despite 
Triamterene/hydrochlorothiazide therapy.  Potassium supplementation should be 
given as needed. 
• If after a two-week trial, furosemide 40 mg oral daily is ineffective, the subject 
may be treated with furosemide 20 mg oral daily plus metolazone 2.5 mg oral 
daily with potassium supplementation as needed. 
Severity of Symptoms 
Treatment Guidelines 
(Grade 1)-Mild  
symptoms: localized cutaneous 
reactions such as mild pruritus, 
flushing, rash 
• 
consider decreasing the rate of infusion until recovery from 
symptoms; stay at bedside and monitor subject 
• 
then, complete docetaxel infusion at the initial planned rate 
(Grade 2)- Moderate symptoms: 
any symptom that is not listed 
above (mild symptoms) or below 
(severe symptoms) such as 
generalized pruritus, flushing, rash, 
dyspnea, hypotension with systolic 
BP > 80 mm Hg  
 
• 
interrupt docetaxel  infusion 
• 
give diphenhydramine 50 mg IV with or without 
dexamethasone 10 mg IV; monitor subject until resolution 
of symptoms  
• 
resume docetaxel infusion after recovery of symptoms; 
depending on the physician’s assessment of the subject, 
docetaxel infusion should be resumed at a slower rate, 
then increased incrementally to the initial planned rate, 
(i.e..  infuse at a 4-hour rate for 3 minutes, then at a 2-h 
rate for 3 minutes, then at a 1-h rate for 3 minutes, then 
finally, resume at the initial planned rate) 
• 
depending on the intensity of the reaction observed, 
additional oral or IV premedication with an antihistamine 
should also be given for the next cycle of treatment and the 
rate of infusion should be decreased initially and then 
increased back to initial planned rate, (i.e. infuse at a 4-
hour rate for 3 minutes, then at a 2-h rate for 3 minutes, 
then at a 1-h rate for 3 minutes, and finally, administer at 
the initial planned rate) 
(Grade 3)- Severe symptoms: any 
reaction such as bronchospasm, 
generalized urticaria, systolic BP ≤ 
80mm Hg, angioedema 
 
• 
immediately discontinue docetaxel infusion  
• 
give diphenhydramine 50 mg IV with or without 
dexamethasone 10 mg IV and/or epinephrine as needed; 
monitor subject until resolution of symptoms 
• 
the same treatment guidelines outlined under moderate 
symptoms (i.e. the third and fourth bullets) should be 
followed. 
(Grade 4)- Life-threatening 
symptoms:  Anaphylaxis  
• 
NO FURTHER docetaxel DRUG THERAPY 
(Grade 5)- Death related to AE 
 

 
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Further therapy should be customized depending upon the clinical situation.  The clinical 
tolerance of the subject, the overall tumor response and the medical judgment of the 
Investigator will determine if it is in the subject’s best interest to continue or discontinue 
treatment.  
 
5.5.8   Hyperlacrimation 
The following guidelines may be taken for subjects experiencing clinically significant 
hyperlacrimation: 
• Withhold docetaxel treatment until resolution. 
• Frequent instillation of artificial tears. 
• Steroid ophthalmic solution starting the day before docetaxel administration in 
subjects without a history of herpetic eye disease. 
• Ophthalmologist consult. 
5.6   Correlative Studies Related to the Research  
Research Samples will be collected at baseline, after cycle 2 and at the end of treatment (See 
Appendix I for instructions). Samples will include: 
• Blood Samples-30 mL including two – 10ml EDTA lavender top tubes and one – 
10ml red top tube 
• Urine Sample - 10 mL.  
 
Samples should be sent overnight at room temperature, Monday through Thursday only to 
Dr. David L. Kelly’s Lab, Attn:  Amy Wells, MS.  Do not send the day before a Holiday.  
 
5.7 Potential Drug Interactions 
5.7.1 Allopurinol 
Oxypurinol, a metabolite of allopurinol can potentially interfere with 5-FU anabolism via 
OPRT'ase.  Although this was originally used as a strategy to protect normal tissues from 5-
FU-associated toxicity, further laboratory studies suggested possible antagonism of the 
anticancer activity of 5-FU in some tumor models.  If a subject is receiving 5-FU (including 
5-FU prodrugs such as capecitabine), it is recommended that the need for taking allopurinol 
be ascertained. If possible, allopurinol should be discontinued prior to starting on this 
regimen and another agent substituted for it. 
 
5.7.2 Warfarin 
Bleeding associated with prolonged prothrombin time (PT) has been noted in several 
subjects receiving 5-FU and concomitant warfarin. These observations suggest a possible 
interaction leading to prolonged PT.  Therefore, it is recommended that all subjects receiving 
5-FU (including 5-FU prodrugs such as capecitabine) and concomitant warfarin at 
therapeutic doses be closely monitored for changes in prothrombin time. 
 

 
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5.7.3 Cimetidine 
Because cimetidine can decrease the clearance of capecitabine/5-FU, subjects should not 
enter on this study until the cimetidine is discontinued.  Ranitidine or another class of anti-
ulcer agents can be substituted for cimetidine, if necessary. 
 
5.7.4 Sorivudine and Brivudine 
A metabolite of the above two investigational antiviral agents, 5-bromovinyluracil, is a 
potent inhibitor of dihydropyrimidine dehydrogenase, the enzyme that catabolizes 5-FU.  
Subjects should not receive concurrent therapy with either of these antiviral agents while 
receiving capecitabine.  If a subject has received prior sorivudine or brivudine, then at least 
four weeks must elapse before the subject receives capecitabine therapy. 
 
5.8 Criteria for Removal from Study 
• Progression of Disease 
• If at any time the constraints of this protocol are detrimental to the subject's well-
being or if the subject is unable to comply with the requirements of the protocol, 
the subject will be removed from protocol therapy.  
• Undue toxicity that would make continued treatment detrimental to the subject’s 
safety.   
• Development of intercurrent medical problems that would make continued 
protocol therapy detrimental to the subject’s safety. If a non-treatment related 
intercurrent illness is expected to be of limited nature, then treatment may be 
delayed for more than 2 weeks. In this case, the patient would need to be re- 
evaluated before resuming protocol therapy. 
• The subject chooses to discontinue treatment or follow-up. 
 
The reason(s) for withdrawing the subject from the treatment portion of the study will be 
documented in the case report form. Where possible and feasible, subjects who received at 
least one dose of study drugs should be subjected to the procedures scheduled at the end of 
the study and should be submitted to the follow up to assess disease progression.  
 
If available, the following information will be recorded in the case report form: (1) date of 
disease relapse, (2) date of death, (3) cause of death and (4) autopsy report. 
 
6.0 Measurement of effect 
6.1 Tumor Response in Subjects with Measurable Disease 
CTEP’s RECIST Version 1.1 Guidelines will be followed. A quick reference to the RECIST 
Guidelines can be downloaded at the following URL:   
https://ctep.cancer.gov/protocolDevelopment/default.htm    
 
Measurable disease is defined as lesions that can be accurately measured in at least 1 
dimension in which the longest diameter to be recorded is 20 mm or larger with conventional 
techniques or 10 mm or larger with spiral CT scan.  Measurable disease is defined by the 

 
IRB#762-14 Version 6.2 dated 01Jul2021 
 
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presence of at least 1 measurable lesion. If the measurable disease is restricted to a solitary 
lesion, its neoplastic nature should be confirmed by cytology/ histology. 
 
Non-measurable disease is defined as all other lesions, including small lesions in which the 
longest diameter is less than 20 mm with conventional techniques or less than 10 mm with 
spiral CT scan and disease that is not detectable or not readily quantifiable with conventional 
techniques.  Lesions considered to be truly non-measurable 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. 
 
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.  
 
6.1.1 Baseline documentation of "Target" & "Non-target" lesions 
Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs (should be identified as target lesions), 
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.  
 
Non-target lesions: All other lesions (or sites of disease) should be identified as non-target 
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.  
 
Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable. Such lesions in a previously irradiated area might be considered 
measurable if there has been a documented increase in the size of the lesion since completion 
of the radiation. 
 
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. 
 
6.1.2  Response criteria 
Evaluation of target lesions (taking into account the measurement of the longest diameter 
only for all target lesions), response criteria are defined as: 
• Complete Response (CR):  the disappearance of all target lesions 
• Partial Response (PR):  at least a 30% decrease in the sum of the longest 
diameter of target lesions, taking as reference the baseline sum longest 
diameter 

 
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• Progressive Disease (PD):  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 (SD):  neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum 
longest diameter since the treatment started 
 
6.2 Progression-Free Survival:  
Progression-free survival will be defined as from the first date of therapy until the first 
notation of clinical progression, relapse or death from any cause. For subjects who are still 
progression-free at the time of the study analysis or are lost to follow-up, progression-free 
survival will be censored at the last recorded date that the subject was known to be 
progression-free.   
 
