Conditions: Obesity Neoplasms
Keywords: Capecitabine pharmacokinetics PK Elevated Body Mass Index (BMI) Advanced Solid Tumors
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 8
Healthy volunteers: no

Brief summary:
The purpose of this research study is to find what happens to capecitabine in the body when dosed using actual versus ideal body weight in subjects with advanced tumors and elevated body mass index.

Detailed description:
Cycle 1 : Capecitabine 1,250 mg/m2 orally Per os (PO) once a day (BID) for 7 consecutive days (D1 - D7) will be administered by subject (with Ideal Body Weight being used to determine BSA) for dosage. Day 8-No drug administered.

Capecitabine 1,250 mg/m2 PO BID for 7 more consecutive days (D9 - D15) will be administered by subject (with Actual Body Weight being used to determine BSA) for dosage. There will be 6 consecutive days that no drug will be administered by subject (Days 16-21).

Cycle 2 and beyond: Capecitabine 1,250 mg/m2 PO BID for 14 consecutive days (D1 - D14) will be administered by subject (with Actual Body Weight being used to determine BSA) for dosage. Days 15-21-No drug administered.

Arms:
arm 1: Cycle 1: Days 1-7 (21 day cycle): 1250 mg/m2 Xeloda orally twice a day using "Ideal Body Weight" to calculate dosage. Cycle 1, Day 8-No drug.

Cycle 1: Days 9-15 (21 day cycle): 1250 mg/m2 Xeloda orally twice a day using Actual Body Weight to calculate dosage. Days 16-21-No drug.

Cycle 2 and greater: Days 1-14 (21 day cycle): 1250 mg/m2 Xeloda orally twice a day using Actual Body Weight to calculate dosage.

Interventions: intervention 1: Xeloda
Intervention descriptions: intervention 1: Cycle 1: Days 1-7 (21 day cycle): 1250 mg/m2 Xeloda orally twice a day using "Ideal Body Weight" to calculate dosage. Cycle 1, Day 8-No drug.

Cycle 1: Days 9-15 (21 day cycle): 1250 mg/m2 Xeloda orally twice a day using Actual Body Weight to calculate dosage. Days 16-21-No drug.

Cycle 2 and greater: Days 1-14 (21 day cycle): 1250 mg/m2 Xeloda orally twice a day using Actual Body Weight to calculate dosage.

Protocol document:
Prot_SAP_000.pdf: 
FootLocal Protocol #: 
OS12903 
 
TITLE:   Pilot Study Evaluating Pharmacokinetic Parameters of Capecitabine Dosing in 
Patients with Advanced Cancer and Elevated Body Mass Index.   
 
Coordinating Center: 
University of Wisconsin Carbone Cancer Center 
 
600 Highland Ave 
 
Madison, WI 53792 
 
University of Wisconsin Participating Site:  
 
University of Wisconsin Health Oncology at 1 South Park 
 
1 South Park St. 
 
Madison, WI 53715 
 
*Principal Investigator: 
Name: 
Kari B. Wisinski, MD 
Address: 1111 Highland Ave. 
WIMR Room 6033 
Madison, WI 53705-2275 
Phone:      608- 262- 2876 
 
 
 
 
       Fax:         608-265-6905 
 
 
 
 
       E-mail:    kbwisinski@medicine.wisc.edu 
 
Co-Investigators: 
Name:  
Jill Kolesar, PharmD, BCPS, FCCP, R.Ph 
 
Address:    600 Highland Avenue 
  CSC Room K4/554 
 Madison, WI 53792 
 
Phone:       608-262-5549 
 
Fax:           608-265-5421 
 
Email:        jmkolesar@pharmacy.wisc.edu 
 
Statistician: 
 
 
     Study Coordinator: 
Name:   
Jens Eickhoff  
Name: 
Jennifer Heideman  
Address: 
600 Highland Avenue 
Address: 
600 Highland Avenue 
 
CSC, Room K6/434   
 
CSC, Room K5/601  
 
Madison WI 53792 
 
Madison, WI 53792 
Telephone: 
(608) 265-5376 
Telephone: (608) 263-6222  
Fax: 
(608) 265-5579 
Fax: 
(608) 263-9132 
E-Mail:       eickhoff@biostat.wisc.edu 
E-Mails:  
   jlv@medicine.wisc.edu 
 
Research Nurses: 
 
Data Managers: 
Kim Binger, BSN, RN  
 
 
 
 
 
Amy Forsyth, BS 
Heidi Brandon, BSN, RN 
 
 
 
 
 
Jess Gunderson, MSc 
Maria Kruse, BSN, RN 
 
 
 
 
 
Jeff Ockuly, BS 
Chris Feierabend, BSN, RN 
    
 
Sandra Black, BS – 1 S. Park 
Kara Mattox, BSN, RN 
 
 
 
 
Karen Schroeder, BSN, RN 
 
 
 
 
 


 
 
 
 
 
Commercial Agent: 
Capecitabine  
 
Protocol Type / Version # / Version Date: 
 Version 1 / 10.15.12  
 
 
 Version 2 / 2.25.13 
 
 
 Version 3 / 12.6.13 
 
 
 Version 4 / 10.1.14 
 
 
 Version 5 / 5.16.16 
 
 
 


 
 
 
 
 
i
 
 
SCHEMA 
 
Cycle 1 
 
Day 1 
Days 2-7 
Day 8 
Day 9 
Days 10-15 
Day 16-
21 
 
Capecitabine 
Dose 
 
(1,250mg/ 
m2 orally 
twice daily) 
 
 
(1,250mg/ m2 
orally twice 
daily) 
 
none 
 
(1,250mg/ 
m2 orally 
twice daily) 
 
(1,250mg/ 
m2 orally 
twice daily) 
 
none 
 
Weight Used 
for BSA 
 
Ideal Body 
Weight 
 
Ideal Body 
Weight 
 
n/a 
 
Actual 
Body 
Weight 
 
Actual 
Body 
Weight 
 
 
 
n/a 
 
PK 
Collection 
 
On CRU 
 
Day 7  
 
 
n/a 
 
On CRU 
 
Day 15  
 
n/a 
 
Cycle 2 and beyond will be dosed using Actual Body Weight at 1,250mg/ m2 orally twice daily 
days 1-14 of 21 day cycles.  


 
 
 
 
 
ii
 
TABLE OF CONTENTS 
 
 
Page 
SCHEMA ........................................................................................................................................ i 
 
1. OBJECTIVES ..........................................................................................................................1 
1.1 
Primary Objectives ......................................................................................................1 
1.2 
Secondary Objectives ..................................................................................................1 
 
2. BACKGROUND ......................................................................................................................1 
2.1 
Study Disease ...............................................................................................................1 
2.2 
Rationale .......................................................................................................................1 
2.3 
Study Drug:  Capecitabine  ........................................................................................2 
2.4 
Hypothesis ....................................................................................................................7 
 
3. PATIENT SELECTION .........................................................................................................7 
3.1 
Eligibility Criteria  ......................................................................................................7 
3.2 
Exclusion Criteria........................................................................................................8 
3.3 
Inclusion of Women and Minorities ..........................................................................9 
 
4. REGISTRATION PROCEDURES........................................................................................9 
4.1  
General Guidelines ......................................................................................................9 
4.2  
Registration Process ..................................................................................................10 
 
5. TREATMENT PLAN ............................................................................................................10 
5.1 
Administration ...........................................................................................................10 
5.2 
General Concomitant Medication and Supportive Care Guidelines ....................11 
5.3 
Duration of Therapy ..................................................................................................12 
5.4 
Duration of Follow Up ...............................................................................................12 
5.5 
Criteria for Removal from Study .............................................................................12 
5.6 
Definition of Evaluable Patients ...............................................................................12 
 
6. DOSING DELAYS/DOSE MODIFICATIONS .................................................................13 
6.1 
General Guidance for Dose Reductions and Modifications ..................................13 
6.2 
Dose Modifications ....................................................................................................13 
 
7. REGULATORY AND REPORTING REQUIREMENTS ...............................................16 
7.1  
Oversight And Monitoring Plan ...............................................................................16 
7.2       Monitoring And Reporting Guidelines ....................................................................16 
7.3      Review And Oversight Requirments ........................................................................16   
 
8. PHARMACEUTICAL INFORMATION ...........................................................................18 
8.1 
Adverse Events and Potential Risks .........................................................................19 
8.2 
Availability .................................................................................................................21 
 


 
 
 
 
 
iii
 
9. PHARMACOKINETIC STUDIES ......................................................................................21 
9.1 
Laboratory Correlative Studies ................................................................................21 
9.2 
PK Sample Collection ................................................................................................22 
 
10. STUDY CALENDAR ............................................................................................................22 
 
11. MEASUREMENT OF EFFECT ..........................................................................................23 
 
11.1 
Antitumor Effect-Solid Tumors ...................................................................................23 
 
12. DATA REPORTING / REGULATORY CONSIDERATIONS .......................................28 
 
13. STATISTICAL CONSIDERATIONS .................................................................................28 
 
13.1 
Study Design/ Endpoints ...........................................................................................28 
 
13.2 
Sample Size/ Accrual Rate ........................................................................................28 
 
13.3 
Stratification Factors .................................................................................................29 
 
13.4 
Analysis of Secondary Endpoints .............................................................................29 
 
13.5 
Reporting and Exclusions .........................................................................................29 
 
REFERENCES ............................................................................................................................31 
 
APPENDICES 
 
APPENDIX A 
Performance Status Criteria ...............................................................................................34 
 
APPENDIX B .........................................................................................................................35 
Patient Pill Diary 
 
APPENDIX C .........................................................................................................................36 
Drug Interaction Table  
 
 
 
 
 


1 1
1. OBJECTIVES 
 
1.1. 
Primary Objective:  To characterize the effect on pharmacokinetic parameters of 
capecitabine, when dosed using actual versus ideal body weight in obese patients 
with advanced solid tumors. 
 
1.2. 
Secondary Objectives:  
 
 
1.2.1  To characterize the response rate and progression free survival with 
capecitabine therapy in obese subjects with advanced solid tumors 
 
 
 
 
 
1.2.2 To determine capecitabine pharmacokinetics in obese patients compared with 
normal weight historical controls. 
  
2. BACKGROUND 
 
2.1 Study Disease 
 
Cancer is the second leading cause of death in the United States.1  The prognosis associated 
with distant metastases from adult solid tumors is poor for most malignancies.  The goal of 
treatment with systemic therapies is primarily palliative for these patients.  Determining the 
optimal dosing of systemic therapies would improve anti-tumor efficacy and limit drug –
related toxicities.   
 
