Clinical trial NCT02324543
Conditions: Metastatic Pancreatic Adenocarcinoma
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Start date: 2015-02-01; Completion date: 2020-02-01
Enrollment: 47 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will be looking at whether gemcitabine, taxotere, and xeloda (GTX) in combination with cisplatin and irinotecan is effective (anti-tumor activity) and safe in patients with metastatic pancreatic cancer.

Detailed description:
The study is being done in 2 parts. The first part is the dose escalation (Phase I) part of the study where the dose of irinotecan is increased until the highest safe dose of irinotecan is defined that can be given with gemcitabine, taxotere, xeloda, and cisplatin.

After the safe dose of irinotecan in combination with gemcitabine, taxotere, xeloda, and cisplatin is defined, the second part of the study (Phase 2) will use these defined doses to look at how effective these drugs are against advanced pancreatic cancer.

Arms: arm 1: * Gemcitabine - 400 mg/m\^2
* Taxotere - 20 mg/m\^2
* Xeloda - 500 mg/twice daily (BID)
* Cisplatin - 15 mg/m\^2
* Irinotecan - 20 mg/m\^2 arm 2: * Gemcitabine - 400 mg/m\^2
* Taxotere - 20 mg/m\^2
* Xeloda - 500 mg/BID
* Cisplatin - 15 mg/m\^2
* Irinotecan - 40 mg/m\^2 arm 3: * Gemcitabine - 400 mg/m\^2
* Taxotere - 20 mg/m\^2
* Xeloda - 500 mg/BID
* Cisplatin - 15 mg/m\^2
* Irinotecan - 60 mg/m\^2 arm 4: * Gemcitabine - 500 mg/m\^2
* Taxotere - 20 mg/m\^2
* Xeloda - 500 mg/BID
* Cisplatin - 20 mg/m\^2
* Irinotecan - 20 mg/m\^2 arm 5: * Gemcitabine - 500 mg/m\^2
* Taxotere - 20 mg/m\^2
* Xeloda - 500 mg/BID
* Cisplatin - 20 mg/m\^2
* Irinotecan - 40 mg/m\^2 arm 6: * Gemcitabine - 500 mg/m\^2
* Taxotere - 20 mg/m\^2
* Xeloda - 500 mg/BID
* Cisplatin - 20 mg/m\^2
* Irinotecan - 20 mg/m\^2
Interventions: intervention 1: Gemcitabine intervention 2: Taxotere intervention 3: Xeloda intervention 4: Cisplatin intervention 5: Irinotecan
Intervention descriptions: intervention 1: IV on days 4 and 11 of a 21 day cycle intervention 2: IV on days 4 and 11 of a 21 day cycle intervention 3: Twice a day orally on days 1 through 14 of a 21 day cycle intervention 4: IV on days 4 and 11 of a 21 day cycle intervention 5: IV on days 4 and 11 of a 21 day cycle

Protocol documents:
Prot_SAP_000.pdf: 
 
TITLE:  Phase 1/2 Study of Gemcitabine/Taxotere/Xeloda (GTX) in combination with 
Cisplatin and Irinotecan in Subjects with Metastatic Pancreatic Cancer   
  
Protocol #:  
  
  
  
  
 J14161, IRB00053208         NCT02324543  
  
*Principal Investigator:  
Dung Le, M.D.  
 
 
Co-Investigators:  
Nafi Aygun  
  
Nilofer Azad  
Bjarne Bartlett  
Cheryl Blair  
Ilene Browner  
Ana DeJesus  
Ross Donehower  
Michael Foote  
Pamela Johnson  
Katherine Judge  
Daniel Laheru  
Valerie Lee  
Keith McIntyre  
Adrian Murphy  
Amy Ryan  
Cara Wilt  
Atif Zaheer  
Lei Zheng  
Stefan Zimmerman   
Rachel Klein  
Amira Hussien  
Cheng Lin  
Nagina Malguria  
William Sharfman  
Franco Verde  
Katherine Bever  
 
 
 
 
 


ii 
  
  
  
  
  
Financial Support – 
Swim Across America 
Laboratory at John 
Hopkins  
  
Protocol Type / Version 
# / Version Date: 
 
Original/ Version 1/ 
October 1, 2014  
  
  
  
 
 
Original/ Version 1.1/ 
November 5, 2014  
  
  
  
  
 
 
Original/ Version 1.2/ 
November 
20, 
2014 
Amendment 1/ Version 
2.0 / May 7, 2015  
Amendment 2/ Version 
3.0/ November 23, 2015  
Amendment 3/ Version 
4.0/ January 8, 2017  
Amendment 4/ Version 
5.0/ June 13, 2017  
Amendment 5/ Version 6.0/ May 3, 2018  
Amendment 5/Version 7.0/ Jan 3, 2019  
Amendment 5/ Version 8.0/ April 17, 2019  
Program Manager:  
 
Katrina Purtell  
Research Nurses:  
Maureen Berg  
Patricia Brothers   
Carol Judkins  
Holly Kemberling  
 
Ellen Lilly  
 
Sheila Linden  
Beth Onners  
  
Alice Pons  
 
Katrina Purtell  
Susan Sartorius-Mergenthaler  
Angie VanTassel   
Rosalind Walker  
Bradley Wilt  
 
Richard Zak  
 
Jane Zorzi  
 
Anna Ferguson  
 
Charlene Rogers  
 
Galina Alexander  
 
Heather Davis Bruning  
 
Susan Petrie  
 
 
 
  
 
Statistician:  
Study Coordinator:  
 
Hao Wang, PhD  
Nicole Thompson 
Lead Research Nurse:  
  
Regulatory Manager:  
 
Katrina Purtell, RN  
Jennifer Uram, PhD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


iii 
  
  
  
  
  
  
TABLE OF CONTENTS  
  
  
Page  
1.  OBJECTIVES .............................................................................................................................1 
1.1.  Primary Objectives .......................................................................................................1 
1.2.  Secondary Objectives ...................................................................................................1 
1.3   Exploratory Objectives ................................................................................................1 
1.4   Study design .................................................................................................................1 
2.  BACKGROUND ........................................................................................................................2 
2.1  Study Disease ................................................................................................................2 
2.2  Rationale .......................................................................................................................2 
3.  PATIENT SELECTION .............................................................................................................4 
3.1  Eligibility Criteria .........................................................................................................4 
3.2  Exclusion Criteria .........................................................................................................5 
3.3  Inclusion of Women and Minorities .............................................................................6 
4.  TREATMENT PLAN .................................................................................................................6 
4.1  Agent Administration ....................................................................................................6 
4.2   Continuation of Therapy ..............................................................................................7 
4.3  Definition of a Dose Limiting Toxicity ........................................................................8 
4.4  General Concomitant Medication and Supportive Care Guidelines .............................9 
4.5  Duration of Therapy ....................................................................................................10 
4.6  Duration of Follow Up ................................................................................................10 
4.7  Criteria for Removal from Study ................................................................................10 
5.   DOSING DELAYS/DOSE MODIFICATIONS .....................................................................10 
5.1 Suggested Dose Modifications for Other Non-Hematologic Toxicity ........................12 
5.2 Suggested Dose Modifications for Hematologic Toxicity ..........................................14 
6.  ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ...................................14 
6.1  Definitions ...................................................................................................................15 
6.2  Relationship ................................................................................................................16 
6.3  Expectedness ...............................................................................................................16 
6.4   Reporting ....................................................................................................................16 
7.  PHARMACEUTICAL INFORMATION .................................................................................19 
7.1 Gemcitabine (Gemzar).................................................................................................19 
7.2 Taxotere (Docetaxel) ...................................................................................................20 
7.3 Xeloda (Capecitabine) .................................................................................................21 
7.4 Cisplatin .......................................................................................................................22 
7.5 Irinotecan .....................................................................................................................24 
8.  CORRELATIVE/SPECIAL STUDIES ....................................................................................25 
8.1   Plasma Marker Studies...............................................................................................25 
8.2  Whole blood Studies ...................................................................................................25 


iv 
  
  
  
8.3  Tumor Tissue Studies..................................................................................................25 
9.  STUDY CALENDAR...............................................................................................................26 
10.  MEASUREMENT OF EFFECT .............................................................................................28 
10.1  Antitumor Effect – Solid Tumors .............................................................................28 
11.   DATA REPORTING / REGULATORY REQUIREMENTS ...............................................34 
11.1 Data Management ......................................................................................................34 
11.2 Safety Meetings .........................................................................................................34 
11.3   Monitoring ...............................................................................................................34 
12.  STATISTICAL CONSIDERATIONS ....................................................................................35 
12.1  Study Design/Endpoints ............................................................................................35 
12.2  Reporting and Exclusions .........................................................................................38 
REFERENCES ..............................................................................................................................38 
APPENDIX A: Performance Status Criteria .................................................................................39 
APPENDIX B: SAE Reporting Form ...........................................................................................41 
APPENDIX C: Gemcitabine Prescribing Information ..................................................................44 
APPENDIX D: Taxotere Prescribing Information ........................................................................45 
APPENDIX E: Xeloda Prescribing Information ...........................................................................46 
APPENDIX F: Cisplatin Prescribing Information ........................................................................47 
APPENDIX G: Irinotecan Prescribing Information ......................................................................48 
APPENDIX H: EORTC QLQ-C30 (version 3) .............................................................................49 
 
  
  
  
  


 
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1. OBJECTIVES  
  
 
1.1.  
Primary Objectives  
  
  
Part 1: The primary objective of the phase I portion is to assess safety of the combination 
of gemcitabine, docetaxel, capecitabine, cisplatin, and irinotecan in patients with untreated 
metastatic pancreatic adenocarcinoma (PDA) and to determine the maximally tolerated 
dose (MTD) of the combination;   
  
Part 2: The primary objective of the phase II portion is to assess the efficacy of the 
combination of gemcitabine, docetaxel, capecitabine, cisplatin, and irinotecan in patients 
with untreated metastatic PDA based on the overall survival (OS) rate at 9 months.    
  
 
1.2.  
Secondary Objectives  
  
To estimate the response rate (RR), disease control rate (DCR), progression-free survival 
(PFS), and overall survival (OS) of the combination of gemcitabine, docetaxel, 
capecitabine, cisplatin, and irinotecan in patients with untreated metastatic PDA.  
  
 
1.3   
Exploratory Objectives  
  
1.3.1 To assess changes in quality of life measures as assessed by the EORTC QLQ-C30 
questionnaire.   
  
1.3.2 To assess tumor burden dynamics using both standard protein biomarkers such as 
CA19-9 and CEA and exploratory biomarkers such as circulating tumor DNA.   
  
1.3.3 To assess baseline characteristics of the patients enrolled and correlate these 
molecular and clinicopathologic criteria with treatment response and toxicity.  
  
 
1.4   
Study design    
  
This is a two part, single-institution, open-label, dose-escalation, phase 1/2 study to 
evaluate the clinical activity of gemcitabine, taxotere, and xeloda (GTX) in combination 
with cisplatin and irinotecan in patients with metastatic pancreatic cancer.   
  
Part 1 of the study is a traditional 3 + 3 dose escalation study designed to evaluate the 
maximally tolerated dose (MTD), dose limiting toxicities (DLTs), and safety of increasing 
doses of irinotecan in combination with GTX-C.    
  