6.3 Time to Treatment Failure:  
The time to treatment failure will be defined as from the first date of therapy until the date 
the subject is removed from study for any reason. 
 
6.4 Survival:  
Survival will be defined as from the first date of therapy until the date of death from any 
cause.  For subjects who are still alive at the time of the study analysis or are lost to follow-
up, survival will be censored at the last recorded date that the subject was known to be alive. 
 
6.5 Toxicity criteria 
The NCI Common Toxicity Criteria for Adverse Events (NCI-CTCAE), version 4.0 will be 
used to grade toxicity and is available at the following internet site:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 

 
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7.0 Study Parameters 
 
 
Required studies 
Time (weeks) 
 
Screen
-ing  
(4 wks) 
1 2 3 
4 
5 
6 
7 
8 9 10 11 12 
131 
141 151 
 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Recurring Cycles 
History and physical 
X 
X  
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Weight &  
Karnofsky PS 
X 
X  
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Toxicity notation 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
QOL5 Assessment 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Laboratory studies 
 
 
CBC w/ diff, plt 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
CMET3 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
PT, PTT/INR 4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research Blood and 
Urine 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X  
end of study 
only 
 
 
Diagnostic biopsy 
only8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Imaging studies 
 
 
CT scan of the neck 
and chest6 
X 
 
 
 
 
 
 
X2 
 
 
 
 
 
X2 
 
 
Chemotherapy 
 
 
Docetaxel, IV day 1 
 
X  
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Capecitabine, PO 
BID days 1-147 
 
X X  
X X 
 
X 
X  
X 
X 
 
X 
X 
 
1 Every subsequent cycle until discontinuation from study. 
2 Every two (2) cycles, even with delays, until discontinuation from study. 
3 Comprehensive metabolic panel (CMET) – electrolytes (sodium, potassium, chloride, 
bicarbonate, creatinine, BUN, AST, ALT, Total protein, albumin, bilirubin, alkaline 
phosphatase, calcium, glucose) 
4 As necessary. Subjects on concomitant warfarin at therapeutic doses should be closely 
monitored for changes in prothrombin time. 
5Quality of Life (QOL) Assessment will be performed using European Organisation for 
Research and Treatment of Cancer QLQ Core 30 (EORTC QLQ-C30, See Appendix G) and 
QLQ Core Head & Neck 35 (QLQ-H&N35, See Appendix H) 
6 The need for further radiologic evaluations for staging, as clinically indicated, and is at the 
discretion of the treating physician.  
7 Missed doses should not be made up. 
8 Diagnostic Biopsy Pathology Report can be used to confirm diagnosis. 

 
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8.0 Drug Formulation and Procurement 
Docetaxel (Taxotere®): Aventis Pharmaceuticals 
Form: Docetaxel for injection. 
Dilution: 80 mg docetaxel in 2 mL polysorbate 80 and Diluent 80 mg (13% (w/w) ethanol in 
water for injection). Both items are in a blister pack in one carton. 
Preparation: Contact of the TAXOTERE concentrate with plasticized PVC equipment or 
devices used to prepare solutions for infusion is not recommended. In order to minimize 
patient exposure to the plasticizer DEHP (di-2-ethylhexyl phthalate), which may be leached 
from PVC infusion bags or sets, the final TAXOTERE dilution for infusion should be stored 
in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered 
through polyethylene-lined administration sets. 
Just prior to use allow the docetaxel to reach room temperature for 5 minutes. Add the contents 
of the diluent vial to the active drug and mix by gently rotating the vial for 15 seconds. Allow 
the vial to stand for 5 minutes at room temperature and check that the solution is homogenous 
and clear (persistent foam is normal). The resulting solution contains 10 mg/mL of docetaxel 
with overfill. 
Storage and stability: Docetaxel infusion solution, if stored between 2 and 25°C (36 and 77°F) 
is stable for 4 hours. Fully prepared docetaxel infusion solution (in either 0.9% Sodium 
Chloride solution or 5% Dextrose solution) should be used within 4 hours (including the 1 
hour IV administration).  
Method of administration: Docetaxel will be administered as a 1-hr infusion, via an infusion 
control device (pump). 
Precautions: Severe hypersensitivity reactions characterized by hypotension, bronchospasms, 
or minor reactions characterized by generalized rash/erythema may occur and can be 
minimized by use of premedications. 
Availability & Drug Ordering:  Docetaxel is commercially available from Aventis 
Pharmaceuticals.  
Significant clinical toxicities:  
Cardiovascular: Fluid retention, including peripheral edema, pleural effusions, and ascites.  
Dermatologic: Alopecia, nail disorder (banding, onycholysis, hypo- or hyperpigmentation)  
Gastrointestinal: Mucositis/stomatitis, nausea and vomiting, diarrhea. 
Hematologic: Myelosuppression, neutropenia, thrombocytopenia, anemia. 
Hepatic: Elevated transaminase levels. 
Neuromuscular & skeletal: Myalgia, neurosensory changes (paresthesia, dysesthesia, pain), 
motor neuropathy (including weakness). 
Miscellaneous: Hypersensitivity reactions - angioedema, rash, flushing, fever, hypotension. 
 
Capecitabine (Xeloda®)(Ro 09-1978): Roche Pharmaceuticals 
Product description: Capecitabine is supplied as a biconvex, oblong film coated tablets for oral 
administration as follows: 150 mg – light peach color, engraved with XELODA on one side 
and 150 on the other; 500 mg – peach color, engraved with XELODA on one side and 500 on 
the other. 
Route of administration: Oral. The total daily dose will be taken in two divided doses in the 
morning and evening about 12 hours apart. The medication should be taken within 30 minutes 
after taking a meal with at least 200 mL of water. If the dose is missed, it should be skipped 
altogether. The patient should NOT double the next dose.  If the treatment is interrupted due 

 
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to toxicity, the missed doses should not be replaced or restored. The total daily dose in mg/m2 
will be rounded down to the nearest tablet size. If the dosing calls for an uneven number of 
pills, the larger dose will be given in the evening. 
Stability: Capecitabine tablets are stable when the bottle is kept tightly closed and stored 
between 15° and 30°C (59° and 86°F). An expiration date is on the bottle. 
Incompatibilities: potentially Allopurinol and Cimetidine  
Drug Interactions: Patients who are on warfarin should have their INR closely monitored while 
taking capecitabine. They should not receive the investigational antiviral drugs brivudine or 
sorivudine. 
Contraindications: Patients with an unusual, life-threatening clinical toxicity with 5-FU. 
Availability & Drug Ordering:  Capecitabine is commercially available from Roche 
Pharmaceuticals (Roche Laboratories, 340 Kingsland St., Nutley, NJ  07110-1199). 
Significant clinical toxicities: 
Cardiovascular: Edema, venous thrombosis, chest pain. 
Central nervous system: Tiredness, weakness, fatigue, fever, pain, headache, dizziness, 
insomnia. 
Dermatologic: Palmar-plantar erythrodysesthesia (hand-and-foot syndrome), the palms of the 
hands and the soles of the feet may tingle or become numb, painful, swollen or red.  A rash 
may occur, and the skin may be dry and itchy (dermatitis). 
Gastrointestinal: Diarrhea, mild to moderate nausea, vomiting, sores in the mouth and throat 
stomatitis, abdominal pain, constipation loss or appetite or decreased appetite, and excessive 
water loss from the body. 
Hematologic: Lymphopenia, anemia, neutropenia, thrombocytopenia. 
Hepatic: Increased bilirubin. 
Neuromuscular & skeletal: Paresthesia, back pain, neuropathy. 
Ocular: Eye irritation. 
Respiratory: Dyspnea. 
 
9.0 Toxicity Reporting Guidelines 
The chemotherapeutic agents used in the protocol are commercially available agents with 
well-characterized toxicity profiles. 
 
This protocol will comply with monitoring and adverse event reporting requirements of the 
UNMC Fred & Pamela Buffett Cancer Center Data Monitoring plan. The protocol will adhere 
to the institutional IRB and FDA Guidelines for the Toxicity Reporting.    
 
All subjects will be closely followed for toxicity/adverse events (AEs). Adverse events will 
be assessed by reports from subjects to their physician/Investigator and by physical 
examinations using the CTCAE Version 4.0. All AEs and SAEs will be followed from the 
time of informed consent until resolution, baseline, or ≤ grade 1 levels.  
 
AEs considered by the Investigator as not related or probably not related to the treatment will 
not be followed beyond 4 weeks (30 days) after the final dose of study drug is administered. 
Concomitant medications will be collected up to 4 weeks (30 days) after the final dose of study 
drug is administered to facilitate AE attribution assessment. 
 

 
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Deaths occurring within 30 days of study treatment regardless of relationship will be reported 
to the University of Nebraska Medical Center Fred & Pamela Buffett Cancer Center Data 
Safety Monitoring Committee (DSMC).    
 
