Conditions: Stage II Lymphoepithelioma of the Nasopharynx Stage II Squamous Cell Carcinoma of the Nasopharynx Stage III Lymphoepithelioma of the Nasopharynx Stage III Squamous Cell Carcinoma of the Nasopharynx Stage IV Lymphoepithelioma of the Nasopharynx Stage IV Squamous Cell Carcinoma of the Nasopharynx
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 26
Healthy volunteers: no

Brief summary:
This phase 2 trial is studying whether giving a combination of docetaxel, cisplatin, and fluorouracil chemotherapy followed by the combination of cisplatin with radiation therapy works in treating patients with advanced nasopharyngeal cancer. Drugs used in chemotherapy, such as docetaxel, cisplatin, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Giving combination chemotherapy together with radiation therapy may kill more tumor cells.

Detailed description:
PRIMARY OBJECTIVE:

• To establish the progression free survival rate at 2 years, using RECIST criteria, to induction treatment with docetaxel, cisplatin, and fluorouracil (TPF) followed by chemoradiotherapy of locoregionally advanced nasopharyngeal carcinoma (NPC)

SECONDARY OBJECTIVE:

• To evaluate complete response rates, safety and feasibility of TPF followed by chemoradiation in patients with NPC

OUTLINE: This is a single site study.

INDUCTION THERAPY: Patients receive docetaxel intravenously (IV) over 60 minutes on Day 1; cisplatin IV over 1 to 3 hours (or carboplatin IV over 30 minutes) on Day 1; and fluorouracil IV continuously over 24 hours on Days 1 to 5. Each cycle is 21 days, with treatment consisting of up to 3 cycles in the absence of disease progression or unacceptable toxicity.

CONCURRENT CHEMO-RADIOTHERAPY: Beginning within 3 to 6 weeks after initiating the last course of induction chemotherapy, patients undergo 3-dimensional conformal or intensity-modulated radiotherapy once daily for 6.5 to 7 weeks. Patients also receive cisplatin IV over 1 hour (or carboplatin IV over 30 minutes) once weekly in weeks 1 to 6 in the absence of disease progression or unacceptable toxicity.

All study treatment is admininstered over the course of 21 weeks. After completion of study treatment, patients are followed periodically for 24 months.

Arms:
arm 1: INDUCTION THERAPY: Patients receive docetaxel intravenously (IV) over 60 minutes on Day 1; cisplatin IV over 1 to 3 hours (or carboplatin IV over 30 minutes) on Day 1; and fluorouracil IV continuously over 24 hours on Days 1 to 5. Each cycle is 21 days, with treatment consisting of up to 3 cycles in the absence of disease progression or unacceptable toxicity.

CONCURRENT CHEMO-RADIOTHERAPY: Beginning within 3 to 6 weeks after initiating the last course of induction chemotherapy, patients undergo 3-dimensional conformal or intensity-modulated radiotherapy once daily for 6.5 to 7 weeks. Patients also receive cisplatin IV over 1 hour (or carboplatin IV over 30 minutes) once weekly in weeks 1 to 6 in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: docetaxel intervention 2: cisplatin intervention 3: carboplatin intervention 4: fluorouracil intervention 5: 3-dimensional conformal radiation therapy intervention 6: intensity-modulated radiation therapy
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV intervention 4: Given IV intervention 5: Undergo 3-dimensional conformal or intensity-modulated radiotherapy intervention 6: Undergo 3-dimensional conformal or intensity-modulated radiotherapy

Protocol document:
Prot_SAP_000.pdf: 
TITLE:  A Phase 2 Study of Sequential and concurrent chemoradiation for patients with advanced 
nasopharyngeal carcinoma (NPC) 
 
IRB-15411  
Page 1 of 56 
5 December 2016 
NCT00896181 
 
Coordinating Center: 
Stanford Cancer Institute 
Stanford, CA 94305 
 
Principal Investigator: 
A. Dimitrios Colevas, M.D. 
Associate Professor of Medicine (Oncology) 
Stanford University Medical Center 
875 Blake Wilbur Drive 
Stanford, CA  94305-5826 
(650) 724-9707 
FAX (650) 498-5800 
colevas@stanford.edu 
 
Co- Principal Investigator: 
Quynh-Thu Le, MD 
Professor 
Clinical Research Director 
Department of Radiation Oncology 
Stanford University 
Tel xxx-xxx-xxxx 
Fax xxx-xxx-xxxx 
 
 
Co- Principal Investigator: 
Wendy Hara, MD 
Clinical Assistant Professor 
Department of Radiation Oncology 
Stanford University 
 
 
Statistician: 
Alex McMillan PhD 
Sr Res Scientist-Basic Ls in Health Research and Policy – Biostatistics 
Redwood Bldg, Stanford, California 94305 
 
 
Study Coordinators 
Mary Anderson May and Stefania Chirita 
800 Welch Road FC3C62 


TITLE:  A Phase 2 Study of Sequential and concurrent chemoradiation for patients with advanced 
nasopharyngeal carcinoma (NPC) 
 
IRB-15411  
Page 2 of 56 
5 December 2016 
 
 


TITLE:  A Phase 2 Study of Sequential and concurrent chemoradiation for patients with 
advanced nasopharyngeal carcinoma (NPC) 
 
IRB-15411  
Page 1 of 56 
5 December 2016 
SCHEMA 
 
 
 
 
 
 
 
 
* Under certain circumstances, carboplatin AUC 6 may be substituted for CDDP in TPF 
and carboplatin AUC 1.5 may be substituted for CDDP during radiation. See the protocol 
for specific circumstances under which this is permitted. 
Patients with nasopharyngeal carcinoma, types WHO I, II, or III 
No prior chemotherapy or radiation 
Prior diagnostic surgical procedures permitted 
AJCC stages II through IVb (IVc patients in separate cohort) 
Clinical imaging as needed 
  
“TPF” = Docetaxel 75 mg/m2, d1 + CDDP * 75 mg/m2, d 1 
 + 5-FU 750 mg/m2/d x 5, d 1-5 IVCI  
 
TPF q 21 d x 3 
Disease progression=> off protocol 
Disease response=> Chemoradiation: 
Cisplatin*, 40 mg/m2/week x 6 
 +radiation therapy, 70 Gy in 33 fractions to PTV,  
56-59.4 Gy in 33 fractions to subclinical regions 
Response evaluation  
Response evaluation (clinical, imaging) between 8 and 16 weeks post radiation 
completion 


TITLE:  A Phase 2 Study of Sequential and concurrent chemoradiation for patients with 
advanced nasopharyngeal carcinoma (NPC) 
 
IRB-15411  
Page 2 of 56 
5 December 2016 
TABLE OF CONTENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 
SCHEMA .............................................................................................................................. 
1. OBJECTIVES .................................................................................................................. 
1.1 Primary Objective ......................................................................................................... 
1.2 Secondary Objectives .................................................................................................... 
2. BACKGROUND .............................................................................................................. 
2.1 Nasopharyngeal Cancer ................................................................................................ 
2.2 Chemoradiation vs Radiation ....................................................................................... 
2.3 Adjuvant vs Neoadjuvant chemotherapy .................................................................... 
2.4 Carboplatin vs Cisplatin ................................................................................................ 
2.5 Taxanes………………………………………………………………………………... 
2.6 Radiation and NPC…………………………………………………………………… 
2.7 Rationale……………………………………………………………………………..... 
3. PATIENT SELECTION ................................................................................................. 
3.1 Eligibility Criteria  ......................................................................................................... 
3.2 Exclusion Criteria .......................................................................................................... 
3.3 Inclusion of Women and Minorities ............................................................................. 
4. REGISTRATION PROCEDURES .............................................................................. 
5. TREATMENT PLAN ...................................................................................................... 
5.1 Prophylactic Gastrostomy Feeding Tube .................................................................... 
5.2 Agent Administration .................................................................................................... 
5.3 Radiation therapy treatment plan ................................................................................ 
5.4 Duration of Follow Up ................................................................................................... 
6. DOSING DELAYS/DOSE MODIFICATIONS ............................................................ 
6.1       Docetaxel Dose Modification…………………………………………………………. 
6.2       Cisplatin and Carboplatin Dose Modification……………………………………… 
6.3      5-Fluorouracil (5-FU) Dose Modification……………………………………………. 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ..........…….. 
7.1  
Adverse Event Characteristics for commercial agents ......................................... 
 
7.1.1 Docetaxel ................................................................................................................ 
 
7.1.2 Cisplatin .................................................................................................................. 
 
7.1.3 Carboplatin .............................................................................................................. 


TITLE:  A Phase 2 Study of Sequential and concurrent chemoradiation for patients with 
advanced nasopharyngeal carcinoma (NPC) 
 
IRB-15411  
Page 3 of 56 
5 December 2016 
 
7.1.4 5-Fluorouracil ......................................................................................................... 
7.2  
Adverse Event Reporting ........................................................................................ 
7.3  
Routine AE collection .............................................................................................. 
8. PHARMACEUTICAL INFORMATION ...................................................................... 
8.1 Commercial Agent(s) Docetaxel, Cisplatin, Carboplatin, and 5- Fluorouracil.  ............. 
9. STUDY CALENDAR ...................................................................................................... 
10. MEASUREMENT OF EFFECT 
 
 
 
 
 
10.1 Antitumor Effect – Solid Tumors ............................................................................... 
11. STATISTICAL CONSIDERATIONS ......................................................................... 
11.1      Study Design/Endpoints……………………………………………………………... 
11.2      Sample Size/ Accrual Rate........................................................................................... 
11.3      Stratification Factors………………………………………………………………… 
11.4      Analysis of Secondary endpoints…………………………………………….. 
11.5      Reporting ……………………………………………………………………. 
REFERENCES ..................................................................................................................... 
APPENDICES 
 
Appendix A: Performance Status Criteria 
Appendix B: Radiation Quality Assurance Form 
Appendix C: Registration and data submission forms 


 
IRB-15411  
Page 1 of 56 
5 December 2016 
1. OBJECTIVES 
 
1.1 Primary Objective: To establish the progression free survival rate at 2 years, 
using RECIST criteria, to TPF followed by chemoradiotherapy of locoregionally 
advanced nasopharyngeal carcinoma 
 
1.2 Secondary Objectives: To evaluate complete response rates, safety and 
feasibility of TFP=> chemoxrt in patients with NPC 
 
2. BACKGROUND 
Background for the rationale of TPF=> chemoradiation 
2.1 Nasopharyngeal cancer   
Nasopharyngeal cancer (NPC) is a significant problem worldwide. The  annual incidence 
rate worldwide is  1.8/100,000  and the rate climbs to as high as 50/100,000 in Southern  
China .1 
2.2 CHEMORADIATION VERSUS RADIATION  
Historically, nonmetastatic NPC has been treated with radiation alone. Because of the 
known chemosensitivity of NPC, a series of randomized controlled trials of 
chemoradiotherapy versus radiotherapy conducted in the 1990’s and early 2000’s 
demonstrated that in patients with advanced local or regional disease, the addition of 
chemotherapy to radiation was associated with a statistically significant and clinically 
meaningful survival advantage. 5 6, 7  A smaller subsequent trial suggested that even in the 
case of patients with advanced local disease but minimal nodal disease (T3-4, N0-1), 
patients  had increased local control with the use of combined chemotherapy and 
accelerated fractionation radiation versus conventional radiation alone. 8  The table below 
is a summary of the RCT data supporting either an OS or LRC advantage of 
chemoradiation versus radiation: 
From IJROBP Volume 66, Number 1, 2006 p 150 8: 
 


 
IRB-15411  
Page 2 of 56 
5 December 2016 
The advantage to chemoradiation over radiation in the RCTs was distributed between 
both local and systemic effects. In the large RCT cited above, there was a substantial 
reduction in both locoregional recurrence and metastatic disease in the combined 
treatment arms versus radiation alone. 
In all of the RCT, the chemotherapy combined cisplatin – based chemotherapy with 
XRT, with cisplatin dosing plans including 40 mg/m2 weekly to 100 mg/m2  every 3 
weeks to 20mg/m2/d x 4 with concurrent 5FU infusion every 3 weeks. In the US 
intergroup study, an additional 3 cycles of cisplatin 80 mg/m2 plus 5FU 1000mg/m2/d x 
4 days was planned, to be administered after radiation had been completed. 
A common theme to all of these recipes is that in all cases cumulative dose of concurrent 
cisplatin exceeded 180mg/m2. However, in the US intergroup trial, where 300 mg/m2 ( 
three 100 mg/m2 doses) was the intent, only 63% of the patients received three cycles of 
CDDP. In the Chan et al. trial in which CDDP was administered weekly to an anticipated 
total of 240 mg/m2, 95% of the patients were compliant with the plan.  9 Therefore, while 
the optimal concurrent CDDP dosing schedule has yet to be defined, it appears that 
weekly dosing is more tolerable and in many cases dosing beyond a cumulative dose of 
200-240 mg/m2 is not feasible.  Additionally, of the 3 RCT discussed here, only one, the 
US intergroup study, administered adjuvant PF. Only about half of the patients 
randomized to the adjuvant PF were able to receive 3 cycles, and a third of the patients 
randomized to that arm received no adjuvant treatment. Therefore, since all 3 RCTs 
showed an overall survival advantage for patients with advanced disease, it is not clear 
that adjuvant PF has benefit beyond concurrent chemoradiation, nor is it clear that 
administration of PF after chemoradiation is feasible.   
2.3 Adjuvant versus neoadjuvant (or induction) chemotherapy 
The rationale behind administration of adjuvant PF in the intergroup trial was that the 
additional chemotherapy might reduce the number of distant relapses and therefore offer 
benefit beyond the concurrent treatment. However, a comparison of the outcome of the 
US intergroup versus the Chan and Lin trials suggests that the reduction in the 
development of distant metastasis was approximately 30 to 50% in patients with 
advanced disease on all of these trials. Therefore the benefit of adjuvant PF on this basis 
is also questionable. Again, this may be because so few patients in the US intergroup 
study were able to receive meaningful doses of PF after chemoradiation. 
Initial studies of induction chemotherapy added to radiation alone in NPC patients failed 
to show disease control or survival benefit. 10  Recent  pooled analysis of cisplatin- based 
induction chemotherapy versus radiation alone in NPC patients demonstrated  
improvement in relapse free and disease specific survival, but did not show an overall 
survival advantage.11  Subset analysis of these trials demonstrated a survival advantage of 
induction chemotherapy for patients with early stage, but not advanced stage disease. 
This subset analysis suggested that in all groups there was a numerical advantage to 
induction in terms of distant metastasis free survival in all groups, but because 
locoregional disease was the major contributor to relapse, it overshadowed any potential 
benefit to systemic control of disease. Therefore, with the development of better radiation 
techniques to control locoregional disease, we hypothesize that a more effective treatment 
of distant disease may translate into an OS advantage now that locoregional control rates 
have improved. 


