Clinical trial NCT02138617
Conditions: Colon Cancer
Keywords: Colon Cancer Irinotecan FOLFIRI Genotyping UGT1A1
Sponsor: UNC Lineberger Comprehensive Cancer Center
Start date: 2014-05-06; Completion date: 2024-08-01
Enrollment: 100 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study involves standard combination chemotherapy treatment for colon cancer, 5-Fluorouracil (5FU), leucovorin and irinotecan (known as FOLFIRI), plus bevacizumab (Avastin). The study is designed to test the FOLFIRI regimen based on certain characteristics of a person's genetic makeup or "genes". Genes are made of DNA and determine not only inherited traits or appearance (hair and eye color, height, body type, etc.) but also play an important role in health and how the body responds to illness and treatments for those illnesses.

In this study, the investigators will examine the relationship between a patient's genes (DNA), or "genotype", and how the patient's body breaks down and removes or "metabolizes" the anti-cancer drug irinotecan. Circulating blood level of irinotecan plays an important role in how well this drug works against a patient's cancer as well as the adverse side effects the patient may experience. The current standard dose of irinotecan was determined in clinical trials without knowing individual genotypes and thus does not take into account a patient's ability to metabolize irinotecan. This means that based on one genotype the current standard dose of irinotecan may be correct or based on other genotypes the standard dose could result in lower and possibly less effective blood levels and result in significant under-dosing of irinotecan.

Based on genotype the patient will be assigned to one of the following doses of irinotecan:

* 180 mg/m2 (standard dose)
* 260 mg/m2
* 310 mg/m2

The purpose of this research study is to determine if dosing irinotecan based on genotype is effective and safe for patients with colon cancer. Patient genotype will be determined from a small sample of blood and a laboratory test or "assay" performed at University of North Carolina Laboratories. For the purpose of this study, this assay is new and considered to be "investigational". This means that the genotype assay used in this study has not yet been approved by the FDA for determining irinotecan dose levels in patients with colon cancer.

Detailed description:
This phase II multicenter clinical trial will use a genotype-guided dosing strategy for irinotecan to prospectively analyze efficacy in 100 metastatic colorectal cancer patients (mCRC) receiving FOLFIRI (5-fluorouracil (5-FU), leucovorin, irinotecan) plus bevacizumab. Irinotecan is detoxified and excreted primarily by glucuronidation in the liver via the isoenzyme uridine diphosphate glucuronosyl transferase (UGT1A1). Common variants in UGT1A1 alter the rate of glucuronidation and thus alter exposure to irinotecan.

The UGT1A1 \*28 allele results in slower irinotecan glucuronidation, and thus greater exposure to its active metabolite SN-38. At the standard irinotecan dose used in FOLFIRI (180 mg/m2; established prior to our understanding of the importance of genotype in the rate of this drug's metabolism), there is a small increased risk of neutropenia in \*28 homozygotes. However, the risk of clinically important consequences of neutropenia, such as febrile neutropenia and infection, are not significantly increased. Patients with other genotypes have a quite low risk of adverse effects suggesting patients with these low risk genotypes may tolerate higher doses of irinotecan in FOLFIRI. This finding was demonstrated in a phase I study in which \*1/\*28 and \*1/\*1 genotypes were able to tolerate escalating doses of irinotecan up to 260 mg/m2 and 310 mg/m2, respectively.

The central hypothesis of this trial is that increasing the irinotecan dose in \*1/\*28 and \*1/\*1 genotypes will increase the overall benefit of FOLFIRI for patients with mCRC as these two groups are likely under-dosed with the current dosing regimen. Eligible patients will be genotyped for UGT1A1 and assigned into 1 of 3 different dosing groups, based on their relative rate of metabolism. The primary objective of this trial is to estimate progression-free survival (PFS), and secondary objectives include characterization of toxicity and objective response rate (OR; complete response (CR) + partial response (PR)).

Arms: arm 1: FOLFIRI (5-fluorouracil (5-FU), leucovorin, irinotecan) Irinotecan dose 310 mg/m2,(IV, Day 1, 15); Bevacizumab (IV, Day 1, 15), repeat treatment cycle every 28 days. arm 2: FOLFIRI (5-fluorouracil (5-FU), leucovorin, irinotecan) Irinotecan dose 260 mg/m2, FOLFIRI (IV, Day 1, 15); Bevacizumab (IV, Day 1, 15), repeat treatment cycle every 28 days. arm 3: FOLFIRI (5-fluorouracil (5-FU), leucovorin, irinotecan) Irinotecan dose 180 mg/m2, FOLFIRI (IV, Day 1, 15); Bevacizumab (IV, Day 1, 15), repeat treatment cycle every 28 days.
Interventions: intervention 1: 5-Fluorouracil intervention 2: Leucovorin intervention 3: Irinotecan intervention 4: Bevacizumab
Intervention descriptions: intervention 1: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV over 46 hours, Day 1 and Day 15 . intervention 2: 200-400 mg/m2 IV over 2 hours, Day 1 and Day 15 intervention 3: IV infusion over 90 minutes, dosed at 180, 260 or 310 mg/m2 based on genotype. intervention 4: Bevacizumab (5 mg/kg IV infused as per institutional policy, IV, Day 1, 15)

Protocol documents:
Prot_SAP_000.pdf: 
UNC LINEBERGER  
CLINICAL ONCOLOGY RESEARCH PROGRAM 
UNVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
PROTOCOL AMENDMENT #05 
LCCC  1317: GENIC, A Genotype-directed Phase II Study of Irinotecan 
Dosing in Metastatic Colorectal Cancer (mCRC) Patients Receiving 
FOLFIRI + Bevacizumab 
AMENDMENT INCORPORATES (check all that apply): 
  X  Editorial, administrative changes 
___ Scientific changes (IRB approval) 
___ Therapy changes (IRB approval) 
___ Eligibility Changes (IRB approval) 
Summary of Changes: 
1. Section 4.3 – clarify that Bevacizumab initiation may be delayed until cycle 2
day 1 at the discretion of the investigator in case of prior minor surgery.
2. Section 6.0, Time and Events Table – a five business day window for when
the clinician should complete the PRO-CTCAE Clinician Form was added to
footnote #11.
3. Section 9.1 – the Clinician or a designee (such as the study coordinator) may
complete the PRO-CTCAE Clinician Form on Day 15. Additionally, mandatory
participation in the PRO-CTCAE sub-study is not required for non-English
speaking patients and they will not be asked to participate.
4. Section 9.6.2 – a designee may complete the PRO-CTCAE Clinician Form on
Day 15.
5. Section 12.8 (Appendix H) – the PRO-CTCAE Clinician Form signature line
was revised to indicate a designee may sign as well as the investigator.
THE ATTACHED VERSION DATED JULY 11, 2018 INCORPORATES THE ABOVE 
REVISIONS 
ATTACH TO THE FRONT OF EVERY COPY OF PROTOCOL 


UNC LINEBERGER  
CLINICAL ONCOLOGY RESEARCH PROGRAM 
UNVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
 
 
 
PROTOCOL AMENDMENT #04 
 
 
LCCC  1317: GENIC, A Genotype-directed Phase II Study of Irinotecan 
Dosing in Metastatic Colorectal Cancer (mCRC) Patients Receiving 
FOLFIRI + Bevacizumab 
 
AMENDMENT INCORPORATES (check all that apply): 
X__Editorial, administrative changes 
X
Scientific changes (IRB approval) 
X__Therapy changes (IRB approval) 
   
Eligibility Changes (IRB approval) 
 
Summary of Changes: 
 
1. Main Consent v10/11/17 - Updates the consent risk language for FOLFIRI and 
include cardiac risks for 5FU 
2. Section 4.2.2 - Clarifies that infusion times are provided as an approximate guide 
but may vary per institutional guidelines  
3. Section 4.3 - Clarifies that stopping and/or dropping irinotecan is allowed after 4 
cycles at treating physician’s discretion as warranted by disease status and side 
effects (ex. low tumor burden while experiencing significant AEs related to irino) 
4. Section 4.3 - Clarifies that leucovorin can be omitted at treating physician’s 
discretion 
5. Section 4.3 - Bevacizumab initiation may be delayed until cycle 1 day at the 
discretion of the investigator in case of prior minor surgery.  
6. Section 4.3.2 Footnote 6 - Clarifies that dose modifications are only required for 
clinically significant grade 3-4 adverse events (ex not required for asymptomatic 
electrolyte disturbances)  
7. Section 6.1 - Clarifies that UGT1A1 genotyping is determined from germline 
sequencing and once collected per protocol is not subject to a collection window. 
 
 
 
 
 
 
 
 
THE ATTACHED VERSION DATED October 04, 2017 INCORPORATES 
THE ABOVE REVISIONS 
ATTACH TO THE FRONT OF EVERY COPY OF PROTOCOL 
 


UNC LINEBERGER  
CLINICAL ONCOLOGY RESEARCH PROGRAM 
UNVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
 
 
 
PROTOCOL AMENDMENT #03 
 
 
LCCC  1317: GENIC, A Genotype-directed Phase II Study of Irinotecan Dosing in 
Metastatic Colorectal Cancer (mCRC) Patients Receiving FOLFIRI + Bevacizumab 
 
AMENDMENT INCORPORATES (check all that apply): 
X__Editorial, administrative changes 
   
Scientific changes (IRB approval) 
X__Therapy changes (IRB approval) 
   
Eligibility Changes (IRB approval) 
 
Summary of Changes: 
 
• Sect 4.3.2 FOLFIRI Dose Modifications:  revised to provide additional guidance 
for  grade 3 and 4 neutropenia and  grade 2 mucositis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
THE ATTACHED VERSION DATED December 09, 2015 INCORPORATES 
THE ABOVE REVISIONS 
ATTACH TO THE FRONT OF EVERY COPY OF PROTOCOL 
 
 
 
 
 


UNC LINEBERGER  
CLINICAL ONCOLOGY RESEARCH PROGRAM 
UNVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
 
PROTOCOL AMENDMENT # 02 
 
 
LCCC  1317: GENIC, A Genotype-directed Phase II Study of Irinotecan Dosing in 
Metastatic Colorectal Cancer (mCRC) Patients Receiving FOLFIRI + Bevacizumab 
 
AMENDMENT INCORPORATES (check all that apply): 
X
Editorial, administrative changes 
X    Scientific changes (IRB approval) 
 Therapy changes (IRB approval) 
X    Eligibility Changes (IRB approval) 
 
Summary of Changes 
1. Title revised to read: “GENIC, A Genotype-directed Phase II Study of Irinotecan 
Dosing in Metastatic Colorectal Cancer (mCRC) Patients Receiving FOLFIRI + 
Bevacizumab.” 
2. Section 9.1  Background , Appendices G and H: Recall interval (days) for 
PROCTCAE questionnaires revised from "previous 7 days" to "previous 14 
days". 
3. Remove Anna Snavely and add Allison Deal as statistician of record. 
4. Section 3.2.6. Added statement “Addition or increase of standard of care 
antihypertensive regimen to control hypertension is allowed.” 
5. Section 6.1 Time and events table: HISTORY footnote 4. The day 1 and 15 
“History” collected by study coordinator /personnel to assess adverse events, this 
revision also occurs in Sections 6.3.1, 6.3.2 and 6.4. 
6. Section 6.3.1, 6.3.2 and 6.4 Concomitant Medications: we are not collecting 
concomitant medication information, section is revised to state “review for 
prohibited concomitant medications”. 
7. Change exclusion 3.2.1.6 to: 
3.2.16 Proteinuria as demonstrated by: 
Urine protein: creatinine (UPC) ratio ≥ 1.0 at screening (patients 
discovered to have a UPC >=1 should undergo a 24 hour urine collection 
and must demonstrate ≤ 1g of protein in 24 hours to be eligible). 
OR  
“Urine dipstick for proteinuria ≥ 2+ (patients discovered to have ≥2+ 
proteinuria on dipstick urinalysis may either undergo Urine protein: 
creatinine (UPC) testing, and may participate if ratio <1. 0 or should 
undergo a 24 hour urine collection and must demonstrate ≤ 1g of protein 
in 24 hours to be eligible) 
8. Revised link in 12.6 Appendix F to http://medicine.iupui.edu/clinpharm/ddis/   
 
THE ATTACHED VERSION DATED February 10, 2015 INCORPORATES 
THE ABOVE REVISIONS 
ATTACH TO THE FRONT OF EVERY COPY OF PROTOCOL 
 


UNC LINEBERGER  
CLINICAL ONCOLOGY RESEARCH PROGRAM 
UNVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
 
 
PROTOCOL AMENDMENT #_01 
 
LCCC  1317: Genotype-directed Phase II Study of Irinotecan Dosing in Metastatic 
Colorectal Cancer (mCRC) Patients Receiving FOLFIRI + Bevacizumab 
 
AMENDMENT INCORPORATES (check all that apply): 
X__Editorial, administrative changes 
X    Scientific changes (IRB approval) 
___ Therapy changes (IRB approval) 
X    Eligibility Changes (IRB approval) 
 
AMENDMENT RATIONALE AND SUMMARY: 
 
Sections: 3.0, 6.0, 9.0, 10.3.2, 10.4.2, 12.7 Appendix G and 12.8 Appendix H -  
This amendment was driven by incorporation of a sub-study in LCCC1317.  This PRO-
CTCAE sub-study will evaluate the feasibility of a proposed system of collecting Patient 
Reported Outcomes (PRO) and corresponding clinician assessed symptomatic adverse 
events of interest in the LCCC 1317 population across multiple participating sites.   This 
change is reflected in the study synopsis, eligibility criterion 3.1.9, the Time and Events 
table, study assessment sections 6.2-6.3, in sections 10.3-10.4, and in detail in section 9.0. 
 
Title Page: Added investigators for the PRO-CTCAE sub-study: William A. Wood, MD, 
MPH; Ethan Basch, MD 
 
Sections: 6.1, 6.3.1, 6.3.3, 6.6.2, 6.6.3 -  In addition, the volume of blood for exploratory 
correlative studies within LCCC1317 was increased from 5mL to 10mLs (D1 cycle 1, 
and every odd numbered cycle thereafter), and from 5 to 5-7mLs (D1 cycle 1). 
 
Sections: 1.4, 3.1.9 and 3.2.2 - Modified eligibility criteria for LCCC1317 to exclude 
Asian patients from study because genotyping assay used does not test for *6 allele, 
which is more common in Asian patients. Patients with this allele would be classified as 
*1 carriers, placing them at increased risk of irinotecan-induced toxicity. Added reference 
#28. 
 