9.1 Adverse Experience Definitions 
Adverse Event: 
An adverse event (AE) is defined as any untoward medical occurrence in a clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have a causal relationship with this treatment.  An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, whether 
or not the event is considered causally related to the use of the product.  
 
An elective surgery or procedure that is scheduled to occur during a study will not be 
considered an adverse event if the surgery or procedure is being performed for a pre-existing 
condition and the surgery or procedure has been planned before study entry.  However, if the 
pre-existing condition deteriorates unexpectedly during the study (i.e.., the surgery is 
performed earlier than planned), then the deterioration of the condition for which the elective 
surgery or procedure is being done will be considered an adverse event.  
 
Any worsening of a pre-existing condition or illness is considered an adverse event.  
Laboratory abnormalities and changes in vital signs are considered to be adverse events if they 
result in discontinuation from the study, necessitate therapeutic medical intervention, meet 
protocol specific criteria and/or if the Investigator considers them to be adverse events.  
 
Unexpected Adverse Event: 
An unexpected adverse event is any adverse drug event that is not listed in the current 
labeling/Investigator’s Brochure. This includes events that may be symptomatically and 
pathophysiologically related to an event listed in the labeling, but differ from the labeled event 
because of greater severity or specificity. For example, under this definition, hepatic necrosis 
would be unexpected (by virtue of greater severity) if the labeling only referred to elevated 
hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis 
would be unexpected (by virtue of greater specificity) if the labeling only listed cerebral 
vascular accidents. “Unexpected,” as used in this definition, refers to an adverse drug 
experience that has not been previously observed (i.e., included in the labeling) rather than 
from the perspective of such experience not being anticipated from the pharmacological 
properties of the pharmaceutical product. 
 
Serious Adverse Event: 
A serious adverse event is one that at any dose (including overdose) and regardless of causality 
that: 
 
Results in death 
 
Is a serious threat to life, health, safety, or welfare of subject1 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Persistent or significant disability or incapacity2 

 
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 
Is a congenital anomaly or birth defect 
 
Another serious important medical event3 
 
Any medical event in an investigational drug study that requires treatment to prevent one 
of the outcomes listed above 
 
The rights, safety, or welfare of subjects is seriously jeopardized. 
 
1“Life-threatening” means that the subject was at immediate risk of death at the time of the serious adverse event; it does not 
refer to a serious adverse event that hypothetically might have caused death if it were more severe. 
2“Persistent or significant disability or incapacity” means that there is a substantial disruption of a person’s ability to carry 
out normal life functions. 
3Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate in situations 
where none of the outcomes listed above occurred.  Important medical events that may not be immediately life-threatening 
or result in death or hospitalization but may jeopardize the subject or may require intervention to prevent one of the other 
outcomes listed in the definition above should also usually be considered serious.  Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse.  A new diagnosis of cancer during 
the course of a treatment should be considered as medically important. 
 
9.2 Adverse Event Reporting and Definitions Per the University of Nebraska Medical 
Center Institutional Review Board (UNMC IRB) and the University of Nebraska 
Medical Center Fred & Pamela Buffett Cancer Center Data and Safety Monitoring 
Committee (DSMC)  
9.2.1 IRB REPORTING 
All internal serious adverse events (SAEs) must be reported to the University of Nebraska 
Medical Center Institutional Review Board (UNMC IRB) promptly, per Institutional Policy 
and in no case later than two (2) business days following PI notification that the event 
occurred.  If the PI determines that conditions A, and B are met:  
a. 
The AE is unexpected, 
 
AND 
b. 
The AE is related to, or possibly related to, the drug biologic, device, or other 
research intervention. 
 
 
All unexpected, internal, fatal AEs must be reported promptly to the local IRB per Institutional 
Policy, but no later than 24 hours following PI notification that the event occurred. If 
documentation is still pending, the IRB office must be notified by a telephone call or e-mail. 
 
All expected, internal, fatal AEs (i.e., due to progressive disease or which reflect a risk 
currently found in the consent form) must be reported to the local IRB per Institutional Policy 
no later than ten (10) business days following PI notification that the event occurred.   
9.2.2 Fred & Pamela Buffett Cancer Center Data and Safety Monitoring Committee 
(DSMC) Reporting 
All grade 3 or greater toxicities (expected and unexpected, regardless of attribution) will be 
reported to the DSMC.  
All AE’s and SAE’s irrespective of attribution, when occurring after the start of the study 
drug, will need to be reported to the DSMC. 
 

 
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Attribution of AE: The Investigator will assign a causal relationship for all reportable AE’s 
according to the NCI Common Toxicity Criteria.  The likelihood of relationship of the AE to 
the study drugs will be determined by the Investigator based on the following definitions: 
 
Not related:  The subject was not exposed to the study treatment or another cause is obvious 
(AE related to underlying or concurrent illness). 
 
Probably not related: The AE is most likely explained by another cause, and the time of 
occurrence of the AE is not reasonably related to the study treatment (AE has no temporal 
relationship to the study drug and/or a more likely etiology exists). 
 
Possibly related:  Study treatment administration and AE occurrence reasonably related in 
time, and the AE is explained equally well by causes other than study treatment or treatment 
administration and AE occurrence are not reasonably related in time, but the AE is not 
obviously a result of other causes (AE has strong temporal relationship to study drug, 
alternative etiology is equal or less likely). 
 
Probably related:  Study treatment administration and AE occurrence are reasonably related 
in time, and the AE is more likely explained by study treatment than by other mechanisms 
(AE has strong temporal relationship to the study drug or recurs on re-challenge, another 
etiology is unlikely or significantly less likely). 
 
Definitely related: There occurrence and timing of the AE are clearly attributable to the study 
treatment.  
 
Severity Grade of AE.  The severity of events reported on the AE case report form will be 
determined by the principal investigator according the NCI Common Toxicity Criteria (CTC 
version 4.0).  
 
AEs will be collected from the time the subject starts the study drugs and ending 30 days 
following the final chemotherapy. All AEs will be followed until resolution, baseline, or ≤ 
grade 1 levels. Prescription medication taken to relieve symptoms of the AE will be recorded 
in addition to the outcome.  
 
AEs judged by the Investigator as not related or probably not related to the study drugs will 
NOT be followed beyond the 30 days after the final chemotherapy.  
 
ALL internal/external Adverse Events (AEs) will be reported to the UNMC Fred & Pamela 
Buffett Cancer Center Data and Safety Monitoring Committee (DSMC) using the DSMC 
approved forms. The DSMC will also review the protocol on at least a quarterly basis.  A 
copy of the Policy and Procedures for this section may be reviewed at: 
http://www.unmc.edu/cancercenter/clinical/prms.html.  
 
9.2.3 FOOD AND DRUG ADMINISTRATION (FDA) REPORTING 
It is the responsibility of the UNMC Sponsor-Investigator, Apar Ganti, M.D., to submit to 
the FDA Post-marketing Safety Reports in accordance with 21 CFR 314.80.  
 

 
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SAEs not meeting Post-marketing 15-day “Alert” will not be made available to FDA by the 
sponsor-investigator pursuant to 21 CFR 314.80 (c)(1)(i).  
 
All sites will utilize the FDA MedWatch Form (See Appendix F) for the reporting of serious 
adverse events (SAEs) and follow up information to those events. The form can be found at the 
following URL: http://www.fda.gov/Safety/MedWatch/default.htm 
 
It is the responsibility of ALL sites to submit the completed MedWatch Form, SAE PI 
Assessment Form and SAE (located in your Study Manual) to the UNMC Project 
Coordinator within 24 hours of his/her knowledge of the SAE:   
 
The SAE information will be routed to the UNMC PI who will further evaluate the SAE. The 
SAE will be submitted to FDA if the PI determines 21 CFR 314.80 (c) criteria are met.  
 
SAE reporting instructions are reiterated and further outlined in the Participating Site Study 
Manual. 
 
9.3 Auditing   
The UNMC Fred & Pamela Buffett Cancer Center Protocol Review & Monitoring System 
(PRMS) Office Audit Committee defines a Participating/Collaborating Site as: a hospital 
clinic, or other provider of medical services who has agreed to participate in a therapeutic 
trial that has been designed and developed by a University of Nebraska Medical 
Center/Nebraska Medicine Investigator and is Sponsored by UNMC. 
 
For participating/collaborating site(s) that are NCI Designated Cancer Centers, the protocol 
specific finding of the site’s Audit Committee will be submitted to the UNMC Audit 
Committee for review on a schedule to be determined by the UNMC Audit Committee. 
 
For participating/collaborating site(s) that are not NCI Designated Cancer Centers, the Audit 
process will be established by the UNMC Audit Committee on a site-by-site basis. 
 