 
IRB-15411  
Page 3 of 56 
5 December 2016 
There are ongoing RCT designed to definitively answer the question concerning the 
possible benefit of the addition of PF induction chemotherapy to concurrent 
chemoradiation in patients with NPC. Lee et al. of the Hong Kong Nasopharyngeal 
Cancer Study Group  are conducting a trial whose primary endpoint is a comparison of 
induction chemotherapy with Cisplatin + 5-Fluorouracil versus adjuvant chemotherapy 
with Cisplatin + 5-Fluororacil (PF-P vs P-PF) in the setting of concurrent chemoradiation 
as a backbone. This trial opened in September 2006 and is planning to enroll 798 patients 
with an estimated completion date of September 2013. See web site ClinicalTrials.gov, 
Identifier: NCT00379262.  Feng et al. of the Taiwan National Health Research Institutes 
opened in 2003 a multicenter Phase III Trial Comparing Induction Mitomycin, 
Epirubicin, Cisplatin, Fluorouracil, and Leucovorin Chemotherapy Followed by 
Concurrent Chemoradiotherapy Versus Concurrent Chemoradiotherapy Alone in Stage 
IV Nasopharyngeal Carcinoma (NPC), based on 5 year OS of 70% and 5 year distant 
metastasis rate of 81% in a phase 2 trial. 12 See ClinicalTrials.gov identifier  
NCT00201396. This 480 patient trial is expected to be completed in 2013. 
Therefore, the question of induction plus concurrent chemoradiation using CDDP based 
chemotherapy in patients with NPC, while still open, should be answered in the next 5 
years with 2 large RCT, at least for the specific chemotherapy recipes discussed above 
2.4 Carboplatin versus Cisplatin 
Carboplatin is probably as efficacious as cisplatin in the treatment of NPC in the curative 
setting. Evidence for equivalence can be drawn be inference from other diseases and from 
one recently published robust direct comparison of CDDP and carboplatin in NPC, 
discussed below. 
Multiple studies in NSCLC and ovarian cancer have demonstrated that despite the fact 
that cisplatin containing regimens often have been associated with higher response rates, 
carboplatin in almost every study is associated with the same survival and better 
tolerability. 13 14-18 
A randomized controlled trial of patients with SCCHN compared weekly carboplatin 
(100 mg/m2/dose x 4) with daily low dose cisplatin (4mg/m2/dose, cumulative dose 64 
mg/m2) , both concurrently administered with definitive radiation ( 65Gy). Both local 
control and overall survival were numerically superior in the carboplatin arm, but OS did 
not reach statistical significance because of the size of the trial, 119 patients. 19 Because 
many experts regard the dose of CDDP in this trial as inadequate, one can conclude that 
there is evidence that carboplatin XRT is associated with a better outcome than XRT and 
suboptimal CDDP dosing, but is silent on the question of standard CDDP dosing in this 
setting. 
A recent study directly compared CDDP versus carboplatin in the curative setting in 
patients with NPC who were receiving concurrent definitive radiation. In this 206 patient 
study, the standard US intergroup concurrent plus adjuvant chemoradiation was 
compared to an identical radiation plan with carboplatin 100mg/m2 weekly instead of 
concurrent cisplatin, and carboplatin AUC5 instead of cisplatin in the adjuvant setting. 20 
There was no difference in overall survival or disease free survival. Toxicity was 
markedly less in the carboplatin arm, and over twice as many patients in the carboplatin 
arm (62 versus 26%) completed all intended chemotherapy treatment. 
2.5 TAXANES 


 
IRB-15411  
Page 4 of 56 
5 December 2016 
Taxanes are among the most active anti- cancer agents available for squamous cell 
carcinoma of the head and neck, with single agent response rates of 40% or higher 
reported in patients with prior platinum exposure. 21, 22 Three recently reported RCT of 
the addition of a taxane to the “ backbone” PF induction regimen as part of a curative 
chemoradiation plan have demonstrated that overall survival with TPF is superior to PF 
when used as induction chemotherapy followed by either radiation alone or 
chemoradiation in patients with squamous cell cancer of the head and neck. 23 24, 25 
Paradoxically, the three drug combination (taxane, platinum, 5-FU) has been associated 
with a superior QOL than the two drug combination (platinum, 5-FU).  This is probably 
because the dose of infusional 5-FU, which induces severe gastrointestinal toxicity, was 
reduced in all versions of the three drug regimen tested. These results let the FDA to 
recently (9/28/07) approve the use of docetaxel explicitly in combination with cisplatin 
and 5-fluorouracil for induction therapy of locally advanced squamous cell carcinoma of 
the head and neck (SCCHN) before patients undergo chemoradiotherapy and surgery. 26 
Additionally, a recent meta- analysis of 5 RCT suggests that TPF was associated with a 
robust 20% two year survival improvement over PF in this setting. 27 
This strategy of using a taxane and cisplatin combination is beginning to be tested in 
NPC. The combination of docetaxel 75 mg/m2 plus cisplatin 75 mg/m2 achieved a 
response rate of 63% in patients with metastatic NPC 28and when docetaxel has been 
combined with PF as induction chemotherapy for NPC patients in early phase 1 and 2 
trials, response rates approaching 100% have been seen . 29-32 
2.6 Radiation and NPC 
For many years, two-dimensional radiation therapy (2DRT) was considered the standard 
of care for patients with locally advanced NPC. Because 2DRT delivers substantial 
radiation doses to the parotid glands, permanent severe xerostomia is a common side 
effect.  Radiation doses as low as 15 Gy can result in permanent dysfunction of the major 
salivary glands. 46, 47 The permanent xerostomia or oral dryness often results in dysphasia 
and poor speech function as well as predisposes the patients to fissures, ulcers, dental 
caries, infection, and in worst cases, osteoradionecrosis. 48 49. 
In addition to the parotid glands, there are multiple critical normal tissues surrounding the 
nasopharynx, such as the optic structures, the temporal lobes and the brain stem, all of 
which are highly sensitive to radiation injury. The location of such structures precludes 
dose escalation with 2DRT.  Therefore, despite the addition of chemotherapy, the local 
control rates for the more advanced T3/T4 tumors were typically in the range of 40-60% 
for 2DRT. 50, 51 52 38, 53 With the introduction of three- dimensional radiation therapy 
(3DRT) and more recently intensity modulated radiation therapy (IMRT), superior tumor 
coverage was achieved without exceeding the radiation tolerance to surrounding critical 
structures.54-56  Several studies have also compared IMRT to 3DRT plans and 
demonstrated that IMRT consistently improves tumor target volume coverage while 
simultaneously significantly reducing radiation exposure to normal structures, in 
particular the parotid glands, in  patients with locally advanced. 57-59 Since then, several 
centers have reported decreased rates of xerostomia in nasopharyngeal cancer (NPC) 
patients treated with IMRT60, 61, 62  There are emerging randomized trial data which 
confirm the advantage of IMRT in improving salivary gland flow when compared to 
conventional RT in early stage NPC patients. 63, 64 Besides the dosimetric advantages, 


 
IRB-15411  
Page 5 of 56 
5 December 2016 
several centers also reported excellent early clinical outcomes in NPC for IMRT. 65 The 
most mature IMRT clinical data came from UCSF60 The 4-year local progression-free 
and regional progression-free rates for 67 loco-regional advanced NPC patients were 
97% and 98%, respectively. An update with more patients (n=118), continued to show 
excellent locoregional control. 60  Several centers from Hong Kong also have shown 
similar findings. 61, 65 A recent experience from MSKCC reported a 91% locoregional 
control rate for IMRT treated NPC with a median follow-up of 35 months. 62 The RTOG 
completed a phase II trial of IMRT with or without chemotherapy for non-stage IVC 
NPC. Preliminary data showed decreased xerostomia when compared to historical RTOG 
trials where conventional RT was used. (Lee N, ASTRO proceedings 2007). Based on 
these results, we propose to use IMRT using the dose and fractionation schedule (70.2 Gy 
over 6.5 weeks) that has been pioneered at UCSF and validated in the Phase II RTOG 
study for the radiation treatment of these patients.   
2.7 Rationale 
Please see the background section for the scientific and clinical basis for this trial. 
Briefly, this trial is intended to ask several questions concerning a new treatment 
paradigm for patients with locoregionally advanced NPC. While many of the questions 
posed will only be definitively answerable in larger controlled trials, there is a need to 
generate preliminary data supporting the below hypotheses before there will be adequate 
enthusiasm for dedicating the resources of a multi-institutional, multi-national effort to 
ask the questions which would definitively address these questions. 
Hypothesis which this trial will address: 
Primary: 
 Sequential TPF=> chemoradiation will be associated with a higher complete response 
rate than the present US standard of care for this group of patients with NPC, 
chemoradiation=> PF. 
Secondary: 
Sequential TPF=> chemoradiation for patients with NPC is more feasible than 
chemoradiation=> PF as administered by the US intergroup 0099 study as measured by 
the percentage of patients who are able to complete the planned total course of treatment. 
Induction TPF is more active than PF and better tolerated, as assessed by complete 
response rate after chemotherapy and incidence and severity of adverse events during 
chemotherapy. 
 
3. PATIENT SELECTION 
3.1 Eligibility Criteria- Inclusion 
Yes______ NO______3.1.1 Patients must have histologically or cytologically 
confirmed nasopharyngeal carcinoma, stages II (minimally T2a,N0,M0 or Tany,N1, M0) 
 through IVb. Patients with metastatic (stage IVc) untreated NPC who otherwise meet all 
eligibility criteria will be enrolled on a separate cohort and evaluated separately.  Stage: 
T_________ N___________ M ___________ 


 
IRB-15411  
Page 6 of 56 
5 December 2016 
Yes______ NO______3.1.2 Patients must have measurable disease, defined as at least 
one lesion that can be accurately measured in at least one dimension (longest diameter to 
be recorded) as >20 mm with conventional techniques or as >10 mm with spiral CT scan. 
 See Measurement of Effect section for details.  
Yes______ NO______3.1.3 Prior treatment- Patients may have had diagnostic 
surgery(s) at the primary site or neck as long as there is still measurable disease present.  
Yes______ NO______3.1.4 Age > 15 years. Because no dosing or adverse event data 
are currently available on the use of the TPF combination in patients <15 years of age, 
children are excluded from this study, but will be eligible for future pediatric trials. 
Yes______ NO______3.1.5 Life expectancy of greater than 3 months. 
Yes______ NO______3.1.6 ECOG performance status <2.  PS = _________ 
Yes______ NO______3.1.7 Patients must have normal organ and marrow function as 
defined below: 
-absolute neutrophil count>1,500/mcL  value_______ date_______ 
-platelets >100,000/mcL value_______ date_______ 
-total bilirubin <1.5 X institutional ULN value_______ date_______ 
-AST(SGOT)/ALT(SGPT)<2.5 X institutional ULN value_______ date_____ 
-creatinine < 1.5 mg/dl value_______ date_______ 
-creatinine clearance > 55 mL/min/1.73 m2 for patients with creatinine levels above 1.5 
mg/dl value_______ date_______  
Patients with creatinine > grade 1 but less than 
grade 3 are eligible but should receive carboplatin throughout the protocol instead 
of cisplatin. 
Yes______ NO______3.1.9 Peripheral motor/sensory neuropathy < grade 2.  If 
peripheral neuropathy is grade 2, patients are still eligible but should receive 
carboplatin throughout the protocol instead of cisplatin. ________neuropathy 
grade________ date assessed. 
***Cisplatin should be substituted with carboplatin for creatinine > grade 1, neuropathy > grade 2 
or hearing loss > grade 2*** 
Yes______ NO______3.1.10 The effects of TPF on the developing human fetus at the 
recommended therapeutic dose are unknown.  For this reason and because these agents 
could be teratogenic or abortifacient, women of child-bearing potential and men must 
agree to use adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry and for the duration of study participation.  Should a 
woman become pregnant or suspect she is pregnant while participating in this study, she 
should inform her treating physician immediately. Patient agrees.  
 
Yes______ NO______3.1.11 Ability to understand and the willingness to sign a 
written informed consent document. 
 
3.2 Exclusion Criteria 
Yes______ NO______3.2.1 Patients who have had chemotherapy or radiotherapy for 
nasopharyngeal carcinoma. 


 
IRB-15411  
Page 7 of 56 
5 December 2016 
Yes______ NO______3.2.2 Patients with known brain metastases should be excluded 
from this clinical trial because of their poor prognosis and because they often develop 
progressive neurologic dysfunction that would confound the evaluation of neurologic and 
other adverse events. No CNS imaging is required if no clinical indication 
Yes______ NO______3.2.3 History of allergic reactions attributed to compounds of 
similar chemical or biologic composition to docetaxel, cisplatin, carboplatin, 5- 
Fluorouracil or other agents used in the study. 
Yes______ NO______3.2.4 Pregnant women are excluded from this study. The effects 
of  TPF on the developing human fetus are unknown.  These agents as well could be 
teratogenic or abortifacient. Because there is an unknown but potential risk for adverse 
events in nursing infants secondary to treatment of the mother with TPF, breastfeeding 
should be discontinued if the mother is treated with TPF. These potential risks may also 
apply to other agents used in this study. 
Yes______ NO______3.2.5 HIV-positive patients on combination antiretroviral therapy 
are ineligible because of the potential for pharmacokinetic interactions with TPF. In 
addition, these patients are at increased risk of lethal infections when treated with 
marrow-suppressive therapy.  Appropriate studies will be undertaken in patients 
receiving combination antiretroviral therapy when indicated. No HIV testing is mandated 
unless clinical indication 
Yes______ NO______3.2.6 Uncontrolled intercurrent illness including, but not limited 
to, ongoing or active infection, symptomatic congestive heart failure, unstable angina   
pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit 
compliance with study requirements. 
Yes______ NO______3.2.7 Patients with clinically significant cardiovascular disease 
are excluded 
Yes______ NO______ 3.2.8 History of CVA within 6 months 
Yes______ NO______3.2.9 Myocardial infarction or unstable angina within 6 months 
Yes______ NO______ 3.2.10New York heart association grade II or greater congestive 
heart failure 
Yes______ NO______3.2.11 Serious and inadequately controlled cardiac arrhythmia 
Yes______ NO______3.2.12 Significant vascular disease (e.g. aortic aneurysm, history 
of aortic dissection) 
Yes______ NO______3.2.13 Clinically significant peripheral vascular disease 
 
3.3  
Inclusion of Women and Minorities 
Both men and women and members of all races and ethnic groups are eligible for this 
trial.  
 
4. REGISTRATION PROCEDURES 
A protocol subject number will be assigned to every patient at the time of signing the 
informed consent. This number will be used to identify specific study information 


 
IRB-15411  
Page 8 of 56 
5 December 2016 
throughout the trial. To meet the study criteria for enrollment, all patients will have their 
eligibility criteria confirmed (prior to the start of Cycle 1) and scanned into OnCore as a 
means for registration. 
 
5. TREATMENT PLAN 
5.1 Prophylactic Gastrostomy Feeding Tubes. 
Investigators are STRONGLY ENCOURAGED to have prophylactic gastrostomy 
feeding tubes placed in patient prior to initiation of treatment.  Chemoradiation for 
NPC patients is known to be associated with a high rate of severe locoregional toxicity 
including severe oropharyngeal mucositis, skin breakdown, nausea, and presence of thick 
copious tenacious secretions, often complicated by oropharyngeal candidiasis and 
superficial ulceration and superficial bleeding oral alimentation and hydration extremely 
difficult.   
5.2 Agent Administration 
Treatment will usually be administered on an outpatient basis.  Reported adverse events 
and potential risks for the chemotherapeutic agents are described in the Agent Adverse 
Events section of each agent.  Appropriate dose modifications for chemotherapeutic 
agents and are described in the DOSING DELAYS/DOSE MODIFICATIONS section 
below.  No investigational or commercial anti-cancer agents or therapies other than those 
described below may be administered with the intent to treat the patient's malignancy.  
Dosing may be +/- 2d of specified cycles start dates to accommodate weekends, holidays, 
etc.  
 