 
 
 
 
 
THE ATTACHED VERSION DATED MAY 2, 2014 INCORPORATES THE ABOVE 
REVISIONS 
ATTACH TO THE FRONT OF EVERY COPY OF PROTOCOL 
 






LCCC1317 
 
CONFIDENTIAL 
PI: Sanoff 
 
UNIVERSITY OF NORTH CAROLINA 
Version:  July 11, 2018 
 
i 
 
TABLE OF CONTENTS 
1.0 
BACKGROUND AND RATIONALE ..................................................................1 
1.1 
Study Synopsis ......................................................................................................1 
1.2 
Colorectal Cancer Therapy....................................................................................1 
1.3 
Irinotecan in mCRC ..............................................................................................2 
1.4 
Rationale................................................................................................................5 
2.0 
OBJECTIVES .........................................................................................................6 
2.1 
Primary Objective .................................................................................................6 
2.2 
Secondary Objectives ............................................................................................6 
2.3 
Exploratory Objective ...........................................................................................6 
2.4 
Endpoints ...............................................................................................................6 
3.0 
PATIENT ELIGIBILITY ......................................................................................7 
3.1 
Inclusion Criteria ...................................................................................................7 
3.2 
Exclusion Criteria ..................................................................................................7 
4.0 
TREATMENT PLAN .............................................................................................9 
4.1 
Schema ..................................................................................................................9 
4.2 
Treatment Dosage and Administration ...............................................................10 
4.3 
Toxicities and Dosing Delays/Dose Modifications .............................................11 
4.4 
Concomitant Medications/Treatments ................................................................17 
4.5 
Duration of Therapy ............................................................................................18 
4.6 
Duration of Follow Up ........................................................................................18 
4.7 
Removal of Patients from Protocol Therapy .......................................................18 
4.8 
Study Withdrawal ................................................................................................19 


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5.0 
DRUG INFORMATION ......................................................................................19 
5.1 
Irinotecan (Camptosar®) .....................................................................................19 
5.2 
5-Fluorouracil (5-FU) ..........................................................................................21 
5.3 
Leucovorin ..........................................................................................................23 
5.4 
Bevacizumab (Avastin®) ....................................................................................24 
6.0 
EVALUATIONS AND ASSESSMENTS ............................................................28 
6.1 
Time and Events Table ........................................................................................28 
6.2 
Pre-Study Assessments .......................................................................................30 
6.3 
On Study Assessments ........................................................................................31 
6.4 
End of Treatment Visit ........................................................................................31 
6.5 
Post-Treatment/Follow-up Assessments .............................................................32 
6.6 
Correlative Studies ..............................................................................................32 
6.7 
Assessment of Safety ..........................................................................................33 
6.8 
Assessment of Efficacy Based on RECIST 1.1...................................................33 
7.0 
ADVERSE EVENTS ............................................................................................36 
7.1 
Definitions ...........................................................................................................37 
7.2 
Documentation of non-serious AEs or SARs ......................................................38 
7.3 
SAEs or Serious SARs ........................................................................................39 
7.4 
Data and Safety Monitoring Plan ........................................................................40 
8.0 
STATISTICAL CONSIDERATIONS FOR LCCC 1317 .................................41 
8.1 
Study Design .......................................................................................................41 
8.2 
Sample Size, Stopping Rule and Safety Rule .....................................................41 
8.3 
Data Analysis Plans .............................................................................................42 
9.0 
PRO-CTCAE Sub-study ......................................................................................43 


LCCC1317 
 
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PI: Sanoff 
 
UNIVERSITY OF NORTH CAROLINA 
Version:  July 11, 2018 
 
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9.1 
Background .........................................................................................................43 
9.2 
Primary Objectives ..............................................................................................44 
9.3 
Secondary Objectives ..........................................................................................44 
9.4 
Exploratory Objectives ........................................................................................45 
9.5 
Primary Endpoints ...............................................................................................45 
9.6 
Methods ...............................................................................................................45 
9.7 
Statistical Considerations ....................................................................................46 
10.0 STUDY MANAGEMENT ....................................................................................47 
10.1 
Institutional Review Board (IRB) Approval and Consent ..................................48 
10.2 
Required Documentation.....................................................................................48 
10.3 
Registration Procedures.......................................................................................49 
10.4 
Data Management and Monitoring .....................................................................49 
10.5 
Auditing ...............................................................................................................50 
10.6 
Adherence to the Protocol ...................................................................................50 
10.7 
Amendments to the Protocol ...............................................................................52 
10.8 
Record Retention .................................................................................................52 
10.9 
Obligations of Investigators ................................................................................53 
11.0 REFERENCES ......................................................................................................54 
12.0 APPENDICES .......................................................................................................57 
12.1 
Appendix A ECOG Performance Status .............................................................57 
12.2 
Appendix B List of Prohibited Drugs and Prohibited Juices and Fruits .............58 
12.3 
Appendix C New York Heart Association Functional Classification .................59 
12.4 
Appendix D List of Drugs to be Used with Caution ...........................................60 
12.5 
Appendix E Dietetic and pharmacologic guidelines for the treatment of drug 
induced diarrhea .............................................................................................................61 


LCCC1317 
 
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PI: Sanoff 
 
UNIVERSITY OF NORTH CAROLINA 
Version:  July 11, 2018 
 
iv 
 
12.6 
Appendix F:  Patient Handout: Prohibited Medications or Those to be used with 
Caution ...........................................................................................................................67 
12.7 
Appendix G:  Subset of PRO-CTCAE Questions ...............................................69 
12.8 
Appendix H:  PRO-CTCAE Clinician Form ......................................................70 
 
 
 


LCCC1317 
 
CONFIDENTIAL 
PI: Sanoff 
 
UNIVERSITY OF NORTH CAROLINA 
Version:  July 11, 2018 
 
1 
 
1.0 
BACKGROUND AND RATIONALE 
1.1 
Study Synopsis 
This phase II multicenter clinical trial will use a genotype-guided dosing strategy 
for irinotecan to prospectively analyze efficacy in 100 metastatic colorectal cancer 
patients (mCRC) receiving FOLFIRI (5-fluorouracil (5-FU), leucovorin, 
irinotecan) plus bevacizumab. Irinotecan is detoxified and excreted primarily by 
glucuronidation in the liver via the isoenzyme uridine diphosphate glucuronosyl 
transferase (UGT1A1). Common variants in UGT1A1 alter the rate of 
glucuronidation and thus alter exposure to irinotecan.  
 
The UGT1A1 *28 allele results in slower irinotecan glucuronidation, and thus 
greater exposure to its active metabolite SN-38. At the standard irinotecan dose 
used in FOLFIRI (180 mg/m2; established prior to our understanding of the 
importance of genotype in the rate of this drug’s metabolism), there is a small 
increased risk of neutropenia in *28 homozygotes.  However, the risk of clinically 
important consequences of neutropenia, such as febrile neutropenia and infection, 
are not significantly increased. Patients with other genotypes have a quite low risk 
of adverse effects suggesting patients with these low risk genotypes may tolerate 
higher doses of irinotecan in FOLFIRI.  This finding was demonstrated in a phase 
I study in which *1/*28 and *1/*1 genotypes were able to tolerate escalating 
doses of irinotecan up to 260 mg/m2 and 310 mg/m2, respectively.   
 
The central hypothesis of this trial is that increasing the irinotecan dose in *1/*28 
and *1/*1 genotypes will increase the overall benefit of FOLFIRI for patients 
with mCRC as these two groups are likely under-dosed with the current dosing 
regimen. Eligible patients will be genotyped for UGT1A1 and assigned into 1 of 3 
different dosing groups, based on their relative rate of metabolism. The primary 
objective of this trial is to estimate progression-free survival (PFS), and   
secondary objectives include characterization of toxicity and objective response 
rate (OR; complete response (CR) + partial response (PR)).  
 
A sub-study of LCCC1317 is described in section 9.0.  This sub-study will 
evaluate the feasibility of a proposed system of collecting Patient Reported 
Outcomes (PRO) and corresponding clinician assessed symptomatic adverse 
events of interest in the LCCC 1317 population across multiple participating sites.   
This sub-study will be mandatory for all patients enrolled in LCCC1317 at UNC, 
and for all patients at Affiliate sites that elect to participate in this optional sub-
study. 
1.2 
Colorectal Cancer Therapy 
Worldwide, colorectal cancer is the fourth most commonly diagnosed malignant 
disease, with more than 500,000 deaths estimated every year. In the US, 
colorectal cancer is the third most common malignant disease and the second 


LCCC1317 
 
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Version:  July 11, 2018 
 
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most frequent cause of cancer-related death, with more than 50,000 deaths 
anticipated in 2013. [1] 
 
Acceptable first-line chemotherapy regimens for mCRC include FOLFIRI or 
FOLFOX (5-FU, leucovorin, oxaliplatin. [2, 3] Bevacizumab, the humanized 
monoclonal antibody against vascular endothelial growth factor (VEGF) approved 
for use in combination with chemotherapy for the treatment of mCRC, is 
routinely used in combination with FOLFIRI or FOLFOX for first-line treatment. 
[4-6]  
 
Epidermal growth factor receptor (EGFR)-targeted therapies (ie, cetuximab and 
panitumumab) are occasionally used in first-line therapy in combination with 
FOLFIRI or FOLFOX (as an alternative to bevacizumab).  However, they should 
only be used after KRAS genotyping of tumor tissue, as neither agent is effective 
in persons with KRAS mutated disease. [7-9]  
 
Unfortunately, regardless of whether FOLFIRI or a FOLFOX regimen with or 
without bevacizumab or EGFR-targeted therapy is used as first-line treatment, all 
patients progress and will require second-line and likely subsequent treatments. 
[2, 3, 6] This highlights the need for innovative systemic therapies or innovative 
approaches in patients with mCRC. 
1.3 
Irinotecan in mCRC 
The most commonly used dose of irinotecan within FOLFIRI is 180 mg/m2 every 
two weeks [2, 10] however, dose-finding studies during the early development of 
irinotecan were conducted before knowledge of the genetic basis of irinotecan 
associated severe toxicity.  When dosed based on body surface area and without 
regard to genotype, the rate of grade 3/4 neutropenia and diarrhea across all cycles 
in patients receiving FOLFIRI as first-line treatment of mCRC is reported to be 
24% and 14%, respectively, with a 7% incidence of febrile neutropenia. [2]  
 
There is extensive clinical experience in non-genotypically selected patients (e.g. 
including *28 homozygotes) with irinotecan at doses of 350 mg/m2 alone [11] 
(and in combination with other chemotherapy [12-14]. Single agent doses of 
irinotecan up to 500 mg/m2every 21 days were tolerated in a non-genotypically 
selected patient population.[15]All of these regimens were deemed to have 
clinically acceptable toxicity. 
1.3.1 Irinotecan Metabolism and Relationship to Toxicity 
Irinotecan exists as the pro-drug CPT-11 that is converted to its active metabolite, 
SN-38. This active metabolite is 100-1000x more cytotoxic than CPT-11, and is 
detoxified and excreted primarily by glucuronidation in the liver via the enzyme 
UGT1A1. [16] UGT1A1 is polymorphic, with variability in the number of TA 
amino acid repeats in the UGT1A1 promoter region, ranging from 5-8.  Six 
repeats are the most common, also denoted as *1.  The 7 TA repeat polymorphism 
is referred to as *28.[17] 


LCCC1317 
 
CONFIDENTIAL 
PI: Sanoff 
 
UNIVERSITY OF NORTH CAROLINA 
Version:  July 11, 2018 
 
3 
 
 
The UGT1A1*1 allele and *28 allele were reported at a rate of ~45% each in one 
study of 250 white patients, with the remainder (~10%) homozygous for *28.[18] 
This *28/*28 genotype is associated with up to a 70% reduction in enzyme 
activity, higher SN-38 concentrations and a subsequent increased risk of toxicity, 
particularly neutropenia. [18, 19]  
 
In a study of 86 advanced cancer patients receiving irinotecan monotherapy, an 
increased SN-38 area under the concentration-time curve (AUC) and the *28/*28 
genotype were significantly associated with a lower absolute neutrophil count 
nadir (p < 0.0001). [20] A study in 60 cancer patients receiving irinotecan 
monotherapy (350 mg/m2 every 3 weeks) demonstrated a relative risk of 9.3 for 
grade 4 neutropenia in *28/*28 patients versus *1/*28 and *1/*1 patients.[21]  
 
A meta-analysis including 10 cohorts of patients (for a total of 821 patients) 
demonstrated a significant increase in grade 3/4 neutropenia for *28/*28 patients 
at medium (150-250 mg/m2) and high doses (>250 mg/m2) of irinotecan (odds 
ratios of 3.22 and 27.8, respectively), as compared to the *1/*1 or *1/*28 
genotype groups.[19] 
 
As a result of these findings, the current US package insert for irinotecan 
(Camptosar®) includes homozygosity of the UGT1A1*28 allele as a risk factor 
for severe neutropenia and recommends consideration of initial dose reduction in 
these patients; a specific recommendation on dose is not provided. Few 
oncologists follow this practice as the strength of the relationship between 
genotype and toxicity is not clear, the data are not consistent, and other factors are 
clearly involved in determining toxicity.[22]  In the largest trial included in the 
meta-analysis (250 patients, >90% of whom received standard-dose FOLFIRI) 
Toffoli et al reported 13.6% grade ≥3 neutropenia in those homozygous for *28 in 
cycle 1, as compared to 5.3% of the *28 heterozygotes and 1.7% in the *1/*1 
group.  While there was a significant association between the *28/*28 genotype 
and ≥Grade 3 hematologic toxicity in cycle 1 as compared to the *1/*1 genotype, 
no significant association was seen with irinotecan-associated non-hematologic 
toxicities (including diarrhea or vomiting) in cycle 1, or in either category of 
toxicities across the full course of treatment.[18]  
 
A key finding was the low rates of toxicity in the *28 heterozygotes and the *1 
groups, rates considerably lower than those reported earlier when results were not 
stratified by genotype.[2]  
1.3.2 Safety and Clinical Activity Associated with Genotypic Dosing of Irinotecan 
within FOLFIRI 
Safety 
The guiding principle for dose escalation in phase I trials is to avoid unnecessary 
exposure of patients to sub-therapeutic doses of an agent while preserving safety 
and maintaining rapid accrual. [23] Our hypothesis that current irinotecan doses 


LCCC1317 
 
CONFIDENTIAL 
PI: Sanoff 
 
UNIVERSITY OF NORTH CAROLINA 
Version:  July 11, 2018 
 
4 
 
are suboptimal in some patient groups was tested in a dose-escalation study of 
mCRC patients treated with FOLFIRI alone. [17] Excluding patients with 
UGT1A1 *28/*28,  irinotecan doses of 370 and 310 mg/m2 administered every 2 
weeks were safely tolerated in *1/*1 and *1/*28 patients, respectively. The most 
common grade ≥3 observed toxicities in cycle 1 across all dose levels and when 
both genotype groups were combined included neutropenia (23%) and diarrhea 
(7%); across all cycles the corresponding toxicities were neutropenia (35%) and 
diarrhea (14%).   This rate of diarrhea is similar to the incidence reported when 
results are not stratified by genotype. [2]  Also of particular importance in this 
UGT1A1 guided dose-escalation trial, although  incidence of neutropenia is 
higher, the rate of febrile neutropenia was no higher than expected with current 
FOLFIRI dosing at 6%. [17] 
 
Similar results were obtained in a subsequent study, demonstrating an irinotecan 
maximum tolerated dose (MTD) of 390, 340, and 130 mg/m2 when used within 
the FOLFIRI regimen every 2 weeks in *1/*1, *1/*28, and *28/*28 patients, 
respectively.[24]  The most common grade 3/4 toxicity reported in cycle 1 across 
all dose levels in the *1/*1 genotype included diarrhea (10%), asthenia (24%) and 
neutropenia (22%).  In the *1/*28 genotype they were diarrhea (5%), asthenia 
(11%) and neutropenia (26%).  The *28/*28 genotype experienced higher levels 
of these toxicities in cycle 1, despite receiving lower doses: diarrhea (21%), 
asthenia (21%), and neutropenia (29%).  There were no reports of febrile 
neutropenia in any of the groups. While higher than for the other genotypes, the 
level of ≥grade 3 neutropenia reported in the *28/*28 is lower than that reported 
for FOLFOX [2], while the rate of diarrhea is comparable to that reported for the 
regimen IFL (with 5-FU and irinotecan dosed weekly at lower doses for 4 weeks 
of every 6 week cycle), the standard of care regimen for mCRC for many 
years.[5]  
 
These data, along with the meta-analysis summarized in section 1.3.1 support the 
proposed dosing of irinotecan in LCCC1317, outlined below and in the Schema.   
 
Clinical Activity 
While the phase I studies just reviewed were designed to establish the safety of 
genotypic dosing, response rates and time to progression (TTP) were also 
explored.  
 