The UNMC Fred & Pamela Buffett Cancer Center Scientific Review Committee (SRC) will 
review this protocol on at least an annual basis.  
 
This study will undergo Audit on at least a semi-annual basis by the UNMC Fred & Pamela 
Buffett Cancer Center Audit Committee.  
 
A copy of the Policy and Procedures for this section may be reviewed at: 
http://www.unmc.edu/cancercenter/clinical/prms.html.  
 
9.4  Monitoring 
9.4.1  Communication 
Various methods will be implemented by the Sponsor to exchange information with 
participating/collaborating sites.  Methods of communication will include: 
 
• Site Initiation/Orientation 

 
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• Regular Teleconferences, including group wide progress within the agenda 
• Investigator meetings, as feasible (remote or TBA, possibly in conjunction with larger 
meetings) 
• Email distributions/reports, as needed. 
 
 9.4.2 Ongoing safety monitoring for all the subjects in this study: 
All Participating/Collaborating sites are required to execute a Data Compliance Policy 
Agreement.  UNMC will monitor the data of sites in adherence to applicable research 
regulations, the protocol and the Policy Agreement. De-identified source documents, which 
support data entered, must be provided to the Sponsor by mail, fax or electronic means for 
centralized compliance monitoring. 
 
9.4.3  Data and Safety Monitoring Plan 
The UNMC Fred & Pamela Buffett Cancer Center Data and Safety Monitoring Plan is 
designed to ensure the safety of participants in clinical trials conducted by the UNMC Fred 
& Pamela Buffett Cancer Center members and to comply with National Cancer Institute 
(NCI) and National Institutes of Health (NIH) requirements.  This protocol will comply with  
all Monitoring Policies and Procedures outlined in the Monitoring Plan.   
 
Under the Guidelines of the Monitoring Plan, the: 
• 
UNMC Fred & Pamela Buffett Cancer Center Scientific Review Committee (SRC) is 
responsible for initial scientific review of protocols requiring informed consent; reviews 
all changes or amendments to previously reviewed protocols and reviews study progress 
at least annually.  The SRC is also responsible for the ongoing annual scientific review 
of UNMC Fred & Pamela Buffett Cancer Center protocols. 
• 
UNMC Fred & Pamela Buffett Cancer Center Data and Safety and Safety Monitoring 
Committee (DSMC) is responsible for the ongoing monitoring of Investigator Initiated 
intervention trials to ensure subject safety (i.e., adverse events). 
• 
UNMC Fred & Pamela Buffett Cancer Center Audit Committee is responsible for 
ensuring protocol compliance. 
 
The Data and Safety Monitoring Plan also includes adherence to Data Safety Monitoring 
Preparation and Reporting. The study PI, Research and Data Coordinator reviews all 
Serious Adverse Events occurring on all Investigator Initiated intervention trials on an 
ongoing basis per the SOP. In addition, the DSMC reviews all safety data of all subjects 
enrolled on these trials every 3 months and may convene for a special session when 
necessary. CTCAE v4.0 will be used to determine grading of adverse events. 
 
A copy of the Policy and Procedures for this section may be reviewed at: 
http://www.unmc.edu/cancercenter/clinical/prms.html. 
 
10.0 Statistical considerations including stopping criteria 
The intent to treat analysis will be conducted for all eligible subjects (See Section 10.5 
Evaluable Subject). 
 

 
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10.1 Primary Endpoint  
The primary endpoint for this study is the overall response rate (complete or partial response 
rate, defined in section 6.1.2) as defined by the RECIST Version 1.1 criteria at 15 weeks of a 
chemotherapy regimen involving docetaxel and capecitabine as front line therapy for subjects 
with advanced squamous cell carcinoma of the head and neck who are not candidates for 
surgery or radiation therapy. 
 
10.2 Secondary endpoints 
• 
Progression-Free Survival 
• 
Survival 
• 
Incidence and severity of adverse events 
• 
Quality of Life of subjects will be assessed using the European Organisation for 
Research and Treatment of Cancer QLQ Questionnaire-Core 30 (QLQ-C30) and QLQ-
Head and Neck 35 (QLQ-H&N35) module 
 
10.3 Sample Size  
 
1st Stage = 18 evaluable subjects  
 
(interim analysis) 
 
2nd Stage = 25 evaluable subjects 
 
For a total of = 43 evaluable subjects 
 
Rationale for sample size parameters: 
The combination of docetaxel and capecitabine has been studied in other solid tumors with 
reasonable efficacy and toxicity. In a randomized phase III study in pre-treated metastatic 
breast cancer, the capecitabine (1250 mg/m2)-docetaxel (75 mg/m2) combination was found 
to have a response rate of 32%30. However 27% of subjects discontinued treatment due to 
adverse events.  
 
Sample size justification: 
This Phase II study will utilize a Simon35 optimal two-stage design and will be employed for 
this study, with 18 evaluable subjects accrued in the first stage.  If 2 evaluable subjects or 
fewer achieve a complete or partial response (defined in section 6.1.2) at week 15 then the 
study will be terminated.  If 3 or more evaluable subjects have achieved a complete or partial 
response, then 25 additional subjects will be accrued in the second stage, for a total of 43 
evaluable subjects.  When accrual to the second stage is complete, if 7 or fewer evaluable 
subjects have achieved a response then we will conclude that the docetaxel and capecitabine 
combination does not give a response rate of at least 25%.  This optimal two-stage design is 
to test the null hypothesis that the complete or partial response is <= 0.10 vs. the alternative 
that complete or partial response rate is ≥ 0.25 at the significance level of 0.05 and with power 
of 0.80. 
 
Currently, the three drug combination of platinum, 5-fluorouracil and cetuximab has a 
response rate of approximately 36%, while the doublet of platinum and fluorouracil has a 
response rate of approximately 20%9. We plan to study the experimental combination of 
docetaxel and capecitabine further only if it has a response rate of at least 25%.   
 

 
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10.4 Stopping Rules 
An interim analysis to include  monitoring of the complete or partial response rate at week 14 
as in Phase II oncology trials as follows: 
 
If 2 or fewer in the first 18 evaluable subjects experience complete or partial response (defined 
in section 6.1.2) at week 14, then STOP; otherwise continue to 43 evaluable subjects and 
declare the overall response rate acceptable if at least 8 complete or partial responses are 
observed.(29) 
 
The Principal Investigator at the University of Nebraska Medical Center will inform all sites 
when the study has enrolled 18 evaluable subjects.  At that time, enrollment will stop 
pending receipt of the interim analysis of the first 18 evaluable patients.  UNMC will require 
UNMC SRC/IRB/DSMB review of the interim analysis and SRC/IRB/DSMB approval to 
continue enrollment. 
 
To evaluate the adverse events profiles associated with the treatment, the maximum grade 
for each type of adverse event will be recorded for each patient and frequency tables will be 
reviewed to determine the overall patterns. The number and severity of grade ≥ 4 adverse 
events will be tabulated and summarized per the DSMC plan. If it is ever determined during 
a DSMC review that an unacceptable incidence of grade 4 neutropenia or other grade 4 non-
hematologic toxicities has occurred, the study will be stopped.   
 
Sequential boundaries will be used to monitor toxicity rate, defined as the proportion of 
patients who are withdrawn from the study due to treatment-related side effects, as 
determined by the treating physician. The accrual will be halted if excessive numbers of 
toxicities are seen, that is, if the number of toxicities is equal to or exceeds bn out of n 
patients with follow-up (See table below). This is a Pocock-type stopping boundary that 
yields the probability of crossing the boundary at most [probability of early stopping] when 
the rate of toxicity is equal to the acceptable rate of 0.30.  
 
The trial will be stopped if the number of toxicities is equal to or exceeds bn out of n 
patients with completed follow-up.  
 
Number of Patients, n 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 
Boundary, bn 
- - - 4 5 5 6 6 7 7 7 8 8 9 9 10 10 10 
Reference: Ivanova, A., Qaqish, B.F., and Schell, M.J. (2005). Continuous toxicity monitoring in 
phase II trials in oncology. Biometrics 61: 540-545. 
 
Subjects may be withdrawn from the study by the Investigator for the following reasons:  
• 
any adverse event or toxicity which compromises the subject’s ability to participate 
• 
disease progression 
• 
discontinuation of study drugs for any reason  
• 
major violation of the study protocol 
• 
suspected pregnancy 
• 
any intercurrent illness or condition which in the opinion of the Investigator would 
necessitate withdrawal from the study 
 

 
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Additionally, the subject may decide to withdraw from the study and will be offered 
consultation with the Investigator to discuss consequences and benefits of such withdrawal.  
 
Subjects, who discontinue treatment for any reason, will be followed for toxicity, relapse, 
and death as per any standard subject.  
 
10.5 Evaluable Subject  
Every subject who fulfills all aspects of subject eligibility who receives at least 2 complete 
courses of chemotherapy will be evaluable for the response endpoint.  
 