Part 2 is an expansion cohort study for the evaluation of efficacy once the MTD has been 
determined. The primary endpoint of Part 2 will be the OS rate at 9 months, which is 
defined as the proportion of subjects alive at 9 months.  The treatment regimen would be 
considered of insufficient activity for further study in this population if OS rate at 9 months 


 
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is 57% or less, and the minimum required level of efficacy that would warrant further study 
with the proposed regimen is a 80% OS rate at 9 months. The study includes one interim 
analysis for futility using a two-stage design   (Section 12).  
  
  
2. BACKGROUND  
  
 
2.1  
Study Disease  
  
In 2013, there was an estimated 45,220 new cases of pancreatic cancer diagnosed in the United 
States1.  Generally, most new cases of pancreatic cancer are advanced with extensive tumor growth 
usually due to the lack of symptoms during the early stages of the disease. As a result, few patients 
are considered candidates for surgical resection. Patients with advanced pancreatic cancer are 
usually treated with chemotherapy in an effort to improve survival and alleviate symptoms. 
Median survival time ranges from 4 to 6 months in patients with metastatic disease. With 
treatment, survival has improved to 6 to 11 months2,3.  Overall, the 5-year survival rate is about 
6% for all stages combined and decreases to 2% for patients with metastatic pancreatic cancer4. 
Currently, there are a few standard therapy options for patients.  Single agent gemcitabine was 
FDA approved based on a comparative study between gemcitabine and 5-FU.  Gemcitabine 
produced significant improvement in disease-related symptoms and prolonged survival (1-year 
survival: 18% versus 2%, respectively)5.  Subsequently, the oral tyrosine kinase inhibitor, 
erlotinib, was approved in combination with gemcitabine based on a slight increase in median 
survival over gemcitabine alone (6.24 months compared to 5.91 months)6.  Other phase III studies 
testing combination regimens have been disappointing.  More recently, a randomized phase III 
study performed in France comparing FOLFIRINOX (5-FU/irinotecan/oxaliplatin) to gemcitabine 
resulted in an improvement in survival of 6.8 months versus 11.1 months2.  While this regimen is 
being used, there are still concerns about its potential toxicity in a North American population and 
is being reserved for the most fit patients. Nab-paclitaxel has now been approved in combination 
for gemcitabine with a median survival of 8.5 months compared to 6.7 months with gemcitabine 
alone7.  Therapies for patients with metastatic pancreatic cancer are urgently needed.  
  
 
2.2  
Rationale  
  
Combination chemotherapy is now extending the lives of those with metastatic PDA, however, 
overall survival (OS) remains less than 1 year2,7. In most cases, responses and prolonged survival 
are limited by the emergence of resistance mutations that render even triplet chemotherapy 
ineffective2,8,9. Increasing the number of agents in a therapeutic cocktail could, in theory, improve 
outcomes and create a scenario where the emergence of solitary resistance mutations would no 
longer result in loss of efficacy. This hypotheses is supported by mathematical modeling that 
evaluates the number of tumor cells at treatment onset and evolution of mutations to predict the 
response to single versus dual versus multi-agent therapy9,10.  These models predict that patients 
with high tumor burden and monotherapy are unlikely to have a prolonged response.  The converse 
is true as well. Patients with lower burden disease and multi-agent therapy are more likely to have 
durable responses.      
  


 
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The rationale for using multi-agent chemotherapy in the first line setting is to deliver combinations 
of drugs when the patients are most likely to tolerate therapy and to decrease the likelihood of 
developing resistant clones which are more likely to occur when drugs are given individually 
and/or sequentially.  The choice of GTX as a backbone is based on our collective experience with 
this regimen and its promise in phase II studies.  Furthermore, we have observed that despite 
multiple dose reductions, usually due to bone marrow toxicity and not clinical symptoms, many 
patients still have a prolonged response to therapy, suggesting that with multi-agent chemotherapy, 
maximal doses are not necessary to show a continued effect.  The doses reported in the phase II 
study are xeloda 1500mg/m2/day, gemcitabine 750mg/m2 at a rate of 10mg/m2/min, and taxotere 
30mg/m2.  We have recently completed a study using a low dose regimen of gemcitabine, taxotere, 
xeloda and added cisplatin (GTX-C) (clinical trial information: NCT01459614).  Gemcitabine was 
administered in a prolonged infusion schedule at 10 mg/m2/min based upon the study published 
by Brand et al11 and Tempero et al12 which demonstrated improved phosphorylation and activation 
of gemcitabine by deoxycytidine kinase with prolonged infusion times. Dr. Fine’s research has 
shown that the order of administration of the drugs is important to the efficacy of the combination.  
The xeloda was started a few days before the rest of the drugs were administered.  Xeloda was 
started on day 1 and administered every 12 hours for the following reasons: 1. xeloda, on an every 
12 h schedule, mimics the continuous infusion of 5-FU; 2. preferential conversion of 5-dFUR to 
5-FU in tumor cells by thymidine phosphorylase (TP) which activates xeloda to 5-FU which is 
more highly expressed in tumor than normal cells of the same histology; 3.taxotere upregulates TP 
levels in some cancer cells, enhancing conversion of xeloda to 5-FU, and 4. ease of administration 
(3). Preclinical studies suggest synergy between gemcitabine (G), taxotere (T) and xeloda based 
on the ability to inhibit MEK-ERK phosphorylation, increase BAX and BAK phosphorylation, 
and to decrease BCL-2 in pancreatic cancer cell lines3.  Cisplatin was chosen based on the 
following observations:  (1) cisplatin is a DNA intercalating agent which works through a different 
mechanism than gemcitabine, taxotere, or xeloda; (2) pancreatic cancers with defects in 
BRCA/Fanconi DNA repair pathway are sensitive to cisplatin; (3) meta-analyses suggest that 
gemcitabine/platinum combinations improve survival in good performance status patients; (4) 
patients with a personal or family history of cancers may benefit from cisplatin-based therapy; (5) 
early neurotoxicity is not a major concern given cisplatin and taxotere are often combined at 2-3X 
the doses proposed in this protocol.  We postulated that a four drug regimens, even at low doses, 
would further improve OS by simultaneously targeting potentially non-redundant oncogenic 
pathways. The treatment doses included capecitabine 500 mg bid on days 1-14, and the 
combination of gemcitabine 500 mg/m2 (10 mg/m2/min), docetaxel 20 mg/m2 and cisplatin 20 
mg/m2 on days 4 and 11. The primary endpoint was progression-free survival (PFS) rate at 6 
months (mos); the regimen would be considered active if the 6-month PFS rate was >75% and 
inactive if < 50%.    


 
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To build on our results, we propose to test a multi-agent regimen of 5 drugs administered at low 
doses (below the effective dose) to patients with metastatic PDA. The regimen proposed consists 
of GTX-C plus irinotecan. Irinotecan is chosen as it a drug known to have activity in PDA with 
5fluorouracil and oxaliplatin in the combination known as FOLFIRINOX. We believe that an 
effective cocktail for the treatment of PDA, using sub-therapeutic multi-agent dosing has the 
potential to significantly extend the survival of these patients while preserving quality of life.  
  
  
3. PATIENT SELECTION  
  
 
3.1  
Eligibility Criteria   
  
1. Subjects must have histologically or cytologically confirmed untreated metastatic 
pancreatic adenocarcinoma. Subjects with islet cell neoplasms are excluded. Subjects 
with mixed histology will be excluded.  
  
2. Subject has one or more tumors measurable by CT scan using RECIST 1.1 criteria.  
MRI is acceptable if a CT scan is contraindicated.  
  
3. Male or non-pregnant and non-lactating female of age >18 years.    
  
4. ECOG performance status <1. ECOG 0 indicates that the patient is fully active and able 
to carry on all pre-disease activities without restriction; and, ECOG 1 indicates that the 
patient is restricted in physically strenuous activity but is ambulatory and able to carry 
out work of a light or sedentary nature.  
  
5. Subjects must have adequate organ and marrow function as defined below:  
  
 WBC   
  
  
  
  
  
>3,500/mcL  
 Absolute Neutrophil Count  
>1,500/mcL  
 Platelets    
  
  
  
  
>100 x 109/L  
 Hemoglobin    
  
  
  
 8 g/dL  
 
 
 
 
 
 
 
 
 
 
 
 


 
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  
 Total Bilirubin 
  
  
  
within normal institutional limits  
 Alkaline phosphatase    
  
 5 X ULN  
 AST(SGOT)/ALT(SGPT)  
 2.5 x ULN ( 5 X ULN for subjects with 
documented liver metastases)  
 
-  
Creatinine  
  
  
  
  
within normal limits (creatinine clearance >60  
mL/min/1.73 m2 for subjects with creatinine 
levels above institutional normal.)  
  
6. Women of child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry and for 
the duration of study participation.  Should a woman become pregnant or suspect she 
is pregnant while she or her partner is participating in this study, she should inform her 
treating physician immediately.  
  
7. Ability to understand and the willingness to sign a written informed consent document.  
  
 
3.2  
Exclusion Criteria  
  
1. Subjects who have had any prior chemotherapy within 5 years of enrollment  
  
2. Subjects who have had radiotherapy for pancreatic cancer.  
  
3. Age > 76 years  
  
4. Subjects who are receiving or have received any other investigational agents within 
28 days prior to Day 1 of treatment in this study.  
  
5. Subject has undergone major surgery, other than diagnostic surgery (i.e.--surgery 
done to obtain a biopsy for diagnosis or an aborted Whipple), within 28 days prior 
to Day 1 of treatment in this study.  
  
6. Subject has known brain metastases.  
  
7. History of hypersensitivity or allergic reactions attributed to compounds of similar 
chemical or biologic composition to gemcitabine, taxotere, xeloda, cisplatin, or 
irinotecan.  
  
8. Uncontrolled intercurrent illness including, but not limited to, uncontrolled 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements.  
  


 
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9. Subject has serious medical risk factors involving any of the major organ systems 
such that the Investigator considers it unsafe for the subject to receive an 
experimental research drug.  
  
10. Subject has a known history of infection with HIV, hepatitis B, or hepatitis C.  
  
11. Subject is pregnant or breast feeding.  
  
12. Subject is unwilling or unable to comply with study procedures.  
  
13. Subject with clinically significant wound.  
  
 
3.3  
Inclusion of Women and Minorities  
  
Both men and women of all races and ethnic groups are eligible for this trial.    
  
4. TREATMENT PLAN  
  
  
  
  
  
  
  
 
4.1  
Agent Administration  
  
Treatment will be administered on an outpatient basis. The description of the regimen is  
further described in Table 3.  Reported adverse events and potential risks are described in 
Section 6 and in Appendices B-E.  Appropriate dose modifications are described in Section 
5.  No investigational or commercial agents or therapies other than those described below 
may be administered with the intent to treat the subject's malignancy.  
  
Table 2: Dose Levels  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
 


 
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Table 3: Regimen Description  
  
Agent  
Suggested pre and/or post 
medications  
Route  
Schedule  
Cycle  
Length  
Gemcitabine  
5-HT3 antagonist IV + 
fosaprepitant IV, decadron 
12mg IV, decadon 8mg orally 
bid on days 2-3,  5-HT3 
antagonist on days 2-5.  
IV at 10mg/m2/min (40 
minutes for 400mg/m2 
or 50 minutes for  
500mg/m2)*  
Days 4 and 11  
21 days  
Taxotere  
See gemcitabine  
IV over 60 minutes*  
Days 4 and 11  
Xeloda  
5-HT3 antagonist oral or 
prochlorperazine oral prn  
PO BID  
Days 1 through  
14  
Cisplatin  
Normal saline 500cc IV pre 
and post  
IV over 60 minutes*  
Days 4 and 11  
Irinotecan  
Atropine should be 
immediately available for anti-
cholinergic reactions  
IV over 60 minutes*  
Days 4 and 11  
*Infusion times are approximate (+/- 15 minutes) and may need to be adjusted based on patient tolerability  
  
The subject will be requested to maintain a medication diary of each dose of Xeloda.  The 
medication diary will be returned to clinic staff at the end of each cycle.  
  