When the data are grouped by dose, OR was similar between the 2 studies. In the 
study by Toffoli et al, the OR in patients treated at the MTD and higher (≥ 310 
mg/m2 in *1/*28 patients and ≥ 370 mg/m2 in *1/*1 patients) was significantly 
greater than in patients treated at doses below the MTD (65% versus 25%, 
respectively).[17] TTP was not different between these two groups.  In a similar 
posthoc analysis by Marcuello et al [24], patients were grouped into 2 cohorts 
based on the median dose received.  Of patients treated with ≥ 260 mg/m2 and < 
260 mg/m2of irinotecan, 67% and 24% respectively achieved an OR. 
Furthermore, the median TTP was higher in patients treated with ≥ 260 mg/m2 


LCCC1317 
 
CONFIDENTIAL 
PI: Sanoff 
 
UNIVERSITY OF NORTH CAROLINA 
Version:  July 11, 2018 
 
5 
 
irinotecan (16 months) than in patients treated with < 260 mg/m2 of irinotecan (7 
months) (p=0.003). Although efficacy was a secondary endpoint, the results are 
suggestive of a beneficial effect of FOLFIRI when higher irinotecan dosing is 
administered in *1/*1 and *1/*28 patients. 
1.3.3 Safety Associated with Genotypic Dosing of Irinotecan within 
FOLFIRI+Bevacizumab 
Safety 
The addition of bevacizumab to FOLFIRI is effective, commonly used, and 
generally well tolerated, with 22-26% and 5-11% experiencing ≥grade 3 
neutropenia and diarrhea respectively, in controlled clinical trials.[25, 26]    
Because of the frequent use of bevacizumab alongside FOLFIRI, a similar 
genotype-guided dose-escalation study in patients receiving FOLFIRI plus 
bevacizumab is currently ongoing in the *1/*1 and *1/*28 groups. At the 260 
mg/m2 dose in *1/*28 patients, only 2 dose limiting toxicities (DLTs) were 
observed among 10 treated patients.  
 
At the 310 mg/m2 dose in *1/*1 patients, only 2 DLTs were observed among 10 
treated patients.[27]  Based on these safety data, we have elected to use these 2 
doses in the present trial.     
1.4 
Rationale  
In the treatment of mCRC, irinotecan is typically prescribed at the same standard 
dose to all patients normalized by body surface area (BSA), as testing for 
UGT1A1*28 is not currently standard of care in most centers.  
 
Robust phase I data support the safety and tolerability of higher than standard 
doses in *1/*1 and *1/*28 patients.[17, 24] These phase I data also suggest that 
genotype-guided dosing may result in considerable improvement in chemotherapy 
efficacy among patients with greater  UGT1A1 activity (*1/*1 and *1/*28) 
treated with irinotecan (90% of white patients).   
 
In our proposed study, eligible patients will be genotyped for UGT1A1 (required) 
and assigned into 1 of 3 different irinotecan dosing groups:*1/*1, *1/*28, 
*28/*28.  The UGT1A1 genotyping assay does not test for the rare *6 allele 
present almost exclusively in people of Asian descent. The *6 allele confers 
UGT1A1 deficiency similar to *28. With the current genotyping assay, Asian 
carriers of the *6 allele would be classified as *1. In order to ensure safety of 
Asian patients, they will not be eligible for this trial. [28] 
 
Patients will be requested to consent to genetic testing of available archival tumor 
tissue.  An additional blood sample on D1 of treatment will also be requested for 
pharmacogenomic and other genetic testing in addition to status of UGT1A1.  
 
Our phase II multicenter single arm study will prospectively analyze efficacy in 
mCRC patients receiving genotype-based dosing of irinotecan within the 




LCCC1317 
 
CONFIDENTIAL 
PI: Sanoff 
 
UNIVERSITY OF NORTH CAROLINA 
Version:  July 11, 2018 
 
7 
 
3.0 
PATIENT ELIGIBILITY 
3.1 
Inclusion Criteria 
Subjects must meet all of the inclusion criteria to participate in this study: 
3.1.1 IRB-approved informed consent obtained and signed 
3.1.2 Age ≥ 18 years 
3.1.3 Histological or cytological documentation of adenocarcinoma of the colon or 
rectum  
3.1.4 Measurable or non-measurable (but evaluable) disease as defined via RECIST 1.1 
3.1.5 Metastatic disease not amenable to surgical resection with curative intent  
3.1.6 No prior chemotherapy for metastatic disease 
3.1.7 Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (see 
section 12.1, Appendix A) 
3.1.8 Adequate bone marrow, renal and hepatic function, as evidenced by the 
following: 
• absolute neutrophil count (ANC) ≥1,500/mm3 
• platelets ≥100,000/mm3 
• hemoglobin ≥9.0 g/dL  
• serum creatinine ≤1.5 x upper limit of normal (ULN) 
• AST and ALT ≤3x ULN ( ≤5.0 × ULN for patients with liver involvement 
of their cancer  
• Bilirubin ≤1.5 X ULN  
• Alkaline phosphatase ≤3 x ULN (≤5 x ULN with liver involvement of 
their cancer) 
3.1.9 Willing to comply with study procedures 
3.1.10 Negative pregnancy test (urine or serum), within 7 day prior to Day 1 of FOLFIRI 
in women of childbearing potential 
3.1.11 Women of childbearing potential and male subjects must agree to use adequate 
contraception for the duration of study participation.  Adequate contraception is 
defined as any medically recommended method (or combination of methods) as 
per standard of care.   
3.2 
Exclusion Criteria 
All subjects meeting any of the exclusion criteria at baseline will be excluded 
from study participation:  


LCCC1317 
 
CONFIDENTIAL 
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UNIVERSITY OF NORTH CAROLINA 
Version:  July 11, 2018 
 
8 
 
3.2.1 UGT1A1 genotype other than *1/*1, *1/*28, or *28/*28 
3.2.2 Patients of Asian descent. The current genotyping assay classifies patients who 
are carriers of the Asian *6 allele as *1 carriers. 
3.2.3 Known dihydropyrimidine dehydrogenase (DPD) deficiency 
3.2.4 Prior treatment with irinotecan and/or bevacizumab 
3.2.5 Unable or unwilling to discontinue (and substitute if necessary) use of prohibited 
drugs for at least 14 days (fruits and juices for at least 7 days) prior to Day 1 of 
FOLFIRI + bevacizumab initiation (see section 12.2, Appendix B, for list of 
prohibited drugs) 
3.2.6 Inadequately controlled hypertension (defined as systolic blood pressure > 140 
mmHg and/or diastolic blood pressure > 90 mmHg.) To control hypertension, the 
addition or increase of standard of care antihypertensive regimen is allowed. 
3.2.7 Prior history of hypertensive encephalopathy 
3.2.8 Active cardiac disease including any of the following: 
• New York Heart Association (NYHA) Grade II or greater congestive heart 
failure (see section 12.3, Appendix C)  
• History of myocardial infarction or unstable angina within 6 months prior 
to Day 1 
• History of stroke or transient ischemic attack within 6 months prior to Day 
1 of FOLFIRI + bevacizumab initiation 
3.2.9 Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or 
recent peripheral arterial thrombosis) within 6 months prior to Day 1 of FOLFIRI 
+ bevacizumab initiation 
3.2.10 History of hemoptysis (≥ 1/2 teaspoon of bright red blood per episode) within 1 
month prior to Day 1 of FOLFIRI + bevacizumab initiation 
3.2.11 Evidence of bleeding diathesis or significant coagulopathy (in the absence of 
therapeutic anticoagulation)  
3.2.12 Major surgical procedure, open biopsy, or significant traumatic injury within 28 
days prior to Day 1 of FOLFIRI + bevacizumab initiation or anticipation of need 
for major surgical procedure during the course of the study 
3.2.13 Core biopsy or other minor surgical procedure, excluding placement of a vascular 
access device, within 7 days prior to Day 1 of FOLFIRI + bevacizumab initiation 
3.2.14 History of abdominal fistula or gastrointestinal perforation within 6 months prior 
to Day 1 of FOLFIRI + bevacizumab initiation 


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UNIVERSITY OF NORTH CAROLINA 
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3.2.15 Serious, non-healing wound, active ulcer, or untreated bone fracture 
3.2.16 Proteinuria as demonstrated by:  
 
Urine protein: creatinine (UPC) ratio ≥ 1.0 at screening (patients discovered to 
have a UPC >=1 should undergo a 24 hour urine collection and must demonstrate 
≤ 1g of protein in 24 hours to be eligible) 
 
OR  
 
Urine dipstick for proteinuria ≥ 2+ (patients discovered to have ≥2+ proteinuria 
on dipstick urinalysis may either undergo Urine protein: creatinine (UPC) testing, 
and may participate if ratio <1. 0 or should undergo a 24 hour urine collection and 
must demonstrate ≤ 1g of protein in 24 hours to be eligible) 
3.2.17 Any serious uncontrolled medical disorder that would impair the ability of the 
subject to receive protocol-driven therapy 
3.2.18 Other anti-cancer or investigational therapy while patients are on study therapy 
4.0 
TREATMENT PLAN 
4.1 
Schema 
 
 
This Phase II multi-center, single arm study is designed to estimate PFS in 
untreated mCRC patients receiving FOLFIRI + bevacizumab when irinotecan 
dose is based on UGT1A1 genotype.  Patients will be assigned to one of 3 dose 
levels of irinotecan based on genotyping results, as part of the FOLFIRI + 
bevacizumab chemotherapy regimen.  Patients will continue on treatment until 
tumor progression, unacceptable toxicity, consent withdrawal, or withdrawal from 
the study at the discretion of the investigator. Archival tissue will be requested 
from all patients at the time of enrollment for genetic sequencing. An additional 
blood sample will be requested D1 of treatment for pharmacogenomic and other 
genetic studies beyond UGT1A1 testing.   


LCCC1317 
 
CONFIDENTIAL 
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UNIVERSITY OF NORTH CAROLINA 
Version:  July 11, 2018 
 
10 
 
4.2 
Treatment Dosage and Administration 
4.2.1 Premedication and Hydration 
Premedication should be provided per institutional guidelines.  It is recommended 
that premedication include antiemetic agents.  An example of a typical 
premedication regimen includes oral dexamethasone 12 mg and a 5HT3 receptor 
antagonist, e.g., oral ondansetron 24 mg, both administered 30 minutes prior to 
irinotecan therapy.  Unless contraindicated, atropine 0.4 mg IV as needed for 
diarrhea every 2 hours during or after irinotecan and prochlorperazine 10 mg 
PO/IV every 6 hours as needed for nausea/vomiting may be prescribed.  Since 
diarrhea may be severe and delayed >24 hours with irinotecan, loperamide 4 mg 
PO may be prescribed for the patient to take at the onset of diarrhea, followed by 
loperamide 2 mg PO as needed every 2 hours until diarrhea-free for 12 hours.   
See Appendix E, section 12.5 for additional information. Hydration during 
FOLFIRI should be provided per institutional guidelines.    
 
4.2.2 FOLFIRI + Bevacizumab Administration 
Drug 
Dose & Route 
Schedulea 
Irinotecanb 
Dose dependent on genotype: 
IV over 90 minutes 
Day 1 and Day 15  
Leucovorin 
(LV)b 
200-400c mg/m2 IV over 2 hours 
Day 1 and Day 15  
5-FU 
400 mg/m2 IV bolus followed by 
2400 mg/m2 IV over 46 hours 
Day 1 and Day 15  
Bevacizumab 
5 mg/kg IV infused as per institutional 
policy  
Day 1 and Day 15 
aRepeat cycles every 28 days 
bBoth irinotecan and leucovorin should be administered prior to 5-FU; 
cLevo-leucovorin may be substituted (if use, dose should be half (50%) of the planned dose of 
leucovorin); folate analogs may also be omitted  at the discretion of the investigator 
 
Irinotecan will be given every two weeks as an approximately 90-minute 
intravenous (IV) infusion. Leucovorin or levo-leucovorin may be initiated 30 
minutes prior to starting irinotecan and both administered via a Y-connector to 
save infusion time at the discretion of each study site. Then 5-FU will be 
administered as an initial 400 mg/m2 IV bolus over 2-5 minutes followed by an IV 
continuous infusion of 2,400 mg/m2 over 46 hours. Bevacizumab will be 
administered at a dose of 5 mg/kg IV at an infusion duration per institutional 
policy.  The aforementioned infusion durations are provided as a guideline. 
Infusions of these standard of care agents should be performed per institutional 
guidelines. Deviations from these guidelines are not considered protocol 
violations.  
 


LCCC1317 
 
CONFIDENTIAL 
PI: Sanoff 
 
UNIVERSITY OF NORTH CAROLINA 
Version:  July 11, 2018 
 
11 
 
Irinotecan dose will depend upon the patient genotype: *1/*1 patients will receive 
310 mg/m2; *1/*28 patients will receive 260 mg/m2; *28/*28 patients will receive 
the standard of care dose of 180 mg/m2. Each cycle is 28 days, with irinotecan, 
LV, 5-FU, and bevacizumab administrations on day 1 and 15 of every cycle.  
 
Treatment will be continued until disease progression or unacceptable toxicity. 
4.3 
Toxicities and Dosing Delays/Dose Modifications 
Any patient who receives treatment on this protocol will be evaluable for toxicity.  
Each patient will be assessed for the development of any toxicity according to the 
Time and Events table (section 6.1).  Toxicity will be assessed according to the 
NCI CTCAE v. 4.0. 
 
If a patient experiences ≥2 AEs simultaneously that require different dose 
reductions, the lowest dose (or greatest dose reduction) should be used.   
 
Treatment may be delayed ≤4 weeks from the expected day of the next treatment 
for any reason.  Subjects whose treatment is delayed will proceed with the next 
cycle of treatment at the dose level recommended according to tables below, 
provided ≤4 weeks has elapsed beyond when their next treatment was due.  If >4 
weeks has elapsed, the agent(s) held must be discontinued. Provided patients 
remain on either irinotecan or 5-FU, patients will remain on protocol therapy.  If 
both of these agents are discontinued, patients will come off of protocol therapy 
and be followed-up per protocol.  
 
NOTE:  
• If a dose of FOLFIRI is held or delayed for toxicity reasons, the original 
day and cycle numbering should be maintained. For example, if cycle 2 
D15 FOLFIRI is held and re-started on Day 21, this visit will be 
considered cycle 2 D15.  
• Leucovorin can be omitted at treating physician’s discretion 
• Irinotecan may be discontinued after cycle 4 at treating physician’s 
discretion as warranted by disease status and adverse side effects. 
• Bevacizumab initiation may be delayed until cycle 2 day 1 at the 
discretion of the investigator in case of prior minor surgery. 
 