2.2 Rationale 
 
In 2012, the American Society of Clinical Oncology (ASCO) published clinical practice 
guidelines regarding appropriate chemotherapy dosing for obese adult patients with cancer.1  
Although these guidelines recommended that full weight-based chemotherapy doses be used 
to treat obese patients, the authors highlighted the limited data for these recommendations 
and emphasized that further research into the role of pharmacokinetics to guide 
appropriate dosing of chemotherapy in obese patients is critically needed.  This issue is 
particularly relevant given the increasing obesity epidemic in the United States and 
worldwide.  Obesity is defined as a body mass index of 30kg/m2 or greater.  Currently, more 
than 1/3 (35.7%) of U.S. Adults are obese, which has doubled since 1980.2  This is also 
pertinent for the University of Wisconsin patient population.  In 2010, the Center for Disease 
Control estimated that 26.3% of Wisconsin adults were obese.2  
 
Optimal doses of oncology treatments are established through clinical trials.  However, the 
majority of chemotherapy agents and many targeted anti-cancer agents are dosed based on 
weight, with chemotherapy most often dosed based on estimated body surface area (BSA).  
The estimated BSA is calculated using standardized formulas.3   BSA was initially used for 
chemotherapy dosing because of its ability to correlate with many of the physiologic 
parameters which impact drug pharmacokinetics, such as blood volume and renal clearance. 4 
 Pharmacokinetic parameters, such as AUC and Cmax, have been associated with clinical 
efficacy and toxicity of chemotherapy agents.5  However, inter-individual pharmacokinetic 
variation remains a challenge, as this can impact drug efficacy and adverse events.  Obesity 
may account for some of this pharmacokinetic variation.  Based on concerns about increased 


 
 
 
 2 
toxicity with higher doses of chemotherapy in obese patients, many oncologists elect to either 
cap chemotherapy dosing or use an adjusted BSA formula for obese patients.6,7   However, 
empirically lowering the dose of chemotherapy may lead to compromised anti-tumor 
efficacy, as several studies have indicated that dose-intensity of chemotherapy correlates 
with outcomes.8,9  Obesity has been associated with poorer cancer outcomes.10  Although this 
correlation is likely multi-factorial, in part this may reflect sub-optimal chemotherapy dosing. 
 
To date, there have been no prospective, randomized studies comparing cancer outcomes 
using a full weight based approach to a limited-weight dosing approach of chemotherapy in 
obese cancer patients.1  The ASCO guidelines for dosing of chemotherapy in obese patients 
based their recommendations on several retrospective and observational studies which 
suggested that there is no increased toxicity in obese patients administered full weight based 
doses.11,12   In order to better understand the impact of full weight based chemotherapy 
dosing, we propose a pilot study evaluating intra-patient changes in pharmacokinetic 
parameters using two dosing approaches of the commonly used chemotherapy agents, 
capecitabine.   
 
2.3  Study Drug:  Capecitabine    
 
Capecitabine is an oral anti-metabolite chemotherapy.  It is a prodrug of 5-FU13 and is FDA 
approved and commonly used in the treatment of gastrointestinal and breast cancers. }  It has 
a short half-life and is typically dosed twice daily for 14 consecutive days, followed by a 1 
week break.14 Capecitabine is converted by three enzymes in the liver and tumors to 5-FU. 
The final step in this being conversion of 5’deoxy-5-fluorouridine to 5FU by thymidine 
phosphorylase. 5FU inhibits thymidilate synthase causing inhibition of DNA synthesis.13 
 
Clinical Experience with Capecitabine:  
  
Colon and rectal cancers rank as the third most common cancer in the United States and 
CRC the second leading cause of U.S. cancer deaths.15  Obesity has been linked with an 
increased risk for development of colorectal cancers.16,17  Although survival rates for limited-
stage disease remain high, metastatic disease has a five-year survival of less than 10%, 
although median survival now approaches two years with combination therapy.18,19 
   
As a single agent in metastatic colorectal cancer, capecitabine has response rates ranging 
from 18.9-25.8% with equal efficacy compared to 5-FU/leucovorin but significantly fewer 
toxicities.20,21 It also has been demonstrated to have activity in 3rd line metastatic colorectal 
cancer. 22 Capecitabine has also been studied in conjunction with oxaliplatin in advanced 
colorectal cancer with response rates of 35-55%.23,24   Capectabine has become a standard 
chemotherapy agent used to treat  metastatic colorectal cancers.  Interesting, there is an 
emerging body of literature suggesting that pharmacokinetically- guided fluorouracil (5-FU) 
dose adjustment versus standard body-surface-area (BSA) dosing in metastatic colorectal 
cancer may be more effective. 25,26  This suggests that understanding the pharmacokinetic 
impact of a limited-weight based dosing approach would be important with this drug, with 
the evidence suggesting that lower steady state concentrations may negatively impact clinical 
outcomes.   


 
 
 
 3 
 
Breast cancer is the most common cancer in women and the second leading cause of cancer 
death in women. Despite the availability of many targeted, endocrine and chemotherapy 
agents, over 40,000 women die each year from metastatic breast cancer.19Interestingly, 
obesity and weight gain have been demonstrated to increase a woman’s risk of developing 
breast cancer, in particular, post-menopausal breast cancer.27,28 
 
Capecitabine has been extensively studied in metastatic breast cancer.  Single agent therapy 
yields response rates of 15-29% in patients pre-treated with anthracyclines and taxanes, 29-31 
As a component of combination therapy with paclitaxel, docetaxel or ixabepilone, 
capecitabine improves response rates and progression-free survival, although the impact of 
doublet therapy on overall survival is less clear.32-34  Capecitabine has also been studied and 
approve in combination with lapatinib, a human epidermal growth factor receptor tyrosine 
kinase inhibitor.35 Based on these results, capecitabine is commonly used to treat patients 
with advanced breast cancer, either as a single agent or as a component of combination 
therapy.   
 
Capecitabine Adverse Events/Toxcity 
 
The main side effects of capecitabine seen across multiple studies include: hand-foot 
reaction, diarrhea, nausea, vomiting, anorexia, stomatitis, dermatitis, hyperbilirubinemia, 
leukopenia, thrombocytopenia, and anemia. (see Tables 1-2 below from package insert 
http://www.gene.com/gene/products/information/xeloda/pdf/pi.pdf).   
 
Patients over 80 years old may experience a greater incidence of gastrointestinal grade 3 or 4 
adverse events.  Capecitabine is contraindicated in patients with severe renal impairment 
(creatinine clearance below 30mL/min or those with known dihydropyrimidine 
dehydrogenase (DPD) deficiency.  Capecitabine may cause fetal harm when given to a 
pregnant woman.   It is not known whether the drug is excreted in human milk. Because 
many drugs are excreted in human milk and because of the potential for serious adverse 
reactions in nursing infants, it is recommended that nursing be discontinued when receiving 
capecitabine therapy. 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 4 
Table 1:  Pooled Phase 3 First Line Colorectal Trials:  Percent Incidence of Adverse Reactions 
in ≥5% of Patients.   
 
 


 
 
 
 5 
 
 
 
 
Table 2:   Percent Incidence of Adverse Reactions Considered Remotely, Possibly or 
Probably Related to Treatment in ≥5% of Patients Participating in the Single Arm Trial in 
Stage IV Breast Cancer 
 
 
 


 
 
 
 6 
 
 
Clinical Pharmacokinetics 
 
Capecitabine is relatively non-cytotoxic in vitro. This drug is enzymatically converted to 5-
fluorouracil (5-FU) in vivo.  Capecitabine is readily absorbed from the gastrointestinal tract. 
In the liver, a 60 kDa carboxylesterase hydrolyzes much of the compound to 5'-deoxy-5-
fluorocytidine (5'-DFCR). Cytidine deaminase, an enzyme found in most tissues, including 
tumors, subsequently converts 5'-DFCR to 5'-deoxy-5-fluorouridine (5'-DFUR). The enzyme, 
thymidine phosphorylase (dThdPase), then hydrolyzes 5'-DFUR to the active drug 5-FU. 
Many tissues throughout the body express thymidine phosphorylase. Some human 
carcinomas express this enzyme in higher concentrations than surrounding normal tissues.36 
Following oral administration of capecitabine 7 days before surgery in patients with 
colorectal cancer, the median ratio of 5-FU concentration in colorectal tumors to adjacent 
tissues was 2.9 (range from 0.9 to 8.0). 
 
The pharmacokinetics of capecitabine and its metabolites have been evaluated in about 200 
cancer patients over a dosage range of 500 to 3500 mg/m2/day.14,37 Over this range, the 
pharmacokinetics of capecitabine and its metabolite, 5'-DFCR were dose proportional and 
did not change over time. The increases in the AUCs of 5'-DFUR and 5-FU, however, were 
greater than proportional to the increase in dose and the AUC of 5-FU was 34% higher on 
day 14 than on day 1. The elimination half-life of both parent capecitabine and 5-FU was 
about 3/4 of an hour. The inter-patient variability in the Cmax and AUC of 5-FU was greater 
than 85%. 
 


 
 
 
 7 
Capecitabine reached peak blood levels in about 1.5 hours (Tmax) with peak 5-FU levels 
occurring slightly later, at 2 hours. Food reduced both the rate and extent of absorption of 
capecitabine with mean Cmax and AUC0-infinity decreased by 60% and 35%, respectively. The 
Cmax and AUC0-infinity of 5-FU were also reduced by food by 43% and 21%, respectively. Food 
delayed Tmax of both parent and 5-FU by 1.5 hours.  Plasma protein binding of capecitabine 
and its metabolites is less than 60% and is not concentration-dependent. Capecitabine was 
primarily bound to human albumin (approximately 35%). 
 
Capecitabine is extensively metabolized enzymatically to 5-FU. The enzyme 
dihydropyrimidine dehydrogenase hydrogenates 5-FU, the product of capecitabine 
metabolism, to the much less toxic 5-fluoro-5, 6-dihydro-fluorouracil (FUH2). 
Dihydropyrimidinase cleaves the pyrimidine ring to yield 5-fluoro-ureido-propionic acid 
(FUPA). Finally, ß-ureido-propionase cleaves FUPA to alpha-fluoro-ß-alanine (FBAL) 
which is cleared in the urine. 
 