 
IRB-15411  
Page 9 of 56 
5 December 2016 
5.2.1 
Induction TPF treatment ( note the first day of each cycle =day “1” 
 
Agent 
Premedications; 
Precautions 
 
Dose 
 
Route 
 
Schedule 
Cycle 
Length  
Docetaxel 
Dexamethasone 
8 mg PO the 
evening of day 
0( patient to 
have taken at 
home) 
75 mg/m2 
 in 250 cc 
NS  
 
IV over 60 
minutes  
Day 1, all cycles 
 
 
 
 
 
 
 
 
 
 
 
3 
weeks( 
21 
days) 
 
Cisplatin 
( if 
substituting 
carboplatin, 
see # for 
directions) 
Antiemetics and 
Hydration per 
text below  
75 mg/m2 
IV  
Day 1, all cycles 
Carboplatin 
(only if 
substituting 
for cisplatin  
Antiemetics and 
Hydration per 
text below 
AUC 6 
using the 
below 
formula* 
IV over 30 
minutes 
Day 1 all cycles 
5- 
Fluorouracil 
Antiemetics and 
Hydration per 
text below 
750 
mg/m2/d  
x 5 doses 
IV 
continuous 
infusion 
over 24 
hours daily 
Days 1,2,3,4,5  
May start 5- FU 
infusion 
CONCURRENTLY 
with Cisplatin 
infusion start. 
Ciprofloxacin 
500 mg 
 
500 mg 
BID 
PO or per G 
tube 
Days 6-15 
Pegfilgrastim   
6mg SQ 
once 
SQ 
Approximately 24 
hours after 5-FU 
infusion end 
#Cisplatin should be substituted with carboplatin for creatinine > grade 1, 
neuropathy > gr2 or hearing loss > grade 2. 
* Carboplatin dose = AUC * (GFR+25)  Where GFR estimate = (140 - age) * weight in 
kg / (72 * serum creatinine). Multiply GFR estimate by 0.85 for females. NOTE: 
Maximum value for GFR is 125 mL/min AND the maximum dose for Carboplatin AUC 
6 = 900 mg. 
 
5.2.2 Premedications , antiemetics and intravenous fluid support for TPF during 
induction chemotherapy 
 
Pre-medications for TPF 
 
On day 1  
 
 
Prior to docetaxel for cycle 1:  
• Dexamethasone 12 mg PO or IV  


 
IRB-15411  
Page 10 of 56 
5 December 2016 
• Famotidine 20 mg IV or PO or therapeutic equivalent. DO NOT USE 
CIMETIDINE 
• Diphenhydramine 25-50 mg PO or IV 
 
 Anti-emetics for TPF 
 
On day 1: 
• Granisetron 2 mg PO or therapeutic equivalent 
• Aprepitant 125 mg PO or therapeutic equivalent 
 
On days 2 and 3: 
• Dexamethasone 8 mg PO or IV 
• Aprepitant 80 mg PO 
 
On day 4: 
• Dexamethasone 8 mg PO or IV 
 
 
On any day of the cycle for breakthrough nausea, additional granisetron, 
metochlopramide, prochlorperazine or lorazepam may be used per local routine. 
Additional standard treatments for prophylax against or to treat nausea and vomiting are  
 acceptable. 
 
Intravenous fluid support for TPF 
Local institutional practices for IV fluid support may be used as long as all patients 
receive 3 liters of IVF with corresponding adequate urine output on day 1 and 1-2 liters 
of IV fluid as needed on days 2 and 3. 
IVF and diuresis recommendations: Patient shall in aggregate have received 1 L IVF 
prior to cisplatin, including fluids in which other agents have been administered. Our 
practice is to give, in addition to IVF received with other agents, 500 -1000 mL NS over 
2 hours, administered concurrently with docetaxel. 
• Give 12.5mg Mannitol IVP immediately prior to cisplatin. 
• Give concurrently with cisplatin 500 cc NSS containing 5 meq KCl, 
1gram Magnesium Sulfate and 25 grams Mannitol. 
• Give post cisplatin:  1 liter NSS containing 10 mEq KCL/liter,1 gm 
Magnesium Sulfate/ l at 500 ml/hr . 
• On days 2 and 3, give 1-2 liters NSS IV PRN for poor oral fluid intake 
 
5.2.3 Growth factor support: 
G-CSF as filgrastim or pegfilgrastim will be administered per treating institution standard 
prophylactically during induction cycles  


 
IRB-15411  
Page 11 of 56 
5 December 2016 
Route: subcutaneously  
Schedule: starting approximately 24 hours after the completion of 5-fluorouracil infusion.  
 
 
5.2.4 Chemotherapy concurrent with radiation:  
All patients will receive chemoradiotherapy after the end of TPF with a minimum 
interval of 3 weeks and no later than 6 weeks after start of the last cycle (day 22 to 42 of 
last cycle). 
Patients must fulfill the following criteria for chemoradiation: 
 Mucositis < grade 2 
 ANC > 1500/ microliter 
 PLT > 100, 000/ microliter 
 Hemoglobin > 10 g/dL or hematocrit  > 30% 
Creatinine < 1.5 mg/dl OR creatinine clearance>55 mL/min/1.73 m2 for patients with 
creatinine levels above 1.5 mg/dl. Cisplatin should be substituted with carboplatin for 
creatinine > grade 1 , neuropathy > gr2 or hearing loss > grade 2 
 
 
Chemotherapy concurrent with radiation 
 
Agent 
Premedications; 
Precautions 
 
Dose 
 
Route 
 
Schedule 
Cisplatin 
( if 
substituting 
carboplatin, 
see text for 
directions) 
Antiemetics and 
Hydration per 
text below  
40mg/m2 
IV  
Weekly during 
radiation for a 
total of 6 doses 
Carboplatin 
(only if 
substituting 
for cisplatin 
per the above 
guidelines) 
Antiemetics and 
Hydration per 
text below 
AUC 1.5 
using the 
below 
formula* 
IV over 30 
minutes 
Weekly during 
radiation for a 
total of 6 doses 
Radiation 
therapy 
Three dimensional conformal or intensity modulated radiation 
therapy to 70 Gy to the  gross target volume + margins in 33 
fractions. See section 5.3 for details 
* Carboplatin dose = AUC * (GFR+25). Where GFR estimate = (140 - age) * weight in 
kg / (72 * serum creatinine). Multiply GFR estimate by 0.85 for females. NOTE: 
Maximum value for GFR is 125 mL/min AND the maximum dose for Carboplatin AUC 
1.5 = 225 mg. 
 
5.2.5 Premedications , antiemetics and intravenous fluid support for TPF during 
concurrent chemoradiation 


 
IRB-15411  
Page 12 of 56 
5 December 2016 
 
 Antiemetics for Concurrent CISPLATIN 
 
On day 1: 
• Granisetron 2 mg PO or therapeutic equivalent 
• Aprepitant 125 mg PO or therapeutic equivalent  
•  
• Dexamethasone 12 mg PO or IV 
 
On days 2 and 3: 
• Dexamethasone 8 mg PO or IV 
• Aprepitant 80 mg PO 
 
 
On any day for breakthrough nausea, additional granisetron, metochlopramide, 
prochlorperazine or lorazepam may be used per local routine. Additional standard   
treatments for prophylax against or to treat nausea and vomiting are   acceptable. 
 
 
Intravenous fluid support Concurrent CISPLATIN 
Local institutional practices for IV fluid support may be used as long as all patients 
receive 2 liters of IVF with corresponding adequate urine output on day 1 and 1-2 liters 
of IV fluid as needed on days 2 and 3. 
 
Antiemetics for concurrent CARBOPLATIN 
 
 
On day 1: 
• Granisetron 2 mg PO or therapeutic equivalent 
• Dexamethasone 8 mg PO or IV. 
 
On any day for breakthrough nausea, additional granisetron, metochlopramide, 
prochlorperazine or lorazepam may be used per local routine 
 
Intravenous fluid support Concurrent CARBOPLATIN- None needed 
 
 
 
5.3  Radiation therapy treatment plan: 
 
5.3.1 Concurrent cisplatin, and radiation: 


 
IRB-15411  
Page 13 of 56 
5 December 2016 
Radiation Therapy: 70 Gy at 2.0-2.12 Gy/fraction in 6.5-7 weeks delivered with either 3-
dimensional conformal radiotherapy (3DCRT) or intensity modulated radiotherapy 
(IMRT). 
 
5.3.2  Radiation Therapy (See also Appendix B– Radiation Quality Assurance form) 
Allowable treatment approaches include a 3DCRT approach or an IMRT. 
Dose specification:  
 
Two different RT dose prescriptions are allowed: 
5.3.2.1. Integrated dose prescription 
PTV70 (planning target volume 70): [GTV (gross target volume) + margin]: will receive 
70 Gy at 2.12 Gy/fraction for 33 fractions. 
PTVhigh risk [CTVhigh risk (clinical target volume high risk) + margin]: the areas of high risk, 
sub-clinical disease will receive between 56-59.4 Gy (at the discretion of the treating 
physician) at 1.7-1.8 Gy/fraction for 33 fractions. 
PTVlow risk (CTVlow risk + margin): The area of low risk, subclinical disease, which is 
predominantly the uninvolved low necks, will receive 52 Gy at 1.57 Gy/fraction.  
Alternatively, the uninvolved low neck can be treated with a conventional AP or APPA 
supraclavicular field to a total dose of 44-50 Gy at 2Gy fraction for 22-25 fractions.  The 
dose is prescribed to a depth of 3 cm from the anterior surface for the AP field and to the 
midplane for the APPA field. The junction between the IMRT or 3DCRT fields and the 
low-neck fields will be dependent on the institutional IMRT techniques; however, each 
institution is required to record the dosimetric details at the match-line to ensure dose 
homogeneity and to prevent overdosing of the spinal cord. 
5.3.2.2. Sequential dose prescription: 
PTV70 (planning target volume 70): [GTV (gross target volume) + margin]: will receive 
70 Gy at 2.0 Gy/fraction for 35 fractions. 
PTVhigh risk [CTVhigh risk (clinical target volume high risk) + margin] (optional): the areas 
of high risk, sub-clinical disease will receive 60 Gy at 2 Gy/fraction for 30 fractions. 
PTVlow risk (CTVlow risk + margin): The area of low risk, subclinical disease, which is 
predominantly the uninvolved low necks, will receive 50 Gy at 2 Gy/fraction in 25 
fractions.  Alternatively, the uninvolved low neck can be treated with a conventional AP 
or APPA supraclavicular field to a total dose of 46-50 Gy at 2Gy fraction for 23-25 
fractions.  The dose is prescribed to a depth of 3 cm from the anterior surface for the AP 
field and to the midplane for the APPA field. The junction between the IMRT or 3DCRT 
fields and the low-neck fields will be dependent on the institutional IMRT techniques; 
however, each institution is required to record the dosimetric details at the match-line to 
ensure dose homogeneity and to prevent overdosing of the spinal cord. 
5.3.2.3 Dose Compliance 
The reported dose for each PTV should include the prescribed dose, maximal point dose, 
mean dose, the % of PTV that receive > 110%, > 115% and < 93% of the prescribed 
dose. 


 
IRB-15411  
Page 14 of 56 
5 December 2016 
All plans should be normalized so that > 95% of the PTV70 receives the prescribed dose.  
In addition, no more than 20% of the PTV70 will receive > 110 % and no more than 5% 
will receive > 115% 
RT will be given as once daily fraction. The first RT treatment should begin on Monday, 
Tuesday or Wednesday.   
5.3.2.4 Technical factors 
External beam equipment and beam delivery methods 
Megavoltage equipments capable of delivering 3DCRT or IMRT (either static or 
dynamic) are required. 
Treatment planning, imaging and localization requirement  
The immobilization device should include at least the head and neck.  It is strongly 
encouraged that the participation centers also utilize shoulder immobilization especially 
when comprehensive nodal IMRT is utilized.  
Treatment planning CT scan will be required to delineate the GTV, CTV and PTV.  
Other imaging studies such as MRI and PET-CT scans can aid in volume delineation.  
The treatment planning CT scan should be acquired with the patient immobilized in the 
same treatment position.  All tissue irradiated should be included in the treatment 
planning CT scan, which should be < 3 mm slice thickness through the regions 
containing the GTV.  Thicker slices (up to 5 mm) may be used for region above or below 
the GTV; however, thicker slices may compromise the image quality of the digitally 
reconstructed radiographs (DRR) 
Treatment planning/target volumes 
The definition of the target volumes should conform to the 1993 ICRU report #50; 
Gross target volume (GTV): All known gross disease determined from clinical (including 
endoscopic) and imaging findings.  Grossly involved nodes are defined as any lymph 
node > 1 cm on CT or MRI in the minimal cross-sectional diameter, any nodes with 
increased metabolic uptake on FDG PET scan, any node with central necrosis and/or 
radiographic evidence of extracapsular extension regardless of size. 
Clinical target volume (CTV):  
CTV70: For grossly positive node, a margin of 5 mm should be added circumferentially to 
account for microscopic extracapsular extension 
CTVhigh risk: should include all regions deemed to be at high risk for microscopic disease, 
all potential routes of spread, and the high risk nodal regions.  
CTVlow risk: nodal regions at low risk for microscopic involvement.  This usually 
constitutes the clinically and radiographically low-neck nodes. 
Planning target volume: A margin should be used to account for intrafraction and 
interfraction set up variability.  The average recommended PTV margin is 5 mm; 
however, it will depend on the accuracy of treatment set up and immobilization at each 
individual treatment site. 
5.3.2.5 Treatment Plan 


 
IRB-15411  
Page 15 of 56 
5 December 2016 
Treatment plan will be based on the analysis of the volumetric dose, including dose-
volume histogram (DVH) analyses of the PTVs and critical normal structures.  A 3D or 
an “inverse” planning using computerized optimization should be used.  The treatment 
aim will be the delivery of radiation to the PTVs and the exclusion of non-involved 
tissues. HETEROGENEITY CORRECTION SHOULD BE USED. 
5.3.2.6 Critical structures 
Surrounding critical normal structures, including the brainstem, temporal lobes (if the 
tumor is near the skull base), spinal cords, optic nerves, eyes, optic chiasm, parotid 
glands, the inner and middle ears (if the targets are near by), oral cavity, mandible and 
glottic larynx should be outlined.  If there is grossly involved tumor in the low neck, then 
the brachial plexus should also be delineated. 
Unspecified tissues, defined as the tissues within the skin, subtracted all target volumes 
and delineated normal tissues, should also be taken into account of the treatment planning 
and evaluation.  No more than 5% of the unspecified tissue can receive > 70 Gy and no 
more than 1% or 1 cc of this tissue can receive >= 77 Gy.  Participants are strongly 
encouraged to remain within these limits. 
Dose constraints for certain normal tissues are shown in the following table. 
Table 1: Required critical structure dose constraints 
Structure 
Maximal dose 
(Gy) 
Brainstem 
54 
Spinal cord 
45 
Optic nerves 
54 
Optic chiasms 
54 
Eyes 
50 
Mandible 
70 
Brachial plexus 
66 
Table 2: Suggested normal structure dose constraints 
Structure 
Mean dose (Gy) 
Parotid 
< 26 for 1 gland or < 30 for 50% of 1 gland or < 20 
for 20 cc volume of both glands 
Oral cavity 
< 40 if tumors outside the oral cavity 
Inner/middle ear 
< 45 or < 5% volume receives > 55 Gy 
Glottic larynx 
< 50 for tumor outside the larynx and hypopharynx 
Esophagus/post cricoid 
pharynx 
< 50 for tumor outside the larynx and hypopharynx 
 
5.3.2.7 Documentation requirements: 


 
IRB-15411  
Page 16 of 56 
5 December 2016 
Weekly verification of orthogonal films through the treatment isocenter is required.  If 
the IMRT or 3DCRT fields are matched to an AP supraclavicular field, then the 
supraclavicular field should also be included during weekly portal verification. Appendix 
B is the radiation quality assurance form that should be submitted at the completion 
of radiation therapy. 
5.3.2.8 Radiation adverse events and allowed interruption 
Radiation adverse events will be graded as per CTCAE v4.0.  RT interruption may be 
necessary due to severe acute RT - related reactions such as severe skin or mucosal 
reaction or any other acute complications.  Interruptions will be left at the discretion of 
the treating physicians but strongly discouraged.  The cause of interruption should be 
recorded.   
Placement of feeding gastrostomy tube may be necessary for nutritional support in this 
frail population. The date and reason for placement of a feeding gastrostomy tube (either 
prophylactic in preparation for RT or for active nutritional support due to significant 
weight loss before or during RT) should also be recorded.  The duration of feeding tube 
dependence after completion of RT should also be recorded. 
5.4 Duration of Follow Up 
Patients will be followed for a minimum of 1 year after removal from study or until 
death, whichever occurs first.  Patients removed from study for unacceptable adverse 
events will be followed until resolution or stabilization of the adverse event. 
Patients will be seen quarterly in follow- up the first year after completion of radiation, 
and subsequently per local standards of care. 
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
Doses will be modified in case of severe hematological and/or non-hematological 
toxicities. Dose adjustments are to be made according to the CTCAE v4  system showing 
the greatest degree of toxicity. Toxicities will be graded using the CTCAE v4 criteria.  
 