4.3.1 FOLFIRI Dose Levels 
For FOLFIRI dose reductions, please refer to the following table.  
 
FOLFIRI DOSING & DOSE LEVELS FOR *1/*1 GENOTYPE 
Agent 
Initial Dose 
Level (-1) 
Level (-2) 
Irinotecan 
310 mg/m2 
260 mg/m2 
180 mg/m2 
Leucovorina 
400 mg/m2a 
320 mg/m2a 
240 mg/m2a 
5-FU bolus 
400 mg/m2 
320 mg/m2 
240 mg/m2 
5-FU infusion 
2400 mg/m2 
2000 mg/m2 
1600 mg/m2 


LCCC1317 
 
CONFIDENTIAL 
PI: Sanoff 
 
UNIVERSITY OF NORTH CAROLINA 
Version:  July 11, 2018 
 
12 
 
a May substitute with levoleucovorin at half (50%) of planned dose of leucovorin, or omit folate analogs at 
discretion of the investigator 
 
 
FOLFIRI DOSING & DOSE LEVELS FOR *1/*28 GENOTYPE 
Agent 
Initial Dose 
Level (-1) 
Level (-2) 
Irinotecan 
260 mg/m2 
180 mg/m2 
140 mg/m2 
Leucovorina 
400 mg/m2a 
320 mg/m2a 
240 mg/m2a 
5-FU bolus 
400 mg/m2 
320 mg/m2 
240 mg/m2 
5-FU infusion 
2400 mg/m2 
2000 mg/m2 
1600 mg/m2 
a May substitute with levoleucovorin at half (50%) of planned dose of leucovorin, or omit folate analogs at 
discretion of the investigator 
 
FOLFIRI DOSING & DOSE LEVELS FOR *28/*28 GENOTYPE 
Agent 
Initial Dose 
Level (-1) 
Level (-2) 
Irinotecan 
180 mg/m2 
140 mg/m2 
110 mg/m2 
Leucovorina 
400 mg/m2a 
320 mg/m2a 
240 mg/m2a 
5-FU bolus 
400 mg/m2 
320 mg/m2 
240 mg/m2 
5-FU infusion 
2400 mg/m2 
2000 mg/m2 
1600 mg/m2 
a May substitute with levoleucovorin at half (50%) of planned dose of leucovorin, or omit folate analogs at 
discretion of the investigator 
 
4.3.2 FOLFIRI Dose Modifications 
 
 
On Day 1 or Day 15 
Toxicity  
Dose Level for Subsequent FOLFIRI  
If ANC <1.0, hold treatment that 
day.2 Re-check weekly. Resume 
per table if ANC ≥1.0 
Neutropenia1 
Irinotecan 
5-FU 
Grade 2 
↓1 dose level of each for rest of cycle. May 
resume prior dose level at the beginning of 
subsequent cycle if ANC >=1.57 
Grade 3 
↓1 dose level of each for rest of cycle. If G-
CSF is initiated, may resume prior dose level 
at the beginning of subsequent cycle if ANC 
>=1.57  at investigator discretion 
Grade 48 
↓1-23 dose levels of each for rest of cycle.  If 
G-CSF is initiated, may resume prior dose 
level at the beginning of subsequent cycle if 
ANC >=1.57  at investigator discretion 
Febrile neutropenia 
↓1 dose level & 
begin G-CSF 
↓1 dose level & begin 
G-CSF 
If platelets <75K, hold treatment 
that day. 2 Re-check weekly. 
Resume per table if platelets 
≥75K 
Thrombocytopenia 
Irinotecan 
5-FU 
Grade 2 
↓1 dose level of each for rest of cycle. May 
resume prior dose level at the beginning of 
subsequent cycle if plts>=100,0007 
Grade 3 
↓1 dose level 
↓1 dose level 
Grade 4 
↓1-23  dose levels 
↓1-23  dose levels 


LCCC1317 
 
CONFIDENTIAL 
PI: Sanoff 
 
UNIVERSITY OF NORTH CAROLINA 
Version:  July 11, 2018 
 
13 
 
 
 
 
 
 
 
 
Footnotes 
 
1 Prophylactic use of G-CSF and other hematopoietic growth factors are prohibited prior to and following cycle 1 day 1. 
They may be used for subsequent doses beginning after cycle 1 day 15 at the investigator’s discretion. Also see 
section 4.4.4. 
 
2Hold offending agent(s) as identified in table  
 
3At discretion of investigator 
 
4See section 4.3.3 
 
5Hand-foot skin reaction  
 
6Do not adjust doses for nausea and vomiting unless they persist for >48 hours despite maximum antiemetic support, 
or grade 3-4 adverse effects deemed not clinically significant (e.g. asymptomatic electrolyte disorders amenable to 
repletion). 
 
7For next cycle, resume at the previous dose levels provided ANC ≥1.5 and platelets ≥ 100,000K at discretion of 
investigator 
If mucositis >Grade 2, hold 
treatment that day. 2 Re-check 
weekly. Resume per table if 
mucositis  Grade 0-1. 
Mucositis 
Irinotecan 
5-FU 
Grade 2 
Maintain dose 
↓1 dose level for the 
rest of cycle. May 
resume prior dose 
level at the beginning 
of the next cycle if 
grade 0-1. 
Grade 3 
Maintain dose 
↓1 dose level 
Grade 4 
Maintain dose 
↓2 dose levels 
On Day 1 or Day 15 
Toxicity  
Dose Level for Subsequent FOLFIRI  
If diarrhea4 >Grade 2, hold 
treatment for that day.2 Re-check 
weekly. Resume per table if 
diarrhea is ≤Grade 2.   
Diarrhea 
Irinotecan 
5-FU 
Grade 2 
↓13 dose level of each for rest of cycle7 
Grade 38 
↓1 dose level 
↓1 dose level 
Grade 48 
↓1-23  dose levels 
↓1-23  dose levels 
If HFSR >Grade 2, hold 
treatment for that day. 2 Re-
check weekly. Resume per table 
if HFSR ≤Grade 1.   
HFSR5 
Irinotecan 
5-FU 
Grade 3 
Maintain dose 
1 dose level 
Hold2 dose of suspected 
offending agent(s), re-check 
weekly.  Resume per table once 
toxicity resolves to ≤Grade 2      
Other non specified6 
Irinotecan 
5-FU 
≥Grade 3 
↓1 dose level 
↓1 dose level 


LCCC1317 
 
CONFIDENTIAL 
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UNIVERSITY OF NORTH CAROLINA 
Version:  July 11, 2018 
 
14 
 
 
8Patients experiencing either grade 4 neutropenia or ≥grade 3 diarrhea that requires a  >14 day dose delay in cycle 1 
will have repeat UGT1A1 genotype testing at UNC, as well as at an outside CLIA-certified laboratory 
 
4.3.3 Management of Irinotecan-associated Diarrhea 
It is recommended that patients be provided loperamide tablets (or prescription) at 
the start of their treatment.  Patients should be instructed to treat diarrhea with 
loperamide at its earliest occurrence (any grade), and to observe the recommended 
dietary modifications as outlined in section 12.5.  This appendix also includes 
pharmacologic guidelines for the treatment of cancer treatment-induced diarrhea.  
 
Subjects should be instructed to first notify their physician/healthcare 
provider at onset of diarrhea of any severity and to start supportive care 
immediately at the first episode of diarrhea (i.e., unformed stool). 
An assessment of diarrhea frequency, consistency and duration as well as 
knowledge of other symptoms such as fever, cramping, pain, nausea, vomiting, 
dizziness and thirst should be taken at baseline. Consequently subjects at high risk 
of diarrhea can be identified.  Subjects should be educated on signs and symptoms 
of diarrhea with instructions to report any changes in bowel patterns to the 
physician.  
If subjects present with diarrhea, obtain information on food (solid and liquid) and 
over the counter (OTC) medication, including herbal supplements, taken during 
the treatment period. 
For grade 3 or 4 diarrhea, or for < grade 3 diarrhea with complicating features 
(e.g. severe cramping, severe nausea/vomiting, decreased performance status, 
grade 3 or 4 neutropenia, sepsis, fever, frank bleeding, dehydration), hydrate 
aggressively with IV fluids as appropriate and consider octreotide therapy.  Begin 
antibiotic therapy as needed for diarrhea lasting longer than 24 hours or if there is 
fever or neutropenia.  Maintain adequate hydration and begin dietary 
modifications according to institutional guidelines for diarrhea management. In 
addition, patients experiencing  ≥grade 3 diarrhea leading to >14 days dose delay 
in cycle 1 will have repeat UGT1A1 genotype testing at UNC, as well as at an 
outside CLIA-certified laboratory. 
 
4.3.4 Bevacizumab Toxicity Management 
There are no reductions in the bevacizumab dose. If adverse events occur that 
require holding bevacizumab, the dose will remain the same once treatment 
resumes provided these events do not require discontinuation of the agent (see 
table below).  
 
Any toxicity associated or possibly associated with bevacizumab treatment should 
be managed according to standard medical practice.  


LCCC1317 
 
CONFIDENTIAL 
PI: Sanoff 
 
UNIVERSITY OF NORTH CAROLINA 
Version:  July 11, 2018 
 
15 
 
4.3.5 Blood Pressure 
Standard practice guidelines should be followed for determining initiation and 
continued infusion of bevacizumab based on blood pressure. Hypertension should 
be managed with appropriate antihypertensive medication. If unmanageable 
toxicity including events such as medically uncontrolled hypertension of 
hypertensive encephalopathy occurs because of bevacizumab at any time during 
the study, treatment with bevacizumab should be discontinued.  
4.3.6 Other Bevacizumab-associated Toxicities 
Adverse events requiring delays or permanent discontinuation of bevacizumab are 
listed in the table below. 
 
Event 
Grade;Description 
Action 
Hypertension 
3 
Hold until ≤Grade 2 and begin or increase 
antihypertensive medication.  If must hold for >4 
weeks, discontinue bevacizumab 
4a 
Discontinue 
Hemorrhage 
3; non-pulmonary 
and non-CNS 
hemorrhage 
Subjects who are also receiving full-dose 
anticoagulation will be discontinued from 
bevacizumab 
 
All other subjects will have bevacizumab held 
until all of the following criteria are met:  
• The bleeding has resolved and hemoglobin is 
stable.  
• There is no bleeding diathesis that would 
increase the risk of therapy.  
• There is no anatomic or pathologic condition 
that significantly increases the risk of 
hemorrhage recurrence.  
 
Subjects who experience a repeat Grade 3 
hemorrhagic event will be discontinued from 
receiving bevacizumab.  
4; non-pulmonary 
and non-CNS 
hemorrhage 
Discontinue bevacizumab 
1; pulmonary or 
CNS hemorrhage 
Subjects who are also receiving full-dose 
anticoagulation will be discontinued from 
bevacizumab 
 
All other subjects will have bevacizumab held 
until all of the following criteria are met:  
• The bleeding has resolved and hemoglobin is 
stable.  
• There is no bleeding diathesis that would 
increase the risk of therapy.  


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UNIVERSITY OF NORTH CAROLINA 
Version:  July 11, 2018 
 
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• There is no anatomic or pathologic condition 
that significantly increases the risk of 
hemorrhage recurrence.  
2, 3 or 4; pulmonary 
or CNS hemorrhage 
 
 
 
Discontinue bevacizumab 
Venous 
Thrombosis 
3 or 4 
Hold bevacizumab until the full-dose  
anticoagulation period is over. If the 
planned duration of full-dose 
anticoagulation is >2 weeks, bevacizumab 
may be resumed during the period of full-
dose anticoagulation if all of the following 
criteria are met:  
• The subject must have an in-range INR 
(usually between 2 and 3) if on warfarin; 
low-molecular weight heparin (LMWH), 
warfarin, or other anticoagulant dosing must 
be stable prior to restarting bevacizumab 
treatment.  
• The subject must not have had a Grade 3 
or 4 hemorrhagic event while on 
anticoagulation.  
Arterial 
Thromboembolic 
eventb 
Any grade 
Discontinue bevacizumab 
Congestive Heart 
Failure 
3 
Hold bevacizumab until resolution to ≤Grade 1 
4 
Discontinue bevacizumab 
Proteinuria 
≥3 
At discretion of investigator 
GI Perforation 
 
Discontinue bevacizumab 
Fistula 
Any grade 
(tracheoesophageal 
fistula) 
Discontinue bevacizumab 
4 
Discontinue bevacizumab 
Bowel 
Obstruction 
1 
Continue patient on study for partial obstruction NOT 
requiring medical intervention 
2 
Hold bevacizumab for partial obstruction requiring 
medical intervention; patient may restart upon 
completion 
3/4 
Hold bevacizumab for complete obstruction.  If 
surgery is necessary, patient may restart 
bevacizumab after full recovery from surgery, at 
investigator’s discretion. 
Wound 
dehiscence 
Any; requiring 
medical or surgical 
Discontinue bevacizumab 


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CONFIDENTIAL 
PI: Sanoff 
 
UNIVERSITY OF NORTH CAROLINA 
Version:  July 11, 2018 
 
17 
 
therapy 
Reversible 
Posterior 
Leukoencephalo-
pathy 
Any; confirmed by 
MRI 
Discontinue bevacizumab 
Other 
unspecified 
bevacizumab-
related AEs 
3 
Hold bevacizumab until recovery to ≤Grade 1 
4 
Discontinue bevacizumab 
aIncluding hypertensive encephalopathy 
bNew onset, worsening or unstable angina, myocardial infarction, transient ischemic attack, cerebrovascular 
accident, or any other arterial thromboembolic event 
4.4 
Concomitant Medications/Treatments 
Standard of care prophylactic antiemetics should be given per institutional 
standard. 
 
Patients will be instructed not to take any additional medications (including OTC  
products) during the course of the study without prior consultation with the 
investigator.  At each visit, the investigator will ask the patient about any new 
medications he/she is taking or has taken since starting  the study therapy.  
 
In general, the use of any concomitant medication/therapies deemed necessary for 
the care of the patient is permitted with the following exceptions: 
4.4.1 Concomitant Palliative Radiotherapy 
Concomitant radiation for palliation is allowed provided that target lesions are not 
included in radiation field, and no more than 10% of the bone marrow is 
irradiated.   
4.4.2 Prohibited Drugs 
CYP3A4 Inhibitors and Inducers 
In addition to conversion to the active metabolite SN-38, irinotecan is also 
metabolized by CYP3A4 and 3A5 to inactive metabolites.   Patients unable or 
unwilling to discontinue (and substitute if necessary) use of CYP3A4 inducing 
drugs and strong CYP3A4 inhibiting drugs are ineligible for LCCC1317  as these 
can significantly change plasma concentrations of  irinotecan and its active 
metabolites.  Patients must not have received any of the prohibited drugs for at 
least 14 days prior to Day 1 of FOLFIRI (see section 12.2, Appendix B) for list of 
prohibited drugs).  See http://medicine.iupui.edu/clinpharm/ddis/table.asp for a 
frequently updated list of inducers and strong inhibitors of CYP3A4.  
 
CYP3A4 and UGT1A1 Inhibitors 
Coadministration of atazanavir sulfate, a CYP3A4 and UGT1A1 inhibitor has the 
potential to increase systemic exposure to SN-38, the active metabolite of 
irinotecan. Therefore it is prohibited for patients enrolled into this study. 


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4.4.3 Drugs to be Used with Caution 
Weak and moderate inhibitors of CYP3A4 should also be used with caution as 
they may potentially increase the plasma concentrations of irinotecan.  Such 
concomitant medications should be avoided, if possible.  See Appendix D (section 
12.4) for a list of drugs to be used with caution.  In addition, see 
http://medicine.iupui.edu/clinpharm/ddis/table.asp for a list of weak and moderate 
CYP3A4 inhibitors that should also be used with caution. 
4.4.4 Hematopoietic Growth Factors 
Prophylactic use of G-CSF (filgrastim or pegfilgrastim) and other hematopoietic 
growth factors are prohibited prior to or following cycle 1 day 1. Prophylaxis may 
be used for subsequent doses beginning after cycle 1 day 15 at the investigator’s 
discretion provided they are not substituted for a required dose reduction.   
Filgrastim or pegfilgrastim should be implemented for any episode of febrile 
neutropenia.  
4.5 
Duration of Therapy 
In the absence of treatment delays due to toxicities, protocol-directed treatment 
may continue until: 
• Disease progression 
• Inter-current illness that prevents further administration of treatment 
• Unacceptable adverse event(s) 
• Both 5-FU and irinotecan have been discontinued 
• Pregnancy 
• Patient decides to withdraw from study treatment, OR 
• General or specific changes in the patient’s condition render the 
patient unacceptable for further treatment in the judgment of the 
investigator. 
4.6 
Duration of Follow Up 
Patients will be followed for up to 5 years after removal from study or until death, 
whichever occurs first.  Patients removed from study for unacceptable AEs will 
be followed until resolution or stabilization of the event(s).   
4.7 
Removal of Patients from Protocol Therapy 
Patients will be removed from protocol therapy and the PI notified when any of 
the criteria listed in section 4.5 apply.  The reason for discontinuation of protocol 
therapy will be documented on the eCRF.   
 
In case a patient decides to prematurely discontinue protocol therapy (“refuses 
treatment”), the patient should be asked if she or he may still be contacted for 
further scheduled study assessments. The outcome of that discussion should be 
documented in both the medical records and in the eCRF. 
 


