A Multi-institutional Open Label, Trial Evaluating the Efficacy of Gemcitabine and Docetaxel in Patients With Relapsed or Refractory Metastatic Colorectal Adenocarcinoma With Methylated CHFR and/or Microsatellite Instability Phenotype
Phase: PHASE2
Conditions: Metastatic Colorectal Adenocarcinoma
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Cover Page for Protocol – J1214 
NCT Number: 
NCT01639131 
Official title of study 
A multi-institutional open label, trial evaluating 
the efficacy of Gemcitabine and 
Docetaxel in patients with relapsed or refractory 
metastatic colorectal adenocarcinoma 
with methylated CHFR and/or microsatellite 
instability phenotype 
Document Date: 
November 19, 2015 

 
 
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OMB No. 0925-0001 
 
eIRB# NA_00069666  / Local Protocol #: J1214 
 
TITLE:  A multi-institutional open label, trial evaluating the efficacy of Gemcitabine and 
Docetaxel in patients with relapsed or refractory metastatic colorectal adenocarcinoma 
with methylated CHFR and/or microsatellite instability phenotype 
 
 
*Study-wide Principal Investigator: 
Nilofer Azad 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Statistician: 
Marianna Zahurak 
 
 
 
 
Responsible Research Nurse:    Rosalind Walker, RN, BSN  
 
 
 
 
 
 
Responsible Coordinator /  
Data Manager: 
 
Thomas Brown 
 
 
 
 
 
 
 
 
 
Participating Institution:  
Vu Cancer Center, Amsterdam, Netherlands 
Participating Institution Principal Investigator:  
Henk Verhuel, MD 
Lead Co-Investigator:  
 
Elske Gootjes, MD 
 
 
Protocol Type / Version # / Version Date: 
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Protocol Synopsis 
 
Title 
A multi-institutional open label, trial evaluating the efficacy of gemcitabine and docetaxel in 
patients with relapsed or refractory metastatic colorectal adenocarcinoma with methylated 
checkpoint with forkhead and ring finger domain (CHFR) promoter and/or microsatellite 
instability phenotype 
 
Background 
 
 
CHFR is a checkpoint protein which causes cell cycle arrest and associated chemotherapy 
resistance when exposed to microtubule inhibitors 
 
Epigenetic silencing of CHFR expression via CpG promoter methylation has been shown to 
increase sensitivity to microtubule inhibitors 
 
Microsatellite instability (MSI-H) colorectal cancer is associated with sensitivity to gemcitabine 
 
Methylation of CHFR and/or microsatellite instability  is/are present in approximately 25-40% of 
all colorectal adenocarcinoma tumors, with significant overlap of CHFR methylation with MSI-H 
 
Gemcitabine and docetaxel have been safely combined in the treatment of non-small cell lung 
cancer and breast cancer 
 
Gemcitabine and docetaxel combination therapy has demonstrated significant preclinical activity 
in colorectal cancer cell lines with CHFR and/or MSI phenotype 
 
Purpose and Objectives 
 
 
Determine the efficacy of combination gemcitabine and docetaxel chemotherapy in the treatment 
of metastatic colorectal cancer with CHFR and/or MSI phenotype 
 
Eligibility 
 
 
Adults with histologically documented metastatic colorectal adenocarcinoma with methylated 
CHFR and/or microsatellite instability phenotype that have relapsed or are refractory to one or 
more line(s) of standard therapy 
 
Patients must be off prior chemotherapy, radiation therapy, hormonal therapy, or biological 
therapy for at least 4 weeks. 
 
ECOG performance status 0 or 1 
 
Adequate organ and marrow function 
 
Design 
 
 
Patients will receive intravenous gemcitabine 500mg/m2 on days 1 and 8 and docetaxel 70mg/m2 
on day 8 of each 21 day cycle 
 
Patients will receive filgrastim (G-CSF) on days 9 through 15 or pegfilgrastim 6mg on day 9 or 
10 of each cycle 
 
Patients will be evaluated for toxicity prior to receiving each cycle and every 6 weeks for 
response using RECIST criteria 1.1 
 
A minimum of 10 and a maximum of 40 patients will be enrolled 

 
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TABLE OF CONTENTS 
 
 
Page 
List of abbreviations ......................................................................................................................v 
 
1. OBJECTIVES ..........................................................................................................................1 
 
1.1  
Primary Objectives 
 
1.2  
Secondary Objectives 
 
2. BACKGROUND ......................................................................................................................1 
      2.1       Colorectal Cancer epidemiology.................................................................................1 
      2.2       Gemcitabine…………………………………………………………………..………1 
      2.3       Docetaxel……………………………………………………………………………...2 
      2.4       Rationale for combination therapy in selected patients with CHFR methylation 
and/or microsatellite instable phenotype……………………………………………………….3 
 
3. PATIENT SELECTION 
 
3.1  
Eligibility Criteria  .......................................................................................................7 
 
3.2  
Exclusion Criteria ........................................................................................................9 
 
3.3  
Inclusion of Women and Minorities .........................................................................10 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines ....................................................................................................10 
 
4.2 
Registration Process ..................................................................................................10 
 
5. TREATMENT PLAN 
 
5.1  
Agent 
Administration .............................................................................................................................11
 
 
 
5.2 
General Concomitant Medication and Supportive Care Guidelines ....................11 
 
5.3  
Duration of Therapy ..................................................................................................11 
 
5.4  
Duration of Follow Up ...............................................................................................12 
5.5 
Criteria for Removal from Study .............................................................................12 
 
6. DOSING DELAYS/DOSE MODIFICATIONS ..................................................................12 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
      7.1  
Adverse Events Associated with Treatment Drugs…………………………….....15 
 
 
7.2 
Adverse Event Characteristics..................................................................................16 
 
7.3 
Adverse Event and Deaths on Study 
Reporting 16...................................................................................................................................... 
 
7.4 
Secondary Malignancy ..............................................................................................18 
7.5 
Second Malignancy ....................................................................................................18 
 

 
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8. PHARMACEUTICAL INFORMATION 
 
8.1  
Gemcitabine................................................................................................................18 
      8.2       Docetaxel…………………………………………………………………………….20 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
9.1 
Laboratory Correlative Studies ................................................................................23 
9.2 
Collection and handling of Specimens....………………………………………….23 
 
10. STUDY CALENDAR ............................................................................................................27 
 
11. MEASUREMENT OF EFFECT 
     11.1    Definitions of Disease ...................................................................................................28 
     11.2    Disease Parameters ......................................................................................................28 
     11.3.   Methods for Evaluation of Measurable Disease ........................................................29 
     11.4.   Response Criteria 
 
11.4.1.     Evaluation of target lesions ....................................................31 
 
11.4.2.     Evaluation of non-target lesions ............................................32 
 
11.4.3.     Evaluation of Best Overall Response ....................................33 
     11.5.    Duration of Response………………………………………………………………..34  
     11.6     Progression Free Survival…………………………………………………………..34 
     11.7     Response Review…………………………………………………………………….34 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
12.1 
Data Reporting ...........................................................................................................35 
 
12.2 
Multicenter Guidelines ..............................................................................................35 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints ............................................................................................36 
 
13.2 
Sample Size/Accrual Rate .........................................................................................40 
 
13.3 
Analysis of Secondary Endpoints .............................................................................40 
 
13.4 
Reporting and Exclusions .........................................................................................40 
 
 
 
 
 
 
 
 
 
REFERENCES………………………………………………………………………………….41 
 
APPENDICES 
 
APPENDIX A 
Performance Status Criteria 
 
APPENDIX B 
Multicenter Guidelines 
 
APPENDIX C 
Medications affecting CYP450 3A4 pathway 

 
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      APPENDIX D 
              EORTC QOL-C30 and QOL-CR29 
 
Abbreviation Key 
 
CHFR: Checkpoint with forkhead and RING finger domains 
MSI/MSS: Microsatellite instable/stable 
MMR: Mismatch repair 
CRC: Colorectal cancer 
PFS: Progression free survival 
OS: Overall survival 
5FU: 5-fluouracil 
PCR: Polymerase chain reaction 
IHC: Immunohistochemistry 
ULN: Upper limit of normal 
ANC: Absolute neutrophil count 
RESIST: Response evaluation criteria in solid tumors 
CR: Complete response 
PR: Partial response 
SD: Stable disease 
PD: Progressive disease 
AE: Adverse event 
SAE: Serious adverse event 
CTCAE: Common Terminology Criteria for Adverse Events 
 
 

 
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1. OBJECTIVES 
 
1.1. 
Primary Objectives 
 
 Determine the response rate of gemcitabine and docetaxel combination therapy for 
treatment of relapsed or refractory metastatic colorectal adenocarcinoma with methylation 
of CHFR and/or microsatellite instability 
 
1.2. 
Secondary Objectives 
 
 Determine the progression free survival with gemcitabine and docetaxel combination 
therapy in the selected patient population 
 Determine the overall survival with gemcitabine and docetaxel combination therapy in 
the selected patient population 
 Assess CHFR methylation in circulating tumor DNA and compare to CHFR methylation 
observed in tumor tissue 
 Assess changes in CHFR methylation in circulating tumor DNA over the time of therapy 
to determine if CHFR demethylation occurs as a predictor of progression 
 Analyze tumor tissue using a global methylation approach to develop a more robust 
predictive signature of treatment response 
 Evaluate changes in quality of life for patients treated with this regimen by serial 
measurements using the QLQ-C30 and QLQ-CR29 questionnaire. 
 
2. BACKGROUND 
 
2.1  Colorectal Cancer 
Globally, colorectal cancer (CRC) is the third most common malignancy with over 1.2 
million estimated new cases and 608,700 deaths in 2008 (1). It is the third most commonly 
diagnosed and third leading cause of cancer death in the United States.  In the US in 2011, it 
is expected that 141,210 new cases of colon cancer will be diagnosed, with 49,380 deaths 
attributed to colon cancer.  Of the new cases, 90% are over the age of 50 with 94% of the 
deaths in this age group, indicating that the disease is not only a significant cause of death 
and a common cancer diagnosis in older patients, but also significant cause of early cancer 
and death in younger patients. (2) 
 
Treatment of CRC by 5-fluorouracil (5FU) has been a component of the standard 
chemotherapy given to these patients for decades (3). The additions of oxaliplatin and 
irinotecan as well as targeted agents including bevacizumab and cetuximab/panitumumab to 
the prior standard of 5-fluouracil have increased the median overall survival of patients from 
10 months to over 2 years.  However, primary or acquired chemoresistance causes patients to 
become refractory to these two or three lines of therapy.  Hence, the five year overall survival 
for metastatic colorectal cancer is only 10%, demonstrating a need for finding novel drug 
combinations to treat these patients (4).  
 