6.1 DOCETAXEL dose modifications 
 
Febrile Neutropenia or Documented Neutropenic Infection  
Adverse event  
Action to be taken for subsequent cycles  
• Febrile 
neutropenia  
• Documented 
infection  
 The first episode of febrile neutropenia or documented grade 3 /4 
neutropenia with documented infection will result in the addition of 
GM-CSF or G-CSF to all subsequent cycles .  
If there is a second episode, the patient will remain on  
Ciprofloxacin and GM-CSF or G-CSF and additionally, during the 
subsequent cycles, Docetaxel dose will be reduced from 75 to 60 mg/m² 
 
 


 
IRB-15411  
Page 17 of 56 
5 December 2016 
 Action Taken Following Results of CBC Counts On first day of each TPF cycle  
ANC  
(x10
9/L)  
Action to be taken  
≥ 1.5 ( grade 1) 
Treat on time  
< 1.5 ( GRADE 2 OR 
HIGHER) 
 
 
 
 
 
 
 
 
 
 
 
1. Delay  TPF 1 week and repeat complete blood count .   
2. If ANC > 1.5 x 10
9/L, then proceed with full dose 
chemotherapy  
3. If ANC < 1.5 x 10
9/L, then consider addition of G-CSF or GM-
CSF for 7 days  
• On day 35, perform complete blood count with differential  
• Proceed with full dose chemotherapy if ANC > 1.5  
• And consider use of GM-CSF or G-CSF in remaining cycles  
4. If there is no recovery by day 35, (ANC < 1.5 x 10
9/L), the 
patient will go off TPF chemotherapy  
 
 
Thrombocytopenia 
Action to be taken 
 Plt <LLN – 75,000/mm3 
(grade 1) 
Treat on time 
  Plt < 75,000 
( grade 2 -4) 
1. Delay  TPF 1 week and repeat complete blood count .   
2. If plt > 100,000, then proceed with full dose chemotherapy  
3. If plt  75,000-<100,000, dose reduction of docetaxel from 75 to 
60 mg/m
2 for all subsequent cycles of TPF. 
4. if  plt < 75,000, patient will go off TPF chemotherapy 
 
If patient has recurrent thrombocytopenia after docetaxel 
reduction to 60 mg/m2 without recovery to 75,000 by day 28 of 
subsequent cycles, patient will go off TPF therapy 
 
Action Taken for other Docetaxel AEs 
Mucositis oral  
 If mucositis oral is present on day 1 of any cycle, treatment should be withheld until 
resolved.  
 If Grade 3/4 mucositis oral occurs at any time, the dose of Docetaxel should be reduced 
for subsequent cycles, Docetaxel dose will be reduced from 75 to 60 mg/m²  
 
Peripheral  motor Neuropathy and peripheral sensory neuropathy 
Docetaxel dose will be reduced from 75 to 60 mg/m² for Grade 2 neuropathies without 
treatment delay.  


 
IRB-15411  
Page 18 of 56 
5 December 2016 
Treatment should be discontinued for Grade 3/4 neuropathies.  
 
Dermatological/ Skin 
Grade 0, 1, and 2: no change  
Grade 3: Delay until < grade 1 and retreat with a dose reduction of Docetaxel from 75 to 
60 mg/m². If no recovery to < grade 1 within 2 weeks delay, patient will go off protocol 
therapy.  
Grade 4: The patient will go off chemotherapy. 
 
Nausea and/or vomiting  
Prophylactic antiemetic regimen with 5-HT3 antagonist should be administered from the 
first cycle. In addition, the corticosteroids used during 3 days for the prophylaxis of fluid 
retention should also reduce the incidence and severity of emesis.  
Patients with nausea and vomiting despite these measures may be treated with another 
antiemetic regimen (i.e. high dose metochlopramide) as appropriate. 
 
Bilirubin and Impaired liver function:  
In the event that bilirubin levels are abnormal during study, the next cycle will be delayed 
by a maximum of 2 weeks. If no recovery, the patient should be taken off chemotherapy.  
In the event that AST and/or ALT and/or alkaline phosphatase levels are abnormal in the 
absence of progressive disease, the following dose modifications will apply: 


 
IRB-15411  
Page 19 of 56 
5 December 2016 
Table :Dose Modifications  for docetaxel for Abnormal Liver Function   
 
                                             AST or ALT: 
ALK 
PHOS #:  
≤ ULN  
>1x but 
≤1.5x  
>1.5x 
but ≤5x  
>5x 
ULN  
≤ ULN  
Full 
Dose  
Full 
Dose  
Full 
Dose  
Hold*  
>1x but 
≤ 2.5x  
Full 
Dose  
Full 
Dose  
Reduce 
Dose to 
60 
mg/m2 
Hold*  
>2.5x 
but ≤ 5x  
Full 
Dose  
Reduce 
Dose  to 
60 
mg/m2 
Hold*  
Hold*  
>5x 
ULN  
Hold*  
Hold*  
Hold*  
Hold*  
 
*Hold until recovered, maximum 2 weeks, then re-treat at a reduced dose. “Recovered” is 
defined as meeting the study baseline eligibility criteria.  
Bilirubin: Docetaxel
 should not be administered to patients with serum total bilirubin 
>ULN. If serum total bilirubin is >ULN on treatment day, hold Docetaxel until serum 
total bilirubin is ≤ ULN (maximum 2 weeks), then re-treat at a reduced dose.  
**Reduced doses of Docetaxel will be at 60mg/m
2. After Docetaxel is dose is reduced, 
there will be no re-escalation. There will be only one dose reduction. 
#  If alkaline phosphatase is clinically related to local bone erosion, for purposes of 
docetaxel dose reductions, consider alk phos < ULN, i.e. dose adjust based on other 
clinical and lab parameters. 
 
6.2 CISPLATIN  and CARBOPLATIN dose modifications: 
Cisplatin dose reductions during TPF for hematologic adverse events: 
There will be no planned CDDP dose reductions for ANC or platelet AEs. See Docetaxel 
section for dose reduction and TPF delay and discontinuance parameters for ANC and 
platelet AEs. Note that after one reduction in docetaxel for hematological AEs, high 
grade persistent or recurrent AEs will result in discontinuance of TPF per the algorithm 
outlined for docetaxel dose modification. 
Cisplatin dose reductions during TPF for non-hematologic adverse events: 
 
CDDP dose levels during TPF 
-1 
Starting dose 


 
IRB-15411  
Page 20 of 56 
5 December 2016 
60 mg/m2 
75 mg/m2 
 
Peripheral motor Neuropathy and peripheral sensory neuropathy  
Grade 0, 1: no change  
Grade > 2: Carboplatin may be substituted for Cisplatin  
Ototoxicity  
Cisplatin is known to cause high frequency hearing loss. If grade 1 or 2 hearing loss 
occurs, the risk of additional hearing loss versus the potential benefit of continuing 
Cisplatin chemotherapy should be made. Grade 3 and 4 hearing loss is an indication to 
discontinue the drug.  In case of grade 3 or 4 ototoxicity, Carboplatin may be used to 
replace Cisplatin .  
Creatinine 
Grade 1 ( creatinine <1.5): no CDDP dose change 
Grade 2 ( creatinine > 1.5-3):   
first incidence decrease one dose level, consider change to carboplatin. 
second incidence: switch to carboplatin. 
Grade 3 -4 ( creatinine >3): discontinue CDDP, switch to carboplatin. 
 
All other non- hematological  AEs attributable to CDDP: 
Grade 1-2 : no dose change of CDDP 
Grade 3-4:Hold TPF up to one week for resolution of AEs to grade 2 or less, then re- 
treat with one level dose reduction of CDDP.  If AEs not resolved to grade 2 after 1 
week, discontinue TPF treatment 
 
Carboplatin dose reductions during TPF  
Hematological AEs during TPF : 
There will be no planned Carboplatin dose reductions for  ANC or platelet AEs. See 
Docetaxel section for dose reduction and TPF delay and discontinuance parameters for 
ANC and platelet AEs.  Note that after one reduction in docetaxel for hematological AEs, 
high grade persistent or recurrent AEs will result in discontinuance of  TPF per the 
algorithm outlined for docetaxel dose modification. 
 
All other non- hematological  AEs attributable to carboplatin: 
Grade 1-2 : No dose change of carboplatin or TPF delay. 
Grade 3-4: Hold TPF up to one week for resolution of AEs to grade 2 or less, then re- 
treat with one level dose reduction.  If AEs not resolved  to grade 2 after 1 week, 
discontinue TPF treatment. 
 
Cisplatin and carboplatin dose reductions during concurrent radiation for hematological 
toxicities 
CDDP dose levels during radiation 
-2 
-1 
Starting dose 


 
IRB-15411  
Page 21 of 56 
5 December 2016 
25 mg/m2/week 
30 mg/m2/week 
40mg/m2/week 
 
Carboplatin dose levels during radiation* 
-2 
-1 
Starting dose 
AUC 0.8/week 
AUC 1.1/week 
AUC 1.5 /week 
*Refer to page 13 for Carboplatin maximum dose value calculation during radiation treatment. 
Maximum GFR value is 125 mL/min AND maximum Carboplatin AUC 1.5 = 225 mg. 
 
CDDP  or Carboplatin  must not be administered  concurrently with radiation until the ANC ≥ 
1,000 and platelets are ≥ 100,000. If not, delay one week. If the patient still has not recovered, 
continue to hold on a week by week basis until the above criteria are met, then resume dosing 
according to the below table.  
ANC 
 
Plt count 
Dose reduction/ delay 
Greater or = 
to 1500 
and 
Greater or = 
75,000 
No change in dose 
1000-1499 
or 
50,000-
74,999 
Decrease by one dose level 
Less than 
1000 
or 
Less than 
50,000 
Hold until ANC>1000 and 
plt> 75,000 and decrease by 
one dose level. 
 
There will be no reduction below dose level -2. If a patient is already at dose level -2 and 
experiences AEs as defined above, discontinue CDDP or carboplatin. 
 
Cisplatin  or carboplatin dose reductions during concurrent radiation for non- 
hematological toxicities: 
Concurrent platinum and radiation for patients with nasopharyngeal cancer is known to 
be associated with a high rate of severe locoregional toxicity including severe mucositis 
oral, skin breakdown, nausea, and presence of thick copious tenacious secretions, often 
complicated by oropharyngeal candidiasis and superficial ulceration and  superficial 
bleeding.  Patients commonly are not able to adequately aliment or hydrate themselves 
orally during chemoradiation and for several weeks afterwards.  Every effort should be 
made to manage patient symptomatically using IV hydration, and clinicians are 
STRONGLY ENCOURAGED to have prophylactic gastrostomy feeding tubes placed 
prior to initiation of treatment.  Severe mucositis oral and skin breakdown in the radiation 
field  based on ulceration and superficial bleeding should not be considered inherently 
dose limiting. 
Radiation associated mucositis oral  or dermatitis: 
Grade 4: hold CDDP or carboplatin until resolution to grade 3 then dose reduce by one 
dose level. There will be no dose reductions below dose level minus 2.  In  the case that a 


 
IRB-15411  
Page 22 of 56 
5 December 2016 
patient is being treated at dose level minus 2, once AEs are grade 3 or less, the patient 
should be treated again at dose level minus 2. 
Peripheral motor Neuropathy and peripheral sensory neuropathy 
Grade 0, 1: no change  
Grade > 2: Carboplatin may be substituted for Cisplatin  Should a new grade > 2 
peripheral motor/sensory neuropathy develop on carboplatin, hold carboplatin until 
resolution to grade 2 then dose reduce 1 level. 
Ototoxicity  
Cisplatin is known to cause high frequency hearing loss. If grade 1 or 2 hearing loss 
occurs, the risk of additional hearing loss versus the potential benefit of continuing 
cisplatin chemotherapy should be made. Grade 3 and 4 hearing loss is an indication to 
discontinue the drug.  In case of grade 3 or 4 ototoxicity, carboplatin may be used to 
replace cisplatin. Should  new grade > 2 ototoxicity develop on carboplatin, hold 
carboplatin until resolution to grade 2 then dose reduce 1 level. 
Creatinine 
Grade 1 (creatinine <1.5): no CDDP dose change 
Grade 2 (creatinine > 1.5-3):   
First incidence decrease one dose level, consider change to carboplatin. 
Second incidence: switch to carboplatin. 
Grade 3 -4 (creatinine >3): discontinue CDDP, switch to carboplatin. Should a new grade 
> 2 creatinine develop on carboplatin, hold carboplatin until resolution to grade 2 then 
dose reduce 1 level. 
Non- hematological  AEs attributable to CDDP or carboplatin excluding AEs 
discussed above: 
Grade 1-2 : No dose change of CDDP or carboplatin. 
Grade 3-4: Hold  CDDP or carboplatin until resolution of AEs to grade 2 or less, then 
dose reduce by one dose level. There will be no dose reductions below dose level minus 
2.  In  the case that a patient is being treated at dose level minus 2, once AEs resolve to 
grade 2 or less, the patient should be treated again at dose level minus 2. 
 