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Excessive patient withdrawals from protocol therapy or from the study can render 
the study un-interpretable; therefore, unnecessary withdrawal of patients should 
be avoided. 
4.8 
Study Withdrawal 
If a patient decides to withdraw from the study (and not just from protocol 
therapy) all efforts should be made to complete and report study assessments as 
thoroughly as possible. The investigator should contact the patient or a 
responsible relative by telephone or through a personal visit to establish as 
completely as possible the reason for the study withdrawal. A complete final 
evaluation at the time of the patient’s study withdrawal should be made with an 
explanation of why the patient is withdrawing from the study. If the reason for 
removal of a patient from the study is an adverse event, the principal specific 
event will be recorded on the eCRF. 
5.0 
DRUG INFORMATION 
5.1 
Irinotecan (Camptosar®)  
Irinotecan hydrochloride is a semisynthetic derivative of camptothecin and is an 
antineoplastic agent of the topoisomerase I inhibitor class.   It is indicated for the 
treatment of metastatic CRC in combination with 5-FU and leucovorin.   
5.1.1 Irinotecan Supply and Supplier 
Irinotecan as Camptosar® is available from Pfizer in single-dose amber glass 
vials containing 40 mg/2 mL or 100mg/5mL, and must be diluted prior to 
intravenous infusion.  See Full Prescribing Information at: 
https://www.pfizeroncology.com/sites/pop/PDFs/uspi_camptosar.pdf for 
complete information.  Commercially available supplies of either Camptosar® or 
generic irinotecan will be used for this study.   
5.1.2 Preparation, Storage and Stability 
The appropriate dose of irinotecan (see section 4.3) should be reconstituted, 
diluted, and stored according to the package insert provided by the manufacturer 
and according to local pharmaceutical regulations. 
5.1.3 Premedication 
Patients should be prescribed medications to prevent and treat nausea and 
vomiting per institutional guidelines. One recommended option is provided in 
section 4.2.1. 
5.1.4 Dosage and Administration 
See section 4.2. 


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5.1.5 Handling and Disposal 
To minimize the risk of dermal exposure, always wear impervious gloves when 
handling vials containing irinotecan.  This includes all handling activities in 
clinical settings, pharmacies, storerooms, and home healthcare settings, including 
during unpacking and inspection, transport within a facility, and dose preparation 
and administration.  If a solution of irinotecan contacts the skin, wash the skin 
immediately and thoroughly with soap and water.  If irinotecan contacts the 
mucous membranes, flush thoroughly with water.  Procedures for proper handling 
and disposal of anti-cancer drugs should be considered.  
5.1.6 Adverse Events Associated With Irinotecan 
Incidence rates of AEs associated with irinotecan are provided in the product’s 
Full Prescribing Information 
(https://www.pfizeroncology.com/sites/pop/PDFs/uspi_camptosar.pdf). Some of 
the AEs expected with irinotecan treatment are listed below. 
 
Nausea, vomiting, and diarrhea are common AEs following treatment with 
irinotecan, and can be severe.  When observed, nausea and vomiting usually occur 
during or shortly after infusion of irinotecan. 
 
Diarrhea:  Irinotecan can induce both early and late forms of diarrhea that appear 
to be mediated by different mechanisms.  Early diarrhea (occurring during or 
shortly after infusion of irinotecan) is cholinergic in nature.  It is usually transient 
and only infrequently is severe.  It may be accompanied by cholinergic symptoms 
of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, and 
intestinal hyperperistalsis that can cause abdominal cramping.  Early diarrhea and 
other cholinergic symptoms may be prevented or ameliorated by administration of 
atropine.  Late diarrhea (generally occurring more than 24 hours after 
administration of irinotecan) can be life-threatening since it may be prolonged and 
may lead to dehydration, electrolyte imbalance, or sepsis.  Late diarrhea should be 
treated promptly with loperamide.  Patients with diarrhea should be carefully 
monitored, given fluid and electrolyte replacement if they become dehydrated, 
and given antibiotic support if they develop ileus, fever, or severe neutropenia.  
 
Hepatic:  In the clinical studies evaluating the weekly dosage schedule, NCI 
CTCAE Grade 3 or 4 liver enzyme abnormalities were observed in fewer than 
10% of patients.  These events typically occur in patients with known hepatic 
metastases.   
 
Hematologic:  Irinotecan commonly causes neutropenia, leukopenia (including 
lymphocytopenia), and anemia.  Deaths due to sepsis following severe 
neutropenia have been reported in patients receiving irinotecan.  Individuals who 
are homozygous for the UGT1A1*28 allele (approximately 10% of North 
American population) are at increased risk for neutropenia following initiation of 
irinotecan treatment.  Serious thrombocytopenia is uncommon. 
 


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Body as a Whole:  Asthenia, fever, and abdominal pain are generally the most 
common events of this type. 
 
Hypersensitivity:  Hypersensitivity reactions including severe anaphylactic or 
anaphylactoid reactions have been observed. 
 
Colitis/Ileus:  Cases of colitis complicated by ulceration, bleeding, ileus, and 
infections have been observed.  Patients experiencing ileus should receive prompt 
antibiotic support. 
 
Renal Impairment/Renal Failure:  Rare cases of renal impairment and acute renal 
failure have been identified, usually in patients who became volume depleted 
from severe vomiting and/or diarrhea.   
 
Thromboembolism:  Thromboembolic events have been observed in patients 
receiving irinotecan; the specific cause of these events has not been determined. 
 
Respiratory:  In clinical studies, ≥Grade 3 dyspnea was reported in 4% of patients.  
Of note, over half of these patients had lung metastases.  Interstitial pulmonary 
disease, which can be fatal, is uncommon.  Risk factors include preexisting lung 
disease, use of pneumotoxic drugs, radiation therapy, and colony stimulating 
factors.   
5.1.7 Drug Interactions 
Exposure to irinotecan and its active metabolite SN-38 is substantially reduced 
when patients are concomitantly receiving CYP3A4 enzyme-inducing drugs such 
as the anti-convulsants phenytoin, phenobarbital, or carbamazepine, as well as 
other agents such as St. John’s Wort.  Strong inhibitors of CYP3A4 enzymes such 
as the anti-fungal ketoconazole and the HIV anti-retrovirals (e.g., atazanavir), 
have increased exposure to irinotecan and SN-38 and should be avoided in 
patients receiving irinotecan.  See https://www.pfizeroncology.com/sites/pop/ 
PDFs/uspi_camptosar.pdf for further information. See section 4.4.2  for further 
information on prohibited concomitant drugs, and section 4.4.3 regarding drugs to 
be used with caution.   
5.2 
5-Fluorouracil (5-FU) 
5-FU is an antineoplastic anti-metabolite that interferes with the synthesis of 
DNA and, to a lesser extent, RNA by blocking the methylation reaction of 
deoxyuridylic acid to thymidylic acid.  It is indicated for the treatment of 
metastatic CRC.   
5.2.1 Supply and Supplier 
The following information was taken from the prescribing information for Teva 
USA’s Adrucil® (5-FU).  Additional details may be found at: 
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Each 10 mL contains 500 mg of FU (50 mg/mL) and sodium hydroxide to adjust 
pH to approximately 9.2.  Commercially available supplies of either Adrucil® or 
another generic 5-FU will be used for this study.   
5.2.2 Preparation, Storage and Stability 
The appropriate dose of 5-FU should be reconstituted, diluted, and stored 
according to the package insert provided by the manufacturer and according to 
local pharmaceutical regulations. 
5.2.3 Premedication/Hydration 
Patients should receive premedication and hydration per institutional guidelines 
for FOLFIRI.  
5.2.4 Dosage and Administration 
See section 4.2 for additional details. 
5.2.5 Handling and Disposal 
To minimize the risk of dermal exposure, always wear impervious gloves when 
handling vials containing 5-FU. This includes all handling activities in clinical 
settings, pharmacies, storerooms, and home healthcare settings, including during 
unpacking and inspection, transport within a facility, and dose preparation and 
administration.  If a solution of 5-FU contacts the skin, wash the skin immediately 
and thoroughly with soap and water.  Procedures for proper handling and disposal 
of anti-cancer drugs should be considered.  
5.2.6 Adverse Events Associated with 5-FU 
The most common toxicities seen with 5-FU therapy include stomatitis, 
esophagopharyngitis (which may result in sloughing and ulceration), diarrhea, 
anorexia, nausea, and vomiting.  Neutropenia commonly follows treatment, with 
white count nadir observed between days 9 and 14 following therapy.  Mild 
alopecia has been reported, though is usually not complete.  Dermatitis, in the 
form of a pruritic maculopapular rash that usually appears on the extremities and 
(less frequently) trunk, is generally reversible and responsive to symptomatic 
treatment.  This dermatitis may be increased with sun exposure.  
  
Other less common adverse reactions are: 
Hematologic: pancytopenia, thrombocytopenia, agranulocytosis, anemia. 
Cardiovascular: myocardial ischemia, angina. 
Gastrointestinal: gastrointestinal ulceration and bleeding. 
Allergic Reactions: anaphylaxis and generalized allergic reactions. 
Neurologic: acute cerebellar syndrome (which may persist following 
discontinuance of treatment), nystagmus, headache. 
Dermatologic: dry skin; fissuring; photosensitivity, as manifested by erythema or 
increased pigmentation of the skin; vein pigmentation; palmar-plantar 


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erythrodysesthesia syndrome, as manifested by tingling of the hands and feet 
followed by pain, erythema and swelling. 
Ophthalmic: lacrimal duct stenosis, visual changes, lacrimation, photophobia. 
Psychiatric: disorientation, confusion, euphoria. 
Miscellaneous: thrombophlebitis, epistaxis, nail changes (including loss of nails) 
5.3 
Leucovorin 
Leucovorin, also known as folinic acid or citrovorum factor, is a chemically 
reduced derivative of folic acid.  Leucovorin is readily converted to another 
reduced folate, 5,10-methylenetetrahydrofolate, which acts to stabilize the binding 
of fluorodeoxyuridylic acid to thymidylate synthase, thereby enhancing the 
inhibition of this enzyme.  It is used to enhance the effects of fluoropyrimidines 
such as 5-FU.   
5.3.1 Supply and Supplier 
The following information was taken from the prescribing information for Teva 
USA’s leucovorin calcium.  Additional details may be found at: 
http://www.tevausa.com/assets/base/products/pi/Leucovorin_PI_9-2007.pdf. 
Leucovorin calcium is commercially available as a sterile, single-use vial 
containing either 100 mg or 350 mg each.  Commercially available supplies of 
generic leucovorin calcium will be obtained from Teva or another manufacturer 
and used for this study.  See section 4.2.2 regarding potential omission of folate 
analogs, or substitution of levo-leucovorin for leucovorin. 
5.3.2 Preparation, Storage and Stability 
The appropriate dose of leucovorin (see section 4.3) should be reconstituted and 
diluted and stored according to the package insert provided by the manufacturer 
and according to local pharmaceutical regulations. 
5.3.3 Dosage and Administration 
See section 4.2 for additional information.  
5.3.4 Adverse Events Associated with Leucovorin 
Leucovorin should not be used for pernicious anemia and other megaloblastic 
anemias secondary to the lack of vitamin B12.  A hematologic remission may 
occur while neurologic manifestations continue to progress.   
 
Leucovorin enhances the toxicity of 5-FU.  When these drugs are administered 
concurrently in the treatment of advanced colorectal cancer, as they are in this 
study, gastrointestinal toxicities (particularly stomatitis and diarrhea) are observed 
more commonly and may be more severe and of prolonged duration.  Seizures 
and/or syncope have been reported rarely in patients with cancer receiving 
leucovorin, usually in combination with fluoropyrimidine administration, and 
most commonly in those with CNS metastases or other predisposing factors; 
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Allergic sensitization, including anaphylactoid reactions and urticaria, has been 
reported following administration of leucovorin.   
5.3.5 Drug Interactions 
Folic acid in large amounts may counteract the antiepileptic effect of 
phenobarbital, phenytoin, and primidone, and increase the frequency of seizures 
in susceptible pediatric patients. 
5.4 
Bevacizumab (Avastin®)  
Bevacizumab, a humanized monoclonal antibody, is a vascular endothelial growth 
factor-specific angiogenesis inhibitor indicated for the treatment of mCRC in 
combination with 5-FU, 5-FU + irinotecan or 5-FU + oxaliplatin, for non-small 
cell lung cancer, glioblastoma, and for metastatic renal cell carcinoma. 
5.4.1 Bevacizumab Supply and Supplier 
Bevacizumab as Avastin® is available from Genentech in 100mg and 400mg 
single-use vials, and must be diluted prior to intravenous infusion.  See Full 
Prescribing Information at: www.gene.com. Commercially available supplies of 
Avastin® will be used for this study.   
5.4.2 Preparation, Storage and Stability 
The appropriate dose of bevacizumab (see section 4.2.2) should be diluted, and 
stored according to the package insert provided by the manufacturer and 
according to local pharmaceutical regulations. 
5.4.3 Premedication 
Patients should be prescribed medications to prevent and treat nausea and 
vomiting per institutional guidelines.  
5.4.4 Dosage and Administration 
See section 4.2.2. 
5.4.5 Adverse Events Associated With Bevacizumab 
The most common (>10%) adverse reactions associated with bevacizumab 
include epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry 
skin, rectal hemorrhage, lacrimation disorder, back pain, and exfoliative 
dermatitis.  See the Avastin® prescribing information for more detailed 
information.   In addition to the Warnings and Precautions outlined below, other 
adverse events of note include venous thromboembolic events, neutropenia and 
infection, and congestive heart failure.  
 
Venous Thromboembolic Events (VTE) 
The overall incidence of Grade 3-4 VTEs in a controlled study in mCRC was 
15.1% in patients receiving irinotecan, bolus 5FU and leucovorin (IFL) plus 


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bevacizumab and 13.6% in the placebo arm. More patients in the bevacizumab 
containing arm experienced deep vein thrombosis  (34 vs.19 patients) and intra-
abdominal venous thrombosis (10 vs. 5 patients).  
 
The risk of developing a second thromboembolic event while on bevacizumab 
and oral anticoagulants was evaluated in two randomized studies. In Study 1, 53 
patients (14%) on the IFL and bevacizumab arm and 30 patients (8%) in the IFL 
and placebo arm received full dose warfarin following a VTE. Among these 
patients, an additional thromboembolic event occurred in 21% of the 
bevacizumab arm and 3% of patients receiving IFL alone.  In a second, 
randomized, 4-arm study in 1401 patients with mCRC, prospectively evaluating 
the incidence of VTE (all grades), the overall incidence of first VTE was higher in 
the bevacizumab containing arms (13.5%) than the chemotherapy alone arms 
(9.6%). Among the 116 patients treated with anticoagulants following an initial 
VTE event (73 in the bevacizumab plus chemotherapy arms and 43 in the 
chemotherapy alone arms), the overall incidence of subsequent VTEs was also 
higher among the bevacizumab treated patients (31.5% vs. 25.6%). In this 
subgroup of patients treated with anticoagulants, the overall incidence of 
bleeding, the majority of which were Grade 1, was higher in the bevacizumab 
treated arms than the chemotherapy arms (27.4% vs. 20.9%).  
 
Neutropenia and Infection 
The incidence of neutropenia and febrile neutropenia is greater in patients 
receiving IFL+ bevacizumab compared to chemotherapy alone. Specifically, the 
incidence of Grade 3 or 4 neutropenia was higher in mCRC patients receiving IFL 
plus bevacizumab (21%) than in  patients on chemotherapy alone (14%).  
 
Congestive Heart Failure 
The incidence of Grade ≥3 left ventricular dysfunction was 1.0% in patients 
receiving bevazicumab compared to 0.6% in the control arm across indications.  
 
The prescribing information contains more detailed information on the following 
Warnings and Precautions. 
 
Gastrointestinal Perforations  
Serious and sometimes fatal gastrointestinal perforation occurs more frequently  
in bevacizumab treated patients compared to controls. The incidence of 
gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies.  
The typical presentation may include abdominal pain, nausea, emesis, 
constipation, and fever. Perforation can be complicated by intra-abdominal 
abscess and fistula formation. The majority of cases occurred within the first 50 
days of initiation of the drug.   
 