2.2  
Gemcitabine 

 
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Background 
Gemcitabine is an FDA approved commercially available antimetabolite.  It is a nucleoside 
pyrimidine analogue. Gemcitabine first received FDA approval in 1996.  It currently has 
approval for the treatment of pancreatic cancer as a single-agent, in combination with 
platinum-based therapy in ovarian and nonsmall cell lung cancer, and in combination with 
paclitaxel in metastatic breast cancer.  The cytotoxic effect is due to the inhibition of DNA 
synthesis via the actions of its metabolites gemcitabine diphosphate and gemcitibine 
triphosphate.  Gemicitabine diphosphate inhibits ribonucleotide reductase.  Gemcitabine 
triphosphate is incorporated into the DNA, inhibiting DNA polymerase. 
 
Gemcitabine has been utilized for the treatment of unselected colorectal cancer patients 
previously without significant efficacy.  Two partial responses were observed in the initial 
phase I study of gemcitabine, one being in advanced colorectal cancer.  However, 
gemcitabine as a single agent has subsequently been studied in phase 2 studies in both 
upfront treatment and refractory disease with minimal activity (5-9).  Gemcitabine has been 
combined with fluouracil with mixed responses.  A review article of the available phase 1 
and 2 studies was published in 2008 but Merl, et al. with response rates ranging from 3.8% to 
38% from 8 studies in both treatment naïve and refractory patients (10).  A more recent study 
demonstrated a partial response in 2 of 22 refractory metastatic CRC patients (11).   
 
Dosing and Toxicity 
The dose of gemicitabine ranges from 800mg/m2 to 1250mg/m2 intravenous infusion over 30 
minutes on days 1 and 8 of a 21 day cycle or days 1, 8, and 15 of a 28 day cycle.  The drug is 
metabolized intracellularly into its two active metabolites gemcitabine diphosphate and 
gemcitabine triphosphate.  The active metabolite intracellular half-life ranges from 1.7 to 
19.4 hours. Its excretion is primarily in the urine. It is not significantly protein bound. 
 
The dose limiting toxicity of gemcitabine is myelosuppression.  Other prominent toxicities 
associated with gemcitabine include fever, nausea, vomiting, fatigue, edema, alopecia, rash, 
and elevated liver enzymes.  These primary toxicities associated with gemcitabine usually 
resolve after cessation of treatment. 
 
2.3  
Docetaxel 
 
Background 
Docetaxel is an FDA approved, commercially available antimicrotubule agent.  It is approved 
for the treatment of locally advanced or metastatic breast cancer, locally advanced or 
metastatic non-small cell lung cancer, hormone refractory prostate cancer, gastric 
adenocarcinoma, and squamous cell carcinoma of the head and neck.  The cytotoxic effect of 
docetaxel is due to the formation and stabilization of microtubules which prevents the 
reorganization necessary during the mitotic phase of the cell cycle. 
 
Docetaxel at a dose of 100mg/m2 every 3 weeks had minimal benefit in unselected colon 
cancer patients including three phase 2 studies of 76 total patients (12-14).  Of these patients 
only 3 had objective responses with one complete response and 2 partial responses.  An 

 
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additional 2 patients experienced a minor response and 9 patients demonstrated stable 
disease.   
 
 
 
Dose and Toxicology 
Docetaxel is given intravenously over 1 hour every 3 weeks.  It can be dosed from 60mg/m2 
to 100mg/m2 as a single agent or used in combination with other cytotoxic agents in doses of 
60mg/m2 or 75mg/m2.  It is 94-97% protein bound.  The primary metabolism is by the CYP 
3A4 isoenyme and its metabolism may be modified by medication which induce, inhibit, or 
metabolized by cytochrome P450 3A4.  The drug is eliminated predominately through feces 
with minor component in the urine. 
 
The primary dose limiting toxicities are myelosuppression and fluid retention.  Other 
significant toxicities include asthenia, neurosensory symptoms including paresthesia, 
dysthesia, and pain, hypersensitivity reactions including rash, hypotension, bronchospasm, 
and rarely anaphylaxis, hepatic injury, alopecia, and cutaneous reactions.  Premedication with 
oral corticosteroids is recommended for all patients to prophylaxis against excessive fluid 
retention and infusion reactions.   
 
2.4  
Rationale for combination therapy in selected colorectal cancer patients 
 
The microsatellite instability phenotype in colorectal cancer is caused by defective mismatch 
repair (MMR) proteins that lead to double-strand DNA breaks in malignant tissue.  The 
defect can occur either by a genetic mutation in MMR genes, such as hMLH1, hMSH2, and 
hMSH6, or by epigenetic inactivation via promoter methylation in as in the majority sporadic 
colon cancer with the MSI phenotype.  Approximately 15% of sporadic colon cancer patients 
have MSI phenotype tumors. (15)  Previously it has been shown that DNA polymerase 
inhibitors such as aphidicolin, gemcitabine and hydroxyurea were more toxic to the hMLH1 
deficient HCT116 cell line than HCT116 with proficient-hMLH1(16).  
.   

 
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Checkpoint with forkhead and RING finger domains (CHFR) is a cell cycle check point 
protein that protects cells from apoptosis following taxane agent microtubule alteration.  
CHFR inhibits Plk1 kinase by ubquination.  Active Plk1 kinase inhibits the cdc2 protein that 
delays G2 to M transition (17). When the CHFR gene is unmethylated and expressed it 
prevents cells treated with taxane agents from proceeding through unregulated mitosis that 
leads to apoptosis.  If the CHFR gene is epigenetically silenced with gene promoter 
methylation, cancer cells are exquisitely sensitive to taxane chemotherapy (18 - 20)
 
 
 
   
 

 
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Colo205-Xenograft 

 
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Gemcitabine and docetaxel have been safely combined in the treatment of non-small cell lung cancer, 
refractory breast cancer, and ovarian cancer (24-27).   The combination of gemcitabine and docetaxel 
has been reported in CRC patients only in phase 1 studies which included a total of 4 patients, none of 
which had a response reported. (28-30).  
  
 
Patients for this study must have CHFR methylation or microsatellite instability.  CHFR methylation 
will be assessed using methylation specific PCR or immunohistochemistry (lack of expression). For 
MSP, DNA is isolated from formalin-fixed, paraffin-embedded (FFPE) specimen.  Molecular analysis 
of the CHFR gene is performed by methylation-specific PCR, which was developed by our 
collaborator on this study, Jim Herman, and is now the standard technique to assess methylation of a 
gene.  An MSP assay entails initial modification of DNA by sodium bisulfite, converting all 
unmethylated, but not methylated, cytosines to uracil, and subsequent amplification with primers 
specific for methylated versus unmethylated DNA. MSP requires only small quantities of DNA, is 
sensitive to 0.1% methylated alleles of a given CpG island locus, and can be performed on DNA 
extracted from paraffin-embedded samples. MSP eliminates the false positive results inherent to 
previous PCR-based approaches, which relied on differential restriction enzyme cleavage to 
distinguish methylated from unmethylated DNA. MDXHealth or the Vu Cancer Center in Amsterdam 
will be conducting these assessments in a CLIA-certified or CCKL-certified laboratory for this 
technique.  Microsatellite instability will be assessed using standard-of-care techniques of PCR-based 
analysis using the Promega kit or immunohistochemistry. The MSI Analysis System kit (Promega, 
Madison, WI) consists of five nearly monomorphic mononucleotide markers (BAT-25, BAT-26, NR-
21, NR-24 and MONO-27) for MSI determination and two polymorphic pentanucleotide markers 
(Penta C and Penta D) for sample identification. The assay involves fluorescent polymerase chain 
reaction (PCR) analysis of tumor samples and matching normal samples. The limit of detection of the 
MSI assay has been determined to be approximately 1 cell in 10-100 total cells (10%). Johns Hopkins 
is a CLIA-certified site for MSI testing using this technique, and patients may also have 
documentation of their MSI status at external laboratories to qualify for the study. 

 
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3. PATIENT SELECTION 
 
3.1  
Eligibility Criteria  
 
3.1.1 Patients must have histologically or cytologically confirmed metastatic or 
unresectable adenocarcinoma of the colon or rectum. 
 
3.1.2    Patients must have measurable disease, defined as at least one lesion that can 
be accurately measured in at least one dimension (longest diameter to be 
recorded for non-nodal lesions and short axis for nodal lesions) as >20 mm 
with conventional techniques or as >10 mm with spiral CT scan, MRI, or 
calipers by clinical exam.  See Section 11 for the evaluation of measurable 
disease. 
 
3.1.3 Patients must be either intolerant or refractory to one or more standard line(s) 
of chemotherapy treatment prior to enrollment.  Toxicity from prior regimens 
must be resolved to less than or equal to grade 1 prior to enrollment.  Patients 
with grade 2 neurotoxicity may be enrolled on a case by case basis at the 
discretion of the principle investigator.  Patients should be off all treatment for 
at least 4 weeks prior to trial enrollment. 
 
3.1.4 Age >18 years.  Because no dosing or adverse event data are currently 
available on the use of gemcitabine in combination with docetaxel in patients 
<18 years of age with colorectal adenocarcinoma, children are excluded from 
this study, but will be eligible for future pediatric trials. 
 
3.1.5 ECOG performance status 0 or 1 (Karnofsky >70%, see Appendix A). 
 
3.1.6 Life expectancy of greater than 12 weeks. 
 
3.1.7 Patients must have normal organ and marrow function as defined below: 
 
 leukocytes  
 
 
 
 
>3,000/mcL 
 absolute neutrophil count  
>1,500/mcL 
 platelets  
 
 
 
 
 
>100,000/mcL 
 total bilirubin 
 
 
 
 
< 1.5 x ULN 
 AST(SGOT)/ALT(SGPT)  
<2.5 X institutional upper limit of normal or  
 
 
 
 
 
 
 
 
5X ULN in the presence of liver metastases 
 creatinine 
 
 
 
 
 
within normal institutional limits 
 
OR 
 creatinine clearance  
 
 
>60 mL/min/1.73 m2 for patients with 
creatinine levels above institutional normal 
 
3.1.8 Additional eligibility criteria 

 
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a. Microsatellite instability phenotype of archival tissue biopsy determined by                 
treating institution by PCR and IHC assay 
 
 
b. Methylation CHFR gene promoter in archival tissue biopsy 
-A patient will be considered to have CHFR methylation if he/she has a methylation specific 
band on MSP for the CHFR gene or lack of expression by IHCs; MSP primers are publicly 
reported and developed at Oncomethylome in a CLIA laboratory. Patients who test positive 
for MSI at any of the 5 loci will be considered MSI+ as per standard convention or who have 
absent expression of MLH1, MSH2, MSH6, or PMS2 by IHC. 
 
 
 
 
 
-Results from another institution’s CLIA-certified MSI/IHC will be considered for eligibility.  
-Patients with microsatellite instability and a family history supportive for a possible 
diagnosis of hereditary nonpolyposis colorectal cancer will be referred to a genetics 
counselor for further evaluation and recommendations. 
 
3.1.9 As gemcitabine and docetaxel are known to be teratogenic, 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.  Men and 
women treated or enrolled on this protocol must also agree to use adequate 
contraception prior to the study, for the duration of study participation, and 3 
months after completion of treatment. 
 