6.3: 5- Fluorouracil  (5-FU) dose modifications during TPF 
5-FU dose levels during TPF 
-2 
-1 
Starting dose 
480 mg/m2 IVCI/d x 5 
d 
600 mg/m2 IVCI/d x 5 
d 
750 mg/m2 IVCI/d x 5 
d 
 
Hematological AEs during TPF: 
There will be no planned 5-FU dose reductions for  ANC or platelet AEs. See Docetaxel 
section for dose reduction and TPF delay and discontinuance parameters for ANC and 
platelet AEs.  Note that after one reduction in docetaxel for hematological AEs, high 


 
IRB-15411  
Page 23 of 56 
5 December 2016 
grade persistent or recurrent AEs will result in discontinuance of  TPF per the algorithm 
outlined for docetaxel dose modification. 
Non- Hematological AEs during TPF: 
Mucositis oral  or dermatitis 
Grade 3 lasting more than 96 hours or grade 4 : Dose reduce one level.  
Diarrhea  
In the case of severe diarrhea, octreotide is recommended. If the patient has a significant 
diarrhea occurrence again (> 3 loose stools/24 hr), the patient should be treated 
prophylactically in the subsequent cycles with 2 tablets of loperamide or diphenoxylate in 
addition to 1 or 2 tablets after each loose stool. The maximum daily dose of Loperamide 
is 16mg and Diphenoxylate is 20mg/day.  
Grade 4 diarrhea, or grade 3 diarrhea lasting > 7 days despite the prophylactic treatment: 
dose reduce one level.  
All other non- hematological  AEs attributable to 5-FU: 
Grade 1-2 : No dose change of 5-FU or TPF delay. 
Grade 3-4: Hold TPF up to one week for resolution of AEs to grade 2 or less, then re- 
treat with one dose level reduction .  If AEs not resolved to grade 2 after 1 week, 
discontinue TPF treatment. 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
7.1 Adverse Event List(s) for Commercial Agent(s) 
7.1.1 Docetaxel is commercially available. See package insert for details.  
Side Effects may include: 
1. Cardiac: arrhythmias, pericardial effusions. 
2. Hematologic: dose-related neutropenia, leukopenia, thrombocytopenia, 
    anemia, hypoglycemia, hypernatremia. 
3. Gastrointestinal: nausea and vomiting, diarrhea, oral mucositis oral, pancreatitis, 
    esophagitis. 
4. Neurologic: reversible dysthesias or paresthesias, peripheral motor/sensory neuropathy 
    mild or  moderate lethargy or somnolence, headache, seizures. 
5. Hypersensitivity: hypersensitivity (local or general skin rash, flushing, 
    pruritus, drug-fever, chills and rigors, low back pain), severe anaphylactoid 
    reactions (flushing with hypo- or hypertension, with or without dyspnea). 
6. Dermatologic: alopecia, desquamation following localized pruriginous 
    maculopapular eruption, skin erythema with edema, extravasation reaction 
    (erythema, swelling, tenderness, pustules), reversible peripheral phlebitis, 
    nail changes. 
7. Hepatic: increased transaminase, alkaline phosphatase, bilirubin; hepatic 


 
IRB-15411  
Page 24 of 56 
5 December 2016 
    failure; hepatic drug reaction. 
8. Pulmonary: dyspnea with restrictive pulmonary syndrome, pleural effusions. 
9. Other: asthenia, dysgeusia, anorexia, conjunctivitis, arthralgia, muscle 
    aches, myopathy, peripheral edema, fluid retention syndrome, ascites. 
    Prolonged treatment with weekly docetaxel results in chronic toxicities, which 
    include asthenia (fatigue), anemia, edema, excessive lacrimation (epiphora),  and     
onycholysis.  
7.1.2 Cisplatin is commercially available. See package insert for details.  
Side Effects may include: 
1. Hematologic: Leukopenia and thrombocytopenia occur, but are rarely 
    dose-limiting; anemia. 
2. Dermatologic: Alopecia (uncommon). 
3. Gastrointestinal: Nausea and vomiting are common and may persist for up 
    to 24-96 hours; anorexia. 
4. Renal: Nephrotoxicity is dose-related and relatively uncommon with 
     adequate hydration and diuresis; elevated serum creatinine and BUN. 
5. Hepatic: Elevated AST and ALT. 
6. Neurologic: Peripheral motor/sensory neuropathy (paresthesias), common and dose-     
    limiting when the cumulative cisplatin dose exceeds 400 mg/m²; rarely seizures; 
    ototoxicity manifested initially by high frequency hearing loss; vestibular  
    toxicity (dizziness) uncommon; tetany (caused by hypomagnesemia); rarely 
    Lhermitte’s sign. 
8. Other: Hypomagnesemia, hypocalcemia, hyponatremia, vein irritation, 
    papilledema, rarely retrobulbar neuritis, rarely anaphylaxis, fatigue. 
7.1.3 Carboplatin  is commercially available. See package insert for details.  
Side Effects may include:  
1. Hematologic: Thrombocytopenia, neutropenia, leukopenia, more pronounced 
    in patients with compromised renal function and heavily pretreated patients; 
    may be cumulative. 
2. Gastrointestinal: Nausea and vomiting (less severe than with cisplatin), 
     treatable with moderate doses of antiemetics. 
3. Dermatologic: Rash, urticaria. 
4. Hepatic: Abnormal liver function tests, usually reversible with standard doses. 
5. Neurologic: Rarely peripheral motor/sensory neuropathy. 
6. Renal: Elevations in serum creatinine, BUN, electrolyte loss (Na, Mg, K, 


 
IRB-15411  
Page 25 of 56 
5 December 2016 
    Ca). 
7.Other: Pain, asthenia. 
7.1.4 5- Fluorouracil is commercially available. See package insert for details.  
Side Effects may include:  
Hematologic: Leukopenia, thrombocytopenia, anemia (can be dose limiting, less common 
with continuous infusion);  Dermatologic: Dermatitis, nail changes, hyperpigmentation, 
Hand-Foot Syndrome with protracted infusions, alopecia; Gastrointestinal: Nausea, 
vomiting, anorexia, diarrhea (can be dose limiting); mucositis oral 
(is common with 5-day infusion, occasionally dose limiting); Neurologic: Cerebellar 
Syndrome (headache and cerebellar ataxia);  Cardiac: Angina, noted with continuous 
infusion; Ophthalmic: Eye irritation, nasal discharge, watering of eyes, blurred vision. 
 
7.2 Adverse Event Reporting 
The Protocol Director (PD) or designee will assess each Adverse Event (AE) to 
determine whether it is unexpected according to the Informed Consent, Protocol 
Document, and related to the investigation. All Adverse Events (AEs) and Serious 
Adverse Events (SAEs) will be tracked until resolution or until 30 after the last dose of 
the study treatment.  
.  
SAEs CTCAE v 4.0 Grade 3 and above, and all subsequent follow-up reports will be 
reported to the CCTO Safety Office regardless of the event’s relatedness to the 
investigation. Following review by the CCTO Safety Officers, any events meeting the 
IRB definition of ‘Unanticipated Problem’ will be reported to the IRB using eProtocol 
within 10 working days of the review, or within 5 working days for deaths or life-
threatening experiences. 
 
     7.3  Routine AE collection 
All AEs grade  2  and above attributed to treatment will be recorded on case report forms 
and saved in a secure environment within the research offices of the PI and scanned into 
Oncore upon their completion. All AEs will be assessed for treatment attribution and 
noted to be either ‘Related to Treatment’ or ‘Not Related’. AEs will be evaluated for all 
patients according the schedule specified in the study calendar. 
 
8. PHARMACEUTICAL INFORMATION 
A list of the adverse events and potential risks associated with the commercial agents 
administered in this study can be found in Section 7.1. 
8.1 Commercial Agent(s) 
8.1.1 Docetaxel - (Commercially available. Please refer to the package insert for further 
information) 
Other Names Taxotere, RP 56976, NSC #628503. Classification: Antimicrotubule agent. 


 
IRB-15411  
Page 26 of 56 
5 December 2016 
Mode of Action: Docetaxel, a semisynthetic analog of paclitaxel, promotes the assembly 
of tubulin and inhibits microtubule depolymerization. Bundles of microtubules 
accumulate and interfere with cell division. 
 
Storage and Stability: 
Docetaxel infusion solution, if stored between 2 and 25ºC (36 and 77ºF) 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 
administration time). Store between 2 and 25°C (36 and 77ºF). Retain in the original package 
toprotect from bright light. Freezing does not adversely affect the product. 
 
Preparation: 
Docetaxel is a cytotoxic anticancer drug and, as with other potentially toxic compounds, caution 
should be exercised when handling and preparing docetaxel solutions. The use of gloves is 
recommended. If docetaxel concentrate, initial diluted solution, or final dilution for infusion 
should come into contact with the skin, immediately and thoroughly wash with soap and water. 
If docetaxel concentrate, initial diluted solution, or final dilution for infusion should come into 
contact with mucosa, immediately and thoroughly wash with water. Docetaxel for Injection 
Concentrate requires two dilutions prior to administration. 
Please follow the preparation instructions provided below. Note: Both the docetaxel for Injection 
Concentrate and the diluent vials contain an overfill. 
A. Preparation of the Initial Diluted Solution 
1. Gather the appropriate number of vials of docetaxel for Injection 
Concentrate and diluent (13% Ethanol in Water for Injection). If the vials were refrigerated, 
allow them to stand at room temperature for approximately 5 minutes. 
2. Aseptically withdraw the contents of the appropriate diluent vial into a syringe and transfer it 
to the appropriate vial of docetaxel for Injection Concentrate. If the procedure is followed as 
described, an initial diluted solution of 10mg docetaxel/mL will result. 
3. Mix the initial diluted solution by repeated inversions for at least 45 seconds to assure full 
mixture of the concentrate and diluent. Do not shake. 
4. The initial diluted docetaxel solution (10 mg docetaxel/mL) should be clear; however, there 
may be some foam on top of the solution due to the polysorbate 80. Allow the solution to stand 
for a few minutes to allow any foam to dissipate. It is not required that all foam dissipate prior to 
continuing the preparation process. The initial diluted solution may be used immediately or 
stored either in the refrigerator or at room temperature for a maximum of 8 hours. 
B. Preparation of the Final Dilution for Infusion 
1. Aseptically withdraw the required amount of initial diluted docetaxel solution (10mg 
docetaxel/mL) with a calibrated syringe and inject into an infusion bag or bottle of either 0.9% 
Sodium Chloride solution or 5% Dextrose solution to produce a final concentration of 0.3 to 
0.74mg/mL. Thoroughly mix the infusion by manual rotation. 


 
IRB-15411  
Page 27 of 56 
5 December 2016 
2. As with all parenteral products, docetaxel should be inspected visually for particulate matter or 
discoloration prior to administration whenever the solution and container permit. If the docetaxel 
for Injection, initial diluted solution, or final dilution for infusion is not clear or appears to have 
precipitation, these should be discarded. The final docetaxel dilution for infusion should be 
administered intravenously as per protocol under ambient room temperature and lighting 
conditions. Contact of the docetaxel 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 docetaxel dilution for infusion should be stored in bottles (glass, 
polypropylene) or plastic bags (polypropylene, polyolefin) and administered through 
polyethylene-lined administration sets. 
Route of Administration: 
Docetaxel will be administered as a 60 minute infusion in saline or D5W through an 
administration set that does not contain phthalate plasticizers along the fluid pathway that is 
connected to the patient’s vascular access catheter. 
Incompatibilities: 
Contact of the undiluted concentrate with plasticized PVC equipment or devices used to prepare 
solutions for infusion should be avoided. Diluted docetaxel solution should be stored in bottles 
(glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through 
polyethylene-lined administration sets.  The metabolism of docetaxel may be modified by the 
concomitant administration of compounds that induce, inhibit, or are metabolized by cytochrome 
P450 3A4, such as cyclosporine, terfenadine, ketoconazole, erythromycin, and troleandomycin. 
Caution should be exercised with these drugs when treating patients receiving docetaxel as there 
is a potential for a significant interaction. 
Availability: 
Docetaxel (Taxotere®) is a commercial drug. The combination of docetaxel, cisplatin, and 5-FU 
for the treatment of patients with SCCHN is approved by the FDA and exempt from the 
requirements of an IND as described under Title 21 CFR 312.2(b).  
Docetaxel vials of 80 mg in 2 ml polysorbate 80 and 20mg in 0.5ml polysorbate 80 with 
accompanying diluent (13% w/w ethanol in Water for Injection) are commercially available from 
Sanofi Pharmaceuticals. (The vials contain 15% overfill to compensate for liquid lost during 
preparation). Docetaxel for Injection Concentrate is supplied in a single-dose vial as a sterile, 
pyrogen-free, non-aqueous, viscous solution with an accompanying sterile, nonpyrogenic, 
diluent (13% ethanol in Water for Injection) vial. The following strengths are available: 
TAXOTERE 80 mg (NDC 0075-8001-80) 
TAXOTERE (docetaxel) 80 mg Concentrate for Infusion: 80 mg docetaxel in 2 mL polysorbate 
80 and diluent for TAXOTERE 80 mg. 13% (w/w) ethanol in Water for Injection. Both items are 
in a blister pack in one carton. 
TAXOTERE 20 mg (NDC 0075-8001-20) 
TAXOTERE (docetaxel) 20 mg Concentrate for Infusion: 20 mg docetaxel in 0.5 mL 
polysorbate 80 and diluent for TAXOTERE 20 mg. 13% (w/w) ethanol in Water for Injection. 
Both items are in a blister pack in one carton.  


 
IRB-15411  
Page 28 of 56 
5 December 2016 
Nursing/Patient Implications: 
1. Monitor CBC with differential and platelet count prior to drug administration. 
2. Symptom management of expected nausea, vomiting, and mucositis oral. 
3. Advise patients of possible hair loss. 
4. Patients should be observed closely for hypersensitivity reactions, especially 
during the first and second infusions. Insure that recommended 
premedications are given. 
5. Resuscitation equipment and medications to treat hypersensitivity reactions 
should be available during docetaxel administration. 
6. Monitor liver function tests. 
7. Evaluate site regularly for signs of infiltration. 
8. Monitor for symptoms and signs of fluid retention, peripheral motor/sensory neuropathy, 
    and cutaneous reactions. 
 
 
8.1.2 Cisplatin- (Commercially available. Please refer to the package insert for 
further information) 
Other Names Cis-diaminedichloroplatinum Cis-diaminedichloroplatinum (II), 
diaminedichloroplatinum,cis-platinum, platinum, Platinol®, Platinol-AQ®, DDP, CDDP, 
DACP, NSC 119875. Classification: Alkylating agent. 
 
Mode of Action: 
 Inhibits DNA synthesis by forming inter- and intra-strand crosslinks. Other possible 
mechanisms include chelation of DNA and binding to cell membranes thereby 
stimulating immune mechanisms. 
 
Storage and Stability: 
Intact vials of cisplatin are stored at room temperature. Solutions diluted with sodium 
chloride or dextrose are stable for up to 72 hours at room temperature. Due to the risk of 
precipitation, cisplatin solutions should not be refrigerated. 
Preparation: 
The desired dose of cisplatin is diluted with 250 - 1000 ml of saline and/or dextrose 
solution. Varying concentrations of 0.225 - 5% sodium chloride and 5% dextrose may be 
used. To maintain stability of cisplatin, a final sodium chloride concentration of at least 
0.2% is recommended. 
Route of Administration: 
Cisplatin should be administered as a 1 mg/ml intravenous infusion. Antiemetics should 
be given in conjunction with Cisplatin.  Cisplatin is highly emetogenic. A suggested 
regimen is aprepitant 125 mg po on day 1 and 80 mg po on days 2 and 3  plus 
ondansetron (8 mg mg IV or 24 mg PO) or granisetron (1 mg IV or 2 mg PO)  plus 
dexamethasone 12 mg po on day 1, 8 mg po on days 2-4) 83 


 
IRB-15411  
Page 29 of 56 
5 December 2016 
Metochlopramide 20-40 mg 2-4 times daily is suggested for patients with delayed nausea. 
Other antidopaminergic  agents such as haloperidol can be used in patients with 
refractory symptoms.  
Incompatibilities: 
Amsacrine, cefepime, gallium nitrate, mesna, piperacillin, sodium bicarbonate, thiotepa. 
Cisplatin may react with aluminum which is found in some syringe needles or IV sets, 
forming a black precipitate. 
Compatibilities: 
Admixture: Amphotericin-B, aztreonam, carmustine, cefazolin, cephalothin, droperidol, 
etoposide, floxuridine, hydroxyzine, ifosphamide, leucovorin, magnesium sulfate, 
mannitol, potassium chloride.  
Y-site: Allopurinol, bleomycin chlorpromazine, cimetidine, cyclophosphamide, 
dexamethasone, diphenhydramine, doxapram, doxorubicin, famotidine, filgrastim, 
fludarabine, fluorouracil, furosemide, ganciclovir, heparin, hydromorphone, lorazepam, 
melphalan, methotrexate, methylprednisolone, metoclopramide, mitomycin, morphine, 
ondansetron, paclitaxel, prochlorperazine, ranitidine, sargramostim, vinblastine, 
vincristine, vinorelbine. 
Consult your pharmacist regarding specific concentrations. 
 