Surgery and Wound Healing Complications  
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trials, administration of bevacizumab was not allowed until at least 28 days after 
surgery. In a controlled clinical trial, the incidence of wound healing 
complications, including serious and fatal complications, was 15% in patients 
with mCRC who underwent surgery during the course of bevacizumab versus  
4% in the control group. The appropriate interval between the last dose of this 
agent and elective surgery is unknown; however, its half-life is estimated to be 20 
days.  Necrotizing fasciitis including fatal cases, has been reported in patients 
treated with bevacizumab, usually secondary to wound healing complications, 
gastrointestinal perforation or fistula formation.  
 
Hemorrhage  
Bevacizumab can result in two distinct patterns of bleeding: minor hemorrhage, 
most commonly Grade 1 epistaxis; and serious, and in some cases fatal, 
hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, 
gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal 
bleeding occurred up to five-fold more frequently in patients receiving 
bevacizumab than in patients receiving only chemotherapy. Across indications, 
the incidence of Grade ≥3 hemorrhagic events among patients receiving 
bevacizumab ranged from 1.2 to 4.6%.  
 
Non-Gastrointestinal Fistula Formation  
Serious and sometimes fatal non-gastrointestinal fistula formation involving 
tracheo-esophageal, bronchopleural, biliary, vaginal, renal and bladder sites 
occurs at a higher incidence in bevacizumab-treated patients compared to 
controls. The incidence of non-gastrointestinal perforation was ≤0.3% in clinical 
studies. Most events occurred within the first 6 months of therapy.  
 
Arterial Thromboembolic Events  
Serious, sometimes fatal, arterial thromboembolic events (ATE) including 
cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and 
a variety of other ATE occurred at a higher incidence in patients receiving 
bevacizumab compared to those in the control arm. Across indications, the 
incidence of Grade ≥3 ATE in the bevacizumab containing arms was 2.6% 
compared to 0.8% in the control arms. When combined with chemotherapy, the 
risk of developing an ATE during therapy was increased in patients with a history 
of arterial thromboembolism, or age greater than 65 years.  
 
Hypertension  
The incidence of severe hypertension is increased in patients receiving 
bevacizumab as compared to controls. Across clinical studies the incidence of 
Grade 3 or 4 hypertension ranged from 5-18%.  
 
Reversible Posterior Leukoencephalopathy Syndrome (RPLS)  
RPLS has been reported to occur in  <0.1% of patients in clinical studies. The 
onset of symptoms occurred from 16 hours to 1 year after initiation of 
bevacizumab. RPLS is a neurological disorder that can present with headache, 


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seizure, lethargy, confusion, blindness and other visual and neurologic 
disturbances. Mild to severe hypertension may be present.  
 
 
Proteinuria  
The incidence and severity of proteinuria is increased in patients receiving 
bevacizumab as compared to controls. Nephrotic syndrome occurred in <1% of 
patients receiving bevacizumab in clinical trials, in some instances with fatal 
outcome. 
 
Infusion Reactions  
Infusion reactions reported in the clinical trials and post-marketing experience 
include hypertension, hypertensive crises associated with neurologic signs and 
symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, 
headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the 
first dose of bevacizumab were uncommon (<3%) and severe reactions occurred 
in 0.2% of patients.  
 
 
 
Ovarian Failure  
The incidence of ovarian failure was higher (34% vs. 2%) in premenopausal 
women receiving bevacizumab in combination with modified (m)FOLFOX 
chemotherapy as compared to those receiving mFOLFOX chemotherapy alone for 
adjuvant treatment for colorectal cancer.   
 
 
 


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6.0 
EVALUATIONS AND ASSESSMENTS 
6.1 
Time and Events Table 
 
Pre- 
Study1 
Day 1 each 
cycle1  
Day 15 each 
cycle1 
Day 1 every 
other cycle 
Treatment 
Discontinuation2 
Follow-
up3 
Informed Consent 
X 
 
 
 
 
 
History4 
X 
X 
X 
 
X 
X 
Physical exam 
X 
X 
 
 
X 
X 
ECOG Performance 
Status 
X 
X  
 
 
X 
X 
Pregnancy Test5 
X5 
 
 
 
 
 
CBC w/diff, serum 
chemistries6 
X 
X 
X 
 
X 
 
LFTs6 
X 
X  
X 
 
X 
 
Urinalysis 
X7 
X7 
 
 
 
 
UGT1A1 testing8 
(required) 
X 
 
 
 
 
 
Tumor 
measurement and 
CEA blood test9 
X9 
 
 
X9 
X9 
 
Concomitant Meds  
X 
Throughout study 
  
FOLFIRI Initiation 
 
X 
X 
 
 
 
Bevacizumab dose 
 
X 
X 
 
 
 
Toxicity 
Assessment 
Throughout study 
Request archival 
tissue 
X10 
 
 
 
 
 
Blood sample for 
correlatives 
 
X10 (cycle 1 only) 
 
X10 
 
 
PRO-CTCAE sub-
study11 
X11 
X11 
X11 
 
 
 
Survival  
 
 
 
 
 
X 
 
 
 


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Key to Footnotes  
1Scans within 28 days prior to Day 1 of FOLFIRI; other evaluations may be within 2 
weeks unless otherwise noted; for D1 cycle 1 evaluation, if screening (baseline) 
evaluations were performed within 7 days of D1 of treatment, these do not need to be 
repeated.  A window of +/- 3 days will apply to all study visits. UGT1A1 genotyping is 
determined from germline sequencing and once collected per protocol is not subject to a 
collection window. 
 
2This visit should occur in patients when treatment stops for whatever reason (toxicity, 
progression, and at discretion of the investigator) 
 
3Follow-up contacts every 3 months +/- 15 days after treatment discontinuation for up to 
2 years and then every 6 months +/- 15 days for the following 3 years or until death 
(whichever is first) and may be conducted via telephone.  See section 6.5.1 for 
information to be collected. Patients who have on ongoing Grade 4 AE or SAE at the 
time of discontinuation from treatment will continue to be followed until the event is 
resolved or deemed irreversible by the investigator. 
 
4Complete history at baseline only, thereafter focused history on symptoms/toxicity,  
study coordinator /personnel to assess adverse events. 
 
5Urine or serum B-HCG, within 7 day prior to Day 1 of FOLFIRI and only if clinically 
appropriate.  
 
6Serum chemistries to include Na, K, Cl, Mg, creatinine, BUN; liver function tests 
(LFTs) to include AST, ALT, total bilirubin, alkaline phosphatase 
 
7Perform urinalysis (UA) at baseline to determine urine protein: creatinine (UPC) ratio ≥ 
1.0 at screening or perform a urine dipstick for proteinuria; see exclusion criteria 3.2.16. 
UA on D1 of each cycle to be performed at the discretion of the investigator, and per 
institutional policy 
 
8 Collect 5-7 mL of whole blood using a purple top (EDTA) tube; see section 6.6 for 
additional information  
 
9Tumor measurements within 5 days prior to D1 every 2 cycles starting with cycle 3 to 
include CT/MRI scans of chest, abdomen and pelvis---any additional suspected sites of 
disease should be evaluated per treating physician discretion; CEA=carcinoembryonic 
antigen; tumor imaging at treatment discontinuation to be done at treatment 
discontinuation at discretion of investigator. If tumor assessments are available for 
patients who have not yet experienced progressive disease (PD) at the time treatment is 
discontinued, the follow-up tumor evaluations will be documented in the eCRF until PD 
or death is confirmed, or until another treatment is initiated. 
 
10Request archival tissue from all patients, and collect two blood samples (1 x 5-7mLs  
and 1 x 10mLs each in purple top) for genetic testing on C1D1. Starting with cycle 3, 


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collect blood sample (10 mLs in purple top) for additional correlatives every odd 
numbered cycle.  See section 6.6.2 and the laboratory manual for additional details.  
 
11 See sections 6.2, 6.3 and  9.0 for details. 
6.2 
Pre-Study Assessments 
The assessments required as part of screening can be completed in one or more visits, 
as long as the assessments are completed within the time frames listed in the Key to the 
Time and Events table.   
 
Clinical evaluation:  complete history, comprehensive physical examination (to also 
include vital signs, height, and weight), ECOG performance status 
Laboratory studies:   
 Pregnancy Test: Serum or urine pregnancy test is required for all 
women of childbearing potential at screening, within 7 days prior to 
the first dose of FOLFIRI  
 Hematology: CBC with differential 
 Serum Chemistries: Na, K, Cl, Mg, creatinine, BUN 
 LFTs: AST, ALT, total bilirubin, alkaline phosphatase 
 Urinalysis or urine dipstick 
 CEA blood test 
 UGT1A1 (required; see section 6.6) 
Tumor measurement:  Tumor imaging should remain consistent throughout study, 
and should include CT/MRI scans of chest, abdomen and pelvis, and any 
additional suspected sites of disease. 
Concomitant medications:  Documentation of all concomitant medications, and in 
particular any drugs that strongly inhibit or induce CYP3A4.  NOTE:  Patients 
will be given a list of medications they should not be taking while on this study 
(see section 12.6, Appendix F).  Patients will be instructed to bring this list with 
them for all study visits for review by their study team and for all visits to 
healthcare professionals (e.g., primary care physicians, consultants) while on 
study. 
Archival tissue: Initiate collection of archival tissue from those patients who 
consent to this optional collection.  
Toxicity:  Toxicity will be assessed according to the NCI CTCAE v. 4.0.  
PRO-CTCAE: Register patient into PRO-Core (see section 10.4.2) if site participating 
in PRO-CTCAE sub-study (see section 9.0); train patient in completing PRO-CTCAE 
questionnaire prior to or on D1 of cycle 1. 


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6.3 
LCCC 1317 
amendment 05 CLINICOn Study Assessments 
6.3.1 Day 1 of Each Cycle 
Clinical evaluation:  focused history on symptoms/toxicity, study coordinator 
/personnel to assess adverse events, comprehensive physical examination (to also 
include vital signs and weight), ECOG performance status 
Laboratory studies:   
 Hematology: CBC with differential 
 Serum Chemistries: Na, K, Cl, Mg, creatinine, BUN 
 LFTs: AST, ALT, total bilirubin, alkaline phosphatase 
 Urinalysis or urine dipstick:  (at discretion of investigator) 
 Cycle 1 only: Two blood samples (1 x5-7 mLs and 1x10mLs in 
purple top tube (see section 6.6) for correlative studies 
Concomitant medications:  review for prohibited concomitant medications  
Toxicity:  Toxicity will be assessed according to the NCI CTCAE v. 4.0.  
PRO-CTCAE: See section 9.0; patient to complete PRO-CTCAE questionnaire, and 
research personnel to ensure completion of PRO-CTCAE Report Form (see section 
12.7 Appendices G and H). 
6.3.2 Day 15 of Each Cycle 
Clinical evaluation:  focused history on symptoms/toxicity, study coordinator 
/personnel to assess adverse events. 
Laboratory studies:   
 Hematology: CBC with differential 
 Serum Chemistries: Na, K, Cl, Mg, creatinine, BUN 
 LFTs: AST, ALT, total bilirubin, alkaline phosphatase 
Concomitant medications:  review for prohibited concomitant medications 
Toxicity:  Toxicity will be assessed according to the NCI CTCAE v. 4.0.  
PRO-CTCAE: See section 9.0; patient to complete PRO-CTCAE questionnaire, and 
research personnel to ensure completion of PRO-CTCAE Report Form. 
6.3.3 Day 1 of Every Other Cycle (starting with cycle 3) 
Tumor measurement:  Tumor imaging should remain consistent throughout study, 
and should include CT/MRI scans of chest, abdomen and pelvis, and any 
additional suspected sites of disease. 
Correlative studies:  10mLs blood in purple top tube (see section 6.6) for correlative 
studies. 
6.4 
End of Treatment Visit 
This visit should occur, at discretion of investigator, in patients when they stop 
treatment, whether due to disease progression or unmanageable toxicity.   
 


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Clinical evaluation:  Focused history on symptoms/toxicity, study coordinator 
/personnel to assess adverse events, comprehensive physical exam to include vital signs 
and weight, ECOG performance status 
Laboratory studies:  Hematology: CBC with differential, CEA blood test, Na, K, 
Cl, Mg, creatinine, BUN, AST, ALT, total bilirubin, alkaline phosphatase 
Tumor measurement:  For patients who discontinue for reasons other than disease 
progression, tumor measurements should take place.  Tumor imaging should remain 
consistent throughout study, and should include CT/MRI scans of chest, abdomen and 
pelvis, and any additional suspected sites of disease.   
Concomitant medications:  review for prohibited concomitant medications 
Toxicity:  Patients who have an ongoing Grade 4 AE or SAE at the time of 
discontinuation from treatment will continue to be followed until the event is 
resolved or deemed irreversible by the investigator. 
6.5 
Post-Treatment/Follow-up Assessments 
Summary of all phone conversation must be documented in the medical record. 
6.5.1 Follow-up  
Follow-up visits should occur every 3 months +/- 15 days after treatment 
discontinuation for up to 2 years and then every 6 months +/- 15 days for the 
following 3 years or until death (whichever is first) and may be conducted via 
telephone.    
 
After study drug treatment ends, anti-cancer medications taken by the patient 
should be documented in the eCRF if this information is available. 
 
If tumor assessments are available for patients who have not yet experienced 
progressive disease (PD), enter the follow-up tumor evaluations in the eCRF until 
PD is confirmed. 
 
Patients who withdraw consent from study drug treatment should enter the 
follow-up period (unless consent to follow-up is specifically withdrawn). 
6.6 
Correlative Studies 
In addition to required UGT1A1 testing, with additional optional consent, other 
correlative studies on archival tissue and blood will be conducted.  Correlative 
studies may include exploratory DNA-based (germline - genotyping of candidate 
variants, high-density SNP chip genotyping and genome sequencing; tumor - 
methylation, sequencing, genotyping of candidate variants) and RNA-based 
analyses (RNA-seq, expression arrays), or other biomarker analyses.        
6.6.1 UGT1A1 Testing (Required) 
Collect 5-7 mL of whole blood using a purple top (EDTA) tube and bring or ship 
to UNC McClendon Clinical Laboratories.  The blood should be received by 
McClendon within 24 hours of collection but can be stored under refrigeration if 


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it will be >24 hours.  Additional details on storage and shipment are provided in 
the LCCC1317 laboratory manual.   Any blood remaining after the DNA is 
isolated and residual DNA will be forwarded or shipped to UNC as per the 
LCCC1317 laboratory manual.  
6.6.2 Archival Tumor Tissue and D1 cycle 1 blood collection (Optional) 
The tissue specimens (blocks or slides) should be requested at the time of study 
enrollment from patients who consent to this. A blood sample (5-7mLs) for 
additional correlative studies beyond UGT1A1 will be collected on D1 of cycle 1. 
Tissue and blood will be stored in UNC’s Tissue Procurement Facility until 
genetic testing is initiated. Detailed information on processing, shipping and 
storage of these samples will be provided in the LCCC1317 laboratory manual.  
Any specimens remaining after protocol directed studies are complete will be 
stored for future research related to cancer in patients who consent to this storage. 
6.6.3 D1 Every Odd Numbered Cycle (Optional) 
An additional 10 mL blood sample for additional genetic studies will be collected 
on D1 of cycle 1 and every odd numbered cycle. Blood will be stored in UNC’s 
Tissue Procurement Facility until genetic testing for sequencing of cell free DNA 
(cfDNA) is initiated. Detailed information on processing, shipping and storage of 
these samples will be provided in the LCCC1317 laboratory manual.  Any 
specimens remaining after protocol directed studies are complete will be stored 
for future research related to cancer in patients who consent to this storage. 
6.7 
Assessment of Safety  
Any patient who receives treatment on this protocol will be evaluable for toxicity.  
Each patient will be assessed for the development of any toxicity according to the 
Time and Events table (section 6.0).  Toxicity will be assessed according to the 
NCI CTCAE v.  4.0. 
6.8 
Assessment of Efficacy Based on RECIST 1.1 
Patients who have received at least 2 cycles of therapy and have their disease re-
evaluated at 2 months will be evaluable for assessment of the primary objective 
(PFS).   Patients who drop out of the study prior to this point will not be evaluable 
for the primary objective unless they meet criteria for disease progression prior to 
this initial disease assessment, and have completed at least 2 doses (1 cycle) of 
FOLFIRI.     
6.8.1 Assessment of Disease-Tumor Measurement Based on RECIST 1.1 
See the international criteria proposed by the Response Evaluation Criteria in 
Solid Tumors (RECIST) Committee, version 1.1 (Eur J Cancer 45;2009:228-247) 
for additional details on RECIST1.1. 
 