3.1.10 Ability to understand and the willingness to sign a written informed consent 
document. 
 
3.2  
Exclusion Criteria 
 
3.2.1 Patients who have had chemotherapy or radiotherapy within 4 weeks prior to 
entering the study or those who have not recovered from adverse events due to 
agents administered more than 4 weeks earlier. 
 
3.2.2 Patients who are receiving any other investigational agents. 
 
3.2.3 Patients with known brain metastases should be excluded from this clinical 
trial because of their poor prognosis and because they often develop 
progressive neurologic dysfunction that would confound the evaluation of 
neurologic and other adverse events. 
 
3.2.4 History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to gemcitabine or docetaxel. 
 
3.2.5 Patients receiving any medications or substances that are inhibitors or 
inducers of CYP 3A4 are ineligible. Investigator can change to a similar agent 
that is a non-CYP3A4 inhibitor/inducer with a washout period of 1 week. 

 
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Lists including medications and substances known or with the potential to 
interact with the cytochrome 450 3A4 isoenzyme are provided in appendix C. 
 
3.2.6 Uncontrolled intercurrent illness including, but not limited to, ongoing or 
active infection, symptomatic congestive heart failure, unstable angina 
pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would 
limit compliance with study requirements. 
 
3.2.7 Pregnant women are excluded from this study because of the potential for 
teratogenic or abortifacient effects of study medications.  Because there is an 
unknown but potential risk for adverse events in nursing infants secondary to 
treatment of the mother with gemcitabine and docetaxel breastfeeding should 
be discontinued if the mother is treated. These potential risks may also apply 
to other agents used in this study including supportive medications. 
 
3.2.8    HIV-positive patients on combination antiretroviral therapy are ineligible 
because of the potential for pharmacokinetic interactions with gemcitabine 
and docetaxel.  In addition, these patients are at increased risk of lethal 
infections when treated with marrow-suppressive therapy.  
 
3.3  
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial.   
 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines 
 
Eligible patients will be entered on study centrally at Johns Hopkins Hospital by the 
Study Coordinator.  All sites should call the Study Coordinator: 
 verify dose level availabilities.  The required forms can be found 
in Appendix D. 
 
Following registration, patients should begin protocol treatment within 21 days.*  
Issues that would cause treatment delays should be discussed with the Principal 
Investigator.  If a patient does not receive protocol therapy following registration, the 
patient’s registration on the study may be canceled.  The Study Coordinator should be 
notified of cancellations as soon as possible. 
 
4.2 
Registration Process 
 
To register a patient, the following documents should be completed by the research 
nurse or data manager and faxed 
  

 
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 Copy of required laboratory tests including MSI testing at treating institution 
(archival tissue biopsy documentation confirming results is acceptable) or 
documentation of CHFR methylation status 
 Signed patient consent form 
 HIPAA authorization form 
 Eligibility Screening Worksheet 
 Registration Form 
 
The research nurse or data manager at the participating site will then call 
r e-mail 
the Study Coordinator to verify 
eligibility.  To complete the registration process, the Coordinator will 
 Assign a patient study number 
 Confirm tissue sample is positive for CHFR methylation or MSI prior to 
formal registration 
 Register the patient on the study  
 Fax or e-mail the patient study number and dose to the participating site 
 Call the research nurse or data manager at the participating site and verbally 
confirm registration. 
 
 
 
5. TREATMENT PLAN 
 
5.1  
Agent Administration 
 
Treatment formulation and supportive care will be administered on an outpatient 
basis, per institutional guidelines.  Reported adverse events and potential risks are 
described in Section 7.  Appropriate dose modifications are described in Section 6.  
No investigational or commercial agents or therapies other than those described 
below may be administered with the intent to treat the patient's malignancy. 
 
 
REGIMEN DESCRIPTION* 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Gemcitabine 
Appropriate 
antiemetic 
 
500mg/m2  
in 100 ml 
NS 
IV over 30 
minutes to 1 
hour 
Days 1 and 
8 
21 days  
(3 
weeks) 
Docetaxel 
Dexamethasone 
8mg po bid on 
days 7, 8, and 9  
70mg/m2 in 
250 ml 
D5W 
IV over 1 hr 
through 
separate IV 
line 
Day 8 
* This  is the protocol used in the coordinating center, and participating sites may have slightly 
different guidelines for administration for these standard agents, with the  dose of the 
chemotherapeutic agents being equal. 

 
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5.1.1 Supportive care for study drugs 
 
a. Dexamethasone should be used for prevention of hypersensitivity reactions, 
nausea, and extravascular fluid retention from docetaxel.  
b. Filgrastim 5mcg/kg on days 9 -14 or pegfilgrastim 6mg one time dose on day 9 or 
10 should be given as primary prophylaxis. 
 
5.2  
General Concomitant Medication and Supportive Care Guidelines 
 
Because there is a potential for interaction of other concomitantly administered drugs 
through the cytochrome P450 system, the case report form must capture the 
concurrent use of all other drugs, over-the-counter medications, or alternative 
therapies.  The Principal Investigator should be alerted if the patient is taking any 
agent known to affect or with the potential to affect selected CYP450 isoenzymes. 
 
5.3  
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, 
 
Radiation treatment required for palliative management of disease, 
 
Intercurrent illness that prevents further administration of treatment, 
 
 
Unacceptable adverse event(s), 
 
 
Patient decides to withdraw from the study, or 
 
 
General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 
In the event that the patient is deemed to be receiving continued clinical benefit in the face of 
progressive disease by RECIST criteria, the patient may continue on therapy with agreement of 
the PI. If progressive disease is confirmed on successive imaging or clinical exam, the date of 
progression will be marked as the first timepoint that progression was noted. 
 
5.4 
Duration of Follow Up 
 
Patients will be followed for 4 weeks after cessation of study treatment for resolution 
of toxicity, and then every three months until death.  Follow-up for survival will be 
via email, phone call, or by checking the electronic patient record system to verify 

 
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subject’s status.  Patients removed from study for unacceptable adverse event(s) will 
be followed until resolution or stabilization of the adverse event. 
 
5.5 
Criteria for Removal from Study  
 
 Patients will be removed from study when any of the following criteria: Death 
 Patient voluntarily chooses to withdraw from the protocol 
.  The reason for study removal and the date the patient was removed must be documented in the 
Case Report Form. 
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Dose Level 
Gemcitabine Dose 
Docetaxel Dose 
-2 
300 mg/m2days 1 and 8 
50mg/m2 day 8 
-1 
400 mg/m2 days 1 and 8 
50mg/m2 day 8 
0 
500 mg/m2days 1 and 8 
70mg/m2 day 8 
 
 
 
 
 
 
Event Name 
Peripheral Neuropathy 
Grade of Event 
Management/Next Dose for Docetaxel 
≤ Grade 1 or 2 
No change in dose 
Event Name 
Nausea/Vomiting* 
Grade of Event 
Management/Next Dose for 
Gemcitabine 
Management/Next Dose for 
Docetaxel 
≤ Grade 1 or 2 
No change in dose 
No change in dose 
Grade 3 
Hold** until ≤  Grade 2.  
Resume at one dose level 
lower, unless toxicity 
resolved within 3 days.*** 
Hold** until ≤  Grade 2.  
Resume at one dose level 
lower, unless toxicity 
resolved within 3 days.*** 
Grade 4 
Hold* until < Grade 2.  
Resume at one dose level 
lower, unless toxicity 
resolved within 3 days.*** 
Hold* until < Grade 2.  
Resume at one dose level 
lower, unless toxicity 
resolved within 3 days.*** 
*  Patients whose symptoms are controlled within three days of onset of grade 3 
or 4 toxicity will not require a dose reduction 
**Patients requiring a delay of >3 weeks should go off protocol therapy. 
***If there are greater than 2 dose reductions in single drug patients should 
discontinue the offending drug and may continue the other drug if desired. 
Recommended management:  Intensify prophylactic antiemetics, e.g. addition of 
aprepitant, benzodiazepine, etc. 

 
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14 
Grade 3 
Hold* until ≤ Grade 2.  Resume at one dose level lower.** 
Grade 4 
Off protocol therapy 
*Patients requiring a delay of >3 weeks should go off protocol therapy. 
** If there are greater than 2 dose reductions of docetaxel patients should 
discontinue docetaxel and may continue gemcitabine if desired. 
 
Event Name 
Diarrhea* 
Grade of Event 
Management/Next Dose for 
Gemcitabine 
Management/Next Dose for 
Docetaxel 
≤ Grade 1 or 2 
No change in dose 
No change in dose 
Grade 3 
Hold** until < Grade 2.  
Resume at one dose level 
lower, if indicated.*** 
Hold** until < Grade 2.  
Resume at one dose level 
lower, if indicated.*** 
Grade 4 
Off protocol therapy 
Off protocol therapy 
*  Patients whose symptoms are controlled within three days of onset of grade 3 
or 4 toxicity will not require a dose reduction 
**Patients requiring a delay of > 3 weeks should go off protocol therapy. 
*** If there are greater than 2 dose reductions in single drug patients should 
discontinue the offending drug and may continue the other drug if desired. 
Recommended management:  Loperamide antidiarrheal 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 
Neutropenia/Thrombocytopenia 
Counts*** 
Management/Next Dose 
for Gemcitabine 
Management/Next Dose for 
Docetaxel 
ANC ≥ 1200, 
Platelets ≥ 100,00 
No change in dose 
No change in dose 
ANC < 1200 and 
≥ 1000, OR 
Platelets 
<100,000 and 
≥75,000 
Hold until ANC ≥ 1200 and 
platelets ≥ 100,000. Resume 
at same dose level. 
Hold until ANC ≥ 1200 and 
platelets ≥ 100,000. Resume 
at same dose level. 
ANC <1000 and 
≥ 500, OR 
Platelets <75,000 
and ≥50,000 
Hold* until ANC ≥1200 and 
platelets ≥ 100,000. Resume 
at one dose level lower. 
Hold* until ANC ≥1200 and 
platelets ≥ 100,000. Resume 
at one dose level lower. 
ANC <500 OR 
Platelets < 50,000 
Hold* until ANC ≥1200 and 
platelets ≥ 100,000. Resume 
at one dose level lower. 
Hold* until ANC ≥1200 and 
platelets ≥ 100,000. Resume 
at one dose level lower. 
ANC = Absolute neutrophil count 
*Patients requiring a delay of >3 weeks should go off protocol therapy. 
** If there are greater than 2 dose reductions in single drug patients should 

 
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discontinue the offending drug and may continue the other drug if desired. 
***Counts on treatment days only (day 1 and 8) 
 
Event Name 
Hypersensitivity 
Grade 
Management for Docetaxel 
Grade 1 
(e.g. mild 
flushing/pruritis) 
Complete infusion.  Supervision at bedside.  Subsequent 
cycles may be given with diphenhydramine and H-2 
blocker in addition to dexamethasone at the discretion of 
treating provider. 
Grade 2 
(e.g. moderate 
flushing, rash, 
dyspnea, chest 
discomfor 
Stop infusion.  Give supportive medications including 
dexamethasone, diphenhydramine.  Restart infusion at 
lower rate once symptoms have resolved.  If moderate 
symptoms during first cycle then dexamethasone should 
be increased to 20mg 12 hours and 6 hours before 
treatment in addition to pretreatment 10mg IV dose.  
Diphenhydramine and H2-blocker premedication should 
be added 30 minutes prior to docetaxel infusion. 
Grade 3 or 4 
Administer supportive care including dexamethasone and 
diphenhydramine in addition to bronchodilation therapy 
and vasopressors as indicated.  Discontinue docetaxel 
and continue gemcitabine per provider and patient 
preference. 
 