Availability: 
Commercially available as a mg/ml solution in 50 and 100 mg vials. Vials of lyophilized 
powder are no longer commercially available, but may be obtained directly from the 
manufacturer for chemoembolization use. 
Nursing Implications: 
1. Assess labs prior to administration (esp. CBC, platelet count, Cr). 
2. Assess urine output prior to each dose. Maintain hydration. Urine output 
should be 500-150 ml/hr. Diuretics may be ordered. 
3. Administer antiemetics before cisplatin, then q 2-4 h for 3-5 doses. 
4. Observe carefully for signs of anaphylaxis. 
5. Monitor for signs of neurotoxicity, hearing loss. 
 
 
8.1.3 Carboplatin - (Commercially available. Please refer to the package insert for 
further information) Other Names: CBDCA, Paraplatin, JM-8, NSC 241240. 
Classification: Second generation tetravalent organic platinum compound. 
Mode of Action: 
Like cisplatin, carboplatin produces predominately interstrand DNA crosslinks rather 
than DNA-protein crosslinks. Cell-cycle nonspecific. 
 
Storage and Stability: 
Intact vials are stored at room temperature and protected from light. The reconstituted 
solution is stable for at least 24 hours. When further diluted in glass or polyvinyl plastic 


 
IRB-15411  
Page 30 of 56 
5 December 2016 
to a concentration of 500 mg/ml, solutions have the following stability: in normal saline, 
8 hours at 25°C; in 5% dextrose (when reconstituted in sterile water), 24 hours at 5 of 
25°C. 
 
Preparation: 
Add 5, 15, or 45 ml sterile water, normal saline, or 5% dextrose to the 50, 150 or 
450 mg vial, respectively. The resulting solution contains 10 mg/ml. The desired 
dose is further diluted, usually in 5% dextrose. 
Administration: 
Administer as a 30 minute infusion  
Incompatibilities: 
Forms a precipitate when in contact with aluminum. 
Compatibilities: 
Carboplatin (0.3 mg/ml) and etoposide (0.4 mg/ml) are chemically compatible in normal 
saline or 5% dextrose for 24 hours at room temperature. 
Availability: 
Commercially available in 50, 150, and 450 mg vials. 
Nursing Implications 
1. Monitor CBC and platelet count; nadir occurs at approximately day 21 with 
recovery by day 28-30. 
2. Premedicate with antiemetics – evaluate effectiveness. 
3. Monitor fluid status – maintain adequate hydration. 
4. Assess skin/mucous membranes. 
5. Assess for signs of peripheral motor/sensory neuropathy – coordination, sensory loss. 
 
8.1.4 5-Fluorouracil- (Commercially available. Please refer to the package insert for 
further information). 
Other Names 
5-FU, Adrucil, Efudex. 
Formulation 
Available in 500 mg/10 mL ampules and vials, and 1 gm/ 20 ml. For further information, 
see package insert. 
Administration:  5- Fluorouracil will be administered as a continuous IV infusion during 
induction chemotherapy following the completion of bevacizumab and docetaxel 
administration. 5-Fluorouracil may be  begin concurrently with the cisplatin or 
carboplatin infusion. 31 
Drug Interactions 


 
IRB-15411  
Page 31 of 56 
5 December 2016 
Cimetidine: Because cimetidine can decrease the clearance of 5-FU, patients should not 
enter on this study until the cimetidine is discontinued. Ranitidine or a drug from another 
anti-ulcer class can be substituted for cimetidine, as necessary.  
Allopurinol: Oxypurinol, a metabolite of allopurinol, can potentially interfere with 5-FU 
anabolism via orotate phosphoribosyltransferase. 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 patient is receiving allopurinol, the need for taking this medicine should be 
ascertained. If possible, allopurinol should be discontinued prior to starting on this 
regimen, and another agent substituted for it. 
 
Storage 
Stable for prolonged periods of time at room temperature, if protected from light. Inspect 
for precipitate; if apparent, agitate vial vigorously or gently heat to not greater than 140°F 
in a water bath. Do not allow to freeze. 
 


 
IRB-15411  
Page 32 of 56 
5 December 2016 
9.  STUDY CALENDAR 
Baseline evaluations are to be conducted within 1 week prior to start of protocol therapy.  Scans 
and x-rays must be done within 1 month prior to the start of therapy.  In the event that the 
patient's condition is deteriorating, laboratory evaluations should be repeated within 48 hours 
prior to initiation of the next cycle of therapy. 
Induction Chemotherapy with TPF study calendar (separate calendar for radiation portion 
and post radiation follow-up is below)  
 
 
Pre 
study 
Induction Week # 
End of 
induction 
(Assessment 
maybe 
combined in 
same visit as 
first week of 
XRT) 
1 
2 
3 
4 
5 
6 
7 
8 
9 
TPF 
 
A 
 
 
A 
 
 
A 
 
 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
x 
x 
 
 
x 
 
 
x 
 
 
x 
Physical exam 
x 
x 
 
 
x 
 
 
x 
 
 
x 
Vital signs 
x 
x 
 
 
x 
 
 
x 
 
 
x 
Height 
x 
 
 
 
 
 
 
 
 
 
 
Weight 
x 
 
 
 
 
 
 
 
 
 
 
Performance status 
x 
 
 
 
 
 
 
 
 
 
x 
CBC w/diff, pltsb 
x 
x 
 
 
x 
 
 
x 
 
 
x 
Comp. metab. profile a,b 
x 
x 
 
 
x 
 
 
x 
 
 
x 
EKG (as indicated) 
x 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
x 
x 
 
 
x 
 
 
x 
 
 
x 
Tumor measurements per 
clinical routine 
x 
x 
 
 
x 
 
 
x 
 
 
x 
Radiological evaluation d 
x 
 
 
 
 
 
 
 
 
 
x 
A: 
TPF: Docetaxel 75 mg/m2  and cisplatin 75 mg/m2 on day 1 of each cycle. 5-FU, 
750 mg/m2 on days 1,2,3,4,5 of each cycle as IVCI, 
a: 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, 
chloride, creatinine, glucose, potassium, total protein, SGOT [AST], SGPT [ALT], 
sodium. 
b:   While the protocol mandates a blood tests only prior to each dose of TPF, good 
clinical practice should be used in ordering additional lab tests as part of routine care for 
patients receiving chemotherapy. 
c:  Basic metabolic panel: calcium, CO2, chloride, creatinine, glucose, potassium, 
sodium, BUN 
d: Radiological evaluation will be tailored to the patient with the following parameters: 
There must be CT or MRI evaluation of the primary site and neck, and a baseline 
evaluation for metastatic disease to include at minimum chest CT or total body FDG 
PET scan. Imaging modality should be consistent for each patient throughout. Response 


 
IRB-15411  
Page 33 of 56 
5 December 2016 
to induction may be made using the planning PET CT for radiation as the primary 
imaging modality response. 
 
Concurrent chemoradiation study calendar (separate calendar for induction TPF is above, 
use same footnotes)  
 
 
Concurrent ChemoXRT Week # 
 
1 mo 
f/u 
3,6,9, 
12 , 
24mo 
f/u 
1 
2 
3 
4 
5 
6 
7 
Radiation 
treatment 
x 
x 
x 
x 
x 
x 
 
 
 
Cisplatin( or 
carboplatin) 
x 
x 
x 
x 
x 
x 
 
 
 
Physical 
exam 
 
 
 
 
 
 
 
 
x 
Vital signs 
 
 
 
 
 
 
 
 
 
CBC 
x 
x 
x 
x 
x 
x 
x 
 
 
Basic 
metabolic 
profile c 
x 
x 
x 
 
x 
x 
 
 
 
Comp. 
metab. 
Profile a 
 
 
 
x 
 
 
x 
 
 
AE 
evaluation 
x 
x 
x 
x 
x 
x 
x 
x* 
 
Tumor 
measure 
 per clinical 
routine 
 
 
 
 
 
 
 
 
x* 
Radiological 
evaluation  
 
 
 
 
 
 
 
 
x# 
 
*= 1-3 months after radiation completion 
# Only at 3, 12, and 24 month followup (+/- 1 month). For the first post- XRT imaging, a 
window of 8-16 weeks post RT is acceptable.  For the 1 and 2 year followup imaging, +/- 2 
months is acceptable. 


 
IRB-15411  
Page 34 of 56 
5 December 2016 
10. MEASUREMENT OF EFFECT 
10.1 
Antitumor Effect – Solid Tumors 
For the purposes of this study, patients should be reevaluated for response after TPF and 
3, 12, and 24 months after the completion of radiation. The primary endpoint of response 
assessment will be based on  MRI and or CT imaging and physical exam using a 
modification of the RECIST criteria (see below).While other modalities for response 
assessment (e.g. PET scanning, serum tumor markers) will be collected and may be used 
for clinical planning, they will not be used to evaluate the primary endpoint. 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) 
Committee [JNCI 92(3):205-216, 2000].  Changes in only the largest diameter 
(unidimensional measurement) of the tumor lesions are used in the RECIST criteria. 
 
10.1.1 Definitions 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment . 
Evaluable for objective response.  Only those patients who have measurable disease 
present at baseline, have received at least one cycle of TPF, and have had their disease re-
evaluated will be considered evaluable for response.   
 
10.1.2 Disease Parameters 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm with 
conventional techniques (CT, MRI, x-ray) or as >10 mm with spiral CT scan.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <20 mm with conventional techniques or <10 mm using spiral CT 
scan), are considered non-measurable disease.  Bone lesions, leptomeningeal disease, 
ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast 
disease, abdominal masses (not followed by CT or MRI), and cystic lesions are all non-
measurable. 
Target lesions.  All measurable lesions up to a maximum of 5 lesions per organ and 10 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter) and their suitability for accurate 
repeated measurements (either by imaging techniques or clinically).  A sum of the longest 
diameter (LD) for all target lesions will be calculated and reported as the baseline sum 
LD.  The baseline sum LD will be used as reference by which to characterize the 
objective tumor response. 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 10 target lesions should be identified as non-target lesions 


 
IRB-15411  
Page 35 of 56 
5 December 2016 
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.  
 
10.1.3 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination when both methods have 
been used to assess the antitumor effect of a treatment. 
Clinical lesions  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes).  In the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, 
is recommended.  
Chest x-ray  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
Conventional CT and MRI  These techniques should be performed with cuts of 10 mm or 
less in slice thickness contiguously.  Spiral CT should be performed using a 5 mm 
contiguous reconstruction algorithm.  This applies to tumors of the chest, abdomen, and 
pelvis.  Head and neck tumors and those of extremities usually require specific protocols. 
Ultrasound (US)  When the primary endpoint of the study is objective response 
evaluation, US should not be used to measure tumor lesions.  It is, however, a possible 
alternative to clinical measurements of superficial palpable lymph nodes, subcutaneous 
lesions, and thyroid nodules.  US might also be useful to confirm the complete 
disappearance of superficial lesions usually assessed by clinical examination. 
Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor 
evaluation has not yet been fully and widely validated.  Their uses in this specific context 
require sophisticated equipment and a high level of expertise that may only be available 
in some centers.  Therefore, the utilization of such techniques for objective tumor 
response should be restricted to validation purposes in reference centers. However, such 
techniques may be useful to confirm complete pathological response when biopsies are 
obtained. 
Tumor markers  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response.  Specific additional criteria for standardized usage of 
prostate-specific antigen (PSA) and CA-125 response in support of clinical trials are 
being developed. 
Cytology, Histology  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 


 
IRB-15411  
Page 36 of 56 
5 December 2016 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
 
10.1.4 Response Criteria 
10.1.4.1 
Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions 
Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) 
of target lesions, taking as reference the baseline sum LD 
Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, 
taking as reference the smallest sum LD recorded since the treatment started or the 
appearance of one or more new lesions 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum LD since the treatment started 
 
10.1.4.2 
Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level 
Note:  If tumor markers are initially above the upper normal limit, they must normalize 
for a patient to be considered in complete clinical response. 
Incomplete Response/ 
Stable Disease (SD): Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of 
the treating physician should prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or Principal Investigator). 
 
10.1.4.3 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  This is a modification of 
RECIST in that confirmatory imaging is not practical at the 3, 12, and 24 month imaging 
intervals, does not contribute to the sense of “ best response” achieved, and is not a 
primary endpoint of the study. 
 
Target 
Lesions 
Non-
Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Response 
following radiation 
for this Category Also 
Requires: 
CR 
CR 
No 
CR 
 
CR 
Non-
CR/Non-
No 
PR 
 
 


 
IRB-15411  
Page 37 of 56 
5 December 2016 
PD 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
 
PD 
Any 
Yes or 
No 
PD 
 
no prior SD, PR or CR 
Any 
PD* 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 
 
Note: Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease 
progression at that time should be reported as “symptomatic 
deterioration”.  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
10.1.5 Duration of Response 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that recurrent disease is objectively documented. 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started.  
10.1.6 Progression-Free Survival 
Progression – free survival will be calculated as the interval between date of registration 
and  date of documented cancer progression or death, whichever occurs first. 
10.1.7 Response Review 
 
All radiological images used for response assessment must be available to the 
principal investigator for response assessment review.  For patients imaged at Stanford 
Cancer center/ Stanford Hospital, images available within the Hospital radiology system 
fulfill this criterion.  For images acquired outside of the Stanford system, images must be 
transferred to a separate , portable medium (i.e. CD or DVD), labeled with the patient’s 
anonymized Oncore protocol registration number and scan date, and sent to the clinical 
trial coordinator at the address on the first page of this protocol. 
 
11. STATISTICAL CONSIDERATIONS 
11.1 
Study Design/Endpoints 


 
IRB-15411  
Page 38 of 56 
5 December 2016 
The primary endpoint for this trial will be progression free survival 2 years following 
chemoradiotherapy. 
The US intergroup CR rate to chemoradiotherapy was 49%, using SWOG response 
criteria that did not include PET imaging. 5  However, many have argued that this CR rate 
was atypically low when compared to  other studies conducted primarily in Asia .  
Because the CR rates reported in many other studies are so high and because PFS rates at 
one year in many RCTS  of chemoradiaton in NPC are so high, 5-7, 11 we have decided to 
make PFS at 2 years following the end of chemoradiation as the primary endpoint of this 
study. In the 4 studies referenced above, the average 2 year PFS for the superior arm was 
0.7 and no single study achieved a PFS greater than 0.85.  Therefore we will evaluate 40 
patients in a single stage design for progression free survival at 2 years post radiation, 
which will give an alpha of 0.1 and a power of 0.9  to distinguish a 2 year PFS of 0.88 
from 0.7 . 
It is not feasible with the accrual rate planned to introduce an early stopping rule for a 
PFS at 2 years.  Therefore, in order to avoid accruing up to 40 patients to a study that is 
unlikely to be of interest, we will have an early stopping rule based on RECIST 
determined CR rates.  If there are less  than 10 CRs in the first 18 patients, we would stop 
the trial.  If the trial goes to the second stage, the treatment will be considered worthy of 
further study if 33 or more of the 40 patients are progression-free at 2 years. 
 