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Measurable disease will be defined as the presence of at least one measurable 
lesion that can be accurately measured in at least one dimension with the longest 
diameter a minimum size of: 
• >10mm by CT scan (CT scan slice thickness no greater than 5 mm) 
• 10mm caliper measurement by clinical exam (lesions that cannot be 
accurately measured with calipers should be recorded as non-
measurable). 
• 20 mm by chest x-ray. 
 
For malignant lymph nodes to be considered pathologically enlarged and 
measurable, a lymph node must be ≥15mm in short axis when assessed by CT 
scan (CT scan slice thickness recommended to be no greater than 5mm).  At 
baseline and in follow-up, only the short axis will be measured and followed.   
 
All other lesions, including small lesions (longest diameter <10mm or 
pathological lymph nodes with ≥10 to <15 mm short axis) as well as truly non-
measurable lesions, will be considered non-measurable.  Lesions considered truly 
non-measurable include leptomeningeal disease; ascites; pleural/pericardial 
effusion; inflammatory breast disease; lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical exam that is 
not measurable by reproducible imaging techniques. 
 
All measurements should be recorded in metric notation, using calipers if 
clinically assessed. All baseline evaluations should be performed as close as 
possible to the treatment start 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 should always be done rather than clinical 
examination unless the lesion(s) being followed cannot be imaged but are 
assessable by clinical exam.  Clinical lesions will only be considered measurable 
when they are superficial and ≥10 mm diameter as assessed using calipers (e.g. 
skin nodules). For the case of skin lesions, documentation by color photography 
including a ruler to estimate the size of the lesions is recommended. 
6.8.2 Baseline Documentation of Target and Non-Target Lesions 
All measurable lesions up to a maximum of 5 lesions total (and a maximum of 
two lesions per organ) 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 longer 
diameter), be representative of all involved organs, but in addition should be those 
that lend themselves to reproducible repeated measurements.  
 
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, only the short axis is 


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added into the sum.  The baseline sum diameters will be used as reference to 
further characterize the objective tumor response of the measurable dimension of 
the disease. 
 
All other lesions (or sites of disease) including pathological lymph nodes should 
be identified as non-target lesions and should also be recorded at baseline. 
Measurements are not required and these lesions should be followed as “present” 
or “absent,” or in rare cases “unequivocal progression.”   
6.8.3 Evaluation of Target Lesions using RECIST 1.1 Criteria 
NOTE: In addition to the information below, also see section 4.3.2 in the 
international criteria proposed by the Response Evaluation Criteria in Solid 
Tumors (RECIST) Committee, version 1.1[31] for special notes on the assessment 
of target lesions.  
 
Complete response (CR)−Disappearance of all target lesions.  Any pathological 
lymph node (LN) (whether target or non-target) must have decreased in short axis 
to <10mm. 
 
Partial response (PR)−At least a 30% decrease in the sum of the longest diameter 
(LD) of the target lesions taking as reference the baseline sum LD. 
 
Progressive disease (PD)−At least a 20% increase in the sum of the LD of the 
target lesions taking as reference the smallest sum LD recorded since the 
treatment started including baseline 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 5mm.  The appearance of one or more new lesions also constitutes PD. 
 
Stable disease (SD)−Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD taking as references the smallest sum LD since the 
treatment started. 
6.8.4 Evaluation of Non-Target Lesions using RECIST 1.1 Criteria 
Complete response (CR)−Disappearance of all non-target lesions and 
normalization of tumor marker levels.  All LN must be non-pathological in size 
(<10mm short axis).   
 
Non-complete response (non-CR)/non-progression (non-PD)−Persistence of one 
or more non-target lesion(s) or/and 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. 


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6.8.5 Evaluation of Best Overall Response using RECIST 1.1 Criteria 
The best overall response is the best response recorded from the start of the study 
treatment until the end of treatment provided the confirmation criteria are met.  To 
be assigned a status of PR or CR, changes in tumor measurements must be 
confirmed by repeat studies that should be performed > 4 weeks after the criteria 
for response are first met. If a CR/PR cannot be confirmed the original "response" 
should be considered stable disease.  The best overall response will be defined 
according to the following table: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Overall 
Response First 
Time Point 
Overall Response 
Subsequent Time 
Point 
BEST Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PR1 
CR 
SD 
SD provided minimum criteria for SD duration met, otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD duration met, otherwise, PD 
CR 
NE2 
SD provided minimum criteria for SD duration met, otherwise, NE2 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, otherwise, PD 
PR 
NE2 
SD provided minimum criteria for SD duration met, otherwise, NE2 
NE 
NE2 
NE2 
1 If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR criteria 
relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR).  Best response 
would depend on whether minimum duration for SD was met.  However, sometimes ‘CR’ may be claimed when 
subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the first time 
point.  Under these circumstances, the original CR should be changed to PR and the best response is PR.  
2  NE=inevaluable  
 
 
7.0 
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7.1 
Definitions  
7.1.1 Adverse Event (AE) 
An adverse event (AE) is any untoward medical occurrence (e.g., an abnormal 
laboratory finding, symptom, or disease temporally associated with the use of a 
drug) in a patient or clinical investigation subject administered a pharmaceutical 
product and which does not necessarily have a causal relationship with this 
treatment.  An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not related to the 
medicinal product.   
 
Hospitalization for elective surgery or routine clinical procedures that are not the 
result of an AE (e.g., surgical insertion of central line) need not be considered 
AEs and should not be recorded as an AE.  Disease progression should not be 
recorded as an AE, unless it is attributable by the investigator to the study therapy. 
7.1.2 Suspected Adverse Reaction (SAR) 
A suspected adverse reaction (SAR) is any AE for which there is a reasonable 
possibility that the drug is the cause.   Reasonable possibility means that there is 
evidence to suggest a causal relationship between the drug and the AE.  A 
suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug.   
 
Causality assessment to a study drug is a medical judgment made in consideration 
of the following factors: temporal relationship of the AE to study drug exposure, 
known mechanism of action or side effect profile of study treatment, other recent 
or concomitant drug exposures, normal clinical course of the disease under 
investigation, and any other underlying or concurrent medical conditions.  Other 
factors to consider in considering drug as the cause of the AE: 
• Single occurrence of an uncommon event known to be strongly associated 
with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson 
Syndrome) 
• One or more occurrences of an event not commonly associated with drug 
exposure, but otherwise uncommon in the population (e.g., tendon 
rupture); often more than once occurrence from one or multiple studies 
would be needed before the sponsor could determine that there is 
reasonable possibility that the drug caused the event.   
• An aggregate analysis of specific events observed in a clinical trial that 
indicates the events occur more frequently in the drug treatment group 
than in a concurrent or historical control group 
7.1.3 Unexpected AE or SAR 
An AE or SAR is considered unexpected if the specificity or severity of it is not 
consistent with the applicable product information (e.g., Investigator’s Brochure 


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(IB) for an unapproved investigational product or package insert/summary of 
product characteristics for an approved product).  Unexpected also refers to AEs 
or SARs that are mentioned in the IB as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not 
specifically mentioned as occurring with the particular drug under investigation.   
7.1.4 Serious AE or SAR 
An AE or SAR is considered serious if, in the view of either the investigator or 
sponsor, it results in any of the following outcomes: 
• Death; 
• Is life-threatening (places the subject at immediate risk of death from 
the event as it occurred); 
• Requires inpatient hospitalization (>24 hours) or prolongation of 
existing hospitalization;* 
• Results in congenital anomaly/birth defect; 
• Results in a persistent or significant incapacity or substantial 
disruption of the ability to conduct normal life functions; 
• Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered a serious 
adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed 
in the definition.  For reporting purposes, also consider the occurrences 
of pregnancy as an event which must be reported as an important 
medical event. 
 
*Hospitalization for anticipated or protocol specified procedures such as 
administration of chemotherapy, central line insertion, metastasis interventional 
therapy, resection of primary tumor, or elective surgery, will not be considered 
serious adverse events. 
 
Pregnancy that occurs during the study must also be reported as an SAE. 
7.2 
Documentation of non-serious AEs or SARs 
For non-serious AEs or SARs, documentation must begin from day 1 of study 
treatment and continue through the 30 day follow-up period after treatment is 
discontinued.   
 
Collected information should be recorded in the Case Report Forms (CRF) for 
that patient.  Please include a description of the event, its severity or toxicity 
grade, onset and resolved dates (if applicable), and the relationship to the study 
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7.3 
SAEs or Serious SARs  
7.3.1 Timing 
After informed consent but prior to initiation of study medications, only SAEs 
caused by a protocol-mandated intervention will be collected (e.g. SAEs related to 
invasive procedures such as biopsies, medication washout, or no treatment run-
in).  
 
For any other experience or condition that meets the definition of an SAE or a 
serious SAR, recording of the event must begin from day 1 of study treatment and 
continue through the 30 day follow-up period after treatment is discontinued.  
7.3.2 Documentation and Notification 
These events (SAEs or Serious SARs) must be recorded in the SAE console 
within Oncore™ for that patient within 24 hours of learning of its occurrence.  
For Affiliate sites, an email must also be sent to the NCCN Study Coordinator 
indicating that an SAE or Serious SAR has been entered into Oncore (email 
contact will be provided at study start-up).  
7.3.3 Reporting  
IRB Reporting Requirements: 
UNC: 
• UNC will submit an aggregated list of all SAEs to the UNC IRB annually 
at the time of study renewal according to the UNC IRB policies and 
procedures. 
• The UNC-IRB will be notified of all SAEs that qualify as an 
Unanticipated Problem per the UNC IRB Policies using the IRB’s web-
based reporting system (see section 10.6) within 7 days of the Investigator 
becoming aware of the problem.   
 
Affiliate sites:   
• For affiliate sites using a local IRB of record, please submit adverse events 
per local IRB policy. 
• For affiliate sites relying on the UNC-IRB, an aggregated list of all SAEs 
will be submitted to the UNC IRB annually at the time of study renewal 
according to the UNC IRB policies and procedures. In addition, any SAEs 
that qualify as an Unanticipated Problem will be entered into Oncore and 
reported to the UNC IRB by the UNCCN Study Coordinator using the 
IRB’s web-based reporting system (see section 10.6) within 7 days of the 
Investigator becoming aware of the problem.   
Pregnancy 
Pregnancies and suspected pregnancies (including a positive pregnancy test 
regardless of age or disease state) of a female subject occurring while the subject 
is on study, or within 28 days of the subject’s last dose of study should be 


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recorded as SAEs.  The patient is to be discontinued immediately from the study. 
For Affiliate sites, the pregnancy, suspected pregnancy, or positive pregnancy test 
must be reported to the UNCCN Study Coordinator immediately via facsimile to 
919-966-4300.  The female subject should be referred to an obstetrician-
gynecologist, preferably one experienced in reproductive toxicity for further 
evaluation and counseling. 
 
The Investigator will follow the female subject until completion of the pregnancy, 
and must document the outcome of the pregnancy (either normal or abnormal 
outcome). If the outcome of the pregnancy was abnormal (e.g., spontaneous or 
therapeutic abortion), the Investigator should report the abnormal outcome as an 
AE. If the abnormal outcome meets any of the serious criteria, it must be reported 
as an SAE.   
7.4 
Data and Safety Monitoring Plan 
The Principal Investigator will provide continuous monitoring of patient safety in 
this trial with periodic reporting to the Data and Safety Monitoring Committee 
(DSMC).  
 
Meetings/teleconferences will be held at a frequency dependent on study accrual, 
and in consultation with the study Biostatistician.  These meetings will include the 
investigators as well as protocol nurses, clinical research associates, regulatory 
associates, data managers, biostatisticians, and any other relevant personnel the 
principal investigators may deem appropriate.  At these meetings, the research 
team will discuss all issues relevant to study progress, including enrollment, 
safety, regulatory issues, and data collection. 
 
The team will produce summaries or minutes of these meetings. These summaries 
will be available for inspection when requested by any of the regulatory bodies 
charged with the safety of human subjects and the integrity of data including, but 
not limited to, the oversight (Office of Human Research Ethics (OHRE) 
Biomedical IRB, the Oncology Protocol Review Committee (PRC) or the North 
Carolina TraCS Institute Data and Safety Monitoring Board (DSMB).   
 
The UNC LCCC Data and Safety Monitoring Committee (DSMC) will review the 
study on a regular (quarterly to annually) basis, with the frequency of review 
based on risk and complexity as determined by the UNC Protocol Review 
Committee.  The UNC PI will be responsible for submitting the following 
information for review: 1) safety and accrual data including the number of 
patients treated; 2) significant developments reported in the literature that may 
affect the safety of participants or the ethics of the study; 3) preliminary response 
data; and 4) summaries of team meetings that have occurred since the last report.  
Findings of the DSMC review will be disseminated by memo to the UNC PI, 
PRC, and the UNC IRB and DSMB.   
 






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along with their corresponding 95% confidence intervals.  Frequency tables will 
be used to summarize toxicity data and any other patient characteristics of 
interest. OR will be reported along with an exact 95% confidence interval.  
 
Cox models and logistic regression models may also be used to adjust for 
additional covariates as sample size permits.  
 
Analyses of potential biomarkers will be exploratory and descriptive in nature. 
For associations between genetic alterations and response, Fisher’s exact tests will 
be used. 
 
9.0 
PRO-CTCAE Sub-study 
9.1 
Background 
The National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) characterizes signs, symptoms and diseases by type and grade 
(severity) and is frequently used for investigator reporting of adverse events in 
oncology clinical trials.[33] A systematic approach to eliciting information on 
side effects experienced by patients may provide a more comprehensive picture of 
these adverse effects within a population, as well as improve safety, symptom 
management and patient satisfaction.[34, 35] A set of questions was developed to 
facilitate direct patient reporting of symptomatic adverse events, with the ultimate 
goal of improving the accuracy and timeliness of grading this subset of adverse 
events(see http://appliedresearch.cancer.gov/pro-ctcae/?&url=/tools/pro-
ctcae.html; accessed April 30, 2014). These questions comprise the Patient 
Reported Outcomes (PRO) version of the CTCAE (the PRO-CTCAE). To date, 
80 of the symptoms listed in the CTCAE have been modified for patient self-
reporting and validated through literature reviews, expert consensus and cognitive 
interviews with patients [33].  
 
A system incorporating PRO-CTCAE into overall toxicity assessment should be 
easy to use, focus on clinically relevant issues and report output to clinicians in an 
accessible format. [36]  In this PRO-CTCAE sub-study, we plan to evaluate the 
feasibility of a proposed system of collecting PRO-CTCAE and corresponding 
clinician assessed symptomatic AEs of interest (on the PRO-CTCAE Clinician 
Form; see section 12.8, Appendix H)  in the LCCC 1317 population across 
multiple participating sites. Thirteen symptomatic adverse events to be scored by 
patients (using the PRO-CTCAE questionnaire) and clinicians (using the NCI 
CTCAE v4.0 criteria) were chosen for this sub-study based on likely symptomatic 
toxicities seen with the FOLFIRI+bevacizumab combination.   
 