Subjects with a global deterioration of health status requiring permanent discontinuation of 
study treatment (taken off study) without objective evidence of disease progression will be 
counted as progressive disease. Every effort should be made to document the objective 
progression even after discontinuation of treatment.  Deaths will be counted as treatment 
failure. 
 
Every subject who fulfills all aspects of subject eligibility who receives a partial or complete 
course of chemotherapy will be evaluable for toxicity. Any exclusion, for any reason, must 
be specified by the responsible Investigator on the flow sheets. 
 
10.6 Analysis of Primary Endpoints 
The primary efficacy endpoint is the complete or partial response rate at week 14.  The best 
response within the first 14 weeks will determine the primary endpoint.  The response rates 
and 95% confidence intervals will be calculated.   
 
10.7 Analysis of Secondary Endpoints 
Partial response rates will be descriptively summarized using percentages and 95% 
confidence intervals.  
   
The Kaplan-Meier method will be used to estimate time to event distributions for 
progression-free survival (defined in section 6.2) and survival (defined in section 6.4). 
 
Adverse events will be summarized using subject level incidence rates so that a subject 
contributes once to any adverse event.  The number and percentage of subjects with any 
adverse event will be summarized for each course. Serious adverse events will be analyzed 
similarly. 
 
Quality of life endpoints will be descriptive summarized using means and 95% confidence 
intervals. The European Organisation for Research and Treatment of Cancer QLQ 
Questionnaire-Core 30 (QLQ-C30) and QLQ-Head and Neck 35 (QLQ-H&N35) module 
will be used for these assessments. 
 
11.0 Records to be kept 
Information regarding the actual treatments, adverse effects, radiographic and laboratory 
information, and pathology are to be recorded on appropriate forms in the eCRF.  Source 

 
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documents which support data entered must be maintained for centralized compliance 
monitoring.  Serious adverse events, when noted, will be recorded on site via the standard 
Serious Adverse Event (SAE) Form. 
11.1  Quality assurance 
Complete records must be maintained on each subject treated on the protocol. These records 
should include primary documentation (i.e., lab results, X-ray reports, scan reports, 
pathology reports, physician notes, etc.), which confirm that: 
- 
The subject met the eligibility criteria. 
- 
Signed informed consent was obtained prior to treatment. 
- 
Treatment was given according to protocol (i.e., dated notes about doses given and 
reasons for any dose modifications). 
- 
Toxicity was assessed according to protocol (i.e., laboratory reports, etc.). 
- 
Response was assessed according to protocol (i.e., x-ray, scan, lab reports, dated 
notes on measurements and clinical assessment, as appropriate) 
 
11.2  Advarra Electronic Data Capturing (EDC) System 
Data will be stored electronically for this study in the Forte EDC system contained on the 
Advarra secure server.  Data forms will not differ from the paper versions with the exception 
of an electronic format containing the UNMC Fred & Pamela Buffett Cancer Center and 
Advarra logo. 
 
Advarra EDC provides for remote data collection that meets FDA 21 CFR Part 11 
requirements as well as HIPAA and other regulatory requirements designed to enhance data 
security and protect subject confidentiality. Authorized users log into Advarra through a 
secure connection and must provide a valid username, password, and database ID.  
 
12.0 
Human Subjects Protection Issues and Subject Consent Process 
12.1 
Human Subjects Research Protection Training 
All personnel involved in this research project will have completed the OHRP-approved 
computer based training course on the Protection of Human Research Subjects. All clinical 
and correlative research included in this application will have approval by the institutional 
review board.  
12.2 
Study Population 
Subjects are from all socio-economic groups and will be entered into the study without bias 
with respect to gender or race. Attempts will be made to recruit minorities. No vulnerable 
subjects will be included in the study. 
12.3 
Sources of Material 
Pathology material will be reviewed, and the diagnosis confirmed by the University 
Nebraska Medical Center Pathology Department, as outlined in the protocol. 
12.4 
Recruitment and Informed Consent 
Subjects with advanced squamous cell carcinoma of the head and neck who are not candidates 
for surgery or radiation therapy will be available for recruitment. These subjects will be 
informed of the nature of this study, and will be asked to participate on a voluntary basis after 

 
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informing them of the possible risks and benefits of the study. A number of public registries 
may be accessible to health care providers and prospective subjects as listed on the title page. 
 
 
12.5 
Subject Competency 
Subjects will be eligible to participate in the study only if they are competent to give 
informed consent. A subject that the investigators judges to be incompetent will not be 
enrolled. 
12.6 
Process of Informed Consent 
If the subject chooses to be a participant in this study, informed consent will be  obtained by 
the investigators. The study and procedures involved including the risks will be explained in 
detail to each subject. It will be clearly explained to the subject that this is a research study 
and that participation is entirely on a voluntary basis. Subjects will be given the option to 
discuss the study with a family member, friend, counselor or, another physician. The 
participating investigators will be available to discuss the study with them. 
12.7 
Subject/Representative Comprehension 
When the process of informed consent is completed, the subject will be asked to state in 
his/her own words the purpose of the study, the procedures that will be carried out, potential 
risk, potential benefits to the subject, the alternatives and the right to withdraw from the 
study. If there are any indications that a given subject's comprehension is anything less than 
accurate, the points of confusion will be discussed and clarified. 
12.8 
Information Purposely Withheld  
No information will be purposely withheld from the subject.  
12.9 
Potential Benefits of the Proposed Research to the Subjects 
It is anticipated that the use of the protocol chemotherapy in this subject population 
represents a reasonable treatment option. There are risks associated with chemotherapy, but 
the risk to benefit ratio is considered acceptable for subjects with advanced squamous cell 
carcinoma of the head and neck.  
12.10 Potential Benefits to Society 
Information obtained from this study may help other subjects by contributing to the 
knowledge of the biology of advanced squamous cell carcinoma of the head and neck and to 
understand the potential clinical benefit of this regimen. 
12.11 Potential Risks 
The use of cytototoxic chemotherapy are associated with numerous potential risks. 
Combined chemotherapy is considered a valid treatment option for subjects with advanced 
squamous cell carcinoma of the head and neck. It is believed the treatment option outlined in 
the study will not pose significant additional risks compared to conventional treatment. 
12.12 Therapeutic Alternatives 
If  subjects choose not to participate in this study they may elect to receive standard therapy 
as per their primary oncologist, which may include other chemotherapy drugs, palliative 
radiation, best supportive care, or a combination of these approaches. The treatment 
recommendations may or may not be similar to treatment as described in this protocol. 

 
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12.13 Risk/Benefit Relationship 
Although there are inherent risks involved because of the use of chemotherapy, we anticipate 
that subjects who receive the treatment phase of the protocol will do no worse than expected 
with standard therapy, and may experience an improved outcome. The risk is considered to 
be acceptable in the setting of cancer. 
12.14 Consent Form Documents 
The consent document used in this study will include the adult consent document.  
 
13.0  References 
1. 
Siegel R, Naishadham D, Jemal A: Cancer statistics, 2012. CA Cancer J Clin 
62:10-29, 2012 
2. 
Carvalho AL, Nishimoto IN, Califano JA, et al: Trends in incidence and 
prognosis for head and neck cancer in the United States: a site-specific analysis 
of the SEER database. Int J Cancer 114:806-16, 2005 
3. 
Vokes EE, Weichselbaum RR, Lippman SM, et al: Head and neck cancer. N 
Engl J Med 328:184-94, 1993 
4. 
Vikram B, Strong EW, Shah JP, et al: Failure at distant sites following 
multimodality treatment for advanced head and neck cancer. Head Neck Surg 
6:730-3, 1984 
5. 
Yao M, Lu M, Savvides PS, et al: Distant Metastases in Head-and-Neck 
Squamous Cell Carcinoma Treated With Intensity-Modulated Radiotherapy. 
Int J Radiat Oncol Biol Phys 83:684-9, 2012 
6. 
Tupchong L, Scott CB, Blitzer PH, et al: Randomized study of preoperative 
versus postoperative radiation therapy in advanced head and neck carcinoma: 
long-term follow-up of RTOG study 73-03. Int J Radiat Oncol Biol Phys 20:21-
8, 1991 
7. 
Grandis JR, Pietenpol JA, Greenberger JS, et al: Head and neck cancer: 
meeting summary and research opportunities. Cancer Res 64:8126-9, 2004 
8. 
Forastiere AA, Metch B, Schuller DE, et al: Randomized comparison of 
cisplatin plus fluorouracil and carboplatin plus fluorouracil versus 
methotrexate in advanced squamous-cell carcinoma of the head and neck: a 
Southwest Oncology Group study. J Clin Oncol 10:1245-51, 1992 
9. 
Vermorken JB, Mesia R, Rivera F, et al: Platinum-based chemotherapy plus 
cetuximab in head and neck cancer. N Engl J Med 359:1116-27, 2008 
10. 
Braakhuis BJ, Kegel A, Welters MJ: The growth inhibiting effect of docetaxel 
(Taxotere) in head and neck squamous cell carcinoma xenografts. Cancer Lett 
81:151-4, 1994 
11. 
Huttmann C, Eckardt A, Fokas K, et al: [Experimental chemotherapy of 
xenotransplanted oral squamous epithelial carcinoma: effectiveness of 
docetaxel (taxotere) in the nude mouse model]. Mund Kiefer Gesichtschir 
3:257-62, 1999 
12. 
Eisenhauer EA, Vermorken JB: The taxoids. Comparative clinical 
pharmacology and therapeutic potential. Drugs 55:5-30, 1998 
 