 
 
 
 
 
Event Name 
Fluid retention 
Severity 
Management/Next Dose for Docetaxel 
Asymptomatic 
peripheral edema or 
pleural effusion 
Initiate diuretic if considered appropriate by patient 
provider. Continue docetaxel. No change in dose. 
Symptomatic peripheral 
edema 
Initiate or intensify diuretic therapy. Continue 
docetaxel.  No change in dose 
Symptomatic pleural 
effusion 
Discontinue docetaxel.  May continue gemcitabine per 
provider and patient preference.  
*Patients should have thoracentesis if effusion is suspected to represent 
progressive disease. 
 
Event Name 
General Toxicity  
Grade of Event 
Management/Next Dose for 
Gemcitabine 
Management/Next Dose for 
Docetaxel 
Grade 1  
No change in dose 
No change in dose 
Grade 2 or 3, 
Hold* until ≤ Grade 1.  
Hold* until ≤ Grade 1.  

 
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16 
clinically 
significant 
Resume at one dose level 
lower, except electrolyte 
abnormalities noted below** 
Resume at one dose level 
lower, except electrolyte 
abnormalities noted below** 
Grade 4 
Off protocol therapy 
Off protocol therapy 
*Patients requiring a delay of > 3 weeks should go off protocol therapy. 
** If there are greater than 2 dose reductions in single drug patients should 
discontinue the offending drug and may continue the other drug if desired. 
1) Electrolyte abnormalities can and should be corrected as clinically indicated 
and do not require dose adjustments unless correction is not possible. 
2) If single offending drug is highly suspected then it should be dose reduced 
while maintaining dose of non-offending drug.  If specific offending drug is not 
clear then dose reduction of both drugs is advised. 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
      7.1 Adverse events associated with treatment drugs 
 
 
7.1.1  Gemcitabine 
1. Hematologic: Neutropenia, anemia, thrombocytopenia, and leukopenia are 
reported. 
2. Dermatologic: A rash is seen in about 25% of patients and is associated with 
pruritus in about 10% of patients. The rash is usually mild, not dose-limiting, 
and responds to local therapy. Desquamation, vesiculation, and ulceration have 
been reported rarely. Alopecia is usually minimal. Injection-site reactions. 
3. Gastrointestinal: Nausea and vomiting are reported in about two-thirds of 
patients and requires therapy in about 20% of patients. It is rarely dose limiting, 
and is easily manageable with standard antiemetics. Diarrhea, constipation, 
mucositis. 
 
4. Hepatic: Abnormalities of hepatic transaminase enzymes occur in two-thirds of 
patients, but they are usually mild, nonprogressive, and rarely necessitate 
stopping treatment. However, gemcitabine should be used with caution in 
patients with impaired hepatic function. 
5. Pulmonary: Bronchospasm and/or dyspnea within a few hours of infusion of the drug, 
cough, rhinitis, pneumonitis. 
6. Neurologic: Somnolence, insomnia, paresthesia, pain. 
7. Cardiovascular: A few cases of hypotension were reported. Some cases of 
myocardial infarction, congestive heart failure, and arrhythmias have been 
reported. Peripheral edema is reported in about 30% of patients. Some cases 
of facial edema have also been reported. Edema is usually mild to moderate, 
rarely dose-limiting, sometimes painful, and reversible after stopping 
gemcitabine treatment. 
8. Other: Flu-like symptoms are reported for about 20% of patients. This includes 
fever, headache, back pain, chills, myalgia, asthenia, and anorexia. Malaise 
and sweating are reported. 
 
 
7.1.2 Docetaxel 

 
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1. Hematologic: The major toxic effect of docetaxel, which limits dose, is neutropenia 
which may lead to fever and infection. Other toxic effects, which may be seen, include 
leukopenia, thrombocytopenia, anemia.  Disseminated intravascular coagulation often in 
association with sepsis or multiorgan dysfunction has been reported. Very rare cases of 
myeloid leukemia or myelodysplasia have occurred in docetaxel, doxorubicin, and 
cyclophosphamide treated patients 
2. Infusional/Allergic reactions: Severe anaphylactoid reactions, characterized by a flush 
associated with hypo- or hypertension, with or without dyspnea, may occur requiring 
immediate discontinuation of the docetaxel infusion and aggressive therapy. All patients 
should be premedicated with an oral 
corticosteroid prior to the initiation of the infusion of docetaxel. If minor reactions 
such as flushing or localized skin reactions occur, interruption of therapy is not 
required. Other hypersensitivity reactions including flushing, pruritis, fever, chills, rigors, 
lower back pain are reported. 
3. Dermatologic: skin rash, desquamation following localized pruriginous maculopapular 
eruption, skin erythema with edema, nail changes, alopecia, extravasation reaction 
(erythema, swelling, tenderness, pustules), nail changes and conjunctivitis.  
4. Respiratory: dyspnea with restrictive pulmonary syndrome, pleural 
effusions 
5. Cardiovascular: arrhythmias, pericardial effusions, fluid retention syndrome. Rare 
cases of congestive heart failure have been reported with docetaxel used in combination 
with other chemotherapy agents. 
6. Gastrointestinal: nausea, vomiting, oral mucositis, diarrhea, anorexia, increase in liver 
function tests, hepatic failure. Patients with SGOT (AST) > 1.5 times normal and alkaline 
phosphatase > 2.5 times normal appear to have decreased docetaxel clearance and appear 
to be more likely to suffer severe toxicity, including drug-related death. 
7.  Neurotoxicity: reversible dysesthesias or paresthesias, peripheral neuropathy, seizure, 
headache, lethargy or somnolence.  
 
 
7.2 
Adverse Event Characteristics  
 
 CTCAE term (AE description) and grade:  The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for AE reporting.  All appropriate treatment 
areas should have access to a copy of the CTCAE version 4.0.  A copy of the 
CTCAE version 4.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
  
 
Attribution of the AE: 
- 
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. 
 

 
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7.3 
Adverse Event and Deaths on Study Reporting 
 
7.3.1 
Expedited Reporting on Adverse Event Form to PI within 48 hours: 
 
a. Serious adverse events (SAEs) are occurrences possibly, probably or definitely 
related to the research.  An SAE is defined as an untoward medical occurrence that: 
 resulted in a death; 
 was life-threatening; 
 required or prolonged hospitalization; 
 caused persistent or significant disability/incapacity; 
 resulted in congenital anomalies or birth defects; or 
 required intervention to prevent permanent impairment or death. 
 
b. All other deaths not included in the SAE category above. 
 
c. All grade 3 and 4 (CTCAE) events that are not in the consent and that are 
possibly, probably or definitely related to the research, but not included in the SAE 
category above. 
 
 
7.3.2 Routine Adverse Event Reporting 
 
 
 
All Adverse Events must be reported in routine study data submissions. Adverse  
 
 
event submission for routine AEs must be submitted by CRF within 28 days of  
 
 
the AE being noted by the study team.  
 
7.4 
Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy 
(e.g., treatment with investigational agent/intervention, radiation or chemotherapy). A 
secondary malignancy is not considered a metastasis of the initial neoplasm.  
Three options are available to describe the event:  
 
 Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic 
leukemia [AML])  
 Myelodysplastic syndrome (MDS)  
 Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should 
also be reported via the routine reporting mechanisms outlined in each protocol.  
 
7.5 
Second Malignancy 

 
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A second malignancy is one unrelated to the treatment of a prior malignancy (and is 
NOT a metastasis from the initial malignancy).   
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the commercial agents 
administered in this study can be found in Section 7.1. 
 
 
8.1  
Gemcitabine 
 
8.1.1 Other Names 
2'-Deoxy-2',2'-difluorocytidine monohydrochloride, Gemzar 
 
8.1.2 Classification 
Antimetabolite (nucleoside pyrimidine analogue) 
 
8.1.3 Mode of Action 
Gemcitabine exhibits cell phase specificity, primarily killing cells undergoing DNA 
synthesis (S phase) and also blocking the progression of cells through the G1/S 
phase boundary. Gemcitabine is metabolized intracellularly by nucleoside kinases to 
the active diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. The 
cytotoxic effect of gemcitabine is attributed to a combination of two actions of the 
diphosphate and the triphosphate nucleosides, which leads to inhibition of DNA 
synthesis. First, gemcitabine diphosphate inhibits ribonucleotide reductase, which is 
responsible for catalyzing the reactions that generate the deoxynucleoside 
triphosphates for DNA synthesis. Inhibition of this enzyme by the diphosphate 
nucleoside causes a reduction in the concentrations of deoxynucleotides, including 
dCTP. Second, gemcitabine triphosphate competes with dCTP for incorporation into 
DNA. The reduction in the intracellular concentration of dCTP (by the action of the 
diphosphate) enhances the incorporation of gemcitabine triphosphate into DNA 
(self-potentiation). After the gemcitabine nucleotide is incorporated into DNA, only 
one additional nucleotide is added to the growing DNA strands. After this addition, 
there is inhibition of further DNA synthesis. DNA polymerase epsilon is unable to 
remove the gemcitabine nucleotide and repair the growing DNA strands (masked 
chain termination). In CEM T lymphoblastoid cells, gemcitabine induces 
internucleosomal DNA fragmentation, one of the characteristics of programmed cell 
death. 
 
8.1.4 Storage and Stability 
Unreconstituted drug vials are stored at controlled room temperature (15ºC to 30ºC, 
59ºF to 86ºF). Reconstituted solution should be stored at controlled room 
temperature and used within 24 hours. Solutions of gemcitabine should not be 
refrigerated; as crystallization may occur. The unused portion should be discarded. 
 
8.1.5 Dose Specifics 

 
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800 mg/m2 IV over 30 minutes on days 1, 8 of each cycle. 
 
8.1.6 Preparation 
Reconstitute the 200 mg vial with 5ml and the 1 gm vial with 25 ml preservative free 
normal saline to make a solution containing 38 mg/ml. Shake to dissolve. 
Gemcitabine may be further diluted with NS as per institutional standards. 
 