Capecitabine and its metabolites are predominantly excreted in urine; 95.5% of administered 
capecitabine dose is recovered in urine. Fecal excretion is minimal (2.6%). The major 
metabolite excreted in urine is FBAL which represents 57% of the administered dose. About 
3% of the administered dose is excreted in urine as unchanged drug.  
 
Drug-Drug Interactions: 
(http://www.gene.com/gene/products/information/xeloda/pdf/pi.pdf) 
 
 
Anticoagulants: In four patients with cancer, chronic administration of capecitabine (1250 
mg/m2 bid) with a single 20 mg dose of warfarin increased the mean AUC of S-warfarin by 
57% and decreased its clearance by 37%. Baseline corrected AUC of INR in these 4 patients 
increased by 2.8 fold, and the maximum observed mean INR value was increased by 91%.  
Patients receiving concomitant capecitabine and oral coumarin-derived anticoagulant therapy 
should have their anticoagulant response (INR, PT) monitored closely with great frequency 
and the anticoagulant dose adjusted accordingly.   
 
Drugs Metabolized by Cytochrome P450 Enzymes: In vitro enzymatic studies with human 
liver microsomes indicated that capecitabine and its metabolites (5'-DFUR, 5'-DFCR, 5-FU, 
and FBAL) had no inhibitory effects on substrates of cytochrome P450 for the major 
isoenzymes such as 1A2, 2A6, 3A4, 2C9, 2C19, 2D6, and 2E1. 
 
Antacid/ Maalox® (20 mL), an aluminum hydroxide- and magnesium hydroxide-containing 
antacid, was administered immediately after capecitabine (1250 mg/m2, n=12 cancer 
patients), AUC and Cmax increased by 16% and 35%, respectively, for  capecitabine and by 
18% and 22%, respectively, for 5'-DFCR. No effect was observed on the other three major 
metabolites (5'-DFUR, 5-FU, FBAL) of capecitabine. 
 
Capecitabine has a low potential for pharmacokinetic interactions related to plasma protein 
binding. 
 
Based on the standard reference resources from the FDA 


 
 
 
 8 
(http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInter
actionsLabeling/ucm093664.htm) capecitabine is a weak inhibitor of CYP2C9.   Thus, based 
on the drug interaction table in Appendix C, no medications would be contraindicated.   
 
      2.4  Hypothesis:   Our hypothesis is that use of full weight based chemotherapy dosing will be 
associated with a significantly higher AUC and Cmax.  The results of this study will  advance 
oncologists’ understanding of the potential impact of using limited weight-based dosing for 
capecitabine and provide preliminary data to demonstrate the need evaluate the importance of 
weight-based dosing for other chemotherapy and targeted agents. 
 
3. PATIENT SELECTION 
 
3.1  
Eligibility Criteria 
 
3.1.1 Patients must have histologically or cytologically confirmed advanced or 
metastatic cancer for which capecitabine treatment is considered a standard 
treatment option.   
 
3.1.2 Patients with measurable or evaluable disease are eligible  
 
3.1.3 Patient’s Body Mass Index must be 30 kg/m2 or higher.   
 
3.1.4 Eastern Cooperative Oncology Group performance status 0-2. 
 
3.1.5 Age >18 years.   
 
3.1.6 Life expectancy of greater than 12 weeks. 
 
3.1.7 Patients must have adequate organ and marrow function as defined below: 
▪ Hematologic: ANC >1000/mcL, Hemoglobin > 8gm/dL (transfusions 
permitted) and platelets > 75,000/mcL 
 
▪ Renal: serum creatinine ≤ upper limit of normal (ULN) or creatinine 
clearance (either estimated or calculated) >60 mL/min/1.73 m for patients 
with creatinine levels above institutional normal. 
 
Females: Crcl =  _(140-age)(weight in kg)(0.85)  
 
72 x Serum creatinine 
 
 
Males: Crcl =  _(140-age)(weight in kg) 
72 x Serum creatinine 
 
▪ Hepatic: Serum Bilirubin ≤ 1.5x ULN and 
-  No liver metastases:  AST and ALT ≤ 2.5x ULN   
-  Liver metastases:  AST and ALT ≤ 5x ULN  
 


 
 
 
 9 
3.1.8 Ability to understand and the willingness to sign a written informed consent 
document. 
 
3.1.9 Capecitabine is contra-indicated in pregnant women because of known 
detrimental effects on the fetus.  A negative pregnancy test is required in all 
premenopausal women within 14 days of study therapy initiation.  Women of 
child-bearing potential and men with an active female sexual partner must 
agree to use adequate contraception (hormonal, surgical, barrier methods or 
abstinence allowed) 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. 
 
3.2  
Exclusion Criteria 
 
3.2.1 Patients who have had systemic chemotherapies or targeted therapies within 3 
weeks or radiotherapy within 2 weeks prior to entering the study or those  
patients whose adverse events from prior therapies have not recovered to  < 
grade 1 (other than grade 2 neuropathy, lymphopenia and alopecia which are 
permitted.) 
 
3.2.2 Patients receiving any other investigational agents for cancer treatment. 
 
3.2.3 Patients with treated, stable brain metastases are allowed to enroll.  Patients 
must be at least 4 weeks from brain radiation and off any medications used to 
treat brain metastases including steroids.  Patients are allowed to be on anti-
epileptic medications that are not contraindicated as listed in Appendix C.   
 
3.2.4 Patients with any condition of the gastrointestinal tract that is expected to 
result in an inability to swallow or absorb oral medications (ie. prior surgical 
procedures affecting absorption and requiring i.v. alimentation).  This will be 
determined at the discretion of the PI. 
 
3.2.5 Patients may not be taking any concomitant drugs that are contraindicated 
based on the drug-interaction table in Appendix C. 
 
3.2.6 Concurrent treatment with warfarin (coumadin) is allowed, but close 
monitoring of the PT/INR is recommended.   
 
3.2.7 Uncontrolled intercurrent illness including, but not limited to, ongoing or 
active severe infection, symptomatic congestive heart failure, unstable angina 
pectoris, clinically significant or symptomatic cardiac arrhythmia, other 
malignancies requiring therapy or psychiatric illness/social situations that 
would limit compliance with study requirements. 
 


 
 
 
 10 
3.2.8 Pregnant women or women who are breastfeeding are excluded from this 
study because capecitabine is a pregnancy category D drug and is known to 
pass to the infant in breastmilk.  
 
3.2.9 Patients with known deficiency of the dihydropyrimidine dehydrogenase 
(DPD) enzyme.   
 
3.2.10 History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to capecitabine. 
 
3.3 
Inclusion of Women and Minorities 
 
Members of all races and ethnic groups are eligible for this trial. 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines 
 
Eligible patients will be entered on study using the University of Wisconsin Carbone 
Cancer Center Oncore Database (uwccc.wisc.edu/oncore) in accordance with 
standard UWCCC guidelines.   
 
In accordance with institutional policies approved by the U.S. Department of Health 
and Human Services, each subject must acknowledge consent for treatment as a 
human subject in this study. Informed consent must be obtained prior to the initiation 
of protocol therapy. 
 
Following registration, patients should begin protocol treatment within 7 days.  Issues 
that would cause treatment delays should be discussed with the Principal Investigator. 
If a patient does not receive protocol therapy following registration, the patient’s 
registration on the study may be canceled.  The Study Coordinator should be notified 
of cancellations as soon as possible. 
 
4.2 
Registration Process 
 
To register a patient, the following documents should be reviewed and compiled by 
the research nurse or data manager prior to registering subject into Oncore, where a 
study ID will be automatically assigned. 
 Copy of all baseline tests/procedures verifying eligibility 
 Signed patient consent form. 
 Signed HIPAA authorization form. 
 Eligibility Screening Worksheet filled out in Oncore. 
 
 
 
 


 
 
 
 11 
5. TREATMENT PLAN 
 
5.1  
Administration 
 
▪  Capecitabine treatment will be administered on an outpatient basis with the 
exception that cycle 1 days 1 and 9 will be administered on the Clinical Research 
Unit for pharmacokinetic blood draws. No investigational or commercial agents or 
therapies other than those described below may be administered with the intent to 
treat the patient’s malignancy.   
 
▪   The minimum number of hours between capecitabine doses should be 10 hours. 
 
▪   Subjects should then be instructed to take the capecitabine dose 30 minutes after 
eating a normal meal. 
 
▪   Subjects will be provided with a Medication Diary for capecitabine, instructed in 
its use, and asked to bring the diary with them to each appointment. Subjects will be 
instructed on what to do if missed, skipped, or vomited dose, and how to record this 
information. Please see Appendix B for the medication diary template. 
 
 
                                                       Capecitabine Dosing  
Cycle 1 
 
Day 1 
Days 2-7 
Day 8 
Day 9 
Days 10-15 Day 16-
21 
 
Capecitabin
e Dose* 
 
(1,250mg/ 
m2 twice 
daily) 
 
(1,250mg/ 
m2 twice 
daily) 
 
 
none 
 
(1,250mg/ 
m2 twice 
daily) 
 
(1,250mg/ 
m2 twice 
daily) 
 
none 
Weight 
Used for 
BSA 
Ideal Body 
Weight 
Ideal Body 
Weight 
n/a 
Actual 
Body 
Weight 
Actual 
Body 
Weight 
n/a 
* The final dose will be rounded to nearest 150mg due to available pill sizes. 
 
Cycle 2 and beyond:  Capecitabine 1,250mg/m2 orally twice daily days 1-14 of a 21 day 
cycle, using actual body weight.  
 
The Mosteller calculation and the patient’s ideal or actual body weight will be used to 
calculate the BSA3 (calculations below).   
 