4.1.1 Other Considerations  
  
The order of administration of the IV chemotherapeutic agents is gemcitabine 
followed by taxotere followed by cisplatin followed by irinotecan.  The hydration for 
cisplatin should occur pre and post infusion as standard of care for 30-60 minutes.   
  
Xeloda tablets should be swallowed with water within 30 minutes after eating.  
Xeloda can have an effect on warfarin or coumadin and phenytoin metabolism.  
  
 
4.2   
Continuation of Therapy  
  
Subjects will be evaluated during the treatment period to determine if continued treatment 
is appropriate. If, at any time during treatment the evaluation criteria are not met, GTX–CI 
 
 


 
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can be held or the dose adjusted.  Suggested dose modification criteria are in Section 5.  
Patients with a hemoglobin of < 8 can be treated and transfused.  
  
To continue therapy, subjects must meet the following criteria (exceptions should be 
approved by the principal investigator):  
  
• 
Absolute Neutrophil Count  
Day 4 of cycle: >1000/mcL  
 
   
  
  
  
  
  
  
  
Day 11 of cycle: >900/mcL  
• 
Platelets    
  
  
  
  
Day 4 of cycle: >80 x 
109/L  
 
   
  
  
  
  
  
  
  
Day 11 of cycle: >70 x 109/L  
• 
Hemoglobin      
  
  
> 8 g/dL  
• 
Total Bilirubin     
  
  
< 2 x ULN  
• 
AST(SGOT)/ALT(SGPT)  
 5 X ULN  
• 
Creatinine  
  
  
  
  
within  normal 
 institutional  limits  
(creatinine clearance >60 mL/min/1.73 
m2 for subjects with creatinine levels 
above institutional normal.)  
  
 
4.3  
Definition of a Dose Limiting Toxicity  
  
The dose-limiting toxicity (DLT) for the combination in this study will be defined as one 
or more of the following possibly or probably related toxicities within the first cycle of 
treatment according to the NCI Common Toxicity Criteria for Adverse Events (CTCAE), 
Version 4:  
  
• 
Any Grade 3 or higher toxicity possibly or probably related to the study 
drug, with the exception of:  
• 
Alopecia   
• 
Grade 3 or 4 anemia, thrombocytopenia, or neutropenia that resolves to  
<grade 2 within 7 days.  Subjects should have repeat labs within 7 days to 
document resolution.  
• 
Grade 3 or 4 leucopenia/lymphopenia.  
• 
Grade 3 or 4 nausea, vomiting, or diarrhea that resolves to <grade 2 within 
72 hours.  
• 
Grade 3 or 4 asymptomatic laboratory values that resolve to < grade 2 
within 7 days.  Subjects should have repeat labs within 7 days to document 
resolution.  
  
 
  
Management and dose modifications are outlined in Section 5.  
  
Dose escalation will proceed within each dose level according to the following scheme.  
Dose-limiting toxicity (DLT) is defined above.  However, the PI has the discretion to 


 
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expand at the current dose level or move to other dose levels to complete and expand that 
level if there are no safety concerns.  
  
Number of Patients with 
DLT at a Given Dose Level  
Escalation Decision Rule  
0 out of 3  
Enter 3 patients at the next dose level.  
>2  
Dose escalation will be stopped.  This dose level will 
be declared the maximally administered dose (highest 
dose administered).  Three (3) additional patients will 
be entered at the next lowest dose level if only 3 
patients were treated previously at that dose.  
1 out of 3  
Enter at least 3 more patients at this dose level.  
• If 0 of these 3 patients experience DLT, proceed to 
the next dose level.  
• If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose.  Three (3) additional 
patients will be entered at the next lowest dose level 
if only 3 patients were treated previously at that 
dose.  
<1 out of 6 at highest dose 
level below the maximally 
administered dose  
This is generally the recommended phase 2 dose. At 
least 6 patients must be entered at the recommended 
phase 2 dose.  
  
 
4.4  
General Concomitant Medication and Supportive Care Guidelines  
  
The concurrent use of all other drugs, over-the-counter medications, or alternative therapies 
must be documented.  The Principal Investigator should be alerted if the subject is taking 
warfarin, coumadin, or phenytoin.  These drugs are not contra-indicated but should be 
monitored closely while on Xeloda.  
  
Subjects may not enroll in any other therapeutic clinical protocol or therapeutic 
investigational trial while enrolled in this study. Irradiation may be allowed during the 
study. Administration of other chemotherapy, immunotherapy, or anti-tumor hormonal 
therapy during the study is not allowed.  
  
Supportive care, including but not limited to anti-emetic medications, may be administered 
at the discretion of the Principal Investigator or Co-Investigators. Concurrent treatment 
with bisphosphonates is allowed. All concomitant treatments, including blood and blood 
products, must be reported on the case report form (CRF). Erythropoietin, G-CSF, or 


 
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Neulasta may be administered at the discretion of the Principal Investigator or 
CoInvestigators.  
  
 
4.5  
Duration of Therapy  
  
In the absence of treatment delays due to adverse event(s), treatment may continue 
indefinitely or until one of the following criteria applies:  
  
• Disease progression: Subjects may be allowed to continue treatment if the Principal 
Investigator feels that the subject is receiving benefit (e.g. a mixed response).  
However, subjects who continue on study with progressive disease by RECIST should 
be taken off study after determination of disease progression on the next study scan.  
  
• Intercurrent illness that prevents further administration of treatment,  
  
• Unacceptable adverse event(s),  
  
• Subject decides to withdraw from the study, or  
  
• General or specific changes in the subject's condition render the subject unacceptable 
for further treatment in the judgment of the investigator.  
  
 
4.6  
Duration of Follow Up  
  
Subjects will be followed for adverse events for a minimum of 28 days after the last dose 
of study drug or death, whichever occurs first. Survival status will be collected every 3 
months (+/- 3 weeks). Subsequent therapies and responses may be collected.  Subjects 
removed from study for unacceptable adverse event(s) will be followed until resolution or 
stabilization of the adverse event or death. Subjects who are on treatment holidays will be 
followed only for progression and survival. Patients with disease stabilization for 2 years 
can receive treatment with their primary oncologist and only scans will be collected until 
progression or new therapy and all patients will be followed for survival. We will no longer 
collect labs, visits, Quality of life Questionnaires, or Adverse Events for these subjects.  
  
 
4.7  
Criteria for Removal from Study  
  
Subjects will be removed from study when any of the criteria listed in Section 4.5 applies.  
The reason for study removal and the date the subject was removed must be documented 
in the Case Report Form.   
  
5. DOSING DELAYS/DOSE MODIFICATIONS  
  


 
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Allowance of chemotherapy breaks of greater than 2 weeks will be decided on a case-by-case basis 
by the principal investigator. When the delay is due to toxicity, then the next cycle may begin with 
a dose reduction.  
  
If the delay is due to personal reasons, there will be no dose reductions. Any treatment delays 
beyond the protocol allowed window must be approved by the principal investigator.  
  
Some discretion is left up to the investigators to account for patients who may be doing 
exceptionally well and request a longer break from therapy or may need a little extra time for 
clinical and laboratory status to recover. Dose reductions will be managed based on Table 3. 
Additional dose reductions (depending on starting dose) are up to the discretion of the principal 
investigator.  Note that there are only 3 dose options for xeloda (500mg po bid, 300mg po bid and 
150mg po bid) and given that palmar-plantar erythrodysesthesia syndrome is typically due to 
xeloda, investigators may choose to hold the xeloda and decrease within a cycle.  In subsequent 
cycles, the xeloda will continue at the lower dose but the other agents do not need to be decreased 
to a lower dose level unless deemed necessary due to another adverse event.  For example, if a 
subject on DL1 (Level 0) develops grade 2 palmar-plantar erythrodysesthesia syndrome during 
cycle 1, the xeloda can be held until < grade 1 and restarted at a lower dose.  The xeloda period, 
however, should not be more than the original 14 day period.  The subject should receive the next 
cycle at DL1 (Level 0) except for the xeloda would remain at the lower dose unless deemed 
necessary to use DL-1 due to another adverse event. Xeloda dose reductions can be done 
independently of the dose reductions for the IV chemotherapy agents.  
  
Table 4: Dose Reduction  
  
  
  
  
  
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
  
  
  
  
  
  
 
 
  
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 


 
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Dose modifications are suggestions, but the final decision is left to the discretion of the 
Principal Investigator or Co-Investigator.  
  
5.1 Suggested Dose Modifications for Other Non-Hematologic Toxicity  
  
Dose modifications are suggestions, but the final decision is left to the discretion of the 
Principal Investigator or Co-Investigator.  
  
Event Name  
Nausea  
 
 
 
 
 
  


 
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Grade of Event  
Management/Next Dose  
≤ Grade 1  
No change in dose  
Grade 2  
No change in dose  
Grade 3  
Hold until < Grade 2.  Resume at one dose level lower, if 
indicated.  
Recommended management:  antiemetics.  
  
Event Name  
Vomiting  
Grade of Event  
Management/Next Dose  
≤ Grade 1  
No change in dose  
Grade 2  
No change in dose  
Grade 3-4  
Hold until < Grade 2.  Resume at one dose level lower, if 
indicated.  
Recommended management:  antiemetics.  
  
Event Name  
Diarrhea  
Grade of Event  
Management/Next Dose  
≤ Grade 1  
No change in dose  
Grade 2  
No change in dose  
Grade 3-4  
Hold until < Grade 2.  Resume at one dose level lower, if 
indicated.  
Recommended management:  Loperamide anti-diarrheal therapy  
Dosage schedule:  4 mg at first onset, followed by 2 mg with each loose motion 
until diarrhea-free for 12 hours (maximum dosage:  16 mg/24 hours)  
Adjunct anti-diarrheal therapy is permitted and should be recorded when used.  
  
Event Name  
Peripheral Neuropathy  
Grade of Event  
Management/Next Dose  
≤ Grade 1  
No change in dose  
Grade 2  
No change in dose  
Grade 3-4  
Hold until < Grade 2.  Resume at one dose level lower, if 
indicated.  
Recommended management: consider medications for neuropathy.  
  
Event Name  
Fatigue  
Grade of Event  
Management/Next Dose  
≤ Grade 1  
No change in dose  


 
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Grade 2  
No change in dose  
Grade 3  
Hold until < Grade 2.  Resume at one dose level lower, if 
indicated.  
  
Event Name  
Palmar-plantar erythrodysesthesia syndrome  
Grade of Event  
Management/Next Dose  
≤ Grade 1  
No change in dose  
Grade 2  
Hold xeloda until ≤ Grade 1.  Resume at xeloda 300mg po bid. 
For 2nd occurrence, resume at 150mg po bid.  
Grade 3  
Hold xeloda until ≤ Grade 1.  Resume at xeloda 300mg po bid. 
For 2nd occurrence, resume at 150mg po bid.  
Recommended management:  moisturizers to intact skin.  
  