8.1.7 Route of Administration 
IV infusion. 
 
8.1.8 Incompatibilities 
No information available. 
 
8.1.9 Availability 
Gemcitabine is commercially available in 200 mg and 1 gm vials. 
 
8.1.10 Side Effects 
1. Hematologic: Neutropenia, anemia, thrombocytopenia, and leukopenia are 
reported. 
2. Dermatologic: A rash is seen in about 25% of patients and is associated with 
pruritus in about 10% of patients. The rash is usually mild, not dose-limiting, 
and responds to local therapy. Desquamation, vesiculation, and ulceration have 
been reported rarely. Alopecia is usually minimal. Injection-site reactions. 
3. Gastrointestinal: Nausea and vomiting are reported in about two-thirds of 
patients and requires therapy in about 20% of patients. It is rarely dose limiting, 
and is easily manageable with standard antiemetics. Diarrhea, constipation, 
 
mucositis. 
 
4. Hepatic: Abnormalities of hepatic transaminase enzymes occur in two-thirds of 
patients, but they are usually mild, nonprogressive, and rarely necessitate 
stopping treatment. However, gemcitabine should be used with caution in 
patients with impaired hepatic function. 
5. Pulmonary: Bronchospasm and/or dyspnea within a few hours of infusion of 
the drug, cough, rhinitis, pneumonitis. 
6. Neurologic: Somnolence, insomnia, paresthesia, pain. 
7. Cardiovascular: A few cases of hypotension were reported. Some cases of 
myocardial infarction, congestive heart failure, and arrhythmias have been 
reported. Peripheral edema is reported in about 30% of patients. Some cases 
of facial edema have also been reported. Edema is usually mild to moderate, 
rarely dose-limiting, sometimes painful, and reversible after stopping 
gemcitabine treatment. 
8. Other: Flu-like symptoms are reported for about 20% of patients. This includes 
fever, headache, back pain, chills, myalgia, asthenia, and anorexia. Malaise 
and sweating are reported. 
 
8.1.11 Nursing/Patient Implications 
1. If the patient reports burning at the injection site, slow down rate to allow the 

 
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dose to run in over 1 hour. 
2. Rash can be treated with topical therapy or the administration of 
 
diphenhydramine prior to administration.  
3. Flu-like symptoms can be treated with acetaminophen. 
 
 
8.2 
Docetaxel 
 
8.2.1 Other names: Taxotere, 4-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1, 7β, 10β-
trihydroxy- 
9-oxotax-11-ene-13α-yl-(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3- 
phenylpropionate 
 
8.2.2 Classification: Antimicrotuble 
 
8.2.3 Mode of action: 
In vitro, docetaxel promotes tubulin assembly into microtubules and inhibits 
depolymerization thus stabilizing microtubules, which is different from the action 
of other spindle poisons in clinical use. This can lead to bundles of microtubules 
in the cell, which by blocking cells in the M phase of the cell cycle, results in the 
inability of the cells to divide. 
 
8.2.4 Storage and stability: Store between 2 and 25°C (36 and 77°F). Retain in the 
original 
package to protect from bright light. Freezing does not adversely affect the 
product. The initial diluted solution may be used immediately or stored either in 
the refrigerator or at room temperature for a maximum of 8 hours. 
Docetaxel infusion solution, if stored between 2 and 25°C (36 and 77°F) is stable 
for 4 hours. Fully prepared docetaxel infusion solution (in either 0.9% Sodium 
Chloride solution or 5% Dextrose solution) should be used within 4 hours 
(including the 15 - 30 minute IV administration). 
 
8.2.5 Dose specifics 
70mg/m2 IV infusion on day 8 of 21 day cycle 
 
8.2.6 Preparation:  
Preparation of docetaxel for infusion requires two separate dilutions. 
First dilution: Gather the appropriate number of vials of docetaxel for Injection 
Concentrate and diluent (13% Ethanol in Water for Injection). If the vials were 
refrigerated, allow them to stand at room temperature for approximately 5 minutes. 
Aseptically withdraw the entire contents of the 
appropriate diluent vial into a syringe by partially inverting the vial and transfer it 
to the appropriate vial of docetaxel for Injection Concentrate. If the procedure 
is followed as described, an initial diluted solution of 10 mg docetaxel/ml 
will result. Mix the initial diluted solution by repeated inversion for at 45 
seconds to assure full mixture of the concentrate and diluent. Do not shake. 

 
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The initial diluted docetaxel solution (10 mg docetaxel/ml) should be clear; 
however, there may be some foam on top of the solution due to the polysorbate 
80. Allow the solution to stand for a few minutes to allow any foam to dissipate. It 
is not required that all foam dissipate prior to continuing the preparation process. 
The initial diluted solution may be used immediately or stored either in the 
refrigerator or at room temperature for a maximum of 8 hours. 
Second dilution for infusion: Aseptically withdraw the required 
amount of initial diluted docetaxel solution (10 mg docetaxel/ml) with a calibrated 
syringe and inject into a 250 ml infusion bag or bottle of either 0.9% Sodium 
Chloride solution or 5% Dextrose solution to produce a final concentration of 0.3 
to 0.74 mg/ml. If a dose greater than 200 mg of docetaxel is required, use a 
larger volume of the infusion vehicle so that a concentration of 0.74 mg/ml 
docetaxel is not exceeded. Thoroughly mix the infusion by manual rotation. As 
with all parenteral products, docetaxel should be inspected visually for particulate 
matter or discoloration prior to administration whenever the solution and 
container permit. If the docetaxel for Injection initial diluted solution or final 
dilution for infusion is not clear or appears to have precipitation, these should be 
discarded. 
 
8.2.7 Route of administration: IV infusion 
 
8.2.8 Incompatibilities:  
Contact of the docetaxel concentrate with plasticized PVC equipment or devices 
used to prepare solutions for infusion is not recommended. In order to minimize 
patient exposure to the plasticizer DEHP (di-2-ethylhexyl phthalate), which may 
be leached from PVC infusion bags or sets, the final docetaxel dilution for 
infusion should be stored in bottles (glass, polypropylene) or plastic bags 
 (polypropylene, polyolefin) and administered through polyethylene-lined 
administration sets. 
 
8.2.9 Availability: Two dosing vials are available, 80mg/2ml for 80mg dose and 
20mg/0.5ml for 20mg dose, each with diluent. 
 
8.2.10 Side effects: Please refer to the package insert for complete product instructions 
and toxicity. 
 
1. Hematologic: The major toxic effect of docetaxel, which limits dose, is 
neutropenia which may lead to fever and infection. Other toxic effects, which may 
be seen, include leukopenia, thrombocytopenia, anemia.  Disseminated 
intravascular coagulation often in association with sepsis or multiorgan 
dysfunction has been reported. Very rare cases of myeloid leukemia or 
myelodysplasia have occurred in docetaxel, doxorubicin, and cyclophosphamide 
treated patients 
2. Infusional/Allergic reactions: Severe anaphylactoid reactions, characterized by 
a flush associated with hypo- or hypertension, with or without dyspnea, may 

 
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23 
occur requiring immediate discontinuation of the docetaxel infusion and 
aggressive therapy. All patients should be premedicated with an oral 
corticosteroid prior to the initiation of the infusion of docetaxel. If minor reactions 
such as flushing or localized skin reactions occur, interruption of therapy is not 
required. Other hypersensitivity reactions including flushing, pruritis, fever, 
chills, rigors, lower back pain are reported. 
3. Dermatologic: skin rash, desquamation following localized pruriginous 
maculopapular eruption, skin erythema with edema, nail changes, alopecia, 
extravasation reaction (erythema, swelling, tenderness, pustules), nail changes and 
conjunctivitis.  
4. Respiratory: dyspnea with restrictive pulmonary syndrome, pleural 
effusions 
5. Cardiovascular: arrhythmias, pericardial effusions, fluid retention syndrome. 
Rare cases of congestive heart failure have been reported with docetaxel used in 
combination with other chemotherapy agents. 
6. Gastrointestinal: nausea, vomiting, oral mucositis, diarrhea, anorexia, increase 
in liver function tests, hepatic failure. Patients with SGOT (AST) > 1.5 times 
normal and alkaline phosphatase > 2.5 times normal appear to have decreased 
docetaxel clearance and appear to be more likely to suffer severe toxicity, 
including drug-related death. 
7.  Neurotoxicity: reversible dysesthesias or paresthesias, peripheral neuropathy, 
seizure, headache, lethargy or somnolence.  
 
Potential Drug Interactions: In in vitro screening assays, docetaxel was a 
significant inhibitor of CYP3A4 and a moderate to weak inhibitor of CYP2D6, 
2C19, 2C9 and 1A2. These preliminary data indicate that there may be some 
potential for interactions with co-administered drugs that are metabolized by 
these isozymes although the results should be treated with caution until definitive 
studies are conducted. 
 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
Laboratory Correlative Studies 
 
9.1.1 Changes in promoter methylation 
 
We have recently designed a highly-sensitive, novel nano-enabled methylation based technology, 
termed Methylation-on-Beads (MOB), as a tool that has enormous potential for detection of 
methylation changes in circulating DNA.  Candidate gene methylation (CHFR and MMR genes) will 
be evaluated in circulating tumor DNA in plasma samples obtained pretreatment and every cycle 
thereafter. DNA will be isolated from blood and treated with sodium bisulfite under denaturing 
conditions. Bisulfite modified DNA from each post treatment specimen will be analyzed for changes 
in DNA methylation at specific gene promoters (to include CHFR, p16, mLH1, MSH6 and O6-
MGMT).  PCR primers for these have been described and are in frequent use in the Ahuja/Herman 
laboratories. Conditions for all stage I multiplexes will be optimized through primer design and PCR 
conditions to achieve equal product intensity. These optimal conditions will ensure a similar 

 
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24 
sensitivity for the detection of methylated alleles across genes in the stage 2 MSP assays. All stage 2 
PCR reactions will be conducted at annealing temperatures (68-70ºC) that exceed the melting 
temperature of the primers to ensure the highest specificity for amplification of only methylated 
alleles present in the DNA sample.  For each gene, separate PCR reactions will be performed with 
methylated-specific primers and unmethylated specific primers (as used in conventional gel based 
MSP analysis). Each reaction will be run in triplicate.  Mixing experiments utilizing DNA from cell 
lines methylated at a given locus and a completely unmethylated DNA source (normal DNA) will be 
performed to determine accuracy of quantification. Assays will be performed on the Bio-Rad I-cycle. 
Two methods of detection will be compared: non-specific quantification of PCR products using Syber 
Green, and specific detection using molecular beacons. A ratio of the inverse of the cycle threshold 
for the methylated gene of interest over the inverse of the cycle threshold for beta-actin will be 
calculated. This ‘methylation index’ will be compared pre- and post-treatment. If changes in 
methylation pattern are observed by MSP, this result will be further validated by bisulfite sequencing 
of selected genes.  
 
Changes in candidate gene promoter methylation will be assessed to determine if there is correlation 
with clinical response to treatment, i.e. progression during treatment. 
 
9.1.2 Advances in array technologies now allow for a comprehensive methylome analysis in 
cancer samples at low cost.  We will also study the global methylation pattern using an Infinium 
Methylation Assay that surveys genome-wide DNA methylation profiles. Using this technology, 
approximately 482,420 CpGs are queried, including 99% of  RefSeq genes; there are 17 CpGs 
studied on average per gene.  Results are analyzed using BeadStudio software which allows for 
data analysis, as well as integration of methylome data with mRNA expression array studies. As 
little as 500ng of input DNA is required for the BeadChip.  We will investigate if the Illumina 
Infinium chip can be used to define more robust epigenetic signatures between responders and 
non-responders to our therapy. 
 