 
11.2 
Sample Size/Accrual Rate 
18-40 evaluable patients. 2-4 per month. All patients who are not evaluable will be 
replaced. Any patient who starts treatment with TPF will be considered evaluable for 
response. 
11.3 
Stratification Factors 
No stratification 
11.4 
Analysis of Secondary Endpoints: 
 
1. Progression free survival and overall survival will be estimated according to the 
methods of Kaplan and Meier.  
      2. Rates of adverse events will be analyzed as follows: 
The acceptable incidence of AEs resulting in protocol treatment discontinuance is 3% or 
less, and the unacceptable rate is 15% or greater. The rates of AEs resulting in protocol 
treatment discontinuation will be estimated using a binomial distribution along with their 
associated 95% confidence intervals. Only adverse events assessed  definitely, probably, 
or possibly related to protocol treatment will be considered. 40 evaluable patients will be 
able to distinguish between the above null and alternative hypothesis with and  alpha 
error  of .03 and power .87. 
11.5 Reporting  
11.5.1 Evaluation of toxicity.  All patients will be evaluable for toxicity from the time of 
their first treatment . 


 
IRB-15411  
Page 39 of 56 
5 December 2016 
11.5.2 Evaluation of response. All patients who receive one cycle of TPF will be 
considered evaluable for response.  Response categories will be: 1) complete response, 2) 
partial response, 3) stable disease, 4) progressive disease, 5) early death from malignant 
disease, 6) early death from toxicity, 7) early death because of other cause, or 9) 
unknown (not assessable, insufficient data).   
 
 


 
IRB-15411  
Page 40 of 56 
5 December 2016 
REFERENCES 
1.Licitra L, Bernier J, Cvitkovic E, et al. Cancer of the nasopharynx. Critical Reviews in 
Oncology-Hematology 2003;45:199-213. 
2.Kantakamalakul W, Chongkolwatana C, Naksawat P, et al. Specific IgA antibody to 
Epstein-Barr viral capsid antigen: a better marker for screening nasopharyngeal 
carcinoma than EBV-DNA detection by polymerase chain reaction. Asian Pacific Journal 
of Allergy & Immunology 2000;18:221-6. 
3.Leung SF, Zee B, Ma BB, et al. Plasma Epstein-Barr viral deoxyribonucleic acid 
quantitation complements tumor-node-metastasis staging prognostication in 
nasopharyngeal carcinoma. Journal of Clinical Oncology 2006;24:5414-8. 
4.Le QT, Jones CD, Yau TK, et al. A comparison study of different PCR assays in 
measuring circulating plasma epstein-barr virus DNA levels in patients with 
nasopharyngeal carcinoma. Clinical Cancer Research 2005;11:5700-7. 
5.Al-Sarraf M, LeBlanc M, Giri PG, et al. Chemoradiotherapy versus radiotherapy in 
patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 
0099. Journal of Clinical Oncology 1998;16:1310-7. 
6.Lin JC, Jan JS, Hsu CY, Liang WM, Jiang RS, Wang WY. Phase III study of 
concurrent chemoradiotherapy versus radiotherapy alone for advanced nasopharyngeal 
carcinoma: positive effect on overall and progression-free survival.[see comment]. 
Journal of Clinical Oncology 2003;21:631-7. 
7.Chan AT, Leung SF, Ngan RK, et al. Overall survival after concurrent cisplatin-
radiotherapy compared with radiotherapy alone in locoregionally advanced 
nasopharyngeal carcinoma. Journal of the National Cancer Institute 2005;97:536-9. 
8.Lee AW, Tung SY, Chan AT, et al. Preliminary results of a randomized study (NPC-
9902 Trial) on therapeutic gain by concurrent chemotherapy and/or accelerated 
fractionation for locally advanced nasopharyngeal carcinoma. International Journal of 
Radiation Oncology, Biology, Physics 2006;66:142-51. 
9.Chan AT, Teo PM, Ngan RK, et al. Concurrent chemotherapy-radiotherapy compared 
with radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: 
progression-free survival analysis of a phase III randomized trial.[see comment]. Journal 
of Clinical Oncology 2002;20:2038-44. 
10.Chua DT, Sham JS, Wei WI, Ho WK, Au G, Choy D. Control of regional metastasis 
after induction chemotherapy and radiotherapy for nasopharyngeal carcinoma. Head & 
Neck 2002;24:350-60. 
11.Chua DT, Ma J, Sham JS, et al. Long-term survival after cisplatin-based induction 
chemotherapy and radiotherapy for nasopharyngeal carcinoma: a pooled data analysis of 
two phase III trials.[see comment]. Journal of Clinical Oncology 2005;23:1118-24. 
12.Hong RL, Ting LL, Ko JY, et al. Induction chemotherapy with mitomycin, epirubicin, 
cisplatin, fluorouracil, and leucovorin followed by radiotherapy in the treatment of 
locoregionally advanced nasopharyngeal carcinoma. Journal of Clinical Oncology 
2001;19:4305-13. 


 
IRB-15411  
Page 41 of 56 
5 December 2016 
13.Paccagnella A, Favaretto A, Oniga F, et al. Cisplatin versus carboplatin in 
combination with mitomycin and vinblastine in advanced non small cell lung cancer. A 
multicenter, randomized phase III trial. Lung Cancer 2004;43:83-91. 
14.Scagliotti GV, De Marinis F, Rinaldi M, et al. Phase III randomized trial comparing 
three platinum-based doublets in advanced non-small-cell lung cancer. Journal of Clinical 
Oncology 2002;20:4285-91. 
15.Fossella F, Pereira JR, von Pawel J, et al. Randomized, multinational, phase III study 
of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced 
non-small-cell lung cancer: the TAX 326 study group.[see comment]. Journal of Clinical 
Oncology 2003;21:3016-24. 
16.Aravantinos G, Fountzilas G, Kosmidis P, et al. Paclitaxel plus carboplatin versus 
paclitaxel plus alternating carboplatin and cisplatin for initial treatment of advanced 
ovarian cancer: long-term efficacy results: a Hellenic Cooperative Oncology Group 
(HeCOG) study. Annals of Oncology 2005;16:1116-22. 
17.du Bois A, Luck HJ, Meier W, et al. A randomized clinical trial of cisplatin/paclitaxel 
versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. Journal of the 
National Cancer Institute 2003;95:1320-9. 
18.Ozols RF, Bundy BN, Greer BE, et al. Phase III trial of carboplatin and paclitaxel 
compared with cisplatin and paclitaxel in patients with optimally resected stage III 
ovarian cancer: a Gynecologic Oncology Group study.[see comment]. Journal of Clinical 
Oncology 2003;21:3194-200. 
19.Homma A, Shirato H, Furuta Y, et al. Randomized phase II trial of concomitant 
chemoradiotherapy using weekly carboplatin or daily low-dose cisplatin for squamous 
cell carcinoma of the head and neck. Cancer Journal 2004;10:326-32. 
20.Chitapanarux I, Lorvidhaya V, Kamnerdsupaphon P, et al. Chemoradiation comparing 
cisplatin versus carboplatin in locally advanced nasopharyngeal cancer: randomised, non-
inferiority, open trial. European Journal of Cancer 2007;43:1399-406. 
21.Forastiere AA, Shank D, Neuberg D, Taylor SGt, DeConti RC, Adams G. Final report 
of a phase II evaluation of paclitaxel in patients with advanced squamous cell carcinoma 
of the head and neck: an Eastern Cooperative Oncology Group trial (PA390). Cancer 
1998;82:2270-4. 
22.Dreyfuss AI, Clark JR, Norris CM, et al. Docetaxel: an active drug for squamous cell 
carcinoma of the head and neck. Journal of Clinical Oncology 1996;14:1672-8. 
23.Hitt R, Grau J, Lopez- Puose A, et al. Randomized phase II/III clinical trial of 
induction chemotherapy (ICT) with either cisplatin/5-fluorouracil (PF) or 
docetaxel/cisplatin/5-fluorouracil (TPF) followed by chemoradiotherapy (CRT) vs. crt 
alone for patients (pts) with unresectable locally advanced head and neck cancer 
(LAHNC). Journal of Clinical Oncology 2006;24:5515. 
24.Vermorken JB, Remenar E, van Herpen C, et al. Cisplatin, fluorouracil, and docetaxel 
in unresectable head and neck cancer. New England Journal of Medicine 2007;357:1695-
704. 


 
IRB-15411  
Page 42 of 56 
5 December 2016 
25.Posner MR, Colevas AD. Induction chemotherapy in the management of squamous 
cell cancer of the head and neck.[comment]. Cancer Journal From Scientific American 
1997;3:73-5. 
26.Administration USFaD. Approval History New Drug Application # 020449  for 
docetaxel. 
27.Pignon JP, Syz N, Posner M, et al. Adjusting for patient selection suggests the 
addition of docetaxel to 5-fluorouracil-cisplatin induction therapy may offer survival 
benefit in squamous cell cancer of the head and neck. Anti-Cancer Drugs 2004;15:331-
40. 
28.Chua DT, Sham JS, Au GK. A phase II study of docetaxel and cisplatin as first-line 
chemotherapy in patients with metastatic nasopharyngeal carcinoma. Oral Oncology 
2005;41:589-95. 
29.Haddad R, Colevas AD, Tishler R, et al. Docetaxel, cisplatin, and 5-fluorouracil-based 
induction chemotherapy in patients with locally advanced squamous cell carcinoma of 
the head and neck: the Dana Farber Cancer Institute experience. Cancer 2003;97:412-8. 
30.Colevas AD, Busse PM, Norris CM, et al. Induction chemotherapy with docetaxel, 
cisplatin, fluorouracil, and leucovorin for squamous cell carcinoma of the head and neck: 
a phase I/II trial.[see comment]. Journal of Clinical Oncology 1998;16:1331-9. 
31.Colevas AD, Norris CM, Tishler RB, et al. Phase II trial of docetaxel, cisplatin, 
fluorouracil, and leucovorin as induction for squamous cell carcinoma of the head and 
neck.[see comment]. Journal of Clinical Oncology 1999;17:3503-11. 
32.Colevas AD, Norris CM, Tishler RB, et al. Phase I/II trial of outpatient docetaxel, 
cisplatin, 5-fluorouracil, leucovorin (opTPFL) as induction for squamous cell carcinoma 
of the head and neck (SCCHN). American Journal of Clinical Oncology 2002;25:153-9. 
33.Kyzas PA, Cunha IW, Ioannidis JP. Prognostic significance of vascular endothelial 
growth factor immunohistochemical expression in head and neck squamous cell 
carcinoma: a meta-analysis. Clinical Cancer Research 2005;11:1434-40. 
34.Wakisaka N, Wen QH, Yoshizaki T, et al. Association of vascular endothelial growth 
factor expression with angiogenesis and lymph node metastasis in nasopharyngeal 
carcinoma. Laryngoscope 1999;109:810-4. 
35.Qian CN, Zhang CQ, Guo X, et al. Elevation of serum vascular endothelial growth 
factor in male patients with metastatic nasopharyngeal carcinoma. Cancer 2000;88:255-
61. 
36.Krishna SM, James S, Balaram P. Expression of VEGF as prognosticator in primary 
nasopharyngeal cancer and its relation to EBV status. Virus Research 2006;115:85-90. 
37.Druzgal CH, Chen Z, Yeh NT, et al. A pilot study of longitudinal serum cytokine and 
angiogenesis factor levels as markers of therapeutic response and survival in patients with 
head and neck squamous cell carcinoma. Head & Neck 2005;27:771-84. 
38.Sanguineti G, Geara FB, Garden AS, et al. Carcinoma of the nasopharynx treated by 
radiotherapy alone: determinants of local and regional control.[see comment]. 
International Journal of Radiation Oncology, Biology, Physics 1997;37:985-96. 


 
IRB-15411  
Page 43 of 56 
5 December 2016 
39.Okunieff P, de Bie J, Dunphy EP, Terris DJ, Hockel M. Oxygen distributions partly 
explain the radiation response of human squamous cell carcinomas. British Journal of 
Cancer - Supplement 1996;27:S185-90. 
40.Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic 
therapy. Science 2005;307:58-62. 
41.Winkler F, Kozin SV, Tong RT, et al. Kinetics of vascular normalization by VEGFR2 
blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, 
and matrix metalloproteinases.[see comment]. Cancer Cell 2004;6:553-63. 
42.Willett CG, Boucher Y, di Tomaso E, et al. Direct evidence that the VEGF-specific 
antibody bevacizumab has antivascular effects in human rectal cancer.[see 
comment][erratum appears in Nat Med. 2004 Jun;10(6):649]. Nature Medicine 
2004;10:145-7. 
43.Taghian AG, Abi-Raad R, Assaad SI, et al. Paclitaxel decreases the interstitial fluid 
pressure and improves oxygenation in breast cancers in patients treated with neoadjuvant 
chemotherapy: clinical implications. Journal of Clinical Oncology 2005;23:1951-61. 
44.Batchelor TT, Sorensen AG, di Tomaso E, et al. AZD2171, a pan-VEGF receptor 
tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in 
glioblastoma patients.[see comment]. Cancer Cell 2007;11:83-95. 
45.Yeh SH, Liu RS, Wu LC, et al. Fluorine-18 fluoromisonidazole tumour to muscle 
retention ratio for the detection of hypoxia in nasopharyngeal carcinoma. European 
Journal of Nuclear Medicine 1996;23:1378-83. 
46.Leslie MD, Dische S. The early changes in salivary gland function during and after 
radiotherapy given for head and neck cancer. Radiotherapy & Oncology 1994;30:26-32. 
47.Mira JG, Wescott WB, Starcke EN, Shannon IL. Some factors influencing salivary 
function when treating with radiotherapy. International Journal of Radiation Oncology, 
Biology, Physics 1981;7:535-41. 
48.Harrison LB, Zelefsky MJ, Pfister DG, et al. Detailed quality of life assessment in 
patients treated with primary radiotherapy for squamous cell cancer of the base of the 
tongue.[see comment]. Head & Neck 1997;19:169-75. 
49.Cooper JS, Fu K, Marks J, Silverman S. Late effects of radiation therapy in the head 
and neck region. International Journal of Radiation Oncology, Biology, Physics 
1995;31:1141-64. 
50.Wang CC. Carcinoma of the nasopharynx. In: Wang CC, ed. Radiation Therapy for 
Head and Neck 
Neoplasms: Indications, Techniques, and Results 2ed. Chicago: Year Book Medical 
Publishers; 1990:261-83. 
51.Bailet JW, Mark RJ, Abemayor E, et al. Nasopharyngeal carcinoma: treatment results 
with primary radiation therapy. Laryngoscope 1992;102:965-72. 
52.Hoppe RT, Goffinet DR, Bagshaw MA. Carcinoma of the nasopharynx. Eighteen 
years' experience with megavoltage radiation therapy. Cancer 1976;37:2605-12. 