5.2 Suggested Dose Modifications for Hematologic Toxicity   
  
  
Event Name  
Neutropenia  
Laboratory Value   
Management/Next Dose  
Day 4 of cycle: <1000/mcL  
Hold until > 1000, no change in dose  
Day 11 of cycle: <900/mcL  
Hold until >900.  Resume at one dose level lower, 
if indicated. Transient grade 3 neutropenia may 
occur during days 15-21 of a cycle.  
The use of growth factors is permitted. 
  
  
Event Name  
Thrombocytopenia  
Laboratory Value   
Management/Next Dose  
Day 4 of cycle: <80 x 109/L  
Hold until > 80, no change in dose  
Day 11 of cycle: <70 x 109/L  Hold until >70, no change in dose  
Grade 3-4  
Hold until >70.  Resume at one dose level lower, if 
indicated.  
A platelet goal of 50K should be considered for those on anticoagulation.  
  
  
6. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS   
  
This study will use the descriptions and grading scales found in the revised National Cancer 
Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 for adverse 


 
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event 
reporting 
that 
can 
be 
found 
at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.    
  
Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or other means, 
will be collected, recorded, and followed as appropriate.   
  
All adverse events experienced by subjects will be collected and reported from the first dose of the 
investigational combination (GTX-CI), throughout the study, and will only be followed for 30 
days unless related to the investigational agent.    
  
Subjects who have an ongoing adverse event related to the study procedures and/or medication(s) 
may continue to be periodically contacted by a member of the study staff until the event is resolved 
or determined to be irreversible by the investigator.  
  
 
6.1  
Definitions  
  
6.1.1 Adverse Event (AE)  
  
Adverse event is defined as any undesirable sign, symptom or medical condition occurring 
after starting the study drug (or therapy) even if the event is not considered to be related to 
the study. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), 
signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., 
laboratory findings, electrocardiogram). Medical conditions/diseases present before 
starting the study treatment are only considered adverse events if they worsen after starting 
the study treatment (any procedures specified in the protocol). Adverse events occurring 
before starting the study treatment but after signing the informed consent form will not be 
recorded. Abnormal laboratory values or test results constitute adverse events only if they 
induce clinical signs or symptoms or require therapy.  
  
 
6.1.2  Serious Adverse Event (SAE)  
  
A serious adverse event is an undesirable sign, symptom or medical condition which:   
• Results in death   
• Is life threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe)   
• Requires inpatient hospitalization or causes prolongation of existing hospitalization 
(see note below for exceptions) > 24 hours  
• Results in persistent or significant disability/incapacity   
• Is a congenital anomaly/birth defect (note: reports of congenital anomalies/birth 
defects must also be reported on the Pregnancy Supplemental Form)   
• Is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the subject or may 


 
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require intervention [eg, medical, surgical] to prevent one of the other serious 
outcomes listed in the definition above.). Examples of such events include, but are 
not limited to, intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization.)  
• Is a new cancer (that is not a condition of the study)  
• Is associated with an overdose  
  
Events not considered to be serious adverse events are hospitalizations for the:   
• Admissions as per protocol for a planned medical/surgical procedure or to facilitate 
a procedure  
• Routine health assessment requiring admission for baseline/trending of health status 
(eg, routine colonoscopy)   
• Medical/surgical admission for purpose other than remedying ill health state and was 
planned prior to entry into the study. Appropriate documentation is required in these 
cases   
• Admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, care-giver respite, family circumstances, administrative).  
  
 
6.2  
Relationship  
  
Definite – The AE is clearly related to the study treatment.  
Probable – The AE is likely related to the study treatment.  
Possible – The AE may be related to the study treatment.  
Unlikely – The AE is doubtfully related to the study treatment.  
Unrelated – The AE is clearly NOT related to the study treatment.  
  
 
6.3  
Expectedness  
  
Unexpected adverse event: An adverse event, which varies in nature, intensity or frequency 
from information on the investigational drug/agent provided in the Investigator’s Brochure, 
package insert or safety reports. Any adverse event that is not included in the informed 
consent is considered “unexpected”.   
  
Expected (known) adverse event: An adverse event, which has been reported in the 
Investigator’s Brochure. An adverse event is considered “expected”, only if it is included 
in the informed consent document as a risk.  
  
 
6.4   
Reporting  
  
6.4.1 Serious Adverse Event Reporting  
  
Deaths, regardless of causality, within 30 days of study treatment and serious adverse 
events which are related and unexpected will be reported to following entity:  


 
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1. Johns Hopkins IRB  
Adverse events that are serious, unexpected, and assessed by the investigator to be 
possibly, probably, or definitely related to the study drug will be reported to the 
postmarketing departments of the following manufacturers:  
1. Eli Lilly and Company (Gemcitabine)  
2. Sanofi-Aventis U.S. (Taxotere)  
3. Genentech (Xeloda)  
4. Bristol-Myers Squibb Company (Cisplatin)  
5. Pfizer (Irinotecan)  
  
Timelines for reporting SAE’s:  
1. Reporting of SAEs to the manufacturers should occur within 24 hours of becoming 
aware of the event occurrence.    
  
2. SAEs must be reported to the Institution IRB per institutional guidelines.  
  
Johns Hopkins Medicine IRB 
Reed Hall B-130 1620 
McElderry St.  
Baltimore, MD 21205-1911  
Phone: 410-955-3008  
  
Follow up on SAE reports should also be sent to all the above agencies upon receipt of 
information per institutional guidelines.  
  
6.4.2 Routine Adverse Event Reporting  
  
If an ongoing AE changes in its intensity or in its perceived relationship to investigational 
product, a new AE entry for the event should be completed. Adverse events should be 
followed to resolution or stabilization, or reported as SAEs if they become serious. 
Followup is also required for AEs that cause interruption or discontinuation of 
investigational product, or those that are present at the end of study participation. Subjects 
with AEs at study completion should receive post-treatment follow-up as appropriate.   
  
All identified non-serious AEs must be recorded and described on the appropriate 
nonserious AE page of the Case Report Form (CRF).  
  
6.4.3 Laboratory Test Abnormalities  
  
Laboratory abnormalities present at the screening visit will be recorded as pre-treatment 
signs and symptoms. After study treatment administration, all grade 3 and 4 clinical 
laboratory results that represent an increase in severity from baseline will be reported as 
adverse events. A grade 1 or 2 clinical laboratory abnormality should be reported as an 
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In addition, the following laboratory abnormalities should also be captured on the 
nonserious AE CRF page or SAE paper CRF page as appropriate:  
  
 Any laboratory test result that is clinically significant or meets the definition of 
an SAE  
 Any laboratory abnormality that required the subject to have the investigational 
product discontinued or interrupted  
 Any laboratory abnormality that required the subject to receive specific 
corrective therapy  
  
It is expected that wherever possible, the clinical, rather than the laboratory term would be 
used by the reporting investigator (e.g., anemia versus low hemoglobin value).  
  
6.4.4  Overdose  
  
An overdose is defined as the accidental or intentional ingestion of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose 
must be reported as an SAE.  
  
 
6.4.5  Pregnancy  
  
Sexually active women of child bearing potential (WOCBP) must use an effective method 
of birth control during the course of the study, in a manner such that risk of failure is 
minimized.  
  
Prior to study enrollment, WOCBP must be advised of the importance of avoiding 
pregnancy during study participation and the potential risk factors for an unintentional 
pregnancy. The subject must sign an informed consent form documenting this discussion.  
  
ALL WOCBP MUST HAVE A NEGATIVE SERUM PREGNANCY TEST 7 DAYS 
PRIOR TO RECEIVING INVESTIGATIONAL PRODUCT. All WOCBP should be 
instructed to contact the investigator immediately if they suspect they may be pregnant 
(e.g., missed or late menstrual period) at any time during study participation.  
  
If, following initiation of the investigational product, it is subsequently discovered that a 
study subject is pregnant or may have been pregnant at the time of the investigational 
product exposure, including during at least 6 half-lives after product administration, the 
investigational product will be permanently discontinued in an appropriate manner. 
Exceptions to the investigational product discontinuation may be considered for 
lifethreatening conditions only after consultation with the sponsor or as otherwise specified 
in this protocol. The investigator must immediately notify the sponsor of this event, record 
the pregnancy on the SAE form. Initial information on a pregnancy must be reported 
immediately to the sponsor and the outcome information provided once the outcome is 
known. Forward these forms to the sponsor according to SAE reporting procedures.  


 
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Protocol-required procedures for study discontinuation and follow-up must be performed 
on the subject unless contraindicated by pregnancy (eg, x-rays studies). Other appropriate 
pregnancy follow-up procedures should be considered if indicated. Follow-up information 
regarding the course of the pregnancy, including perinatal and neonatal outcome must be 
reported. Infants should be followed for a minimum of 8 weeks.  
  
 
6.4.6  Other Safety Considerations  
  
Any significant changes noted during interim or final physical examinations, 
electrocardiograms, x-rays, and any other potential safety assessments, whether or not these 
procedures are required by protocol, should also be recorded on the appropriate nonserious 
AE or SAE page of the CRF.  
  
7. PHARMACEUTICAL INFORMATION  
  
7.1 Gemcitabine (Gemzar)  
  
Description, Formulation, and Storage  
  
For complete details on preparation instructions, storage, clinical pharmacology, a 
comprehensive list of adverse events and the human pharmacokinetics of Gemcitabine, please 
see the Gemcitabine prescribing information (Appendix C).  
  
Gemcitabine (difluorodeoxycytidine) is a pyrimidine antimetabolite, which is an analogue of 
deoxycytidine. It was initially synthesized as a potential antiviral drug but selected for 
anticancer development because of its activity in in-vivo and in vitro tumors. Gemcitabine is 
approved for the treatment of patients with pancreatic cancer and will be obtained 
commercially. Gemcitabine is commercially supplied as a powder for reconstitution in 200 mg 
and 1 gm vials.  
  
Intact vials containing sterile powder are stored at room temperature (20° to 25°C) (68° to  
77°F). Gemcitabine solutions are stable for 24 hours at controlled room temperature of 20° to 
25°C (68° to 77°F). Do not refrigerate as crystallization can occur. The diluted solution 
should be clear and colorless to light straw-colored solution  
  
Preparation and Administration  
  
Reconstitute the 200 mg vial with 5 mL 0.9% NaCl and the 1 g vial with 25 mL 0.9%NaCl. 
The resulting solution is approximately 38 mg/mL, but the concentration varies. It is suggested 
that when the desired dose is less than the entire vial, the entire volume be drawn up into a 
syringe in order to determine the actual concentration. Then the desired amount should be 
measured and diluted in 0.9%NaCl for infusion. Reconstituted solution should be further 
diluted in 100 ml NS for intravenous infusion.  
  


 
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In this study, Gemcitabine may be administered on an outpatient basis. Gemcitabine should be 
administered by intravenous infusion weekly over approximately 10mg/m2/min which for 
400mg/m2 is 40 minutes or 500mg/m2 is 50 minutes. Infusion times are approximate and may 
need to be adjusted based on patient tolerability.  
  