9.2 Collection and Handling of Specimens 
 
9.2.1 Blood 
Blood samples for methylation analysis will be collected from all 
participants into the enclosed purple tubes (4 mL EDTA BD 
Vacutainer cell preparation tubes, Becton Dickinson, Franklin Lakes, 
NJ). These tubes are designed to separate plasma and mononuclear 
cells from whole blood. Each collection will remove 18 mL of blood 
from the patient (6 tubes of 3mL each). Each purple tube holds near 
3mL of blood. Tubes will be collected and transported on ice to each 
center’s research blood processing and storage area within 30 
minutes. 
 
 
Processing of the blood: 
1. Take six enclosed 15 mL conical tubes. 
2. Add 3 mL of Ficoll-Paque PLUS buffer to each conical tube. 
(BUFFER MUST BE KEPT IN 4ºC for storage) 
a. The volume of buffer should be roughly equal to the 
volume of blood in the purple tops. 
3. Layer the blood of a purple top tube above the ficoll buffer. 

 
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a. To do this, carefully pour the blood into the plasma 
conical tubes by tilting the conical tube at an angle 
close to horizontal and letting the blood from the 
purple-top tube run very slowly down the side of the 
conical tube. THIS IS IMPORTANT. If done correctly, 
the blood should sit right on top of the buffer as shown 
below. 
Layer the rest of the blood samples. 
4.  
 
5. Next spin the samples in a centrifuge for 10 minutes at 2000 
rpm at 4ºC. Be sure that the centrifuge is balanced.The layers 
will now separate as shown below: 
 
Carefully pipet the plasma layer (the clear yellow layer on top) from 
the conical tube into the enclosed 1.5 mL sterile eppendorf tubes. 
Add no more than 1.2mL of plasma to each eppendorf tube to give 
the plasma room to expand during freezing. 
6. Pay careful attention that you do not draw from the white 
buffy coat. 
7. Pipet the white buffy coat (white layer or monocytes) into the 

 
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26 
enclosed 1.5mL eppendorf tubes. Similarly, leave room for 
expansion. 
a. When collecting the white blood cells (WBC), keep 
the tip of the pipette close to the wall of the tube, this 
is where the wbc accumulate 
b. Try not to pipette ficoll with the WBC. 
8. Transfer plasma and WBC for each spun conical tube to 
corresponding eppendorf tubes. Depending on the patient, you 
may have from 8-10 eppendorf tubes filled with plasma and 3-6 
tubes filled with WBC. 
9. Freeze plasma and WBC at least -70ºC. 
10. At time of shipping, ship on dry ice to 
 (Specimen 
Accessioning Core) Lab. 
11. All tubes should be labeled with the unique patient identifier, Cycle number, 
Day on cycle on the tube. 
 
9.2.2 Archival Tissue 
Archival tissue will be utilized to test for CHFR methylation in order to determine eligibility.  We 
will also possibly explore other predictive methylation biomarkers or a biomarker panel that may 
be more predictive of clinical benefit than CHFR methylation or MSI alone.  These exploratory 
analyses are dependent on observing some clinical benefit.  Whole methylome expression arrays 
using the Illumina Infiunium platform would be utilized for these exploratory analyses, with 
which we have significant experience and is appropriate for FFPE tissues. 
 
Archival tissues will be requested for each patient from all priorsurgeries. Paraffin blocks 
containing tumor sections will be 
requested. Paraffin blocks will be sectioned in 10micron cuts with 
total 25 cuts. In addition, one stained hematoxylin and eosin slide and 
two unstained slides will be requested. 
 
9.2.3 Shipping of correlative samples 
 
Blood samples will be shipped from the centers to the Specimen Accessioning Core Lab 
at Johns Hopkins. 
 
 

 
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27 
Biopsy samples will be shipped from the centers to
lab at 
Johns Hopkins. 
 
 
9.2.4 Handling of specimen(s) 
A unique patient identifier will be assigned to each patient by the 
coordinating center. The same unique patient identifier linked to the 
tumor biopsies will be used to shield the archived blood samples. The 
protocol scientific investigator(s) handling the samples will be 
blinded as to the patient identification, patient data and outcome. 
After shipping, samples, and associated data, will be stored at Johns 
Hopkins unless the patient withdraws consent. 
 
10. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 21 days prior to start of protocol therapy.  
Scans and x-rays must be done <4 weeks prior to the start of therapy.  In the event that the 
patient’s condition is deteriorating, laboratory evaluations should be repeated within 48 hours 
prior to initiation of the next cycle of therapy. 
 
 
Pre-
enrollment 
Day 1 of 
each cycle 
Day 8 of each 
cycle 
Time of 
progressione 
Treatment 
 
 
 
 
Gemcitabine 
 
X 
X 
 
Docetaxel 
 
 
X 
 
Tests and 
Observations 
 
 
 
 
H & P 
X 
X 
 
X 
CHFR and MSI testinga 
Xa 
 
 
 
Vital signs 
X 
X 
X 
X 
Height 
X 
 
 
 
Weight/BSA 
X 
X 
 
X 
Performance status 
X 
X 
 
X 
Tumor measurements 
X 
A 
 
X 
QOL assessment 
[(screening and q 2 cycles) 
C3D1, C5D1, etc] d 
X d 
X d 
 
X 
Laboratory Studies 
 
 
 
 
CBC with differential 
X 
X 
X 
X 
Complete Metabolic 
Xb 
Xb 
Xb 
Xb 

 
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28 
panelb 
Serum or urine HCG 
B 
 
 
 
CEA 
X 
X 
 
 
Urinalysis 
X 
 
 
 
Staging 
 
 
 
 
CT scan chest, 
abdomen, pelvis 
X 
C 
 
X 
Laboratory Correlates 
 
 
 
 
Research Bloodc 
X 
Xc 
 
Xc 
Archival Tissuea 
Xa 
 
 
 
 
 
A – Within 2 days of treatment if accessible by physical exam 
B – For women of child-bearing potential 
C – CT scan required every 2 cycles beginning prior to start of cycle 3 
 
a:  MSI testing via IHC and PCR will be assessed and 10 unstained slides are needed for CHFR analysis 
and 20 unstained slides from archival tissue for other planned methylation analyses. 
b:  Sodium, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, albumin, alkaline 
phosphatase, total bilirubin, total protein, SGOT [AST], SGPT [ALT]  
c:  Research blood: 6 purple top tubes, 3ml each processed per protocol section 9.2.1 
d: The quality of life assessments will be completed at screening, after every two cycles (C3D1, 
C5D1, C7D1, etc), and at time of progression (EOT)  
e: Per Section 5.4, subjects will be followed for 4 weeks after cessation of study treatment for 
resolution of toxicity, and then every three months until death. Follow-up for survival will be via 
email, phone call, or by checking the electronic patient record system to verify subject’s status.   

 
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29 
11. MEASUREMENT OF EFFECT 
 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 6 
weeks.  In addition to a baseline scan, confirmatory scans should also be obtained 6  
(not less 4) weeks following initial documentation of objective response. 
 
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) [Eur J Ca 45:228-247, 2009].  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. 
 
11.1 
Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of 
their first treatment. 
 
Evaluable for objective response.  Only those patients who have measurable 
disease present at baseline, have received at least one cycle of 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.  
 
 
 
11.2 
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 or as >10 mm with CT scan, MRI, or calipers by clinical 
exam.  All tumor measurements must be recorded in millimeters (or decimal 
fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or 
might not be considered measurable. 
 

 
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30 
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. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small 
lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 
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 non-
measurable) 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 not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up.  
 
11.3 
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 

 
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31 
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.  
 
Chest x-ray  Lesions on chest x-ray are acceptable as measurable lesions when 
they are clearly defined and surrounded by aerated lung.  However, CT is 
preferable.  
 
Conventional CT and MRI  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 breath-hold scanning techniques, if 
possible. This study will only use standard CT scans, and not MRI, or PET-
CT / FDG PET scans. 
 
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not 
be used as a method of measurement.  Ultrasound examinations cannot be 
reproduced in their entirety for independent review at a later date and, because 
they are operator dependent, it cannot be guaranteed that the same technique and 
measurements will be taken from one assessment to the next.  If new lesions are 

 
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32 
identified by ultrasound in the course of the study, confirmation by CT or MRI is 
advised.  If there is concern about radiation exposure at CT, MRI may be used 
instead of CT in selected instances. 
 
Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm 
complete pathological response when biopsies are obtained or to determine 
relapse in trials where recurrence following complete response (CR) or surgical 
resection is an endpoint. 
 
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 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]. 
 
Cytology, Histology  These techniques can be used to differentiate between 
partial responses (PR) and complete responses (CR) in rare cases (e.g., residual 
lesions in tumor types, such as germ cell tumors, where known residual benign 
tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears 
or worsens during treatment when the measurable tumor has met criteria for 
response or stable disease is mandatory to differentiate between response or stable 
disease (an effusion may be a side effect of the treatment) and progressive 
disease. 
 
 
11.4 
Response Criteria 
 
11.4.1 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 

 
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33 
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. 
 
11.4.2 Evaluation of Non-Target Lesions 
 
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). 
 
 

 
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34 
 
11.4.3 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. 
Confirmation** 
CR 
Not 
evaluated 
No 
PR 
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 or 
No 
PD 
no prior SD, PR or 
CR 
Any 
PD*** 
Yes or 
No 
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 

 
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35 
“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 
 
 
11.5 
Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded 
since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that 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.  
 
11.6 
Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of 
progression or death, whichever occurs first. 
 
11.7 
Response Review 
 
All responses will be reviewed by experts independent of the study at the study’s 
completion.  Simultaneous review of the patients’ files and radiological images 
will be performed. 

 
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36 
 
12.  
DATA REPORTING / REGULATORY REQUIREMENTS 
 
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 
(9/22/2011). The Clinical Research Office QA Group will perform an audit at the end of 
the first year 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. 
 
12.1 
Data Reporting 
 
 
 
12.1.1 Method  
 
This study will be monitored by Johns Hopkins SKCCC Clinical Research Office 
(CRO).  Cumulative protocol- and patient-specific data will be recorded 
electronically in the  SKCCC CRMS web-based database with study specific 
electronic CRFs.  Data must be submitted with 28 days of each study visit. All 
sites will have access to the CRMS database.   
 
Non-lead sites will submit all source documents for eligibility and registration 
verification for monitoring by the SKCCC.  In addition, every third patient will be 
monitored by the lead site with full research chart review to be submitted, 
deidentified, and on site monitoring may be applicable as well. 
 
 
12.1.2 Responsibility for Data Submission 
 
 
Study participants are responsible for submitting data and/or data forms to either 
the Coordinating Center.  The date for submission to the Coordinating Center is 
described above (28 days from patient visit).   
 