 
 
Mosteller BSA formula:  BSA (m²) = ( [Height(cm) x Weight(kg) ]/ 3600 )½ 
 
Ideal Body Weight (men) = 50 + 2.3 (Height in inches - 60 ) 
Ideal Body Weight (women) = 45.5 + 2.3 (Height in inches - 60 )  
 


 
 
 
 12 
5.2  
General Concomitant Medication and Supportive Care Guidelines 
 
Capecitabine (Xeloda) and Coumadin 
Capecitabine (XELODA) Warfarin Interaction: Patients receiving concomitant 
capecitabine and oral coumarin-derivative anticoagulant therapy should have their 
anticoagulant response (INR or prothrombin time) monitored frequently in order to 
adjust the anticoagulant dose accordingly. A clinically important XELODA-Warfarin 
drug interaction was demonstrated in a clinical pharmacology trial. Altered coagulation 
parameters and/or bleeding, including death, have been reported in patients taking 
XELODA concomitantly with coumarin-derivative anticoagulants such as warfarin and 
phenprocoumon. Postmarketing reports have shown clinically significant increases in 
prothrombin time (PT) and INR in patients who were stabilized on anticoagulants at 
the time XELODA was introduced. These events occurred within several days and up 
to several months after initiating XELODA therapy and, in a few cases, within one 
month after stopping XELODA. These events occurred in patients with and without 
liver metastases. Age greater than 60 and a diagnosis of cancer independently 
predispose patients to an increased risk of coagulopathy. 
 
Bone Metastases:  For patients with documented bony metastases, treatment with 
zolendronic acid, pamidronate or denosumab per standard UWCCC protocol is 
recommended.   
 
Nausea/Emesis:  Patients must be counseled on the use of antiemetics for treatment 
of nausea and vomiting with a standard antiemetic regimen (for example, 
prochlorperazine 10 mg orally every 6 hours as needed for nausea, or lorazepam 0.5 
mg orally every 4 hours as needed for nausea).  Any patient who is vomiting 
medications or pill fragments should be instructed NOT to repeat dosing.  If nausea 
or emesis leads to the patient feeling lightheaded or dizzy or unable to stay hydrated 
at home should be instructed to seek medical attention. 
 
Colony Stimulating Factors:  CSFs should not be used during the first course of 
therapy and should not be used subsequently unless there are significant medical 
circumstances that require CSFs.  Use of any CSFs must be discontinued at least 24 
hours prior to initiation of the next cycle of chemotherapy and must be documented in 
the patient record.   
 
Diarrhea:  Patients should be instructed prior to cycle 1, day 1 in the proper use of 
antidiarrhea agents (such as loperamide [Imodium AD]). For example, with 
loperamide [Imodium AD], instruct patients to take 4 mg (2 capsules) after the first 
loose stool of the day, and 2 mg each loose stool thereafter.  4 mg may be taken every 
4 hours overnight.  Instruct the patient to stop taking the Imodium when they have not 
had a bowel movement for 12 hours.  Total daily dose should not exceed 16 mg.  
Patients should be instructed to call for any diarrhea not improved by Imodium. 
 
 


 
 
 
 13 
5.3  
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue 
until one of the following criteria applies: 
 
 Disease progression. 
 
 Intercurrent illness that prevents further administration of treatment. 
 
 Unacceptable adverse event(s). 
 
 Patient decides to withdraw from the study or is unevaluable after cycle 1. 
 
 General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 
 Treatment delay greater than 2 weeks 
 
5.4 
Duration of Follow Up 
 
All patients enrolled in the study will be followed until both of the following criteria 
are met: 
1.  Study drug is discontinued (for any reason) 
2  All study drug related adverse events have either resolved to grade 1 or stable per 
the discretion of the treating physician.    
 
5.5 
Criteria for Removal from Study 
 
Patients will be removed from study when any of the criteria listed in Section 5.3 
applies.  The reason for study removal and the date the patient was removed must be 
documented in the Case Report Form. 
 
5.6 
Definition of Evaluable Patients 
 
Patients will be evaluable for the primary endpoint if he or she takes 100% of their 
capecitabine dose days 1 through 9 and at least 90% of their capecitabine dose days 
10 through 15 in cycle one.  Unevaluable patients will go off study after cycle 1, but 
may continue to be treated with commercial capecitabine per the discretion of the 
treating physician.   
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
6.1 
General Guidance for Dose Reductions and Modifications 
 
Additional cycles of therapy may be administered provided that the patient meets the 
following criteria on Day 1 of each cycle: 
 


 
 
 
 14 
 ANC > 1,000/mcL 
 Platelets > 75,000/mcL 
 Non-hematologic toxicity recovered to < grade 1   
 No evidence of progressive disease 
 
Dose Modifications:  Dose modification for toxicity will be based on the worst toxicity 
observed during the previous course.  Dose modifications apply only when the event(s) are 
felt to be probably or definitely attributable to the study drugs. After recovery, dose 
adjustments for toxicity should be applied as below.  Patients will be instructed to call with 
any new or worsening symptoms between clinical evaluations. Held doses will not be made 
up.  All dose modifications will be permanent and continue through subsequent cycles. 
 
Toxicities which are manageable with supportive therapy (ie. antiemetics or anti-diarrhea agents 
unless occurring despite maximal medical management.) do not require dose reductions.  
Toxicities which are determined to be clinically insignificant (ie. Lymphopenia) do not require 
dose reductions. 
 
 If an adverse event is not covered in section 6.2, doses may be reduced or held at the discretion 
of the investigator for the subject’s safety.  
 
Table 3. Capecitabine Dose Levels 
 
 
 
Initial Dose 
1st reduction 
2nd reduction 
Capecitabine 
1,250 mg/m2  orally 
twice daily 
1,000mg/m2 orally 
twice daily 
750mg/m2 orally 
twice daily 
 
Dose delays for more than 2 weeks or subjects requiring more than 2 dose reductions will be 
removed from the study. 
 
6.2  Dose modifications  
 
All adverse events will be graded using the NCI Common Terminology Criteria for Adverse 
Events v4.0. 
 
Hematologic toxicity (Neutropenia, Anemia, Thrombocytopenia): No dose modification 
for grade 1-2 toxicities.  For Grade 3 hematologic toxicity, hold dose until ≤ grade 1 or 
baseline. The may resume capecitabine with dose reduced to the next lower dose level. For 
grade 4 hematologic toxicity, the patient should discontinue drug and be removed from study. 
 Consider testing for DPD deficiency.   
 
Stomatitis/pharyngitis and other GI toxicities (excluding diarrhea, nausea and 
vomiting) For grade 1-2 toxicities, initiate supportive care measures.  For grade 3 or 4 
toxicities, hold capecitabine until the toxicity returns to ≤ grade 1  and then restart 
capecitabine with a dose reduction to the next lower dose level. 
 


 
 
 
 15 
Diarrhea:  For grade 1 toxicities, initiate supportive care measures such as loperamide.  For 
grade 2 toxicities, hold capecitabine and give loperamide or other anti-diarrhea medications 
until ≤ grade 1, then resume capecitabine at same dose level.  If grade 2 diarrhea occurs a 
second time at a specific dose level, hold capecitabine and give anti-diarrhea medications 
until ≤ grade 1, then resume capecitabine at the next lower dose level. 
 
For grade 3-4 diarrhea, hold capecitabine, start anti-diarrhea medications, and consider iv 
fluids/electrolyte replacement.  Once resolved to ≤ grade 1, then may resume capecitabine at 
the next lower dose level.   
 
Nausea and vomiting:  For grade 1-2 toxicities, initiate supportive care measures such as 
lorazepam or prochlorperazine.  For grade 3-4 toxicities (or intolerable grade 2), hold 
capecitabine and give antiemetics and consider iv fluids/electrolytes as needed.  Once 
resolved to  ≤ grade 1, then resume capecitabine at same dose level unless grade 3-4 (or 
intolerable grade 2) nausea/vomiting occurred despite maximal medical management (at least 
2 anti-emetics), then reduce by 1 dose level.    
 
Hepatic Toxicity: For grade 1-2 toxicities, no dose adjustment required.  For Grade 3-4 
elevation in AST (SGOT), ALT (SGPT), alkaline phosphatase or bilirubin, hold capecitabine 
dose until ≤ grade 1 or back to baseline (whichever is higher).  Then may resume 
capecitabine with dose  reduced to the next lower dose level. 
 
Hand-foot reaction (HFR or Palmar-plantar erythrodysesthesia syndrome): Please see table 
below.   
 
Other toxicity: For other grade 3 or greater toxicities that are considered clinically 
significant by the treating physician and thought to be at least probably related to study drug, 
hold treatment until toxicity resolves to grade 1 or less, then reduce the dose of capecitabine 
to the next lowest dose level. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 4:  Dose Modifications for HFR or Palmar-plantar erythrodysesthesia syndrome 


 
 
 
 16 
 
 
 
 
 
 
 
 
 
7. REGULATORY AND REPORTING REQUIREMENTS 
Skin Toxicity Grade 
Occurrence 
Suggested Dose Modification 
Grade 1: Painless 
swelling, erythema or 
discomfort of the hands 
or feet which does not 
disrupt the patients 
normal activity 
Any 
occurrence 
Institute supportive measures immediately  
Grade 2: Painful 
erythema and swelling 
of the hands or feet 
and/or discomfort 
affecting the patient’s 
normal activities 
1st 
occurrence 
Institute supportive measures and hold capecitabine until toxicity resolves 
to Grade 1 or less.  Institute at full dose when restarting therapy. 
 
 
2nd or 3rd 
occurrence 
Continue supportive measures and hold capecitabine until toxicity 
resolves to Grade 1 or less.  Upon resuming capecitabine treatment, 
decrease capecitabine to next lower dose level 
4th  
occurrence 
Off study  
Grade 3:  Moist 
desquamation, 
ulceration, blistering or 
severe pain of the 
hands or feet, or severe 
discomfort that causes 
the patient to be unable 
to work or perform 
activities of daily 
living 
1st 
occurrence 
Institute supportive measures and hold capecitabine treatment for a 
minimum of 7 days and until toxicity has resolved to Grade 1 or less.  
When resuming treatment after dose interruption, resume  capecitabine at 
next lower dose level 
 
2nd  
occurrence 
Institute supportive measures and interrupt capecitabine treatment for a 
minimum of 7 days and until toxicity has resolved to Grade 1 or less.  
When resuming treatment after dose interruption, resume  capecitabine at 
next lower dose level 
 
3rd  
occurrence 
Off study 


 
 
 
 17 
 
7.1 
Oversight And Monitoring Plan 
 
The UWCCC Data and Safety Monitoring Committee (DSMC) is responsible for 
monitoring data quality and subject safety for all UWCCC clinical studies.  A 
summary of DSMC activities follows: 
• 
Review of all clinical trials conducted at the UWCCC for data integrity and 
safety 
• 
Review of all serious adverse events requiring expedited reporting as defined in 
the protocol 
• 
Review of reports generated by the UWCCC data quality control review process  
• 
Submit recommendations for corrective action to the CRC 
• 
Notify the Study Chair of the DSMC’s recommendation to the CRC 
• Work in conjunction with the Health Sciences IRB in the review of protocol 
deviations, violations and unanticipated problems reported by the UWCCC 
DOWGs.  
• 
The committee ensures that notification is provided to all external sites 
participating in multiple-institutional clinical trials coordinated by the UWCCC 
of serious adverse events requiring expedited reporting. 
 