Toxicities of Gemcitabine  
  
Please see the Gemcitabine prescribing information (Appendix C) for more details on the 
known precautions, warnings, and adverse reactions of Gemcitabine. Gemcitabine can 
suppress bone marrow function as manifested by leukopenia, thrombocytopenia and anemia, 
and myelosuppression is usually the dose-limiting toxicity. Subjects should be monitored for 
myelosuppression during therapy. Hemolytic-Uremic Syndrome (HUS) has been reported 
rarely with the use of Gemcitabine. Gemcitabine is a Pregnancy Category D drug. Gemcitabine 
can cause fetal harm when administered to a pregnant woman. Gemcitabine is embryotoxic 
causing fetal malformations (cleft palate, incomplete ossification) at doses of 1.5 mg/kg/day 
in mice (about 1/200 the recommended human dose on a mg/m2 basis). Gemcitabine is 
fetotoxic causing fetal malformations (fused pulmonary artery, absence of gall bladder) at 
doses of 0.1 mg/kg/day in rabbits (about 1/600 the recommended human dose on a mg/m2 
basis). Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, 
and developmental delays. There are no studies of Gemcitabine in pregnant women. If 
Gemcitabine is used during pregnancy, or if the subject becomes pregnant while taking 
Gemcitabine, the subject should be apprised of the potential hazard to the fetus.  
  
7.2 Taxotere (Docetaxel)  
  
Description, Formulation, and Storage  
  
For complete details on drug administration, storage, clinical pharmacology, and the human 
pharmacokinetics of Taxotere please see the Taxotere prescribing information (Appendix D).  
  
Taxotere is an antineoplastic agent of the taxoid family that acts by disrupting the microtubular 
network in cells essential for mitotic and interphase cellular functions. Docetaxel binds to free 
tubulin and promotes the assembly of tubulin into stable microtubules while simultaneously 
inhibiting their disassembly. This leads to the production of microtubule bundles without 
normal function and to the stabilization of microtubules, which results in the inhibition of 
mitosis in cells.   
  
Taxotere Injection Concentrate is a clear yellow to brownish-yellow viscous solution. Taxotere 
is sterile, non-pyrogenic, and is available in single-dose vials containing 20 mg (1 mL) or 80 
mg (4 mL) Taxotere (anhydrous). Each mL contains 20 mg Taxotere (anhydrous) in 0.54 grams 
polysorbate 80 and 0.395 grams dehydrated alcohol solution.  
  
Taxotere should be stored, reconstituted and administered according to the manufacturer’s 
recommendation.  
  


 
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Taxotere should be stored between 2 and 25°C (36-77°F) in a secure and dry place. Retain in 
the original package to protect from bright light. Freezing does not adversely affect the product.   
  
Preparation and Administration  
  
Preparation and administration of Taxotere should be per the Taxotere prescribing information 
(Appendix D).  
  
Taxotere may be administered on an outpatient basis. Taxotere should be administered by 
intravenous infusion weekly following the gemcitabine infusion.  
  
The Injection Concentrate is supplied in a single-dose vial as a sterile, pyrogen-free, 
nonaqueous, viscous solution with an accompanying sterile, nonpyrogenic, diluent (13% 
ethanol in Water for Injection) vial.  
  
Taxotere infusion solution, if stored between 2 and 25°C (35.6 and 77°F) is stable for 4 hours. 
Fully prepared Taxotere infusion solution (in either 0.9% Sodium Chloride solution or 5% 
Dextrose solution) should be used within 4 hours (including the administration).  
  
Directions for the preparation of Taxotere can be found in the Taxotere prescribing information 
(Appendix D).  
  
Taxotere is a cytotoxic anticancer drug and, as with other potentially toxic compounds, caution 
should be exercised when handling and preparing Taxotere solutions. The use of gloves is 
recommended.   
  
If Taxotere concentrate, initial diluted solution or final dilution for infusion should come into 
contact with the skin, immediately and thoroughly wash with soap and water.   
  
Toxicities of Taxotere  
  
Please see the Taxotere prescription information (Appendix C) for more details on the known 
precautions, warnings, and adverse reactions of Taxotere. The most common adverse reactions 
across all Taxotere indications are infections, neutropenia, anemia, febrile neutropenia, 
hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, 
nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, 
skin reactions, and myalgia. Fetal harm can occur when administered to a pregnant woman. 
Women of childbearing potential should be advised not to become pregnant when receiving 
Taxotere.  
  
7.3 Xeloda (Capecitabine)  
  
Description, Formulation, and Storage  
  


 
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For complete details on drug administration, storage, clinical pharmacology, and the human 
pharmacokinetics of Xeloda, please see the Xeloda prescribing information (Appendix E). 
Xeloda is a fluoropyrimidinecarbamate with antineoplastic activity. It is an orally administered 
systemic prodrug of 5’-deoxy-5-fluorouridine (5’-DFUR) which is converted to 5-fluorouracil. 
Normal cells, as well as tumor cells metabolize 5- Fluorouracil into 5-fluoro-2’-deoxyuridine 
monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). Both are metabolites that 
cause cell injury by two different mechanisms.  FdUMP and the folate factor, N5-
10methylenetetrahydrofolate, bind to thymidylate synthase (TS) to inhibit the formation of 
thymidylate. This deficiency of thymidylate causes cell cycle division to halt. This is because 
thymidalate is necessary for thymidine triphosphate production, which is essential for DNA 
synthesis. FUTP works by incorporating itself into transcription in place of uridine 
triphosphate therefore interfering with RNA transcription and protein synthesis.  
  
Xeloda is supplied as biconvex, oblong film-coated tablets for oral administration. Each light 
peach-colored tablet contains 150 mg xeloda and each peach-colored tablet contains 500 mg 
xeloda.   
  
Xeloda will be provided as an outpatient prescription. Xeloda should be stored at 25C (77F); 
excursions permitted to 15° to 30°C (59° to 86°F). Keep tightly closed.  
  
Dosing and Administration of Xeloda  
  
Xeloda will be administered on an outpatient basis. Xeloda will be given by oral administration 
twice daily. Xeloda tablets should be taken within 30 minutes after the end of a meal and 
swallowed with water.    
  
Toxicities of Xeloda  
  
Please see the Xeloda prescribing information (Appendix E) for more details on the known 
precautions, warnings, and adverse reactions of Xeloda. The most common side effects of 
Capecitabine are diarrhea, nausea, vomiting, stomatitis, abdominal pain, upset stomach, 
constipation, loss of appetite, dehydration, hand-and-foot syndrome (palms of the hands or 
soles of the feet tingle, become numb, painful, swollen or red), rash, dry, itchy or discolored 
skin, nail problems, hair loss, tiredness, weakness, dizziness, headache, fever, pain (including 
chest, back, joint, and muscle pain), trouble sleeping, and taste problems. Xeloda is a 
Pregnancy Category D drug. Women of childbearing potential should be advised to avoid 
becoming pregnant while receiving treatment with Xeloda. If Xeloda is used during pregnancy, 
or if the subject becomes pregnant while taking Xeloda, the subject should be apprised of the 
potential hazard to the fetus.  
  
7.4 Cisplatin  
  
Description, Formulation, and Storage  
  


 
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For complete details on drug administration, storage, clinical pharmacology, and the human 
pharmacokinetics of Cisplatin, please see the Cisplatin prescribing information (Appendix F).  
  
Cisplatin (cis-diamminedichloroplatinum) is a heavy metal complex containing a central atom 
of platinum surrounded by two chloride atoms and two ammonia molecules in the cis position. 
Cisplatin inhibits DNA synthesis by forming inter- and intra-strand crosslinks. Other possible 
mechanisms include chelation of DNA and binding to cell membranes thereby stimulating 
immune mechanisms.  
  
Cisplatin Injection is a sterile aqueous solution, available commercially in 50, 100 and 200 mL 
multiple dose vials, each mL containing 1 mg of cisplatin and 9 mg sodium chloride in water 
for injection. HCl and/or sodium hydroxide added to adjust pH to 3.5 to 4.5.  
  
Intact vials should be stored at room temperature and be protected from light. Solutions diluted 
in 0.9% or 0.45% NaCl to a concentration of 0.05-2mg/mL are stable for up to 72 hours at 
room temperature and protected from light.  
  
Preparation and Administration  
  
Unopened vials of dry powder are stable for the lot life indicated on the package when stored 
at room temperature (25° C, 77° F). The reconstituted solution is stable for 20 hours at room 
temperature (25° C, 77° F). Solution removed from the amber vial should be protected from 
light if it is not to be used within six hours. Once reconstituted, the solution should be kept at 
room temperature (25° C, 77° F). If the reconstituted solution is refrigerated a precipitate will form.  
  
Cisplatin may be administered on an outpatient basis. Cisplatin should be administered by 
intravenous infusion following the Taxotere infusion. Cisplatin should be administered in 250 
mL NaCl, following intravenous hydration with at least 500 ml of normal saline. 500ml of 
normal saline may also be administered after cisplatin.  Needles, syringes, catheters, or IV 
administration sets containing aluminum parts should not be used, as contact with cisplatin 
yields a black precipitate.  
  
Toxicities of Cisplatin  
  
Please see the Cisplatin prescribing information (Appendix F) for more details on the known 
precautions, warnings, and adverse reactions of Cisplatin. Common side effects include 
myelosuppression, nausea, vomiting, anorexia, elevation of BUN and creatinine, 
hyperuricemia, renal tubular damage, rare cardiac abnormalities, taste alteration, peripheral 
neuropathy, seizures, anaphylactoid and urticarial reactions (acute), rash, fatigue, otoxicity 
including hearing loss or tinnitus, and loss of muscle function. Cisplatin can cause fetal harm 
when administered to a pregnant woman. Cisplatin is mutagenic in bacteria and produces 
chromosome aberrations in animal cells in tissue culture. In mice, cisplatin is teratogenic and 
embryotoxic. If this drug is used during pregnancy or if the subject becomes pregnant while 
taking this drug, the subject should be apprised of the potential hazard to the fetus. Subjects 
should be advised to avoid becoming pregnant.  


 
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7.5 Irinotecan  
  
Description, Formulation, and Storage  
  
For complete details on drug administration, storage, clinical pharmacology, and the human 
pharmacokinetics of Irinotecan, please see the Cisplatin prescribing information (Appendix 
G).  
  
Irinotecan is a derivative of camptothecin. Camptothecins interact specifically with the enzyme 
topoisomerase I, which relieves torsional strain in DNA by inducing reversible single-strand 
breaks. Irinotecan and its active metabolite SN-38 bind to the topoisomerase IDNA complex 
and prevent religation of these single-strand breaks. Current research suggests that the 
cytotoxicity of irinotecan is due to double-strand DNA damage produced during DNA 
synthesis when replication enzymes interact with the ternary complex formed by 
topoisomerase I, DNA, and either irinotecan or SN-38. Mammalian cells cannot efficiently 
repair these double-strand breaks.  
  
Irinotecan is a sterile, pale yellow, clear, aqueous solution. It is available in three single-dose 
sizes in brown glass vials: 2 mL-fill vials contain 40 mg irinotecan hydrochloride, 5 mL-fill 
vials contain 100 mg irinotecan hydrochloride, and 15 mL-fill vials contain 300 mg irinotecan 
hydrochloride. Each milliliter of solution contains 20 mg of irinotecan hydrochloride (on the 
basis of the trihydrate salt), 45 mg of sorbitol, NF, and 0.9 mg of lactic acid, USP. The pH of 
the solution has been adjusted to 3.5 (range, 3.0 to 3.8) with sodium hydroxide or hydrochloric 
acid.  
  
Store at controlled room temperature 15° to 30°C (59° to 86°F). Protect from light. It is 
recommended that the vial should remain in the carton until the time of use.   
  