12.2 
Multicenter Guidelines 
 
This protocol will adhere to the policies and requirements of the Multicenter 
Guidelines.  The specific responsibilities of the Principal Investigator and the 
Coordinating Center (Study Coordinator) and the procedures for auditing are 
presented in Appendix B. 
 The Principal Investigator/Coordinating Center is responsible for distributing all 
IND Action Letters or Safety Reports to all participating institutions for 
submission to their individual IRBs for action as required. 
 Each institution will be responsible for ordering treatment drugs. 
 

 
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37 
 
13. 
STATISTICAL CONSIDERATIONS 
 
 
13.1 
Study Design/Endpoints 
 
Statistical Methods 
 
Patients with early colorectal cancer can often undergo curative resection. Metastatic disease, however, is 
common at the time of diagnosis, and prognosis in these cases is poor. Gene mutations and other tumor 
biomarkers have recently been identified for screening and treatment selection. This study will evaluate the 
combination of gemcitabine and docetaxel for  treatment in late stage colon cancer patients after resistance 
to at least first line therapy.  Patients with either microsatellite instability (MSI) or CHFR methylation will 
be chosen for this targeted therapy.  It is estimated that 20-30% of colon cancers will be positive for one or 
the other of these markers.     
 
Primary objective:  The primary objective for this study will be the response rate.   
 
Secondary objectives: 
1) Progression-free survival (PFS) will be defined from the date of study entry to the date of 
progression or death.  The median PFS will be compared to a historical median, estimated to be 8 
weeks. 
 
Study design:  Considerations for the design of this study included efficiency with a small number of 
patients, aggressive early stopping if the treatment is ineffective, and an improvement of the response rate 
from a historical rate of 20% to a rate of 30% with the targeted combined therapy.  The Bayesian hypothesis 
testing approach by Johnson and Cook1 was chosen to accommodate these requirements.  This design has 
increased efficiency compared to Bayesian designs defined from posterior credible intervals.  The increase 
in efficiency results from using non-local prior densities to define the alternative hypothesis.  Unlike vague 
prior specification or local prior densities, non-local prior densities are not positive at values of the 
parameter that are consistent with the null hypothesis, i.e. they are restricted to an interval consistent with 
the alternative.  This increases the rate at which a trial can accumulate evidence in favor of a true null 
hypothesis.  The class of non-local prior densities used in this design is called inverse moment (iMOM) 
densities2.  For this trial, the null hypothesis of interest is a point null hypothesis that the response rate is 
20% (i.e. Ho: θ = θ0).  With this null hypothesis, the form of an iMOM prior for the alternative hypothesis 
of 30% is given below with parameters: θ0=0.20, τ=.015, k=1 and ν=2, for 0.20<θ<1.0.  This prior assigns 
a value of zero outside the interval (0.20, 1.0) since, under the alternative hypothesis, θ is greater than 0.20.   
 
π1[θ; 𝜃0, k, 𝜈, 𝜏] =
𝑘𝜏
𝜈
2
Gamma[ 𝜈
2𝑘]
((𝜃−𝜃0)2)−𝜈+1
2 Exp[−((𝜃−𝜃0)2
𝜏
)−𝑘] 
 
When plotted over the range of 0 to 1 this prior takes the form shown in Figure 4.  This density exponentially 
approaches zero as θ approaches the null, 0.20.  τ represents a parameter that determines the dispersion of 
the prior around θ0 and it is set so that the mode of the prior density occurs at values deemed most likely 
under the alternative, 0.30.  k and ν have been set to recommended default values of 1 and 2 respectively.       
 
Figure 4.  Normalized iMOM prior density with parameters: θ0=0.20, τ=.015, k=1 and ν=2 
 

 
Version 6 
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38 
 
    
Sample size: For this trial a maximum of 40 patients are available for enrollment.  The design is based on 
a hypothesis test using the iMOM prior with the null and alternative hypotheses:  
 
 
 
 
   Ho: θ=0.20 
Ha: π1(θ) α π1(θ; θ0=0.20, k=1, ν=2, τ=0.015)I(0.20,1)(θ) 
 
This will test the null hypothesis that the combination treatment has a 20% response rate compared to an 
alternative hypothesis of greater than or equal to 20% with the specified iMOM prior (Figure 1.).  It will be 
stopped for inferiority if the posterior probability for the alternative model is less than 0.15, and the trial 
will not be stopped for superiority.  The stopping boundaries for this design call for accrual to stop if there 
are 0 responses out of 10 patients, 1 response in 14 patients, 2 responses in 18 patients, 3 responses in 21 
patients, 4 responses in 25 patients, 5 responses in 29 patients, 6 responses in 33 patients, or 7 responses in 
37 patients. 
 
 
Operating characteristics:  The exact operating characteristics3 of this stopping boundary, given 
hypothetical true response rates of 0.05 to 0.40 by 0.05, are shown in Figure 2.  If the study response rate 
is 10%, the probability the trial would be terminated early is 98% and the average sample size would be 
16.1 patients.  If the response rate is 20%, the trial would terminate early 64% of the time and have an 
average of 27.6 patients.  A study with a 30% response rate would only terminate early 18% of the time 
and the average sample size would be 36.6. 
 
Analysis of primary objective:  If the trial is terminated early, the gemcitabine/docetaxel combination 
therapy for this group of patients will not be pursued further.  If the trial is not terminated before the 40th 
patient accrues, the treatment may be worthy of further investigation.  At the end of the trial the response 
rate and the 95% exact binomial confidence interval will be calculated.  The logarithm of the Bayes Factor 
(BF), considered the weight of evidence, against the null hypothesis will also be calculated.  This will be 
negative if the null hypothesis is more supported by the data and positive if the alternative is more 
supported.  For this study, with a sample size of 40 and the specified null and alternative hypotheses, the 
expected (average) weight of evidence against the null when the null hypothesis is true is -1.56.  Weights 
of evidence, positive or negative, in the range of 0-1 are considered inconclusive.  The trial is stopped early 
for futility if the BF is less than -1.74 indicating moderate evidence for the null hypothesis.  The treatment 
may not be considered further if the BF is between -1.74 and 1.6 and we would continue study of this 
treatment combination if the BF is greater than 1.6, suggesting moderate evidence against the null 
hypothesis.  For this study, a response rate of 13/40 (32.5%) would correspond to a log(BF) of 1.3 and a 
response rate of 14/49 (35%) would yield a log(BF) of 2.0.       
0.2
0.4
0.6
0.8
1.0
1
2
3
4
5
6
7
prior : f

 
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39 
 
 
 
       
 
Analysis of secondary objectives:  
 
1) Progression free survival: Standard life table methods will be used to analyze PFS.  We will report 
the one and two-month PFS with 95% confidence intervals.  The one-month PFS will be compared 
to the null PFS of x% with a Z-score and a one-sided alpha level of 0.05. 
2) Quality of life: An overall quality of life score will be obtained from the QLQ-C30 and QLQ-CR29 
standardized questionnaire pre-treatment and at the time of the 2nd radiologic assessment or time of 
progression, whichever comes first.  The change in score will be evaluated with a paired t-test.  
Subscale scores of the quality of life questionnaire will be similarly analyzed 
3) Definitions and Analyses of Translational Endpoints: 
All analyses described in this section are based on the availability of the 
data. We recognize that sample sizes are not sufficient to carry out 
formal hypothesis testing and the analyses will be of an exploratory 
fashion, to generate hypotheses for validation in subsequent studies. 
 
The statistical analyses described in this paragraph will be applied all the 
biomarkers listed in sections ‘a’ through ‘c.’ Associations between 
biomarkers listed below and endpoints of interest (confirmed response and 
PFS) will be analyzed using variety of methods. Biomarker measures will 
be analyzed as continuous variables (suitable transformation to assure 
normality may be applied), and as categorical variables by splitting into 
quantiles of the distribution. The Wilcoxon Rank Sum test (or Kruskal- 
Wallis test) and Fisher’s exact test will be used to compare continuous and 
categorical variables between groups if applicable, respectively. Logistic 
regression and Cox proportional hazard regression techniques will be 
applied for dichotomous and time-to-event outcomes, respectively. These 
models may include baseline factors to adjust for confounding effect, 
when applicable. Additional exploratory analyses including, but not 
limited to, alternative approaches are expected and may be performed. 
a) Gene expression by qRT-PCR. Associations between measures 
of Gene expression and outcome of interest (tumor response and 
PFS) will be analyzed according the statistical methods described 
above. 
b)  Gene methylation status for selected genes (tumor). 
Associations between measures of Gene methylation status in 
tumors and outcome of interest (tumor response and PFS) will be 
analyzed according the statistical methods described above. In 
addition, the associations between measures of gene methylation 
status in tumor and gene expression measures assessed in section 
13.331 will be summarized by Trellis scatterplot matrix, along 
with the estimated Spearman correlation coefficients. 
c) Gene methylation status for selected genes (circulating). 
Associations between measures of Gene methylation status in 
circulating DNA and outcome of interest (tumor response and 
PFS) will be analyzed according the statistical methods described 

 
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above. In order to explore whether circulating DNA can be used as 
a surrogate for tissue base methylation measurements, the 
associations between measures of gene methylation in circulation 
DNA and those in tumor will be assessed using variety of methods, 
including to, not limit to, simple correlation method (Spearman 
correlation), linear regression. 
 
Figure 5.
 
 
 
References: 
1Johnson, V.E. and Cook, J.D.  Bayesian design of Single-Arm Phase II Clinical Trials with Continuous 
Monitoring. Clinical Trials 2009; 6(3):217–26. 
 
2Johnson, V. and Rossell, D. On the use of non-local prior densitites in Bayesian hypothesis tests.  J. R. 
Statist. Soc. B (2010) 72, Part 2, 143–170. 
 
3Cook, J.  Exact operating characteristics for single-arm Phase II trials (2008). UT MD Anderson Cancer 
Center Department of Biostatistics Working Paper Series.  Working Paper 45.   
 
0.0
0.2
0.4
0.6
0.8
1.0
0
3
6
9
12
16
20
24
28
32
36
40
   
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
Exact operating characteristics for single-arm phase II trial
Denominator of stopping boundary
Probability of treating the jth patient
True probability of response
Boundary:
0
10
1
14
2
18
3
21
4
25
5
29
6
33
7
37
p
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
PET
1
0.98
0.87
0.64
0.38
0.18
0.07
0.03
Avg
12.4
16.1
21.5
27.6
33
36.6
38.5
39.4

 
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41 
 
 
13.2 
Sample Size/Accrual Rate:  The target sample size is 40 patients.  We would expect 
to accrue approximately 2 patients per month with target completion within 20 months of study 
opening. 
 
 
13.3 
Analysis of Secondary Endpoints: Secondary endpoints for this study are standard 
progression free survival and overall survival.  Progression free survival is the time from the start 
of study enrollment to the first evidence of radiographic progression or death.  Overall survival is 
the time from the start of study enrollment to death. 
 