 
IRB-15411  
Page 44 of 56 
5 December 2016 
53.Chu AM, Flynn MB, Achino E, Mendoza EF, Scott RM, Jose B. Irradiation of 
nasopharyngeal carcinoma: correlations with treatment factors and stage. International 
Journal of Radiation Oncology, Biology, Physics 1984;10:2241-9. 
54.Teo PM, Ma BB, Chan AT. Radiotherapy for nasopharyngeal carcinoma--transition 
from two-dimensional to three-dimensional methods. Radiotherapy & Oncology 
2004;73:163-72. 
55.Sultanem K, Shu HK, Xia P, et al. Three-dimensional intensity-modulated 
radiotherapy in the treatment of nasopharyngeal carcinoma: the University of California-
San Francisco experience. International Journal of Radiation Oncology, Biology, Physics 
2000;48:711-22. 
56.Liu WS, Su MC, Wu MF, Tseng HC, Kuo HC. Nasopharyngeal carcinoma treated 
with precision-oriented radiation therapy techniques including intensity-modulated 
radiotherapy: preliminary results. Kaohsiung Journal of Medical Sciences 2004;20:49-55. 
57.Xia P, Fu KK, Wong GW, Akazawa C, Verhey LJ. Comparison of treatment plans 
involving intensity-modulated radiotherapy for nasopharyngeal carcinoma.[see 
comment]. International Journal of Radiation Oncology, Biology, Physics 2000;48:329-
37. 
58.Wolden SL, Zelefsky MJ, Hunt MA, et al. Failure of a 3D conformal boost to improve 
radiotherapy for nasopharyngeal carcinoma. International Journal of Radiation Oncology, 
Biology, Physics 2001;49:1229-34. 
59.Hunt MA, Zelefsky MJ, Wolden S, et al. Treatment planning and delivery of intensity-
modulated radiation therapy for primary nasopharynx cancer. International Journal of 
Radiation Oncology, Biology, Physics 2001;49:623-32. 
60.Lee N, Xia P, Quivey JM, et al. Intensity-modulated radiotherapy in the treatment of 
nasopharyngeal carcinoma: an update of the UCSF experience.[see comment]. 
International Journal of Radiation Oncology, Biology, Physics 2002;53:12-22. 
61.Kwong DL, Pow EH, Sham JS, et al. Intensity-modulated radiotherapy for early-stage 
nasopharyngeal carcinoma: a prospective study on disease control and preservation of 
salivary function. Cancer 2004;101:1584-93. 
62.Wolden SL, Chen WC, Pfister DG, Kraus DH, Berry SL, Zelefsky MJ. Intensity-
modulated radiation therapy (IMRT) for nasopharynx cancer: update of the Memorial 
Sloan-Kettering experience. International Journal of Radiation Oncology, Biology, 
Physics 2006;64:57-62. 
63.Pow EH, Kwong DL, McMillan AS, et al. Xerostomia and quality of life after 
intensity-modulated radiotherapy vs. conventional radiotherapy for early-stage 
nasopharyngeal carcinoma: initial report on a randomized controlled clinical trial. 
International Journal of Radiation Oncology, Biology, Physics 2006;66:981-91. 
64.Kam M, Leung S, Zee B, et al. Prospective Randomized Study of Intensity-Modulated 
Radiotherapy on Salivary Gland Function in Early-Stage Nasopharyngeal Carcinoma 
Patients. Journal of Clinical Oncology 2007;25:4873-9. 
65.Kam MK, Teo PM, Chau RM, et al. Treatment of nasopharyngeal carcinoma with 
intensity-modulated radiotherapy: the Hong Kong experience. International Journal of 
Radiation Oncology, Biology, Physics 2004;60:1440-50. 


 
IRB-15411  
Page 45 of 56 
5 December 2016 
66.Presta LG, Chen H, O'Connor SJ, et al. Humanization of an anti-vascular endothelial 
growth factor monoclonal antibody for the therapy of solid tumors and other disorders. 
Cancer Research 1997;57:4593-9. 
67.Kim KJ, Li B, Winer J, et al. Inhibition of vascular endothelial growth factor-induced 
angiogenesis suppresses tumour growth in vivo. Nature 1993;362:841-4. 
68.Borgstrom P, Gold DP, Hillan KJ, Ferrara N. Importance of VEGF for breast cancer 
angiogenesis in vivo: implications from intravital microscopy of combination treatments 
with an anti-VEGF neutralizing monoclonal antibody and doxorubicin. Anticancer 
Research 1999;19:4203-14. 
69.Shaheen RM, Ahmad SA, Liu W, et al. Inhibited growth of colon cancer 
carcinomatosis by antibodies to vascular endothelial and epidermal growth factor 
receptors. British Journal of Cancer 2001;85:584-9. 
70.Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D. Benefits of targeting 
both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors.[see 
comment]. Journal of Clinical Investigation 2003;111:1287-95. 
71.Cobleigh MA, Langmuir VK, Sledge GW, et al. A phase I/II dose-escalation trial of 
bevacizumab in previously treated metastatic breast cancer. Seminars in Oncology 
2003;30:117-24. 
72.Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, 
fluorouracil, and leucovorin for metastatic colorectal cancer.[see comment]. New 
England Journal of Medicine 2004;350:2335-42. 
73.Miller KD, Chap LI, Holmes FA, et al. Randomized phase III trial of capecitabine 
compared with bevacizumab plus capecitabine in patients with previously treated 
metastatic breast cancer. Journal of Clinical Oncology 2005;23:792-9. 
74.Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab, an anti-
vascular endothelial growth factor antibody, for metastatic renal cancer.[see comment]. 
New England Journal of Medicine 2003;349:427-34. 
75.Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National 
Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: 
the JNC 7 report.[see comment][erratum appears in JAMA. 2003 Jul 9;290(2):197]. 
JAMA 2003;289:2560-72. 
76.Novotny W, Holmgren, E., Griffing, S., et al. Identification of squamous cell 
histology and central, cavitary tumors as possible risk factors for pulmonary hemorrhage 
in patients with advanced NSCLC receiving bevacizumab. Proc Am Soc Clin Oncol  
2001:20:A1318. 
77.Scappaticci FA, Skillings JR, Holden SN, et al. Arterial thromboembolic events in 
patients with metastatic carcinoma treated with chemotherapy and bevacizumab. Journal 
of the National Cancer Institute 2007;99:1232-9. 
78.Scappaticci FA, Fehrenbacher L, Cartwright T, et al. Surgical wound healing 
complications in metastatic colorectal cancer patients treated with bevacizumab. Journal 
of Surgical Oncology 2005;91:173-80. 


 
IRB-15411  
Page 46 of 56 
5 December 2016 
79.Karp JE, Gojo I, Pili R, et al. Targeting vascular endothelial growth factor for relapsed 
and refractory adult acute myelogenous leukemias: therapy with sequential 1-beta-d-
arabinofuranosylcytosine, mitoxantrone, and bevacizumab. Clinical Cancer Research 
2004;10:3577-85. 
80.Allen JA, Adlakha A, Bergethon PR. Reversible posterior leukoencephalopathy 
syndrome after bevacizumab/FOLFIRI regimen for metastatic colon cancer. Archives of 
Neurology 2006;63:1475-8. 
81.Glusker P, Recht L, Lane B. Reversible posterior leukoencephalopathy syndrome and 
bevacizumab. New England Journal of Medicine 2006;354:980-2; discussion -2. 
82.Ozcan C, Wong SJ, Hari P. Reversible posterior leukoencephalopathy syndrome and 
bevacizumab. New England Journal of Medicine 2006;354:980-2; discussion -2. 
83.American Society of Clinical O, Kris MG, Hesketh PJ, et al. American Society of 
Clinical Oncology guideline for antiemetics in oncology: update 2006. Journal of Clinical 
Oncology 2006;24:2932-47. 
84.Rajendran JG, Krohn KA. Imaging hypoxia and angiogenesis in tumors. Radiologic 
Clinics of North America 2005;43:169-87. 
85.Ziemer LS, Evans SM, Kachur AV, et al. Noninvasive imaging of tumor hypoxia in 
rats using the 2-nitroimidazole 18F-EF5. European Journal of Nuclear Medicine & 
Molecular Imaging 2003;30:259-66. 
86.Reischl G, Dorow DS, Cullinane C, et al. Imaging of tumor hypoxia with [124I]IAZA 
in comparison with [18F]FMISO and [18F]FAZA--first small animal PET results. 
Journal of Pharmacy & Pharmaceutical Sciences 2007;10:203-11. 
87.Graham MM, Peterson LM, Link JM, et al. Fluorine-18-fluoromisonidazole radiation 
dosimetry in imaging studies. Journal of Nuclear Medicine 1997;38:1631-6. 
 


 
IRB-15411  
Page 47 of 56 
5 December 2016 
APPENDIX A:  Performance Status Criteria 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
 
 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
 
 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
 
 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
 
 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 


 
IRB-15411  
Page 48 of 56 
5 December 2016 
APPENDIX B: Radiation Quality Assurance Form 
 
Patient Initials: 
 Patient No.: 
 Sex: M 
 F 
 
Radiotherapy Dept.: 
 Radiation Oncologist:  
 
 
 
DOSE PRESCRIPTION 
 
Target Volume: 
 Date of first treatment: 
 
 
 
 
Dose per Fraction to Prescription 
Volume (cGy) 
 
 
Maximum Dose per 
Fraction in the Planning 
Target Volume 
 
 
Prescription to which Isodose Surface 
(e.g. 95%) 
 
 
Minimum Dose per 
Fraction in the Planning 
Target Volume 
 
 
 
Intended Number of Fractions 
 
 
Patient’s weight pre-
tretment 
 
 
Intended Dose to Prescription Volume 
 
 
Patient’s weight post-
treatment 
 
 
Planning 
System 
 
Treatment 
Machine 
 
Patient 
Position 
 
 
List Names Of Target Volumes Corresponding To Those On RT-1 Forms, Record Boost Volumes Separately 
Names of Target Volume 
(i.e. PTV1, Chest) 
 
 
 
Date of First Treatment 
 
 
 
IMRT 
 
OR 
3D 
 
Form of IMRT 
SMLC (step & shoot):_________        
   
DMLC (sliding window):_______ 
Serial tomotherapy 
(MIMiC):_________________ 
Other:______________________ 
Integrated 
boost 
 
OR 
Sequential 
boost 
 
Supraclavicular 
field matching: 
Yes   
 
No     
 


 
IRB-15411  
Page 49 of 56 
5 December 2016 
to the Target Volume 
Number of Treatments 
 
 
 
Date of Last Treatment 
 
 
 
Total Dose To 
Prescription Point 
 
 
 
Number of Fields 
 
 
 
Beam Energy 
 
 
 
Monitor Unit/Fraction 
 
 
 
 
Critical Structure 
Max Dose 
(Gy) 
Critical 
Structure 
Max Dose (Gy) 
A. Brainstem 
54 
F . Optic 
nerves 
54 
B. Spinal cord 
45 
G. Optic 
chiasms 
54 
C. Eyes 
50 
H. Other 
 
D. Brachial plexus 
66 
I. Other 
 
E. Mandible 
70 
J. Other 
 
Interruptions 
 
 
 
From: 
To: 
Reason: 
 
From: 
To: 
Reason: 
 
From: 
To: 
Reason: 
 
From: 
To: 
Reason: 
 
Off Protocol Therapy 
Date: 
Reason: 
 
 
Discontinued Radiotherapy 
Date: 
Reason: 
 
 
 
 
 
APPENDIX C: Provide all supporting documentation for confirmation of patient 
eligibility. 
            Inclusion/Exclusion Criteria 
Inclusion Criteria 
___Yes ___NO 
Patient has histologically or cytologically confirmed nasopharyngeal carcinoma, stages II  
(minimally  T2a,N0,M0 or Tany,N1, M0)  through IVb. Patients with metastatic (stage 
IVc) untreated NPC who otherwise meet all eligibility criteria will be enrolled on a 
separate cohort and evaluated separately.  Stage: T_____N_____ M _____ 
___Yes ___NO 
Patient has measurable disease, defined as at least one lesion that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm with 
conventional techniques or as >10 mm with spiral CT scan.  See Measurement of Effect 


 
IRB-15411  
Page 50 of 56 
5 December 2016 
section for details. 
___Yes ___NO 
Has patient received any prior treatment(s)? [Patients may have had diagnostic surgery(s) 
at the primary site or neck as long as there is still measurable disease present.] 
___Yes ___NO 
Patient is at least Age >15 years.  [No dosing or adverse event data are currently available 
on the use of   the TPF combination in patients <15 years of age, children are excluded 
from this study but will be eligible for future pediatric trials] 
___Yes ___NO 
Patient has a life expectancy of greater than 3 months. 
___Yes ___NO 
Patients’ ECOG performance status <2.  PS = ____ 
___Yes ___NO 
Patients has normal organ and marrow function as defined below: 
-absolute neutrophil count>1,500/mcL  value_______ date_______ 
-platelets 
>100,000/mcL value_______ date_______ 
-total bilirubin <1.5 X institutional ULN value_______ date_______ 
-AST(SGOT)/ALT(SGPT)<2.5 X institutional ULN value_______ date_____ 
-creatinine < 1.5 mg/dl value_______ date_______ 
-creatinine clearance>55 mL/min/1.73 m2 for patients with creatinine levels above 1.5 
mg/dl value_______ date_______  Patients with creatinine > grade 1 but less than 
grade 3 are eligible but should receive carboplatin throughout the protocol instead of 
cisplatin. 
___Yes ___NO 
-Peripheral  motor/sensory neuropathy < grade 2.  If peripheral neuropathy is grade 2, 
patients are still eligible but should receive carboplatin throughout the protocol 
instead of cisplatin. ________neuropathy grade________ date assessed. Cisplatin 
should be substituted with carboplatin for creatinine > grade 1 , neuropathy > grade 
2 or hearing loss > grade 2 
___Yes ___NO 
Patient agrees to use adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry and for the duration of study participation if a women of 
child-bearing potential or male.  [Should a woman become pregnant or suspect she is 
pregnant while participating in this study, she should inform her treating physician 
immediately. ] 
___Yes ___NO 
Patient has the ability to understand and the willingness to sign a written informed consent. 
Exclusion Criteria 
___Yes ___NO 
Has patient had chemotherapy or radiotherapy for nasopharyngeal carcinoma? 
___Yes ___NO 
Does patient have  known brain metastases? No CNS imaging is required  if no clinical 
indication 
___Yes ___NO 
Does patient have a history of allergic reactions attributed to compounds of similar 
chemical or biologic composition to docetaxel, cisplatin, carboplatin, 5- Fluorouracil, or 
other agents used in the study? 
___Yes ___NO 
Is the patient HIV-positive and on combination antiretroviral therapy? No HIV testing is 
required  if no clinical indication 
___Yes ___NO 
Does patient have an uncontrolled intercurrent illness including, but not limited to, ongoing 
or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with study 
requirements? 
___Yes ___NO 
Does patient have clinically significant cardiovascular disease? 
___Yes ___NO 
Does patient have a history of CVA within 6 months? 
___Yes ___NO 
Has patient had a myocardial infarction or unstable angina within 6 months? 


 
IRB-15411  
Page 51 of 56 
5 December 2016 
___Yes ___NO 
Does patient have a New York heart association grade II or greater congestive heart 
failure? 
___Yes ___NO 
Does patient have a serious and inadequately controlled cardiac arrhythmia? 
___Yes ___NO 
Does patient have significant vascular disease (e.g. aortic aneurysm, history of aortic 
dissection)? 
___Yes ___NO 
Does patient have clinically significant peripheral vascular disease? 
 
 
Confirmation of Eligibility: 
My signature below attests the eligibility for this patient was confirmed by at least two (2) personnel prior 
to being enrolled onto study. Patient was found to be: Eligible / Not Eligible 
 
Primary Investigator / Treating Physician___________________________________ 
 
 
 
 
 
 
 
 
 
 
Signature & Date 
 
 
 
 
Secondary Reviewer ___________________________________ 
 
 
 
 
 
 
 
 
 
 
Signature & Date