13. 
Catimel G, Verweij J, Mattijssen V, et al: Docetaxel (Taxotere): an active 
                      drug for  
the treatment of patients with advanced squamous cell carcinoma of the head 
and neck. EORTC Early Clinical Trials Group. Ann Oncol 5:533-7, 1994 

 
IRB#762-14 Version 6.2 dated 01Jul2021 
 
Page 37 of 51 
14. 
Dreyfuss AI, Clark JR, Norris CM, et al: Docetaxel: an active drug for 
squamous cell carcinoma of the head and neck. J Clin Oncol 14:1672-8, 1996 
15. 
Couteau C, Yakendji K, Terret C, et al: [Taxotere (docetaxel) and CPT 11 
(irinotecan): phase I trials]. Bull Cancer 83:3-10, 1996 
16. 
Inuyama Y, Kataura A, Togawa K, et al: [Late phase II clinical study of 
RP56976 (docetaxel) in patients with advanced/recurrent head and neck 
cancer]. Gan To Kagaku Ryoho 26:107-16, 1999 
17. 
Jacobs C, Lyman G, Velez-Garcia E, et al: A phase III randomized study 
comparing cisplatin and fluorouracil as single agents and in combination for 
advanced squamous cell carcinoma of the head and neck. J Clin Oncol 10:257-
63, 1992 
18. 
Judson IR, Beale PJ, Trigo JM, et al: A human capecitabine excretion balance 
and pharmacokinetic study after administration of a single oral dose of 14C-
labelled drug. Invest New Drugs 17:49-56, 1999 
19. 
Reigner B, Blesch K, Weidekamm E: Clinical pharmacokinetics of 
capecitabine. Clin Pharmacokinet 40:85-104, 2001 
20. 
Miwa M, Ura M, Nishida M, et al: Design of a novel oral fluoropyrimidine 
carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours 
by enzymes concentrated in human liver and cancer tissue. Eur J Cancer 
34:1274-81, 1998 
21. 
Malet-Martino M, Jolimaitre P, Martino R: The prodrugs of 5-fluorouracil. 
Curr Med Chem Anticancer Agents 2:267-310, 2002 
22. 
Malet-Martino M, Martino R: Clinical studies of three oral prodrugs of 5-
fluorouracil (capecitabine, UFT, S-1): a review. Oncologist 7:288-323, 2002 
23. 
Schuller J, Cassidy J, Dumont E, et al: Preferential activation of capecitabine 
in tumor following oral administration to colorectal cancer patients. Cancer 
Chemother Pharmacol 45:291-7, 2000 
24. 
Martinez-Trufero J, Isla D, Adansa JC, et al: Phase II study of capecitabine as 
palliative treatment for patients with recurrent and metastatic squamous head 
and neck cancer after previous platinum-based treatment. Br J Cancer 
102:1687-91, 2010 
25. 
Pivot X, Chamorey E, Guardiola E, et al: Phase I and pharmacokinetic study 
of the association of capecitabine-cisplatin in head and neck cancer patients. 
Ann Oncol 14:1578-86, 2003 
26. 
Sawada N, Ishikawa T, Fukase Y, et al: Induction of thymidine phosphorylase 
activity and enhancement of capecitabine efficacy by taxol/taxotere in human 
cancer xenografts. Clin Cancer Res 4:1013-9, 1998 
27. 
O'Shaughnessy J, Miles D, Vukelja S, et al: Superior survival with capecitabine 
plus docetaxel combination therapy in anthracycline-pretreated patients with 
advanced breast cancer: phase III trial results. J Clin Oncol 20:2812-23, 2002 
28. 
Fujimoto-Ouchi K, Tanaka Y, Tominaga T: Schedule dependency of antitumor 
activity in combination therapy with capecitabine/5'-deoxy-5-fluorouridine and 
docetaxel in breast cancer models. Clin Cancer Res 7:1079-86, 2001 
29. 
Nadella P, Shapiro C, Otterson GA, et al: Pharmacobiologically based 
scheduling of capecitabine and docetaxel results in antitumor activity in 
resistant human malignancies. J Clin Oncol 20:2616-23, 2002 
30. 
Chan S, Romieu G, Huober J, et al: Phase III study of gemcitabine plus 
docetaxel compared with capecitabine plus docetaxel for anthracycline-

 
IRB#762-14 Version 6.2 dated 01Jul2021 
 
Page 38 of 51 
pretreated patients with metastatic breast cancer. J Clin Oncol 27:1753-60, 
2009 
31. 
Ferrero JM, Chamorey E, Oudard S, et al: Phase II trial evaluating a docetaxel-
capecitabine combination as treatment for hormone-refractory prostate cancer. 
Cancer 107:738-45, 2006 
32. 
Zhang J, Lee J, Urba S, et al: A phase II trial evaluating weekly docetaxel and 
capecitabine in patients with metastatic or advanced, locally recurrent head and 
neck cancers. Cancer Invest 28:910-6, 2010 
33. 
Frances N, Woloch C, Marouani H, et al: Optimize administration protocol of 
capecitabine plus docetaxel combination in metastatic breast cancer patients. 
Curr Top Med Chem 12:1665-8, 2012 
34. 
Gralla RJ, Osoba D, Kris MG, et al: Recommendations for the use of 
antiemetics: evidence-based, clinical practice guidelines. American Society of 
Clinical Oncology. J Clin Oncol 17:2971-94, 1999 
35. 
Simon R: Optimal Two-Stage Designs for Phase II Clinical Trials. Controlled 
Clinical Trials 10:1-10, 1989 
 
 
14.0 Data Forms       
Please refer to the Study Site Manual for the forms. 
 
 

 
IRB#762-14 Version 6.2 dated 01Jul2021 
 
Page 39 of 51 
 
APPENDIX A - Karnofsky Scale for Performance Status 
 
Scale (%)  
Description  
100  
 
Normal; no complaints  
90  
 
Able to carry on normal activities; minor signs or symptoms of disease  
80  
 
Normal activity with effort  
70  
 
Cares for self. Unable to carry on normal activity or to do active work  
60  
 
Requires occasional assistance but able to care for most of needs  
50  
 
Requires considerable assistance and frequent medical care  
40  
 
Disabled; requires special care and assistance  
30 
 
Severely disabled; hospitalization indicated though death not imminent  
20  
 
Very sick. Hospitalization necessary. Active supportive treatment  
                          necessary  
10  
 
Moribund  
0  
 
Dead  
Reference: Karnofsky DA, et al. Cancer 1:634-656, 1948.  
 
 
 
 
GRADE 
ECOG PERFORMANCE STATUS 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities; 
up and about more than 50% of waking hours 
3 
Capable of only limited selfcare; confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled; cannot carry on any selfcare; totally confined to bed or chair 
5 
Dead 
Reference: Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin 
Oncol. 1982;5:649-655. 
 