 
 
 
 
 
13.4 
Reporting and Exclusions 
 
13.4.1 Evaluation of toxicity – All patients will be evaluable for toxicity from the time 
of their first treatment. 
 
13.4.2 Evaluation of response – All patients included in the study must be assessed for 
response to treatment, even if there are major protocol treatment deviations or if 
they are ineligible.  Each patient will be assigned one of the following 
categories:  1) complete response, 2) partial response, 3) stable disease, 4) 
progressive disease, 5) early death from malignant disease, 6) early death from 
toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data).  [Note:  By arbitrary convention, category 9 usually 
designates the “unknown” status of any type of data in a clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of 
those who received no study medication) should be included in the main 
analysis of the response rate.  Patients in response categories 4-9 should be 
considered to have a treatment failure (disease progression).  Thus, an incorrect 
treatment schedule or drug administration does not result in exclusion from the 
analysis of the response rate.  Precise definitions for categories 4-9 will be 
protocol specific.  
 
All conclusions should be based on all eligible patients.  Subanalyses may then 
be performed on the basis of a subset of patients, excluding those for whom 
major protocol deviations have been identified (e.g., early death due to other 
reasons, early discontinuation of treatment, major protocol violations, etc.).  
However, these subanalyses may not serve as the basis for drawing conclusions 
concerning treatment efficacy, and the reasons for excluding patients from the 
analysis should be clearly reported.  The 95% confidence intervals should also 
be provided.  
 
 
 

 
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42 
References 
1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D.  CA Cancer J Clin. 2011 Mar-
Apr;61(2):69-90. 
2. American Cancer Society. Colorectal Cancer Facts & Figures 2011-2013. Atlanta: American Cancer 
Society, 2011.  
3. Tebbutt, N. C., E. Cattell, et al. Eur J Cancer. 2002 May;  38(7): 1000-1015. 
4. Davies JM, Goldberg RM. Semin Oncol. 2011 Aug;38(4):552-60. 
5. Mani S, Kugler JW, Knost JA, Sciortino DF, Gibbons J, Ansari RH, Schilsky RL, Vokes EE. Invest 
New Drugs. 1998-1998; 16(3): 275-278. 
6. Abbruzzese JL, Grunewald R, Weeks EA, Gravel D, Adams T, Nowak B, Mineishi S, Tarassoff P, 
Satterlee W, Raber MN, et al. J Clin Oncol. 1991 Mar; 9(3): 491-498. 
7. Poplin EA, Corbett T, Flaherty L, Tarassoff P, Redman BG, Valdivieso M, Baker L. Invest New 
Drugs. 1992 Aug; 10(3): 165-170. 
8. Moore DF Jr, Pazdur R, Daugherty K, Tarassoff P, Abbruzzese JL. Invest New Drugs. 1992 Nov; 
10(4): 323-325. 
9. Chong G, Starling N, Norman AR, Brown G, Thomas J, Ross PJ, Cunningham D. J Clin Oncol. 2006 
ASCO Annual Meeting Proceedings Part I. Vol 24, No 18S. 2006 Jun 20. 13558. 
10. Merl M, Hoimes C, Pham T, Saif MW. Expert Opin Investig Drugs. 2009 Sep; 18(9): 1257-1264. 
11. Saif MW, Kaley K, Penney R, Hotchkiss S, Syrigos KN, Strimpakos AS. Anticancer Res. 2011 Sep; 
31(9): 2971-2974. 
12. Stemnberg CN, W.W. Ten Bokkel Huinink, WW, Smyth JF, Bruntsch, V, Dirix, LY, 
Pavhdis NA, Franklin, H, Wanders, S, Le Bail, N, Kaye SB. Br J Cancer. 1994 Apr; 70: 376-379. 
13. Pazdur R, Lassere Y, Soh LT, Ajani JA, Bready B, Soo B, Sugarman S, Patt Y, Abbruzzese JL, Levin 
B. Ann Oncol. 1994 May; 5(5): 468-470. 
14. Clark TB, Kemeny NE, Conti JA, Huang Y, Andre AM, Stockman J. Cancer Invest. 1998;16(5):314-
8. 
15. Kurzawski, G., J. Suchy, et al. Ann Oncol. 2004; 15 Suppl 4: iv283-284. 
16. Takahashi T, Min Z, Uchida I, Arita M, Watanabe Y, Koi M, Hemmi H. Cancer Lett. 2005 Mar 18; 
220(1):85-93.  
17. Kang D, Chen J, et al. J Cell Biol. 2002 Jan 21; 156(2): 249-260. 
18. Koga, Y, Kitajima Y, et al. J Gastroenterol. 2006 Feb; 41:133–139 
 
19. Wang X, Yang Y, et al. Int J Gynecol Cancer. 2011 Aug; 21(6):996-1003. 
20. Banno K, Yanokura M, Kawaguchi M, Kuwabara Y, Akiyoshi J, Kobayashi Y, Iwata T, Hirasawa A, 
Fujii T, Susumu N, Tsukazaki K, Aoki D. Int J Onc. 2007 Oct; 31(4): 713-720, 2007 
21. Yoshida, K., Y. Hamai, et al. Anticancer Res. 2006 Jan-Feb; 26(1A): 49-54. 
22. Koga Y, Kitajima Y, Miyoshi A, Sato K, Sato S, Miyazaki K. J Gastroenterology. 2006 Feb;  
41(2): 133-9 
23. Brandes JC, van Engeland M, Wouters KA, Weijenberg MP, Herman JG. Carcinogenesis. 2005  
Jun; 26(6):1152-6. 
24. Georgoulias V, Papadakis E, Alexopoulos A, Tsiafaki X, Rapti A, Veslemes M, Palamidas P, 
Vlachonikolis I. Lancet. 2001 May 12; 357(9267):1478-84. 
25. Binder D, Schweisfurth H, Grah C, Schäper C, Temmesfeld-Wollbrück B, Siebert G, Suttorp N, 
Beinert T. Cancer Chemother Pharmacol. 2007 Jun; 60(1):143-50. 
26. Metro G, Fabi A, Russillo M, Papaldo P, De Laurentiis M, Ferretti G, Pellegrini D, Nuzzo C, 
Graziano V, Vici P, Introna M, Felici A, Cognetti F, Carlini P. Anticancer Res. 2008 Mar-
Apr;28(2B):1245-58. 
27. Itani Y, Hosokawa K, Ito K, Takeuchi S, Tabata T, Tsubamoto H, Fujita H, Akiyama M, Adachi S. 
Anticancer Res. 2009 May;29(5):1521-6. 
28. Spiridonidis CH, Laufman LR, Jones J, Rhodes VA, Wallace K, Nicol S. J Clin Oncol. 1998 Dec; 
16(12): 3866-3873. 

 
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Version date: November 19, 2015 
 
43 
29. Ryan DP, Lynch TJ, Grossbard ML, Seiden MV, Fuchs CS, Grenon N, Baccala P, Berg D, 
Finkelstein D, Mayer RJ, Clark JW. Cancer. 2000 Jan 1; 88(1): 180-185. 
30. Mekhail T, Hutson TE, Elson P, Budd GT, Srkalovic G, Olencki T, Peereboom B, Pelley R, 
Bukowski RM. Cancer. 2003 Jan; 97(1): 170-178. 
 

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

 
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APPENDIX B 
 
 
MULTICENTER GUIDELINES 
 
Responsibility of the Protocol Chair  
 The Protocol Chair is responsible for the coordination, development, submission, and 
approval of the protocol as well as its subsequent amendments.  The protocol must not be 
rewritten or modified by anyone other than the Protocol Chair.  There will be only one 
version of the protocol, and each participating institution will use that document.  The 
Protocol Chair is responsible for assuring that all participating institutions are using the 
correct version of the protocol. 
 The Protocol Chair is responsible for the overall conduct of the study at all participating 
institutions and for monitoring its progress.  All reporting requirements are the 
responsibility of the Protocol Chair.  
 The Protocol Chair is responsible for the timely review of Adverse Events (AE) to assure 
safety of the patients. 
 The Protocol Chair will be responsible for the review of and timely submission of data 
for study analysis. 
 
Responsibilities of the Coordinating Center 
 The Coordinating Center is responsible for assuring that each participating institution has 
an IRB approval and must maintain copies of IRB approvals from each participating site.  
 The Coordinating Center is responsible for central patient registration.  The Coordinating 
Center is responsible for assuring that IRB approval has been obtained at each 
participating site prior to the first patient registration from that site. 
 The Coordinating Center will maintain documentation of AE reports.  Participating 
institutions report to the Coordinating Center.  The Coordinating Center will submit AE 
reports to the Protocol Chair for timely review. 
 Selected patient records may be audited on-site at participating sites.  If the Coordinating 
Center chooses to have an audit at the participating institution, then the Coordinating 
Center is responsible giving notice to the site to have all source documents, research 
records, all IRB approval documents, patient registration lists, response assessments 
scans, x-rays, etc. available for the audit. Though the Coordinating Center may schedule 
an audit, the sites will be responsible for their own internal monitoring and auditing on a 
regular basis. The Coordinating Center may request documentation of these internal 
processes.  
 
Participating Sites 
 
Participating sites are responsible for performing the following tasks: 
 Following the protocol as written, and the guidelines of Good Clinical Practice 
(GCP). 
 Submitting data to the Coordinating Center. 
 Registering all patients with the Coordinating Center by submitting patient 
registration form, and signed informed consent promptly. 

 
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 Providing sufficient experienced clinical and administrative staff and adequate 
facilities and equipment to conduct a collaborative trial according to the protocol. 
 Maintaining regulatory binders on site and providing copies of all required documents 
to the Coordinating Center. 
 
Collecting and submitting data according to the schedule specified by the protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix C  

 
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Cytochrome 450 3A4 interations 
 
Inducers 
Aminoglutethimide 
Bexarotene 
Bosentan 
Carbamazepine 
Dexamethasone 
Efavirenz 
Fosphenytoin 
Griseofulvin 
Modafinil 
Nafcillin  
Nevirapine 
Oxcarbazepine 
Phenobarbital 
Phenytoin 
Primidone 
Rifabutin 
Rifampin 
Rifapentine 
St. John's wort  
 
Inhibitors 
 
Amiodarone 
Amprenavir 
Aprepitant 
Atazanavir 
Chloramphenicol 
Clarithromycin 
Conivaptan 
Cyclosporine 
Darunavir 
Dasatinib 
Delavirdine 
Diltiazem 
Erythromycin 
Fluconazole 
Fluoxetine 
Fluvoxamine 
Fosamprenavir 
Grapefruit juice  
Imatinib 
Indinavir 
Isoniazid 
Itraconazole 
Ketoconazole 
Lapatinib 
Miconazole 
Nefazodone 
Nelfinavir 
Posaconazole 
Ritonavir 
Quinupristin 
Saquinavir 
Tamoxifen 
Telithromycin 
Troleandomycin 
Verapamil 
Voriconazole  
 
 
 
 
 
 
APPENDIX D 

 
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