7.2 
Monitoring And Reporting Guidelines 
 
Investigators will conduct continuous review of data and subject safety at their weekly 
Phase I/Disease Group meetings where the results of each subject’s treatment are 
discussed and the discussion is documented in the minutes. The discussion will include 
for each dose level: the number of subjects, significant toxicities as described in the 
protocol, doses adjustments, and responses observed. Quarterly Protocol Summary 
Reports (PSR) are required for submission to the Data and Safety Monitoring Committee 
(DSMC) for review.  
 
7.3 
REVIEW AND OVERSIGHT REQUIREMENTS   
 
 
 
a)  Serious Adverse Event – Reported within 7 Days 
 
 
Serious Adverse Events requiring reporting within 7 calendar days (as described in the 
protocol) will also be sent to the UWCCC DSMC Chair via email to 
saenotify@uwcarbone.wisc.edu. A 7 day “SAE Details” report, generated in the 
UWCCC database must be attached to the email along with pertinent information 
regarding the SAE and the UWCCC SAE Routing Form. The Committee Chair will 
review the information and determine if further action is required.  This information is 
entered and tracked in the UWCCC database. 
 
 
 


 
 
 
 18 
 
 
 
b)  Study Progress Review 
 
Study Progress Review- Protocol Summary Reports 
 
 
Protocol Summary Reports (PSR) are required to be submitted to the DSMC 
commensurate with the Phase of the study. The PSR provides a cumulative report of 
serious adverse events, as well as any protocol violations, deviations or unanticipated 
problems, toxicities and responses that have occurred on the protocol in the timeframe 
specified. PSRs are reviewed at each DSMC meeting. 
 
 
Protocol Summary Reports enable DSMC committee members to assess whether 
significant benefits or risks are occurring that would warrant study closure. This 
information is also provided by Disease Oriented Working Group meeting minutes, 
internal audit and/or response review reports.  In addition, the DSMC requires the 
DOWG or protocol Study Chair to submit external DSMB reports or any other significant 
study-related information.  
 
 
In the event that there is significant risk warranting study suspension or closure, the 
DSMC will notify the PI of the DSMC findings.  The DSMC ensures that the PI reports 
any temporary or permanent suspension of a clinical trial to the sponsor (e.g., NCI 
Program Director, Industry Sponsor Medical Monitor, Cooperative Group Study Chair, 
etc.) and other appropriate agencies. 
 
EXPEDITED REPORTING OF SERIOUS ADVERSE EVENTS 
Depending on the nature, severity, and attribution of the serious adverse event an SAE 
report will be phoned in, submitted in writing, or both according to the table below. All 
serious adverse events must also be reported to the UWCCC Data and Safety Monitoring 
Committee Chair.  All serious adverse events must also be reported to the UW IRB (if 
applicable), and any sponsor/funding agency not already included in the list. 
 
Determine the reporting time line for the SAE in question by using the following table.   
 
SAE Requiring 7 Day Reporting Occurs at UWCCC:  
 
1. 
Report to the UWCCC: 
 
Reference the SAE SOP and the SAE Reporting Workflow for DOWGs on the 
UWCCC website (http://www.uwccc.wisc.edu) for specific instructions on how 
and what to report to the UWCCC for 7 day reports.   
 
For this protocol, the following entities are required to be notified: 
 
a) 
saenotify@uwcarbone.wisc.edu 
b) 
Any appropriate parties listed on SAE Routing Form 
 
 
 


 
 
 
 19 
2. 
Report to the IRB: 
 
       
 
Consult the UW-IRB website for reporting guidelines. 
 
3.  
Reporting to the FDA 
Serious Adverse Events occurring on studies on which a UW PI is acting as 
sponsor-investigator must be reported to the FDA within the appropriate time 
frame.  Mandatory and voluntary reporting guidelines and instructions are 
outlined on the FDA website: 
http://www.fda.gov/Safety/MedWatch/HowToReport/default.htm 
 
Report the SAE using the FDA Med Watch form available at      
http://www.fda.gov/downloads/Safety/MedWatch/HowToReport/DownloadForms
/UCM082728.pdf .   
 
Print the completed Med Watch form and fax it to the FDA.      
 
Expedited reporting requirements for adverse events experienced by patients on arm(s) with 
commercial agents only—Arms I, A, B, and C. 
Attribution 
Grade 4 
 
                     Grade 5a 
 
Unexpected 
Expected 
    Unexpected 
        Expected 
Unrelated 
or Unlikely 
 
 
7 calendar days 
7 calendar days 
 
Possible, 
Probable,  
Definite 
 
7 calendar days 
 
7 calendar days 
7 calendar days 
7 Calendar Days:  Indicates a full MedWatch report is to be submitted within 7 calendar days 
of learning of the event. 
a  This includes all deaths within 30 days of the last dose of treatment regardless of attribution. 
 NOTE:  Any death that occurs > 30 days after the last dose of treatment and is attributed 
possibly, probably, or definitely to the treatment must be reported within 7 calendar days 
of learning of the event. 
 
Serious Events:  Any event following treatment that results in persistent or significant 
disabilities/incapacities, congenital anomalies, or birth defects must be reported via MedWatch 
within 7 calendar days of learning of the event. 
 
 
 
 
 
 
 
8. PHARMACEUTICAL INFORMATION:  CAPECITABINE 


 
 
 
 20 
 
Other Names: Xeloda 
 
Chemical name: 5’-deoxy-5-fluoro-N-[(pentyloxy) carbonyl]-cytidine. 
  
Molecular Weight:  359.35 
 
Description:  Capecitabine is a fluoropyrimidine carbamate with antineoplastic activity.  It 
is an orally administered prodrug of 5’-deoxy-5-fluorouridine (5’-DFUR) which is 
converted to 5-fluorouracil. 
 
How Supplied: Capecitabine (Xeloda) is supplied as biconvex, oblong film-coated tablets 
for oral administration. Each light peach colored tablet contains 150 mg capecitabine and 
each peach-colored tablet contains 500 mg capecitabine. 
  
 
 
Solution Preparation: Not applicable. 
 
Route of Administration: Oral. 
 
Availability: Commercial supplies of capecitabine will be used for this study. 
 
Storage and Stability: Store tightly closed at 25 degrees C (77 degrees F); stable for brief 
periods at 15 to 30 degrees C (59 to 86 degrees F). 
 
8.1 Adverse events and potential risks of Capecitabine (see also tables 1 and 2) 
Hand-and-Foot Syndrome: Hand-and-foot syndrome (palmar-plantar erythrodysesthesia or 
chemotherapy-induced acral erythema) is a cutaneous toxicity (median time to onset of 79 
days, range from 11 to 360 days).  This is much more commonly observed with capecitabine 
or infusional 5-FU rather than bolus 5-FU. 
Cardiotoxicity: The cardiotoxicity observed with capecitabine includes myocardial 
infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, 
electrocardiographic changes, and cardiomyopathy. These adverse events may be more 
common in patients with a prior history of coronary artery disease. 
Hepatic Insufficiency: Patients with mild to moderate hepatic dysfunction due to liver 
metastases should be carefully monitored when capecitabine is administered. The effect of 
severe hepatic dysfunction on the disposition of capecitabine is not known.  
Hyperbilirubinemia: In the overall clinical trial safety database of capecitabine 
monotherapy (N=875), grade 3 (1.5-3 x ULN) hyperbilirubinemia occurred in 15.2% (n=133) 
and grade 4 (>3 x ULN) hyperbilirubinemia occurred in 3.9% (n=34) of 875 patients with 
either metastatic breast or colorectal cancer who received at least one dose of capecitabine 
1250 mg/m2 twice daily as monotherapy for 2 weeks followed by a 1-week rest period. Of 
566 patients who had hepatic metastases at baseline and 309 patients without hepatic 
metastases at baseline, grade 3 or 4 hyperbilirubinemia occurred in 22.8% and 12.3%, 
respectively. Of the 167 patients with grade 3 or 4 hyperbilirubinemia, 18.6% (n=31) also 


 
 
 
 21 
had postbaseline elevations (grades 1 to 4, without elevations at baseline) in alkaline 
phosphatase and 27.5% (n=46) had postbaseline elevations in transaminases at any time (not 
necessarily concurrent). The majority of these patients, 64.5% (n=20) and 71.7% (n=33), had 
liver metastases at baseline. In addition, 57.5% (n=96) and 35.3% (n=59) of the 167 patients 
had elevations (grades 1 to 4) at both prebaseline and postbaseline in alkaline phosphatase or 
transaminases, respectively. Only 7.8% (n=13) and 3.0% (n=5) had grade 3 or 4 elevations in 
alkaline phosphatase or transaminases. In the 596 patients treated with capecitabine as first-
line therapy for metastatic colorectal cancer, the incidence of grade 3 or 4 hyperbilirubinemia 
was similar to the overall clinical trial safety database of capecitabine monotherapy. The 
median time to onset for grade 3 or 4 hyperbilirubinemia in the colorectal cancer population 
was 64 days and median total bilirubin increased from 8 µm/L at baseline to 13 µm/L during 
treatment with capecitabine. Of the 136 colorectal cancer patients with grade 3 or 4 
hyperbilirubinemia, 49 patients had grade 3 or 4 hyperbilirubinemia as their last measured 
value, of which 46 had liver metastases at baseline. 
Hematologic: In 875 patients with either metastatic breast or colorectal cancer who received 
a dose of 1250 mg/m2 administered twice daily as monotherapy for 2 weeks followed by a 1-
week rest period, 3.2%, 1.7%, and 2.4% of patients had grade 3 or 4 neutropenia, 
thrombocytopenia or decreases in hemoglobin, respectively.  Carcinogenesis, Mutagenesis 
and Impairment of Fertility: Adequate studies investigating the carcinogenic potential of 
capecitabine have not been conducted. Capecitabine was not mutagenic in vitro to bacteria 
(Ames test) or mammalian cells (Chinese hamster V79/HPRT gene mutation assay). 
Capecitabine was clastogenic in vitro to human peripheral blood lymphocytes but not 
clastogenic in vivo to mouse bone marrow (micronucleus test).  
Reproductive: In studies of fertility and general reproductive performance in mice, oral 
capecitabine doses of 760 mg/kg/day disturbed estrus and consequently caused a decrease in 
fertility. In mice that became pregnant, no fetuses survived this dose. The disturbance in 
estrus was reversible. In males, this dose caused degenerative changes in the testes, 
including decreases in the number of spermatocytes and spermatids. In separate 
pharmacokinetic studies, this dose in mice produced 5'-DFUR AUC values about 0.7 times 
the corresponding values in patients administered the recommended daily dose. 
Coagulopathy:  See Boxed WARNING regarding interaction with Coumadin in Section 5.2. 
Diarrhea:  Capecitabine can induce diarrhea, sometimes severe. Patients with severe 
diarrhea should be carefully monitored and given fluid and electrolyte replacement if they 
become dehydrated. This is expected to be common for this combination therapy. 
Necrotizing enterocolitis (typhlitis) has been reported with capecitabine.  Toxic deaths have 
been reported for the combination of oxaliplatin with 5-FU and leucovorin in patients with 
diarrhea and concomitant neutropenia.  Consideration of hospitalizing any such patients 
should be given.  
Drug-Drug Interactions with Capecitabine  
Capecitabine (Xeloda) and Coumadin:  see boxed warning in Section 5.2 