Preparation and Administration  
  
Dilute irinotecan with 5% Dextrose Injection, USP (D5W), or 0.9% Sodium Chloride 
Injection, USP, prior to intravenous infusion. The solution is physically and chemically stable 
for up to 24 hours at room temperature and in ambient fluorescent lighting. Solutions diluted 
in 5% dextrose Injection, USP, and stored at refrigerated temperatures (approximately 2° to 
8°C, 36° to 46°F), and protected from light are physically and chemically stable for 48 hours. 
Refrigeration of admixtures using 0.9% Sodium Chloride Injection, USP, is not recommended 
due to a low and sporadic incidence of visible particulates. Freezing irinotecan and admixtures 
of irinotecan may result in precipitation of the drug and should be avoided.  
  
The irinotecan injection solution should be used immediately after reconstitution as it contains 
no antibacterial preservative. Irinotecan may be administered on an outpatient basis and should 
be administered by intravenous infusion following the Cisplatin infusion.  
  


 
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Toxicities of Irinotecan  
  
Please see the Irinotecan prescribing information (Appendix G) for more details on the known 
precautions, warnings, and adverse reactions of Irinotecan. Common adverse reactions (≥30%) 
observed in combination therapy clinical studies are: nausea, vomiting, abdominal pain, 
diarrhea, 
constipation, 
anorexia, 
mucositis, 
neutropenia, 
leukopenia 
(including 
lymphocytopenia), anemia, thrombocytopenia, asthenia, pain, fever, infection, abnormal 
bilirubin, alopecia. Common adverse reactions (≥30%) observed in single agent therapy 
clinical studies are: nausea, vomiting, abdominal pain, diarrhea, constipation, anorexia, 
neutropenia, leukopenia (including lymphocytopenia), anemia, asthenia, fever, body weight 
decreasing, alopecia.   
  
8. CORRELATIVE/SPECIAL STUDIES  
  
 
8.1   
Plasma Marker Studies  
  
To assess tumor burden dynamics over the course of this study we will collect plasma at 
baseline, every 3 cycles thereafter, and at the off study evaluation.  Whole blood will be 
collected in two 10 milliliter plasma preparation tubes with EDTA (PPT, BD Vacutainer, 
Franklin Lakes, NJ) at the designated time points and processed using standard laboratory 
procedures within one hour of collection.  Using a pipette, plasma will be transferred to 
sterile 15 mL conical tube and stored at -80oC.    
  
Stored samples will be used to measure circulating tumor DNA14.  
  
 
8.2  
Whole Blood Studies  
  
To assess the baseline characteristic of the subjects enrolled and to correlate these 
molecular and clinicopathologic criteria with treatment response and toxicity, whole blood 
will be collected in a 10 milliliter plasma preparation tube with EDTA (PPT, BD 
Vacutainer, Franklin Lakes, NJ).   Within two hours of collection, aliquots of 1 mL of 
whole blood will be transferred into 2 mL tubes and stored at -80oC.  This will be collected 
at baseline only.  
  
DNA may be extracted from whole blood and used to evaluate for any germline mutations 
that may correlate with response or toxicity.  These may include, but are not limited to 
FANC GENES, PALB2, BRCA1 and BRCA2.  In addition, a SNP array may be performed 
on each case using the Affymetrix Genome-wide Human SNP Array 6.0 (Santa Clara, CA).  
  
 
8.3  
Tumor Tissue Studies  
  
Tumor tissue specific somatic genetic changes and aberrations in protein expression may 
be explored in archived tumor tissue obtained prior to treatment on this protocol if blocks 
or slides are readily available.     


 
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9. STUDY CALENDAR  
  
Baseline evaluations are to be conducted within 28 days prior to start of protocol therapy.  
Scans and x-rays must be done < 14 days prior to the start of therapy.  In the event that the 
subject’s condition is deteriorating, laboratory evaluations should be repeated within 48 hours 
prior to initiation of the next cycle of therapy. If a patient starts xeloda on days 1-3 and becomes 
ineligible for the intravenous chemotherapy, then this course would not be considered a cycle.    
  
  
  
  
Cycle (21 Days)  
Off  
  
Pre- 
Study  
(baseline)  
Days 
1-3  
Day 4 Days 
5-6  
Days 
7-10  
Day 
11  
Days 
12-14  
Days 
15-21 
Study  
Visit Windows (days)1  
-28 to 0  
+/- 3  
-3 to 
+14  
  
  
+/- 3  
  
  
+/- 28  
Gemcitabine  
  
  
A  
  
  
A  
  
  
  
Taxotere  
  
  
B  
  
  
B  
  
  
  
Xeloda  
  
C  
 
  
  
Cisplatin  
  
  
D  
  
  
D  
  
  
  
Irinotecan  
  
  
E  
  
  
E  
  
  
  
Informed consent  
X  
  
  
  
  
  
  
  
  
Demographics  
(ethnicity and religion)2  
X  
  
  
  
  
  
  
  
  
Medical history  
X  
  
  
  
  
  
  
  
  
Family history of 
cancer  
X  
  
  
  
  
  
  
  
  
Concurrent meds  
X  
  
X  
  
  
X  
  
  
X  
Physical exam  
X  
  
X  
  
  
  
  
  
X  
Vital signs3  
X  
  
X  
  
  
X  
  
  
X  
Height4  
X  
  
  
  
  
  
  
  
  
Weight  
X  
  
X  
  
  
X  
  
  
X  
Performance status  
X  
  
X  
  
  
  
  
  
X  
Quality of life survey  
X  
  
X  
  
  
  
  
  
X  
CBC w/diff, plts5  
X  
  
X7  
  
  
X7  
  
  
X  
Serum chemistry5,6  
X  
  
X7  
  
  
X7  
  
  
X  


 
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CA19-9/CEA  
X  
  
X7  
  
  
  
  
  
X  
  
  
  
Cycle (21 Days)  
Off  
  
Pre- 
Study  
(baseline)  
Days 
1-3  Day 4 
Days 
5-6  
Days 
7-10  Day 11 Days 
12-14  
Days 
15-21 
Study  
AE evaluation  
  
  
X  
  
  
X  
  
  
X  
Radiologic evaluation/  
RECIST8  
X  
  
X  
  
  
  
  
  
X  
B-HCG9  
X  
  
  
  
  
  
  
  
  
Plasma Sample10  
X  
  
X  
  
  
  
  
  
X  
Whole Blood Sample11  
X  
  
  
  
  
  
  
  
  
Archived Tumor  
Sample12  
X  
  
  
A: Gemcitabine:  Dose as assigned; administration schedule B: 
Taxotere:  Dose as assigned; administration schedule  
C:  Xeloda:  Dose as assigned; administration schedule  
D:  Cisplatin:  Dose as assigned; administration schedule  
E: Irinotecan: Dose as assigned; administration schedule  
  
1:   Longer delays to be approved by the Principal Investigator.  
2: Specifically, Ashkenazi Jewish decent  
3: Temperature, blood pressure, respiration rate, heart rate.   
4:  Height collected prior to study entry may be used.  
5: Repeat labs within 7 days to follow and document the resolution of a limiting toxicity (Section 
4.3)  
6: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, 
creatinine, glucose, phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], 
sodium, magnesium.  
7: Three day window  
8: CT scan (chest/abdomen/pelvis) or MRI (if patient has contrast allergy); to be assessed at 
baseline (baseline scan must be within 14 days of the first dose) and every three cycles. CT 
scans may be done within 3 weeks prior to or after on study scheduled visit. If a scan is 
performed early for clinical reasons, the investigator can re-start the 3 cycle count as to not 
overuse imaging.  
9: Urine pregnancy test (women of childbearing potential).  
10: Plasma collection (approximately 20 cc) will occur at baseline, every 3 cycles thereafter, and 
at the off study evaluation.  
11: Whole blood collection (approximately 10 cc) will occur at baseline only.  


 
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12: Attempts to obtain archival tumor samples will be made for every patient until the sample is 
obtained or documentation that the sample cannot be obtained.   
  
  
10. MEASUREMENT OF EFFECT  
  
Although response is not the primary endpoint of this trial, patients with measurable disease 
will be assessed by standard criteria. For the purposes of this study, patients should be 
reevaluated every 3 cycles.   
  
 
10.1  Antitumor Effect – Solid Tumors  
  
For the purposes of this study, patients should be re-evaluated for response every 8   
weeks. Response and progression will be evaluated in this study using the new 
international criteria proposed by the revised Response Evaluation Criteria in Solid 
Tumors (RECIST) guideline (version 1.1)15.  Changes in the largest diameter 
(unidimensional measurement) of the tumor lesions and the shortest diameter in the 
case of malignant lymph nodes are used in the RECIST criteria.  
  
10.1.1 Definitions  
  
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of 
their first treatment with GTX-CI.  
  
Evaluable for objective response.  Only those patients who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their 
disease re-evaluated will be considered evaluable for response.  These patients will 
have their response classified according to the definitions stated below.  (Note:  
Patients who exhibit objective disease progression prior to the end of cycle 1 will 
also be considered evaluable.)  
  
Evaluable Non-Target Disease Response.  Patients who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease, 
have received at least one cycle of therapy, and have had their disease re-evaluated 
will be considered evaluable for non-target disease.  The response assessment is 
based on the presence, absence, or unequivocal progression of the lesions.   
  
10.1.2 Disease Parameters  
  
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm 
by chest x-ray, as >10 mm with CT scan, or >10 mm with calipers by clinical exam.  
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters).  
  


 
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Note:  Tumor lesions that are situated in a previously irradiated area might or might 
not be considered measurable.  If the investigator thinks it appropriate to include 
them, the conditions under which such lesions should be considered must be defined 
in the protocol.  
  
Malignant lymph nodes.  To be considered pathologically enlarged and measurable,  
a lymph node must be >15 mm in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm).  At baseline and in 
follow-up, only the short axis will be measured and followed.  
  
 
mm short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed 
by CT or MRI), are considered as non-measurable.  
  
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor 
nonmeasurable) since they are, by definition, simple cysts.  
  
‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions.  
  
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 
5 lesions in total, representative of all involved organs, should be identified as 
target lesions and recorded and measured at baseline.  Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion which can be measured reproducibly 
should be selected.  A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters.  If lymph nodes are to be included in the sum, then only 
the short axis is added into the sum.  The baseline sum diameters will be used as 
reference to further characterize any objective tumor regression in the measurable 
dimension of the disease.  
  
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target 
lesions and should also be recorded at baseline.  Measurements of these lesions are 


 
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not required, but the presence, absence, or in rare cases unequivocal progression of 
each should be noted throughout follow-up.   
  
10.1.3 Methods for Evaluation of Measurable Disease  
  
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment.  
  
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination unless 
the lesion(s) being followed cannot be imaged but are assessable by clinical exam.  
  
Clinical lesions  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the 
lesion, is recommended.   
  
Conventional CT and MRI  This guideline has defined measurability of lesions on 
CT scan based on the assumption that CT slice thickness is 5 mm or less.  If CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable 
lesion should be twice the slice thickness.  MRI is also acceptable in certain 
situations (e.g. for body scans).    
  
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and 
temporal resolution; however, there are many image acquisition variables involved 
in MRI, which greatly impact image quality, lesion conspicuity, and measurement.  
Furthermore, the availability of MRI is variable globally.  As with CT, if an MRI 
is performed, the technical specifications of the scanning sequences used should be 
optimized for the evaluation of the type and site of disease.  Furthermore, as with 
CT, the modality used at follow-up should be the same as was used at baseline and 
the lesions should be measured/assessed on the same pulse sequence.  It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence 
parameters for all scanners, body parts, and diseases.  Ideally, the same type of 
scanner should be used and the image acquisition protocol should be followed as 
closely as possible to prior scans.  Body scans should be performed with breathhold 
scanning techniques, if possible.  
  