 
 

 
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APPENDIX B - ELIGIBILITY CHECKLIST  
 
 
 
Date Completed 
(ddMMMyyyy): 
    
IRB# 762-14 - Phase II Study of Docetaxel and Capecitabine in Advanced 
Squamous Cell  Carcinoma of the Head and Neck 
PI: Apar Kishor Ganti, MD 
Checklist #:  
Version 6.1  
Dated: 16Oct2019 
Institution:     
Subject ID:     
Subject Initials:     
Waiver #:       
INCLUSION CRITERIA:  Response should be YES 
YES 
NO 
N/A 
1.  Histologically proven squamous cell carcinoma of the head and neck with measurable disease that is either 
recurrent after    attempted cure with surgery and/or radiation therapy or newly diagnosed disease with distant 
metastases or incurable at diagnosis. 
☐ 
☐ 
☐ 
2. Performance Status: Karnofsky score ≥70 or ECOG 0-2 (See Appendix A).     Enter PS:      
☐ 
☐ 
☐ 
3. Age 19 years or older (the age of consent in Nebraska); Age 18 years or older applicable to States where the age 
of majority is 18.                                                                                                   Enter Age:     
☐ 
☐ 
☐ 
4.  No prior cytotoxic chemotherapy for metastatic squamous cell carcinoma of the head and neck. Subjects who 
have received chemotherapy as part of a multi-modality curative approach for head and neck cancer will be 
eligible as long as they have not received either docetaxel or capecitabine (or 5-FU) as part of that regimen.  
Patients who have received single agent immune checkpoint inhibitors for metastatic disease will be eligible. 
☐ 
☐ 
☐ 
5. Adequate pre-treatment bone marrow reserve; WBC count ≥3,500/mm3, platelet count ≥100,000/mm3).                 
Enter WBC:                     Enter Platelet count:      
☐ 
☐ 
☐ 
6. Adequate renal function; serum creatinine less than 1.5 times the upper limits of normal.                               
Enter creatinine:         
☐ 
☐ 
☐ 
7. Adequate hepatic function: serum AST and ALT less than 1.5 times the upper limits of normal, serum alkaline 
phosphatase less than 2.5 times the upper limits of normal, serum total bilirubin is less than or equal to the upper 
limits of normal. 
      Enter AST:                        Enter ALT:                Enter Alk Phos:                Enter Total Bilirubin:       
☐ 
☐ 
☐ 
8.  PT or INR, and PTT ≤ 1.5 x upper limit of normal unless subject is receiving anticoagulants. If the subject is 
on anticoagulation therapy, levels should be within therapeutic range.  
      Enter PT or INR:       /                                          Enter  PTT:       
☐ 
☐ 
☐ 
9. Women of reproductive potential must be non-pregnant and non-nursing and must agree to employ 2 effective 
methods of birth control throughout the study and for up to 6 months following treatment. 
☐ 
☐ 
☐ 
10. Women of child-bearing potential must have a negative pregnancy test within 7 days of initiating study. (No 
childbearing potential is defined as age 55 years or older and no menses for two years or any age with 
surgical removal of the uterus and/or both ovaries).   Enter date: __/___/____ and  Result        
☐ 
☐ 
☐ 
11. The subject must be aware of the neoplastic nature of his/her disease and willingly provide written informed 
consent after being informed of the procedure to be followed, the experimental nature of the therapy, 
alternatives, potential benefits, side-effects, risks, and discomforts. 
☐ 
☐ 
☐ 
All of the above must be yes to be eligible.  

 
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APPENDIX B - ELIGIBILITY CHECKLIST (Continued) 
 
 
 
Date Completed 
(ddMMMyyyy): 
    
IRB# 762-14 - Phase II Study of Docetaxel and Capecitabine in Advanced 
Squamous Cell  Carcinoma of the Head and Neck 
PI: Apar Kishor Ganti, MD 
Checklist #:  
Version 6.1  
Dated: 16Oct2019 
Institution:     
Subject ID:     
Subject Initials:     
Waiver #:       
EXCLUSION CRITERIA: Response should be NO 
YES 
NO 
N/A 
1. Prior cytotoxic chemotherapy for metastatic squamous cell carcinoma of the head and neck. Subjects who have 
received chemotherapy as part of a multi-modality curative approach for head and neck cancer will be eligible 
as long as they have not received either docetaxel or capecitabine (or 5-FU) as part of that regimen. 
☐ 
☐ 
☐ 
2. Patients who have received chemotherapy in combination with immunotherapy for metastatic disease. 
☐ 
☐ 
☒ 
3. Allergy to either of the study medications or 5-fluorouracil. 
☐ 
☐ 
☐ 
4. Simultaneous participation in other therapeutic clinical trials. 
☐ 
☐ 
☐ 
5. Because of potential drug interactions between allopurinol/cimetidine/antivirals and  5-FU, if a subject is 
receiving any of these drugs they must be discontinued prior to starting this protocol. 
☐ 
☐ 
☐ 
6. Prior malignancy, except for adequately treated basal cell or squamous cell carcinoma ofthe skin, or thyroid 
cancer.; carcinoma in situ of the cervix or breast; prostate cancer of Gleason Grade 6 or less with stable PSA 
levels (GnRH analogs or androgen receptor blockers acceptable); or other cancers from which the subject has 
been disease-free for at least five years. 
☐ 
☐ 
☐ 
7. Uncontrolled intercurrent illnesses including, but not limited to symptomatic congestive heart failure, severe 
oxygen dependent chronic obstructive pulmonary disease, unstable angina or uncontrolled cardiac arrhythmia 
that could jeopardize the subject’s ability to receive the chemotherapy described in the protocol safely. 
☐ 
☐ 
☐ 
8. Pregnant OR nursing woman. 
☐ 
☐ 
☐ 
9. Inability to co-operate with the study visit schedule and other requirements of the protocol. 
☐ 
☐ 
☐ 
10. Any other clinically significant medical disease or condition laboratory abnormality or psychiatric illness that, 
in the Investigator’s opinion, may interfere with protocol adherence or a subject’s ability to give informed 
consent. 
☐ 
☐ 
☐ 
All of the above must be no to be eligible. 
Eligibility: 
☐  Patient satisfies all criteria 
☐  Patient not formally eligible, but admitted to this study because (state reason):      
☐  Patient is not eligible for this study. 
 
ELIGIBILITY reviewed and confirmed.  
 
Investigator Signature _________________________________     Date_________________        
 
Printed Name of Investigator:  __________________________________________________ 
 

 
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APPENDIX C - Body Surface Area Calculation 
 
Body surface area (BSA) should be calculated using a standard nomogram that yields the 
following results in meters squared (m2):  
 
BSA = 
3131
)
(
)
(
lbs
Wt
inches
Ht
×
 
or 
BSA = 
3600
)
(
)
(
kg
Wt
cm
Ht
×
 
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX D - Oral, Sublingual, and/or Buccal Route Medication Adherence Standard 
Procedure  (V 1.0 11-25-2013) 
 
PURPOSE 
To provide a means of ensuring oral, sublingual and/or buccal routes of medication 
adherence to patients while participating in a clinical trial. 
1. A physician’s order will be completed by study patients or representative for oral, 
sublingual and/or buccal administration per IRB approved protocol. 
2. To ensure the consistent and safe administration of medications not given under the 
direct supervision of study staff (at home), there will be a “Medication Information 
Sheet” and a calendar to document times of drug administration. 
3. To record medication adherence Study staff will document results of medication 
reconciliation and or medication return in the patient’s chart. 
4. Maintain documentation of medications returned or sent to investigational pharmacy 
for destruction (if applicable).  
PROCEDURE 
1. Protocol specific information regarding the individual medication(s) should be listed 
on the form “Medication Information Sheet” and given to the patient at the start of 
the study and throughout treatment if necessary to help ensure adherence. (See Form 
A) 
 
2. Name, dose and route of each medication should be listed under ‘How to take your 
Medication’ on the “Medication Information Sheet”. 
 
3. Patients will be given a monthly “Medication Calendar”.  The calendar will have a 
place for the patient to record the time that the medication(s) were taken. (See Form 
B for example) 
 
4. The research nurse will review the patient’s “Medication Calendar” for adherence to 
the study regimen for oral medication administration. Adherence will be noted in the 
patient’s chart.  Medication reconciliation will be done and if there is medication to 
be returned/destroyed it will be sent to the Nebraska Medical Center Investigational 
Pharmacist for return/destruction in accordance to the Nebraska Medical Center 
Destruction of Investigational product, Policy #4.860.   

 
IRB#762-14 Version 6.2 dated 01Jul2021 
 
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Medication Information Sheet (Form A) 
 
Patient Name:          ___________________          Study or MRN #: ___________________ 
 
Title of protocol: Phase II Study of Docetaxel and Capecitabine in Advanced Squamous 
Cell Carcinoma of the Head and Neck 
 
 
IRB# 762-14 
 
 
Medication: Capecitabine (Xeloda®) is a chemotherapy pill. 
 
How to take your medication: Capecitabine (Xeloda®)  The total daily dose _____mg 
(___tablets) should be taken by mouth in two divided doses _____mg (___tablets) in the 
morning and _____mg (___tablets) evening about 12 hours apart every day for 14 days in a 
row. The total daily dose in mg will be rounded down to the nearest tablet size. If the 
dosing calls for an uneven number of pills, the larger dose will be given in the evening.  
Follow your Medication Calendar that is provided to you by the research nurse. 
 
Things to know about your medication:  
 
1. You should take your medication at the same time each day and it should be taken 
within 30 minutes after taking a meal. 
2. Tablets should be swallowed whole with a full glass of water. If the tablets are 
accidentally opened or damaged, precaution should be taken to avoid inhalation or 
contact with the skin or mucous membranes. 
3. If you miss a dose of your medication, it should be skipped altogether. You should 
NOT double the next dose.  If a dose is missed make sure to mark it on your 
Medication Calendar (Form B). 
4. If the treatment is interrupted due to toxicity, the skipped doses should not be 
replaced. 
5. Return unused medication to your research nurse for proper procedures for 
handling and disposal of chemotherapy. 
 