 
 
 
 22 
CYP2C9 substrates: Other than warfarin, no formal drug-drug interaction studies between 
XELODA and other CYP2C9 substrates have been conducted. Care should be exercised 
when XELODA is co-administered with CYP2C9 substrates. 
Phenytoin: The level of phenytoin should be carefully monitored in patients taking 
capecitabine and phenytoin dose may need to be reduced.  Postmarketing reports indicate 
that some patients receiving capecitabine and phenytoin had toxicity associated with elevated 
phenytoin levels. Formal drug-drug interaction studies with phenytoin have not been 
conducted, but the mechanism of interaction is presumed to be inhibition of the CYP2C9 
isoenzyme by capecitabine and/or its metabolites. 
 
8.2  Availability 
Capecitabine (Xeloda®) is an FDA approved medication and is available by prescription at 
pharmacies throughout the United States. 
 
9. CORRELATIVE/SPECIAL STUDIES 
 
9.1 
Laboratory Correlative Studies 
 
Capecitabine pharmacokinetics:  Plasma samples for the analysis of capecitabine and 
metabolites (5-FU, DFCR, and DFUR) will be obtained at baseline (prior to dosing) and 
1, 2, 3, 4, 6, and 8 hours after administration on day 1 and day 9 of cycle 1 and at steady 
state on cycle 1 days 7 and 15.  Plasma and tissue concentrations will be measured by 
HPLC as previously described.38. For 5FU, the standard curve is linear from 0.019 to 20 
μg/ml, r2 = 0.999, with an intraday variability ranging from 4.49%-5.52% over the 
standard curve.  Inter-day variability over 2 weeks ranges from 4.33-5.42% over the 
standard curve and the lower limit of quantitation (LLOQ) is 0.0195 μg/ml. For 
capecitabine, the standard curve is linear from 0.019 to 20 μg/ml, r2 = 0.999, with 
intraday variability ranging from 1.2-7.8% and inter-day variability from 7.6-13.9% over 
3 months and a LLOQ of 0.019 μg/ml. The standard curves for DFCR and DFUR are 
both linear from 0.625 to 40 ug/ml, r2 = 0.999, with an intraday variability ranging from 
4.21%-4.66% and 0.74%-2.08%, interday variability over 4 weeks ranging from 3.45%-
6.36% and 4.24-6.45% and LLOQ of 0.312 μg/ml and 0.0195 μg/ml, respectively. 
 
Pharmacokinetic variables will be determined by noncompartmental methods with 
WinNonlin Pro version 5.2 (Pharsight Corporation, Cary, N.C.). Area under the plasma 
concentration–time curve is estimated using the trapezoidal rule from time 0 to peak 
concentration and the log-trapezoidal rule from the peak concentration to the last 
measurable plasma concentration (AUClast). AUC(0− ∞) is then calculated from the 
time of dosing and extrapolated to infinity. 
 
 
 
 
 
 


 
 
 
 23 
 
9.2    PK Sample Collection 
Blood samples are collected in 6-mL EDTA (purple top) tubes at the timepoints 
described in Table 5, below on day 1, 7, 9 and 15  of cycle 1. Samples are then 
centrifuged at 3500RPM at 4ºC to obtain plasma, aliquotted into cryovials and stored at -
70C until analysis.  
 
Time  
Time 
C1D1 
C1D9  
0 (prior to first capecitabine dose) 
0 (prior to AM capecitabine dose) 
1 hr post capecitabine dose 
1 hr post capecitabine 
2 hr post  
2 hr post 
3 hr post 
3 hr post 
4 hr post 
4 hr post 
6 hr post  
6 hr post 
8 hr post 
8 hr post 
 
 
C1D7 
C1D15 
0 (prior to AM dose of capecitabine) 
0 (prior to AM capecitabine dose) 
 
10. STUDY CALENDAR 
 
Pre-study evaluations are to be conducted within 2 weeks prior to start of protocol therapy.  
Scans, x-rays and informed consent must be done <4 weeks prior to the start of therapy.  
 
 
Pre-
Study 
C1 
Day 
1 
C1 
Days 
    2-7 
C1 
Day 8 
C1 
Day 9 
C1 
Days 10-
15 
C2+ 
Day 1i 
C2+ 
Days 
 2-14 
Off 
Study 
Capecitabinea 
 
X 
X 
 
X 
X 
X 
X 
 
Informed Consent 
 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
Concurrent Meds 
X 
 
 
 
 
 
X 
 
X 
Physical Examb  
X 
X 
 
 
 
 
X 
 
X 
Vital Signs  
X 
 
 
 
 
 
X 
 
X 
Performance 
Status 
X 
 
 
 
 
 
X 
 
X 
CBC, ANC 
X 
Xg 
 
 
X 
 
Xh 
 
X 
Chemistriesc 
X 
Xg 
 
 
X 
 
Xh 
 
X 
Pregnancy testd 
X 
 
 
 
 
 
 
 
 
Adverse Event 
evaluation 
X------------------------------------------------------------------------------------------------------X 
Tumor 
Measurements 
including 
radiology 
assessmentse 
X 
 
 
 
 
 
X 
(every 
2-3 
cycles) 
 
X 


 
 
 
 24 
Pharmacokineticsf 
 
X 
X 
 (day 7) 
 
X 
X 
(day 15) 
 
 
 
a.  See schema for capecitabine dosing 
b. Including height and weight at pre-study evaluation and weight on day 1 of each cycle for 
first 2 cycles, then every other cycle allowed.  If treatment delayed, physical exam may 
be done at the investigator’s discretion. 
c. Na, K, Cl, bicarbonate, BUN, Creatinine, ALT, AST, Alk Phos, Tbili, and albumin.   
d. For premenopausal women only (Postmenopausal women are those who are age >60, or 
age < 60 who have had oophorectomy or have not had a menses for > 1 year without 
another etiology for amenorrhea). 
e. Tumor measurements by exam and imaging every 2 -3 cycle per discretion of treating 
MD.  Imaging should include chest (CXR or CT of chest) and abdomen (CT or MRI) 
with optional imaging for pelvis (CT or MRI) or bones (bone scan or PET) depending on 
known sites of disease.  A PET/CT can be used to replace CT chest, abdomen and pelvis. 
f. See Table 5 for timing of pharmacokinetic blood draws.  
g. Do not need to repeat if done within 1 week prior to course 1 day 1.  If done on c1d1 
don’t use as eligibility labs, use pre-study labs 
h.  may be done within 72 hours of each cycle 
i. May be delayed for holidays and unforeseen circumstances 
 
11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response once at 6-
9 weeks (+/- 1 week) after initiation of therapy, and then per discretion of treating 
physician.  
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the Response Evaluation Criteria in Solid Tumors version 1.1 
(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 
1.1 criteria. 
 
11.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of 
their first treatment with capecitabine. 
 
Evaluable for Pharmacokinetic Comparison:  Patients will be evaluable for the 
primary endpoint if he or she takes 100% of their capecitabine dose days 1 
through 9 and at least 90% of their capecitabine dose days 10 through 15 in cycle 
one.   
 
Evaluable for objective response.  Only those patients who have measurable 
disease present at baseline who have received at least one cycle of therapy (21 


 
 
 
 25 
days) will be considered evaluable for response.  These patients will have their 
response classified according to the definitions stated below.   
 
11.1.2 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). 
 
Note:  Tumor lesions that are situated in a previously irradiated area will not be 
considered measurable. 
 
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 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. 
 
11.1.3 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 


 
 
 
 26 
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 
and subcutaneous lesions. 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. 
 
Cytology, Histology  These techniques can be used to differentiate between 
partial responses (PR) and complete responses (CR) in rare cases (e.g., residual 
lesions in tumor types, such as germ cell tumors, where known residual benign 
tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears 
or worsens during treatment when the measurable tumor has met criteria for 
response or stable disease is mandatory to differentiate between response or 
stable disease (an effusion may be a side effect of the treatment) and progressive 
disease. 
 


 
 
 
 27 
 
11.1.4 Response Criteria 
 
11.1.4.1 
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. 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): 
Disappearance of all non-target lesions and 
normalization of tumor marker level. 
 
 
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). 
 
11.1.4.3 
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 


 
 
 
 28 
treatment started).  The patient's best response assignment will depend on 
the achievement of both measurement and confirmation criteria at least 4 
weeks after initial response is documented. 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Response for this 
Category Also Requires: 
CR 
CR 
No 
CR 
>4 wks. confirmation 
CR 
Non-CR/Non-
PD 
No 
PR 
 
>4 wks. confirmation 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
documented at least once >4 
wks. from baseline 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
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. 
 
11.1.5 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. 
 
11.1.6 Progression-free survival:  
Progression-free survival (PFS) will be defined as time from first dose of 
capecitabine  to time to clinical or imaging evidence of progressive disease. 
 