Tumor markers  Tumor markers alone cannot be used to assess response.  If markers 
are initially above the upper normal limit, they must normalize for a patient to be 
considered in complete clinical response.  Specific guidelines for both CA-125 
response (in recurrent ovarian cancer) and PSA response (in recurrent prostate 


 
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cancer) have been published [JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 
1999; J Clin Oncol 26:1148-1159, 2008].  In addition, the Gynecologic Cancer 
Intergroup has developed CA-125 progression criteria which are to be integrated 
with objective tumor assessment for use in first-line trials in ovarian cancer [JNCI 
92:1534-1535, 2000].  
  
10.1.4 Response Criteria  
  
 
10.1.4.1  Evaluation of Target Lesions  
  
 
Complete Response (CR):  
Disappearance of all target lesions.  Any  
pathological lymph nodes (whether target or 
non-target) must have reduction in short axis 
to <10 mm.  
 
Partial Response (PR):  
 
At least a 30% decrease in the sum of the 
diameters of target lesions, taking as 
reference the baseline sum diameters.  
Progressive Disease (PD):  
 
At least a 20% increase in the sum of the 
diameters of target lesions, taking as 
reference the smallest sum on study (this 
includes the baseline sum if that is the 
smallest on study).  In addition to the relative 
increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 
mm.  (Note:  the appearance of one or more 
new lesions is also considered progressions).  
Stable Disease (SD):  
Neither sufficient shrinkage to qualify for PR 
nor sufficient increase to qualify for PD, 
taking as reference the smallest sum 
diameters while on study.  
  
 
10.1.4.2  Evaluation of Non-Target Lesions  
  


 
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Complete Response (CR):  
 
 
Disappearance of all non-target lesions and 
normalization of tumor marker level.  All 
lymph nodes must be non-pathological in 
size (<10 mm short axis).  
Note:  If tumor markers are initially above the 
upper normal limit, they must normalize for 
a patient to be considered in complete clinical 
response.  
  
Non-CR/Non-PD:   
 
Persistence of one or more non-target 
lesion(s) and/or maintenance of tumor 
marker level above the normal limits.  
Progressive Disease (PD):  
Appearance of one or more new lesions  
and/or unequivocal progression of existing 
non-target lesions.  Unequivocal progression 
should not normally trump target lesion 
status.  It must be representative of overall 
disease status change, not a single lesion 
increase.      
Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and 
the progression status should be confirmed at a later time by the review 
panel (or Principal Investigator).  
  
 
10.1.4.3  Evaluation of Best Overall Response  
  
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the treatment 
started).  The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria.  
     
For Patients with Measurable Disease (i.e., Target Disease)  
  
Target  
Lesions  
Non-Target  
Lesions  
New  
Lesions  
Overall  
Response 
Best Overall Response 
when Confirmation is 
Required*  
CR  
CR  
No  
CR  
>4 wks.  
Confirmation**  
CR  
Non-CR/Non-PD  
No  
PR  
>4 wks.  


 
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CR  
Not evaluated  
No  
PR  
Confirmation**  
PR  
Non-CR/Non- 
PD/not evaluated  
No  
PR  
SD  
Non-CR/Non- 
PD/not evaluated  
No  
SD  
Documented at least 
once >4 wks. from 
baseline**  
PD  
Any  
Yes 
No  
or  PD  
no prior SD, PR or CR  
Any  
PD***  
Yes 
No  
or  PD  
Any  
Any  
Yes  
PD  
*  
See RECIST 1.1 manuscript for further details on what is evidence of a 
new lesion.  
**  
Only for non-randomized trials with response as primary endpoint.  
*** In exceptional circumstances, unequivocal progression in non-target lesions 
may be accepted as disease progression.  
  
Note: Patients with a global deterioration of health status requiring discontinuation 
of treatment without objective evidence of disease progression at that time 
should be reported as “symptomatic deterioration.” Every effort should be 
made to document the objective progression even after discontinuation of 
treatment.  
  
  
For Patients with Non-Measurable Disease (i.e., Non-Target Disease)  
  
Non-Target Lesions  
New Lesions  
Overall Response  
CR  
No  
CR  
Non-CR/non-PD  
No  
Non-CR/non-PD*  
Not all evaluated  
No  
not evaluated  
Unequivocal PD  
Yes or No  
PD  
Any  
Yes  
PD  
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease 
since SD is increasingly used as an endpoint for assessment of efficacy in some 
trials so to assign this category when no lesions can be measured is not advised 
  
10.1.5 Duration of Response  
  


 
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Duration of overall response:  The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded 
since the treatment started).  
  
The duration of overall CR is measured from the time measurement criteria are first 
met for CR until the first date that progressive disease is objectively documented.   
  
Duration of stable disease:  Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started, including the baseline 
measurements.   
  
10.1.6 Progression-Free Survival (PFS)   
  
PFS is defined as the duration of time from start of treatment to time of first 
documented progression or death, whichever occurs first.  
  
 
  
10.1.7 Overall Survival (OS)  
  
  
  
OS is defined as the duration of time from start of treatment to time of death.  
  
  
 
11.   
DATA REPORTING / REGULATORY REQUIREMENTS  
  
 
11.1  Data Management  
  
All information will be collected on study-specific case report forms (CRFs) by study staff. 
These data will be reviewed for completeness and accuracy by the Principal Investigator.   
  
 
11.2  Safety Meetings  
  
Scheduled meetings will take place weekly and will include the protocol principal 
investigator, study coordinator(s), data manager(s), sub-investigators (as appropriate), 
collaborators (as appropriate), and biostatisticians (as appropriate) involved with the 
conduct of the protocol. During these meetings matters related to the following will be 
discussed: safety of protocol participants, validity and integrity of the data, enrollment 
rate relative to expectation, characteristics of participants, retention of participants, 
adherence to protocol (potential or real protocol violations), data completeness, and 
progress of data for objectives.  
  
 
11.3   Monitoring  
  


 
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Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 
7.0 (Adverse Events: List and Reporting Requirements).  
  
This is a DSMP Level I study under the SKCCC Data Safety Monitoring Plan (12/6/2012).  
The Clinical Research Office QA Group will perform an audit after the first subject has 
been treated and then periodically depending on the rate of accrual and prior audit results.  
All trial monitoring and reporting will be reviewed annually by the SKCCC Safety 
Monitoring Committee.  
  
The PI is responsible for monitoring the study.  Data must be reviewed to assure the validity 
of data, as well as, the safety of the subjects.  The PI will also monitor the progress of the 
trial, review safety reports, and clinical trial efficacy endpoints, and confirm that the safety 
outcomes favor continuation of the study.  
  
12. STATISTICAL CONSIDERATIONS  
  
 
12.1  Study Design/Endpoints  
  
  
The phase I portion will evaluate up to 3 dose levels of the regimen to determine the MTD. 
The dose escalation will commence in a standard 3+3 design. The MTD will be defined as 
the dose level in which < 2 of 6 patients experiences a dose limiting toxicity (DLT) with 
the next higher dose having at least 2 of 3 or 2 of up to 6 patients experiencing a DLT. A 
total of 6 – 30 patients will be enrolled, and the actual number will vary depending on the 
number of DLTs.  
  
The phase II portion will evaluate the efficacy of the regimen.  The PI has discretion on 
selection of the dose level for expansion based on considerations of general tolerability and 
efficacy if the dose level is deemed safe.  The primary endpoint will be the OS rate at 9 
months, which is defined as the proportion of subjects alive at 9 months.  The treatment 
regimen would be considered of insufficient activity for further study in these population 
if OS rate at 9 months is 57% or less, and the minimum required level of efficacy that 
would warrant further study with the proposed regimen is a 80% OS rate at 9 months.   
  
Six to 30 subjects will be enrolled in the dose escalation phase.  Up to an additional 24 
subjects will be enrolled at the recommended dose from phase I.  The 6 subjects treated at 
that dose during the dose escalation phase will be counted toward the total sample size of 
30 subjects.  Subjects will be replaced if they do not receive any study treatment.  Subjects 
will be considered efficacy evaluable if they received any study treatment. Subjects whose 
death is unequivocally accidental and unrelated to cancer or its treatment may also be 
replaced. A two-stage design based on Green and Dahlberg method will be used to enable 
early stopping for futility if sufficient clinical activity is not demonstrated.  Enrollment will 
continue while we wait for the interim data to mature.  The decision rule of the design is 
the following:  
1. A total of 15 patients will be entered in the first stage.   


 
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• If 8 or fewer subjects are alive 9 months after the initiation of the treatment 
(i.e. 7 or more die in 9 months), the treatment regimen will be terminated 
and we will conclude the regimen is ineffective.   
• If ≥9 subjects are alive, then   
2. An additional 15 patients will be enrolled.    
• 
If a total of 21 or fewer subjects survive past 9 months in stage one and two 
combined (i.e. 9 or more deaths in 9 months), we consider this regimen 
ineffective.   
• 
If a total of 22 or more is alive, we conclude the regimen is promising and 
warrant further study. The maximum sample size of the phase II portion will be 
30.   
  
The study could be terminated also as soon as we observe 22 patients to be alive at 9 months 
to indicate sufficient efficacy.  
  
This design provides 90% power to detect an absolute increase of 23% points in 9-months 
OS rate with a type I error of 0.1. The probability of early termination is 49% if the null 
hypothesis of 57% survival rate is true.  
  
Safety monitoring  
The study will be continuously monitored for adverse events after the dose escalation 
phase. If the limiting toxicity events appear to be higher than 33%, we will temporarily halt 
the study pending dose modification. Specifically, we will apply a Bayesian toxicity 
monitoring rule that suspends the enrollment if the posterior probability of risk being larger 
than 0.33 is 70% or higher. The monitoring rule uses beta (1.5, 5.5) as prior distribution. 
This means that our prior guess at the proportion of toxicity is 21%, and there is 90% 
probability that this proportion is between 3% and 49%.  Starting from the 7th patient in the 
phase II portion, the decision rule for safety stopping is as follows:  
  
Stop if:  
# of 
patients 
with AE  
3  
4  
5  
6  
7  
8  
9  
10  
 
11  
Out of   
3  
4  
7  
10  
13  
15  
18  
21  
24  
  
 
5  
8  
11  
14  
16  
19  
22  
 
  
 
6  
9  
12  
 
17  
20  
23  
 
  
For example, starting with the 7th patients, if three out of the next 3 patients have limiting 
toxicity events, we will stop the accrual. If four or more out of the first 4-6 patients have 
limiting toxicity events, we will stop.   
  
The operating characteristics of the stopping rule are shown below and are based on 5000 
simulations:  


 
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True AE rate  
% simulated trials 
declaring unsafe  
Average sample size 
(out of 24)  
0.2  
4.6  
23.3  
0.25  
12.4  
22.3  
0.3  
22.3  
20.9  
0.35  
40.0  
18.8  
0.4  
56.8  
16.6  
0.45  
75.1  
13.9  
  
Data analysis   
The primary objective is to evaluate the efficacy of the combination drugs of GTX with 
cisplatin and irinotecan in metastatic pancreatic cancer patients.  OS rate at 9 months is 
used as a primary outcome of efficacy. It is estimated as the proportion of patients alive at 
9 months after the initiation of the treatment with corresponding 95% confidence interval 
(CI).    
  