 
Your research nurse is:  ___________________________ 
 
Contact information: phone _______________  
 
After hours, nights, weekends and holidays please call 402-559-5600 and ask for the 
Oncologist on call. 
 

 
IRB#762-14 Version 6.2 dated 01Jul2021 
 
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IRB#762-14 Version 6.2 dated 01Jul2021 
 
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APPENDIX E - NCI Common Toxicity Criteria Version 4.0 (CTCAE) Active Date: May 
29, 2009 
 
Toxicity will be scored using NCI CTC Version 4.0 for toxicity and adverse event reporting.  
A copy of the NCI CTC Version 4.0 can be downloaded from the CTEP homepage:  
 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm   
 
All appropriate treatment areas have access to a copy of the CTC Version 4.0.  
 
Minor editorial updates have been made to CTCAE v4.0, which are represented in 
v4.03.  These edits do not change the meaning of v4.0 content and all previous versions 
(CTCAE v4.0, v4.01, v4.02) are still valid and referred to as CTCAE v4.0.  V4.03 includes 
clarifications for a select few grading scales and adverse event term definitions.  Most of 
the revisions are associated with grading scales that include a quantitative component.  A 
list of changes is located at :  
 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html  
 
An updated version (4.03) is now in use as of June 14, 2010. 
 
 
 
 
 
APPENDIX F - FDA MEDWATCH form 3500A 
 
Available on-line at:  
https://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM048334.pdf 
http://www.fda.gov/medwatch/SAFETY/3500.pdf 
 
 
 

 
IRB#762-14 Version 6.2 dated 01Jul2021 
 
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APPENDIX G - European Organisation for Research and Treatment of Cancer Quality 
of Life Questionnaire Core 30 (EORTC QLQ-C30) 
 
 
 

 
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IRB#762-14 Version 6.2 dated 01Jul2021 
 
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APPENDIX H - Quality of Life Questionnaire Core Head and Neck 35 (QLQ-HN35) 
 
 
EORTC QLQ - 
H&N35 
 
Patients  sometimes  report  that  they  have  the  following  symptoms  or  problems.  Please  
indicate  the extent  to  which  you  have  experienced these  symptoms  or  problems  during  
the  past  week.  Please answer by circling the number that best applies to you. 
 
During the  past week: 
Not 
at all 
A 
little 
Quite 
a bit 
Very 
much 
31. 
Have you had pain in your mouth? 
1 
2 
3 
4 
32. 
Have you had pain in your jaw? 
1 
2 
3 
4 
33. 
Have you had soreness in your mouth? 
1 
2 
3 
4 
34. 
Have you had a painful throat? 
1 
2 
3 
4 
35. 
Have you had problems swallowing liquids? 
1 
2 
3 
4 
36. 
Have you had problems swallowing pureed food? 
1 
2 
3 
4 
37. 
Have you had problems swallowing solid food? 
1 
2 
3 
4 
38. 
Have you choked when swallowing? 
1 
2 
3 
4 
39. 
Have you had problems with your teeth? 
1 
2 
3 
4 
40. 
Have you had problems opening your mouth wide? 
1 
2 
3 
4 
41. 
Have you had a dry mouth? 
1 
2 
3 
4 
42. 
Have you had sticky saliva? 
1 
2 
3 
4 
43. 
Have you had problems with your sense of smell? 
1 
2 
3 
4 
44. 
Have you had problems with your sense of taste? 
1 
2 
3 
4 
45. 
Have you coughed? 
1 
2 
3 
4 
46. 
Have you been hoarse? 
1 
2 
3 
4 
47. 
Have you felt ill? 
1 
2 
3 
4 

 
IRB#762-14 Version 6.2 dated 01Jul2021 
 
Page 50 of 51 
48. 
Has your appearance bothered you? 
1 
2 
3 
4 
 
During the  past week: 
Not 
at all 
A 
little 
Quite 
a bit 
Very 
much 
49.  
Have you had trouble eating?  
1 
2 
3 
4 
 
50.  
Have you had trouble eating in front of your family?  
1 
2 
3 
4 
 
51.  
Have you had trouble eating in front of other people?  
1 
2 
3 
4 
 
52.  
Have you had trouble enjoying your meals?  
1 
2 
3 
4 
 
53.  
Have you had trouble talking to other people?  
1 
2 
3 
4 
 
54.  
Have you had trouble talking on the telephone?  
1 
2 
3 
4 
 
55.  
Have you had trouble having social contact with your family?  
1 
2 
3 
4 
 
56.  
Have you had trouble having social contact with friends?  
1 
2 
3 
4 
 
57.  
Have you had trouble going out in public?  
1 
2 
3 
4 
 
58.  
Have you had trouble having physical 
contact with family or friends?  
1 
2 
3 
4 
 
59.  
Have you felt less interest in sex?  
1 
2 
3 
4 
 
60.  
Have you felt less sexual enjoyment?  
1 
2 
3 
4 
 
 
During the past week: 
No  
Yes 
 
61.  
Have you used pain-killers? 
1 
2 
 
62.  
Have you taken any nutritional supplements (excluding vitamins)?  
1 
2 
 
63.  
Have you used a feeding tube?  
1 
2 
 
64.  
Have you lost weight?  
1 
2 
 
65.  
Have you gained weight?  
1 
2 
 
 
 
© Copyright 1994  EORTC Quality of Life Study  Group, version  1.0  All rights reserved 
 
 
 

 
IRB#762-14 Version 6.2 dated 01Jul2021 
 
Page 51 of 51 
APPENDIX I - Schedule of HBM Sample Assessments (for research purposes only) 
 
Sample Collection: Source and Human Biologic Material (HBM) to be used: We will use 
two- 10 mL EDTA (lavender top tubes) and one- 10 mL (red top tube) for blood sample 
collection.  We will collect 10 mL urine sample from the patient to store for future research 
purposes including DNA sequencing. (See Protocol Section 5.6 for details).  
 
No therapeutic intervention will be undertaken and the results of these studies will not have any 
influence on the medical management of the subjects.  
Facility 
Sample 
Contact Person(s) and 
Shipping Address 
Date and Time Points 
 
Laboratory of David L. 
Kelly, PhD 
Fred & Pamela Buffett 
Cancer Center 
 
 
Blood: (30 mL total) two-10ml 
EDTA (lavender top) and  
one- 10ml (red top) blood 
collection  
Urine: 10 mL urine collection 
Deliver or ship same day at room 
temperature 
 
 
 
 
 
 
 
 
 
David L. Kelly PhD 
Tel: (402) 559-9157 
Cell: (402) 699-1132 
Fax: (402) 559-4651 
Email:  dkelly@unmc.edu 
 
Amy Wells, MS 
Research Technologist 
Tel: (402) 559-6015 
Email:  awells@unmc.edu  
 
Shipping address: 
Attn:  Amy Wells, MS 
University of Nebraska Medical 
Center 
601 S. Saddle Creek Rd. 
Fred & Pamela Buffett Cancer 
Center, Room # BCC 5.12.429 
Omaha, Nebraska  68106 
 
☐  Baseline Blood Sample  
      Date: ___/___/____ 
☐  Baseline Urine  Sample  
      Date: ___/___/____ 
 
 
☐  After cycle 2, Blood Sample 
       Date: ___/___/____ 
☐  After cycle 2, Urine Sample 
       Date: ___/___/____ 
 
☐  End of study, Blood Sample 
      Date: ___/___/____ 
☐  End of study, Urine Sample 
      Date: ___/___/____ 
Please contact Amy Wells above to advise of planned shipments and/or the Research Support Nurse Manager at 402-559-5286 to discuss 
 appropriate procedures.   
 
Visit 
Specimen 
Type 
Collection 
amount 
Tube 
Handling 
Instructions 
Baseline 
Whole blood 
 
 
 
Urine 
30 mL 
 
 
 
10 mL 
• 
2 - 10 mL lavender 
top tubes  
• 
1 10 mL red top tub 
 
• 
Urine cup 
 
Whole blood - Store and 
Ship at 4ºC 
 
Plasma sample – The 
samples should be 
maintained at 2-8°C while 
handling. Gently invert tube 
with blood.  Centrifuge for 
15min at 3,000 rpm at 4°C 
(no breaks).  Transfer 
plasma to clean tube and 
store at 2–8°C.  Deliver or 
ship the same day as 
collection at room 
temperature. 
After 2 cycles  
Whole blood 
 
 
 
Urine 
30 mL 
 
 
 
10 mL 
• 
2 - 10 mL lavender 
top tubes  
• 
1 10 mL red top tub 
 
• 
Urine cup 
End of Study 
Whole blood 
 
 
 
Urine 
30 mL 
 
 
 
10 mL 
• 
2 - 10 mL lavender 
top tubes  
• 
1 10 mL red top tub 
 
• 
Urine cup