11.1.7 Response Review 
The imaging for any subjects obtaining a CR or PR will be reviewed centrally at 
the University of Wisconsin by an independent investigator. 
 
 
 


 
 
 
 29 
 
12. 
DATA REPORTING / REGULATORY CONSIDERATIONS 
 
Guidelines and instructions for AE reporting can be found in Section 7.0 (Adverse Event 
 Reporting Requirements). 
 
Study sites are responsible for entering case report forms directly into the Oncore 
database in accordance with the UWCCC data management policy. Data must be 
submitted within 2 weeks of a subject visit and will be monitored monthly by the Phase I 
Cancer Research office at the UWCCC. 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
The primary endpoints are the PK parameters (AUC and Cmax) of capecitabine when  
dosed using actual versus ideal body weight. Secondary endpoints are response and 
progression-free survival.  
 
A single arm study design will be used to characterize the effect on pharmacokinetic 
parameters of capecitabine, when dosed using actual versus ideal body weight. Ideal 
body with based dosing of capecitabine when be used for cycle 1 from day 1 to day 7 
followed by an actual body weight based dosing from Day 9 to Day 15. There will be a 
wash-out period on Day 8. 
 
PK parameters will be summarized in terms of number of observations, means, standard 
deviations, medians, and ranges, stratified by assessment time point. The non-
compartmental method will be used to estimate PK parameters. AUC will be estimated 
using the Lagrange approximation method. A paired t-test will be used to compare the 
PK parameters between the full weight and limited weight based dosing. If the PK 
parameters are not normally distributed, then an appropriate transformation will be 
identified before conducting the comparison. The comparison of AUC and Cmax 
between full weight and limited based dosing will be also performed using a population 
pharmacokinetics analysis, based on a nonlinear mixed effects modeling approach. 
 
13.2 
Sample Size/Accrual Rate 
 
The primary objective is to characterize the effect on pharmacokinetic parameters when 
capecitabine is dosed on actual versus ideal body weight results in obese patients with 
advanced solid tumors. A mean difference in the AUC and Cmax of at least 30% 
between the ideal body weight dosing versus the actual body with based dosing will be 
considered as a minimal important difference. Based on the results of several previous 
PK studies involving capecitabine, it is anticipated that the overall standard deviation for 
the difference between the two dosing strategies is at most 25% of the mean difference.  
The following table shows the required sample sizes to detect various mean differences 
in PK parameters between the two dosing strategies at the two-sided 0.025 (=0.05/2 – a 
Bonferroni adjustment for comparing both AUC and Cmax)  significance level with 80% 


 
 
 
 30 
power, assuming a standard deviation ranging from 20-30%.  
 
Table 13.1: Required sample sizes to detect various mean differences in PK parameters 
with 80% power at the two-sided 0.025 significance level 
 
Mean difference in PK parameters between the ideal versus actual weight 
based dosing strategy 
Standard 
Deviation 
20% 
25% 
30% 
35% 
40% 
20% 
13 
9 
7 
6 
6 
25% 
18 
13 
10 
8 
7 
30% 
24 
17 
13 
10 
9 
 
A sample size of n=10 patients is proposed for this study.  With a sample size of 10 
patients, a clinically important difference of 30% between the ideal and actual body 
weight based dosing will be detected with 82% power at the one-sided 0.025 (=0.05/2 – a 
Bonferroni adjustment for evaluating both AUC and Cmax) significance level, assuming 
an overall standard deviation of 25%. A mean difference of only 25% will be detected 
with 68% power. Patients will be evaluable for the primary endpoint if he or she 
completes cycle 1, capecitabine therapy without dose reduction or skipped doses.  Any 
patient who does not meet these criteria will be replaced.   
 
The anticipated accrual is 1-2 patients per month.  Therefore, the study is expected to be 
completed within 6-12 months after first accrual. 
 
13.3 
Stratification Factors 
 
n/a 
 
13.4 
Analysis of Secondary Endpoints 
 
Responses will be determined using RECIST as described in Section12 and summarized 
in tabular format. The complete and partial response rates will be calculated and reported 
along with the corresponding 95% confidence intervals. All eligible subjects (intent-to-
treat population) will be included in the calculation of the response rate. Progression-free 
survival will be analyzed using the Kaplan-Meier method.   
PK parameters (based on ideal body weight and actual body weight) of the study 
participants will be summarized using standard descriptive statistics in terms means, 
standard deviations and ranges. A two-sample t-test will be used to compare the mean 
values in the PK parameters in obese patients with normal weight historical controls. 
 
13.5 
Reporting and Exclusions 
 
13.5.1 Evaluation of toxicity.  All patients will be evaluable for toxicity from the 
time of their first treatment with capecitabine.  
 


 
 
 
 31 
13.5.2 Evaluation of response.  All patients included in the study must be assessed 
for response to treatment, even if there are major protocol treatment deviations 
or if they are ineligible.  Each patient will be assigned one of the following 
categories:  1) complete response, 2) partial response, 3) stable disease, 4) 
progressive disease, 5) early death from malignant disease, 6) early death 
from toxicity, 7) early death because of other cause, or 9) unknown (not 
assessable due to measurable disease only or insufficient data).  [Note:  By 
arbitrary convention, category 9 usually designates the “unknown” status of 
any type of data in a clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception 
of those who received no study medication) should be included in the main 
analysis of the response rate.  Patients in response categories 4-9 should be 
considered to have a treatment failure (disease progression).  Thus, an 
incorrect treatment schedule or drug administration does not result in 
exclusion from the analysis of the response rate. 
 
All conclusions should be based on all eligible patients.  Subanalyses may 
then be performed on the basis of a subset of patients, excluding those for 
whom major protocol deviations have been identified (e.g., early death due to 
other reasons, early discontinuation of treatment, major protocol violations, 
etc.).  However, these subanalyses may not serve as the basis for drawing 
conclusions concerning treatment efficacy, and the reasons for excluding 
patients from the analysis should be clearly reported.  The 95% confidence 
intervals should also be provided. 


 
 
 
 32 
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Rosner GL, Hargis JB, Hollis DR, et al. Relationship between toxicity and obesity in 
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Georgiadis MS, Steinberg SM, Hankins LA, Ihde DC, Johnson BE. Obesity and therapy-
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Ishikawa T, Fukase Y, Yamamoto T, Sekiguchi F, Ishitsuka H. Antitumor activities of a 
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Reigner B, Blesch K, Weidekamm E. Clinical pharmacokinetics of capecitabine. Clin 
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Siegel R, Desantis C, Virgo K, et al. Cancer treatment and survivorship statistics, 2012. 
CA Cancer J Clin 2012;62:220-41. 
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Larsson SC, Wolk A. Obesity and colon and rectal cancer risk: a meta-analysis of 
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Pischon T, Lahmann PH, Boeing H, et al. Body size and risk of colon and rectal cancer 
in the European Prospective Investigation Into Cancer and Nutrition (EPIC). J Natl Cancer Inst 
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Grothey A, Sargent D, Goldberg RM, Schmoll HJ. Survival of patients with advanced 
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Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 
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Hoff PM, Ansari R, Batist G, et al. Comparison of oral capecitabine versus intravenous 
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Van Cutsem E, Twelves C, Cassidy J, et al. Oral capecitabine compared with intravenous 
fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase 
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Gubanski M, Naucler G, Almerud A, Lidestahl A, Lind PA. Capecitabine as third line 
therapy in patients with advanced colorectal cancer. Acta Oncol 2005;44:236-9. 
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Boige V, Raoul JL, Pignon JP, et al. Multicentre phase II trial of capecitabine plus 
oxaliplatin (XELOX) in patients with advanced hepatocellular carcinoma: FFCD 03-03 trial. Br 
J Cancer 2007;97:862-7. 
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Cassidy J, Tabernero J, Twelves C, et al. XELOX (capecitabine plus oxaliplatin): active 
first-line therapy for patients with metastatic colorectal cancer. Journal of clinical oncology : 
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Capitain O, Asevoaia A, Boisdron-Celle M, Poirier AL, Morel A, Gamelin E. Individual 
Fluorouracil Dose Adjustment in FOLFOX Based on Pharmacokinetic Follow-Up Compared 
With Conventional Body-Area-Surface Dosing: A Phase II, Proof-of-Concept Study. Clin 
Colorectal Cancer 2012. 
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Gamelin E, Delva R, Jacob J, et al. Individual fluorouracil dose adjustment based on 
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Huang Z, Hankinson SE, Colditz GA, et al. Dual effects of weight and weight gain on 
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Morimoto LM, White E, Chen Z, et al. Obesity, body size, and risk of postmenopausal 
breast cancer: the Women's Health Initiative (United States). Cancer causes & control : CCC 
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29. 
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paclitaxel-refractory metastatic breast cancer. Journal of clinical oncology : official journal of 
the American Society of Clinical Oncology 1999;17:485-93. 
30. 
Fumoleau P, Largillier R, Clippe C, et al. Multicentre, phase II study evaluating 
capecitabine monotherapy in patients with anthracycline- and taxane-pretreated metastatic breast 
cancer. Eur J Cancer 2004;40:536-42. 
31. 
Lee SH, Lee J, Park J, et al. Capecitabine monotherapy in patients with anthracycline- 
and taxane-pretreated metastatic breast cancer. Med Oncol 2004;21:223-31. 
32. 
Gradishar WJ, Meza LA, Amin B, et al. Capecitabine plus paclitaxel as front-line 
combination therapy for metastatic breast cancer: a multicenter phase II study. Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology 2004;22:2321-7. 
33. 
O'Shaughnessy J. Capecitabine and docetaxel in advanced breast cancer: analyses of a 
phase III comparative trial. Oncology 2002;16:17-22. 
34. 
Thomas ES, Gomez HL, Li RK, et al. Ixabepilone plus capecitabine for metastatic breast 


 
 
 
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cancer progressing after anthracycline and taxane treatment. Journal of clinical oncology : 
official journal of the American Society of Clinical Oncology 2007;25:5210-7. 
35. 
Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive 
advanced breast cancer. The New England journal of medicine 2006;355:2733-43. 
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Schuller J, Cassidy J, Dumont E, et al. Preferential activation of capecitabine in tumor 
following oral administration to colorectal cancer patients. Cancer Chemother Pharmacol 
2000;45:291-7. 
37. 
Mackean M, Planting A, Twelves C, et al. Phase I and pharmacologic study of 
intermittent twice-daily oral therapy with capecitabine in patients with advanced and/or 
metastatic cancer. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology 1998;16:2977-85. 
38. 
Mulkerin D, LoConte NK, Holen KD, et al. A phase I study of an oral simulated 
FOLFOX with high dose capecitabine. Invest New Drugs 2009;27:461-8. 
 