The secondary outcomes include toxicity, RR, PFS, and OS. We will characterize toxicity 
as percentage by grade.  DCR is defined as percentage of patients who achieved complete 
response (CR), partial response (PR), or stable disease (SD) among all evaluable patients. 
95% CIs will be computed.  PFS is defined as the time from the date of initial dose to the 
date of disease progression or to death due to any cause, whichever occurs first. PFS will 
be censored on the date of the last evaluable tumor assessment documenting absence of 
progressive disease for patients who are alive and progression free. OS is defined as the 
time from the date of initial dose to death due to any cause. For patients who still alive at 
the time of analysis, the OS time will be censored on the last date the patients are known 
to be alive.  PFS and OS will be summarized by the Kaplan-Meier method.   
  
As exploratory analysis, the correlations between baseline characteristics of subjects and 
treatment response and toxicity will be examined using two-sample t-tests or fisher exact 
test depending on the variable type. To evaluate the correlations between tumor tissue 
specific somatic mutations and treatment response and toxicity, fisher exact test will be 
performed. In addition, regression analysis will be used to include other covariates. P-value 
less than 0.05 will be considered as statistically significant. We will not adjust for 
multiplicity in the hypothesis testing for these exploratory analyses.  
  
Quality of Life will be assessed via EORTC QLQ-C30 (v3.0) questionnaires. For our study 
population of pancreatic cancer patients, the analysis will be focused on Global Health 
Status/QoL scale, symptom scale (fatigue, pain), and functional scale (physical 
functioning, role functioning, emotional functioning). For each module, summary statistics 
of the scores will be reported at baseline and each follow-up time. Changes in quality of 
life scores pre- and post- treatment will be computed, and their significance will be 
evaluated by paired-sample t-tests. In addition, mixture effect models will be fitted for 
accessing the quality of life changes over time. Frequency of patients who reach minimal 


 
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clinically important difference of 10-points change from baseline will be tabulated by time. 
Time to definitive deterioration in quality of life will be analyzed using Kaplan-Meier 
method. Other modules will be examined as an exploratory manner.  
  
Although a comparison of quality of life data to completed combination chemotherapy 
research outcomes may not be statistically appropriate, the data will offer exploratory 
information to establish the tolerability of this new treatment regimen, and its effect on 
quality of life.  
  
 
12.2  Reporting and Exclusions  
  
12.2.1 Evaluation of toxicity – All patients will be evaluable for toxicity from the time 
of their first treatment with GTX-CI.  
  
12.2.2 Evaluation of response – All patients who start treatment 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 unless accidental, or 8) unknown (not 
assessable, insufficient data).    
  
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 4-8 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 and treated 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.   
REFERENCES  
  
1. 
American Cancer Society. Cancer Facts & Figures 2013. In. Atlanta: American Cancer 
Society: American Cancer Society; 2013.  
2. 
Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic 
pancreatic cancer. The New England journal of medicine 2011;364:1817-25.  


 
J14161, Version 8.0, April 17, 2019   
39 
  
3. 
Fine RL, Fogelman DR, Schreibman SM, et al. The gemcitabine, docetaxel, and 
capecitabine (GTX) regimen for metastatic pancreatic cancer: a retrospective analysis. Cancer 
chemotherapy and pharmacology 2008;61:167-75.  
4. 
Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: the impact of eliminating 
socioeconomic and racial disparities on premature cancer deaths. CA: a cancer journal for 
clinicians 2011;61:212-36.  
5. 
Burris HA, 3rd, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit 
with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized 
trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 
1997;15:2403-13.  
6. 
Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with 
gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National 
Cancer Institute of Canada Clinical Trials Group. Journal of clinical oncology : official journal of 
the American Society of Clinical Oncology 2007;25:1960-6.  
7. 
Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with 
nabpaclitaxel plus gemcitabine. The New England journal of medicine 2013;369:1691-703.  
8. 
De Jesus-Acosta A, Oliver GR, Blackford A, et al. A multicenter analysis of GTX 
chemotherapy in patients with locally advanced and metastatic pancreatic adenocarcinoma. Cancer 
chemotherapy and pharmacology 2012;69:415-24.  
9. 
Diaz LA, Jr., Williams RT, Wu J, et al. The molecular evolution of acquired resistance to 
targeted EGFR blockade in colorectal cancers. Nature 2012;486:537-40.  
10. 
Bozic I, Reiter JG, Allen B, et al. Evolutionary dynamics of cancer in response to targeted 
combination therapy. eLife 2013;2:e00747.  
11. 
Brand R, Capadano M, Tempero M. A phase I trial of weekly gemcitabine administered as 
a prolonged infusion in patients with pancreatic cancer and other solid tumors. Investigational new 
drugs 1997;15:331-41.  
12. 
Tempero M, Plunkett W, Ruiz Van Haperen V, et al. Randomized phase II comparison of 
dose-intense gemcitabine: thirty-minute infusion and fixed dose rate infusion in patients with 
pancreatic adenocarcinoma. Journal of clinical oncology : official journal of the American Society 
of Clinical Oncology 2003;21:3402-8.  
13. 
Le DT, Laheru, DA, Purtell, K, Uram, JN, Wang, H, Lawrence, S, Parkinson, R, Foreman, 
E, Savage, DT, David, JJ, Donehower, RC, Rasheed, Z, Zheng, L, Azad, NS, Cosgrove, D, De 
Jesus-Acosta, A, Browner, I, Diaz, LA. A phase 2 trial of low-dose multiagent chemotherapy with 
gemcitabine, docetaxel, capecitabine, and cisplatin (GTX-C) in subjects with metastatic pancreatic 
cancer. J Clon Oncol 2014;32;5s (suppl; abstr 4135).  
14. 
Wang Q, Chaerkady R, Wu J, et al. Mutant proteins as cancer-specific biomarkers. 
Proceedings of the National Academy of Sciences of the United States of America 2011;108:2444- 
9.  
15. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47.  
  
  
APPENDIX A: Performance Status Criteria  
  


 
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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 
selfcare, 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 
selfcare.  Totally confined to bed or 
chair.  
20  
Very sick, hospitalization indicated. 
Death not imminent.  
10  
Moribund,  
fatal  processes 
progressing rapidly.  
5  
Dead.  
0  
Dead.  
  
  
  
  
  
  
  
  
  
  
  
  


 
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APPENDIX B: SAE Reporting Form  
  
  
  
 


 
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Serious Adverse Event Reporting Form   
  
  
  
  
 


 
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Relationship to:  
Gemcitabine  Taxotere Xeloda  Cisplatin  Irinotecan  Underlying  
Disease  
Unrelated  
  
  
 
  
  
  
Probably Unrelated  
  
  
 
  
  
  
Possible Related  
  
  
 
  
  
  
Probably Related  
  
  
 
  
  
  
Definitely Related  
  
  
 
  
  
  
Section C: Brief Description of the Event:  
  
Section D: Relevant Medical History  
  
Section E: Concomitant Drug (Not related to SAE)  
Name of the Drug  
Start Date 
Stop Date 
Route  
Dose 
Frequ 
ency 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  


 
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Section F: Comments  
  
Additional Documents:  
 Please specify  
  
  
  
  
  
  
  
APPENDIX C: Gemcitabine Prescribing Information  
  
 


 
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APPENDIX D: Taxotere Prescribing Information  
  
 


 
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APPENDIX E: Xeloda Prescribing Information  
  
 


 
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APPENDIX F: Cisplatin Prescribing Information  
  
  
  
 


 
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APPENDIX G: Irinotecan Prescribing Information   
 


 
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 APPENDIX H: EORTC QLQ-C30 (version 3)  
  
  
  
 


 
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EORTC QLQ-C30 (version 3)  
  
We are interested in some things about you and your health. Please answer all of the questions yourself by 
circling the number that best applies to you. There are no "right" or "wrong" answers. The information that you 
provide will remain strictly confidential.  
  
Please fill in your initials:  
Your birthdate (Day, Month, Year):   
Today's date (Day, Month, Year):   
_________________________________________________________________________________________  
 
  
  
  
  
  
  
  
  
Not at     A     
Quite        Very  
 
All   
Little     a Bit        Much  
1. Do you have any trouble doing strenuous activities, like carrying a heavy shopping bag or a suitcase?                            
1  
    2   
    3               4      
  
2. Do you have any trouble taking a long walk?                                                  1              2            3              4  
  
3. Do you have any trouble taking a short walk outside of the house?                1              2            3              4  
  
4. Do you need to stay in bed or a chair during the day?                                      1             2            3              4  
  
5. Do you need help with eating, dressing, washing  
yourself or using the toilet?                                                                                  1             2              3             4  
  
 
During the past week:   
  
  
  
  
  
Not at     A     
Quite        Very  
 
All   
Little     a Bit        Much  
  
6. Were you limited in doing either your work or other daily activities?            1              2             3             4  
  
7. Were you limited in pursuing your hobbies or other  
leisure time activities?                                                                                          1              2             3               4  
  
8. Were you short of breath?                                                                                 1             2              3              4   
9. Have you had pain?                                                                                           1             2              3              4   
10. Did you need to rest?                                                                                       1             2             3              4   
11. Have you had trouble sleeping?                                                                       1             2             3              4   
12. Have you felt weak?                                                                                        1              2             3             4   
13. Have you lacked appetite?                                                                               1              2             3             4  
  
14. Have you felt nauseated?                                                                                 1              2             3             4   
15. Have you vomited?                                                                                          1              2             3             4   
16. Have you been constipated?                                                                            1              2             3              4  
  
Please go on to the next page  
  
 
During the past week:   
  
  
  
  
  
Not at     A     
Quite        Very  
 
All   
Little     a Bit        Much  


 
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17. Have you had diarrhea?                                                                                    1              2             3             4   
18. Were you tired?   
  
  
  
  
  
  
     1              2             3             4       
  
19. Did pain interfere with your daily activities?     
                                 1              2             3             4  
  
20. Have you had difficulty in concentrating on things,  
like reading a newspaper or watching television?                                                  1              2             3             4  
  
21. Did you feel tense?                                                                                            1              2             3             4   
22. Did you worry?     
  
  
  
  
  
  
      1              2             3             4  
  
23. Did you feel irritable?   
  
  
  
  
                    1              2             3             4  
  
24. Did you feel depressed?   
  
  
  
                                  1              2             3             4  
  
25. Have you had difficulty remembering things?             
  
  
       1              2             3            4  
  
26. Has your physical condition or medical treatment  
interfered with your family life?                                                                              1              2             3             4  
  
27. Has your physical condition or medical treatment  
 
interfered with your social activities?   
                                                             1              2             3             4  
  
28. Has your physical condition or medical treatment  
caused you financial difficulties?                                                                              1              2             3            4   
For the following questions please circle the number between 1 and 7 that best 
applies to you  
  
29. How would you rate your overall health during the past week?              
  
1 
2  
 3  
 4  
 5  
 6  
 7  
  
 
Very poor   
  
  
  
  
  
Excellent  
  
  
30. How would you rate your overall quality of life during the past week?  
  
1 
2  
 3  
 4  
 5  
 6  
 7  
  
 
Very poor   
  
  
  
  
  
Excellent  
  
  
  
  
  
© Copyright 1995 EORTC Quality of Life Group. All rights reserved. Version 3.  


 
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