 
 
 
 35 
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. 
 


 
 
 
 36 
APPENDIX B: Pill Diary  
 
PATIENT’S MEDICATION DIARY - TEMPLATE 
 
Today’s date _____________________ 
Agent:  Capecitabine 
Patient Name_____________________(initials acceptable)  
 Patient Study ID 
__________________________ 
INSTRUCTIONS TO THE PATIENT: 
1. 
Complete one form for each cycle of treatment. 
2. 
You will take _____ Capecitabine tablets twice daily.  You should take the tablets in the morning 30 minutes after 
eating and in the evening 30 minutes after eating at approximately same time each day.. 
3. 
Record the date, the number of tablets of each size of tablet that you took, and when you took them.   
4. 
If you have any comments or notice any side effects, please record them in the Comments column.   
5. 
Please bring this form and your bottles of Capecitabine tablets when you return for each appointment. 
 
Day 
 
Date 
 
Time of AM 
dose  
Time of PM dose 
Comments 
 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
 
Patient’s signature  
_________________________________________________________________________ 
 
Physician’s Office will complete this section: 
1. Date patient started protocol treatment _______________________________________________________________  
2. Date patient was removed from study ________________________________________________________________  
3. Patient’s planned total daily dose ___________________________________________________________________  
4. Total number of tablets taken this month  _____________________________________________________________  
5. Physician/Nurse/Data Manager’s Signature  __________________________________________________________  


 
 
 
 37 
 
 
 
APPENDIX C:  UWinRx: The University of Wisconsin Policy for Standardizing 
Assessment of CYP Mediated Drug Interaction in Clinical Trials 
 
Effective Date: October 1, 2011 
Version: New 
Section: Phase I 
 
I. Purpose 
The purpose of this policy is to provide a framework for standardizing assessment of 
cytochrome p450 drug interactions with respect to clinical trial eligibility. 
 
II. Definitions 
A. Investigational drug(s)  is/are the drug(s) being evaluated in the clinical trial as 
determined by the study chair, lead investigator and Drug Interaction Task Force 
(DITF).  In some cases these agents are commercially approved, but for the 
purpose of this policy they will be considered investigational. 
B. Concurrent medications are commercially available prescription and OTC being 
taken by the study subject but not mandated by the study protocol  
C. Pharmacokinetic Definitions 
a. Inhibitors  
i. Strong inhibitor is one that causes a ≥ 5-fold increase in the 
plasma AUC values or more than 80% decrease in clearance. 
ii. 
Moderate inhibitor is one that causes a ≥ 2-fold, but <5-
fold increase in the plasma AUC values or 50-79% decrease in 
clearance. 
iii. 
Weak inhibitor is one that causes a > 1.25-fold but < 2-fold 
increase in the plasma AUC values or 20-49% decrease in 
clearance. 
b. Inducers are drugs which cause ≥30% change in plasma AUC values.  
Drugs with < 30% change are defined as noninducers.  Lexi-comp defined 
major or moderate inducers are defined as inducers. 
c. Substrates are categorized as sensitive or not sensitive.   


 
 
 
 38 
i. Sensitive refers to drugs whose plasma AUC values have been 
shown to increase 5-fold (CYP3A) or 2-fold (All other CYP) when 
co-administered with a known inhibitor.  
ii. 
Lexi-comp defined major substrates are sensitive, minor 
substrates are not sensitive. 
d. Narrow therapeutic index drugs are those where exposure-response 
indicates that increases in their exposure levels by the concomitant use of 
interacting medications may lead to serious toxicity  
D. Cmax is the maximum plasma concentration of the investigational agent 
E. Ki is the dissociation constant of enzyme inhibitor, which is needed to categorize 
an agents metabolic profile  
F. IC50 is the inhibitory concentration 50% and is not interchangeable with the Ki. 
G.  Km, or the Michaelis–Menten concentration is when the rate of enzyme binding 
equals the rate of enzyme unbinding (steady state).  If the IC50 determination was 
conducted at Km, the Ki=IC50/2  
H. In vitro Definitions 
a. Inhibitors 
Strong inhibitors:  Cmax/Ki ≥ 1 
Moderate inhibitors:  Cmax/Ki  = 0.1-0.91 
Weak inhibitors:  Cmax/Ki <  0.1 
b. Inducers: > 100% increase in enzyme activity 
c. Substrates  
Sensitive: ≥ 30% of metabolism occurs via a given CYP 
Not sensitive: < 30% of metabolism occurs via a given CYP 
 
III. Policy 
a. UWCCC clinical trials must include a section in the protocol or a “cheat sheet” in 
Oncore that defines the metabolic pathway (CYP enzyme and whether it is a 
substrate, (sensitive or not sensitive), inducer or inhibitor (strong, moderate or 
weak) of the investigational agent as well as the contraindicated concurrent 
medications.   


 
 
 
 39 
b. If there is no metabolic pathway section in the protocol, the study chair and/or 
lead investigator will prepare this section of the protocol or cheat sheet. 
c. The DITF, or subcommittee of the DITF, including one medical oncologist and 
one pharmacist, has responsibility for reviewing and approving the metabolic 
pathway section within 1 week.  
d. Patient concurrent medications,  
i. Medications including route and schedule, for study candidates will be 
collected by Phase I nurses by patient interview 
ii. 
List will be reviewed and categorized (CYP enzyme and whether it 
is a substrate, inducer and inhibitor) by PRC.   
e. Pharmacokinetic definitions from previous in vivo trials are the preferred method 
for categorizing interaction potential.  In vitro data (Ki values) will be utilized if 
clinical definitions are not available. 
f. If only IC50 values are available, they should be converted to Ki values, as 
recommended by Cer et al, using the relationship Ki=IC50/2 with the assumption 
that the IC50 was conducted at the Km. 
g. The most recent version of the Drug Information Handbook (Lexi-Comp) will be 
used as the primary reference for assessment of interaction potential of concurrent 
medications.  This reference is updated annually.  The secondary references will 
be Micromedix and drug information leaflets (package inserts). 
h. The most recent version of the investigational drug brochure (IDB) will be used 
for assessment of interaction potential of the investigational agent. 
i. Transdermal products designed for systemic delivery must be assessed for 
interaction potential.  Topical products not designed to provide systemic delivery, 
(including inhaled products, ophthalmologic products and transvaginal 
preparations) do not need to be considered since they do not have appreciable 
systemic absorption. 
j. All protocol mandated anti-cancer medications will be considered to be “narrow 
therapeutic index” drugs 
k. Concurrent medication that are “narrow therapeutic index” are defined as agents 
where a  small change in plasma concentrations may result in substantial clinical 
impact, such as warfarin and drugs that affect the QT interval (Class I and III 
antiarrhythmics, antipsychotics, azoles, bepridil, dolasetron,  fluoroquinolones, 


 
 
 
 40 
fluoxetine, loratadine, macrolide antibiotics, methadone, ondansetron, 
phenothiazines,  sulfamethoxazole, tolterodine, trazodone, tricyclic 
antidepressants, trimethoprim).  Definition of narrow therapeutic index will be 
left to physician discretion 
 
IV. Procedure for Eligibility Determination 
a. Phase I office will review medication regimens, including OTCs ; and email this 
medication profile to the PRC. 
b. PRC will evaluate investigational agents and concurrent medications for 
interactions using table 1 or as stipulated in the protocol and categorize 
medications as Contraindicated, Use with Caution or Allowed. 
i. PRC will determine the metabolic pathway of the investigational agent 
from the cheat sheet or protocol and locate on grey panel of table 1.  
ii. 
PRC will determine the metabolic pathway of each concurrent 
medication from the most recent version of Lexi-Comp and locate on pink 
panel of table 1. 
iii. 
PRC will determine the intersecting box. 
c. Contraindicated medications must be discontinued for a patient to be eligible for 
the clinical trial.  Since time frame for discontinuation will vary with type of 
interaction and drug half-life, this will be determined on a case by case basis by 
the study chair, PCR and/or DITF. 
d. If patient is on one or more “Use with Caution” medications, the study chair and 
treating physician must be contacted for an eligibility determination. 
e. Allowed medications are allowed without consultation with the study chair or 
treating physician 


 
 
 
 41 
 
Table 1: Matrix for Assessment of Interactions 
Investigationa
l Agent 
Concurrent Medication 
No CYP 
Interactio
n 
 
Nonsensitiv
e Substrate 
but narrow 
therapeutic 
index 
Sensitive 
Substrate 
Weak 
Inhibitor 
Strong and 
Moderate 
Inhibitor 
Inducer 
No CYP 
Interaction 
Allowed 
Allowed 
Allowed 
Allowed Allowed 
Allowed 
Nonsensitive 
Substrate  
Allowed 
Allowed 
Allowed 
Allowed Use with caution 
Use with caution 
Sensitive 
Substrate 
Allowed 
Allowed 
Use with caution 
Use 
with 
caution 
Contraindicated Contraindicated 
Weak Inhibitor 
Allowed 
Allowed 
Use with caution 
Allowed Use with caution 
Use with caution 
Strong and 
Moderate# 
Inhibitor 
Allowed 
Use with** 
caution 
Contraindicated* Use 
with 
caution 
Use with 
caution 
Contraindicated 
Inducer 
Allowed 
Use with** 
caution 
Contraindicated* Use 
with 
caution 
Contraindicated Contraindicated 
*Contraindicated unless close monitoring with labs or drug levels and dose 
adjustment feasible  
**Use with caution and consider monitoring with labs or drug levels and dose 
adjustment if feasible  
# If an investigational agents is categorized as a moderate inhibitor based on in vitro 
data only, follow recommendations for weak inhibitors 
 
V. References 
www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInte
ractionsLabeling/ucm080499.htm  
 
Cer RZ, Mudunuri U, Stephens R,  and Lebeda FJ.  IC50-to-Ki: a web-based tool for 
converting IC50 to Ki values for inhibitors of enzyme activity and ligand binding. 
Nucleic Acids Res. 2009 July 1; 37 
 
VI. Coordination 
Phase 1 research office