Patients will be asked about symptom frequency, severity and interference with 
usual activities over the last 14 days (see appendix G, section 12.7) on D1 and 
D15 of each cycle.  The PRO-CTCAE information being collected is for research 
purposes only. Therefore, patients will be advised to directly discuss any 


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symptoms of concern with their clinicians during conduct of the parent study. 
Clinicians will also grade the same symptoms based on the NCI CTCAE v4.0 on 
D1 and D15 of each cycle. Either the Clinician or a designee (such as the study 
coordinator) may complete the Clinician portion of the questionnaire on D15. 
 
This sub-study will be mandatory for all patients enrolled in LCCC1317 at UNC, 
and for all patients at Affiliate sites that elect to participate in this optional sub-
study. Non-English speaking patients are not required to participate and will not 
be asked to participate. Once feasibility is established, future studies will be 
designed to compare the documentation and use of routine clinician assessed 
CTCAEs within clinical trials with the method outlined in this sub-study. 
9.2 
Primary Objectives 
9.2.1 Estimate the proportion of patients who complete all the PRO-CTCAE questions 
at least 80% of the time the patient questionnaire is available (on D1 and D15 of 
each cycle) in the parent trial (1317)  
9.2.2 Estimate the proportion of patients with completed PRO-CTCAE Clinician Forms 
(i.e., both patient and clinician fully completed) at least 80% of the time the 
patient questionnaire is available (on D1 and D15 of each cycle) in the parent trial 
(1317) 
9.3 
Secondary Objectives 
9.3.1 Estimate concordance between PRO-CTCAE grades of toxicity and investigator-
assigned CTCAE grades of toxicity for each symptom of interest separately 
9.3.2 Compare proportion of patients with PRO-CTCAE  maximum score (≥2 for 
diarrhea, ≥3 for all other symptoms) to proportion of patients with investigator-




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If done on the iPad, patient responses will be converted to a PRO-CTCAE grade 
for each symptom, which will then automatically populate the PRO-CTCAE 
Clinician Form. If done on paper, research personnel will either: (1) convert 
patient responses to a PRO-CTCAE grade using a simple scoring system 
(research personnel will be trained on this scoring system at study start-up) and 
then transfer the grades by hand to the PRO-CTCAE Clinician Form or (2) enter 
the patient responses into PRO-Core to generate a PRO-CTCAE Clinician Form 
with patient grades.  
 
Research staff will then present the PRO-CTCAE Clinician Form (populated with 
patient grades) to the clinician (or designee on D15)for completion of clinician-
assessed CTCAE grade. (NOTE: Research personnel should consult clinician 
investigator for any  noted discrepancies between the clinician-assessed grade on 
the PRO-CTCAE Report Form and clinic notes).  The decision regarding dose 
modifications based on toxicity (Yes/No) will also be documented on the PRO-
CTCAE Clinician Form by research personnel.  Data from the completed PRO-
CTCAE Clinician Form will be entered by research personnel into PRO-Core (see 
section 10.4.2).   
9.7 
Statistical Considerations  
9.7.1 Sample Size 
There are two primary feasibility objectives for this sub study: (1) to estimate the 
proportion of patients who complete all the PRO-CTCAE questions at least 80% 
of the time the patient questionnaire is available (on D1 and D15 of each cycle) in 
the parent trial (1317) and (2) to estimate the proportion of patients with 
completed PRO-CTCAE Clinician Forms (i.e., both patient and clinician fully 
completed) at least 80% of the time the patient questionnaire is available (on D1 
and D15 of each cycle) in the parent trial (1317). Patients will be evaluable for 
these objectives if they enroll in LCCC1317 and are treated at UNC or at a site 
that agrees to participate in the sub-study. We plan to enroll 100 patients in 
LCCC1317.  The number of patients included in the sub-study will depend on site 
participation.  The table below includes precision estimates (exact 95% 
confidence intervals for a proportion of 50% and maximum half-widths) for 
various potential sample sizes. For example, if there are 90 patients evaluable for 
the sub-study, we will be able to estimate both proportions of interest within at 
least 10.7%. 
 
Sample Size (n) 
Exact 95% CI  
Maximum Half-Width 
100 
(39.8%, 60.2%) 
10.2% 
               90 
(39.3%, 60.7%) 
10.7% 
80 
(38.6%, 61.4%) 
11.4% 
 


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9.7.2 Data Analysis Plans 
The proportion of patients who complete all the PRO-CTCAE questions at least 
80% of the time the patient questionnaire is available (on D1 and D15 of each 
cycle) and the proportion of patients with completed PRO-CTCAE Clinician 
Forms (i.e., both patient and clinician fully completed) at least 80% of the time 
the patient questionnaire is available will both be estimated and reported along 
with exact 95% confidence intervals. Each patient will have a different number of 
possible questionnaires available because the questionnaires will only be available 
on D1 and D15 of each cycle as long at the patient is on treatment in LCCC1317. 
Therefore, “80% of the time” will be calculated for each patient individually 
based on that patient’s number of possible questionnaires. The first primary 
objective addresses the feasibility of the patient component of the toxicity 
assessment process. We will consider having patients report their own symptoms 
using this process feasible if at least 80% of patients complete all the questions at 
least 80% of the time.  The second primary objective addresses the feasibility of 
the overall process of collecting PRO-CTCAE and corresponding clinician 
assessed symptomatic AEs of interest in the LCCC 1317 population across 
multiple participating sites. The overall process will be considered feasible if at 
least 80% of patients have completed PRO-CTCAE Clinician Forms (i.e., both 
patient and clinician fully completed) at least 80% of the time. The denominator 
for both proportions will be all patients included in the sub-study (enrolled at 
UNC or an Affiliate site agreeing to participate in the sub-study). 
 
The weighted Kappa statistic will be used to estimate concordance between PRO-
CTCAE grades of toxicity and investigator-assigned CTCAE grades of toxicity 
for each symptom of interest as documented on the PRO-CTCAE Clinician 
Forms. The blocked bootstrap will be used to estimate standard errors to account 
for the fact that toxicity assessments are made at multiple time-points. 
McNemar’s tests will be used to compare the proportion of patients with a PRO-
CTCAE maximum score (≥2 for diarrhea, ≥3 for all other symptoms) to the 
proportion of patients with investigator-assigned CTCAE maximum score (≥2 for 
diarrhea, ≥3 for all other symptoms) for each symptom. Time to first PRO-
CTCAE score of ≥2 for diarrhea, ≥3 for all other symptoms and time to first 
investigator-assigned CTCAE score of ≥2 for diarrhea, ≥3 for all other symptoms 
(with time measured from D1 of cycle 1) will be estimated using the method of 
Kaplan and Meier and will be compared using the log-rank test. 
 
Fisher’s exact tests will be used to explore the association between patient-
reported toxicities of ≥ grade 2 diarrhea or ≥ grade 3 for all other symptoms and 
dose modifications (as reported on the PRO-CTCAE Clinician Forms) and to 
explore the association between patient reported maximum score (≥2 for diarrhea, 
≥3 for all other symptoms) and irinotecan starting dose. The bootstrap method 
will be used as appropriate to account for correlation. 
10.0 STUDY MANAGEMENT 


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10.1 
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in 
accordance with federally mandated regulations.  The IRB should approve the 
consent form and protocol. 
 
In obtaining and documenting informed consent, the investigator should comply 
with the applicable regulatory requirement(s), and should adhere to Good Clinical 
Practice (GCP) and to ethical principles that have their origin in the Declaration 
of Helsinki. 
 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent 
form. Each consent form must include all the relevant elements currently required 
by the FDA Regulations and local or state regulations. Once this essential 
information has been provided to the patient and the investigator is assured that 
the patient understands the implications of participating in the study, the patient 
will be asked to give consent to participate in the study by signing an 
IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form 
should be signed and personally dated by the patient and by the person who 
conducted the informed consent discussion. 
10.2 
Required Documentation 
Before the study can be initiated at any site, the following documentation must be 
provided to the Clinical Protocol Office (CPO) at the University of North 
Carolina. 
 
• A copy of the official IRB approval letter for the protocol and 
informed consent 
• IRB membership list 
• CVs and medical licensure for the principal investigator and any sub-
investigators who will be involved in the study. 
• Form FDA 1572 appropriately filled out and signed with appropriate 
documentation (NOTE: this is required if UNC holds the IND.  
Otherwise, the Investigator’s signature documenting understanding of 
the protocol and providing commitment that this trial will be 
conducted according to all stipulations of the protocol is sufficient to 
ensure compliance.) 
• CAP and CLIA Laboratory certification numbers and institution lab 
normal values 
• Executed clinical research contract 


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10.3 
Registration Procedures  
10.3.1 LCCC1317 
All UNC patients must be registered with the CPO at the University of North 
Carolina before enrollment to study.  For UNC patients, prior to registration, 
eligibility criteria must be confirmed with the UNC Study Coordinator. To 
register a patient, call the Oncology Protocol Office at 919-966-4432 Monday 
through Friday, 9:00AM-5:00PM.  
 
For Affiliate patients, please contact the UNCCN Study Coordinator for the 
potential subject (direct line 919-966-7359), Monday through Friday, 
9:00AM-5:00PM. To register a patient, please fax registration forms and 
eligibility documents to 919-966-4300.  
10.3.2 PRO-CTCAE Sub-study 
At participating sites at baseline, all patients will be registered into the PRO-Core 
by research personnel at each site (see section 10.4.2).   
10.4 
Data Management and Monitoring 
10.4.1 LCCC1317 
The CPO UNCCN of the UNC LCCC will serve as the coordinating center for 
this trial. Data for LCCC1317 will be collected through a web based clinical 
research platform, OnCore®.  Other study institutions will be given a password to 
directly enter their own data onto the web site via electronic case report forms 
(eCRFs).  UNCCN personnel will coordinate and manage data for quality control 
assurance and integrity. 
 
All data will be collected and entered into OnCore® by Clinical Research 
Associates (CRAs) from UNC LCCC and participating institutions.  The 
investigators at each site will allow monitors to review all source documents 
supporting data entered into OnCore®.   The UNCCN Data Coordinator can be 
reached at 919-843-2742 or 1-877-668-0683. 
10.4.2 PRO-CTCAE Sub-study 
Data from the PRO-CTCAE sub-study will be entered into PRO-Core. The PRO-
Core (Patient-Reported Outcomes Core Facility) is a shared resource that builds 
electronic questionnaires and other tools for use in cancer outcomes research.  
The PRO-Core is housed in the Cancer Outcomes Research Program, Lineberger 
Comprehensive Cancer Center, University of North Carolina.  PRO-Core features 
include development and administration of surveys via the web or interactive 
voice response (IVR) automated telephone systems, as well as study participant 
tracking and computer-assisted telephone interviewing (CATI).  Data are stored in 
a secure enterprise-level Oracle database managed by the ITS Research 
Computing group at UNC, and web servers are hosted by the UNC Center for 


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Bioinformatics.  Data transmitted between the server and end-users are encrypted 
using SSL, and all databases are encrypted.   
 
PRO-Core Faculty Director: Antonia Bennett (avbenn@email.unc.edu) 
PRO-Core Director of Systems Development: Mattias Jonsson 
(jonsson@unc.edu) 
 
PRO-Core: http://pro.unc.edu/ 
ITS Research Computing: http://its.unc.edu/research/its-research-computing/ 
UNC Center for Bioinformatics: http://bioinformatics.unc.edu/ 
10.5 
Auditing 
As an investigator initiated study, this trial will also be audited by the Lineberger 
Cancer Center audit committee every six or twelve months, depending on the 
participation of affiliate sites. 
10.6 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, 
and well-being of the study patient requires alternative treatment, the study shall 
be conducted exactly as described in the approved protocol.   
10.6.1 Emergency Modifications 
UNC and Affiliate investigators may implement a deviation from, or a change of, 
the protocol to eliminate an immediate hazard(s) to trial subjects without prior 
UNC or their respective institution’s IRB/IEC approval/favorable opinion.   
 
For Institutions Relying on UNC’s IRB: 
For any such emergency modification implemented, a UNC IRB modification 
form must be completed by UNC Research Personnel within five (5) business 
days of making the change.   
 
For Institutions Relying on Their Own IRB: 
For Affiliate investigators relying on their own institution’s IRB, as soon as 
possible after the modification has been made, the implemented deviation or 
change and the reasons for it should be submitted to: 
 
• To UNC Principal Investigator for agreement  
• The Affiliate institution’s IRB for review and approval.  (Once 
IRB’s response is received, this should be forwarded to the 
UNCCN Regulatory Associate). 
10.6.2 Single Patient/Subject Exceptions 
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Any request to enroll a single subject who does not meet all the eligibility criteria 
of this study requires the approval of the UNC Principal Investigator and the UNC 
IRB.  
 
For Institutions Relying on Their Own IRB: 
Any request to enroll a single subject who does not meet all the eligibility criteria 
of this study requires the approval of the UNC Principal Investigator and the 
participating institution’s IRB, per its policy.  Please forward the IRB response to 
the UNCCN Regulatory Associate by facsimile or via email within 10 business 
days after the original submission.   
10.6.3 Other Protocol Deviations/Violations 
According to UNC’s IRB, a protocol deviation is any unplanned variance from an 
IRB approved protocol that:  
• Is generally noted or recognized after it occurs 
• Has no substantive effect on the risks to research participants 
• Has no substantive effect on the scientific integrity of the research plan 
or the value of the data collected  
• Did not result from willful or knowing misconduct on the part of the 
investigator(s).  
 
An unplanned protocol variance is considered a violation if the variance meets 
any of the following criteria:  
• Has harmed or increased the risk of harm to one or more research 
participants. 
• Has damaged the scientific integrity of the data collected for the study. 
• Results from willful or knowing misconduct on the part of the 
investigator(s). 
• Demonstrates serious or continuing noncompliance with federal 
regulations, State laws, or University policies. 
 
If a deviation or violation occurs please follow the guidelines below: 
 
For Institutions Relying on UNC’s IRB: 
Protocol Deviations: UNC or Affiliate personnel will record the deviation in 
OnCore®, and report to any sponsor or data and safety monitoring committee in 
accordance with their policies.  Deviations should be summarized and reported to 
the IRB at the time of continuing review. 
 
Protocol Violations: Violations should be reported by UNC personnel within one 
(1) week of the investigator becoming aware of the event using the same IRB 
online mechanism used to report Unanticipated Problems.   
 
For Institutions Relying on Their Own IRB: 


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In addition to adhering to the policies regarding protocol compliance set forth by 
your institution’s IRB, the following is also required: 
 
Protocol Deviations: In the event a deviation from protocol procedures is 
identified, record the deviation in OnCore®. 
 
Protocol Violations: Any protocol violation that occurs must be reported to your 
IRB per institutional policies and reported to the UNCCN Study Coordinator 
within 5 days. UNC-CH will determine if the violation affects the safety of the 
patient and integrity of the data.  Once your institution’s IRB response is received, 
please forward to the UNCCN Regulatory Associate. 
 
Unanticipated Problems: 
Affiliate Sites: 
Any events that meet the criteria for “Unanticipated Problems (UPs)” as defined 
by UNC’s IRB must also be reported to the UNCCN Study Coordinator.   The 
UNCCN Study Coordinator will report the event to the UNC IRB using the IRB’s 
web-based reporting system.  Examples of such UPs include a lost or stolen 
laptop computer that contains sensitive study information. 
 
UNC 
Any events that meet the criteria for “Unanticipated Problems” as defined by 
UNC’s IRB must be reported by the Study Coordinator using the IRB’s web-
based reporting system.   
10.7 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be 
originated and documented by the Principal Investigator at UNC.  It should also 
be noted that when an amendment to the protocol substantially alters the study 
design or the potential risk to the patient, a revised consent form might be 
required.   
 
For Institutions Relying on UNC’s IRB: 
The written amendment, and if required the amended consent form, must be sent 
to UNC’s IRB for approval prior to implementation.   
 
For Institutions Relying on Their Own IRB: 
Investigators must submit the UNC IRB approved amendment to their 
institution’s IRB for approval.  For multi-center studies, any affiliate site must 
submit their informed consent revisions to the UNCCN Regulatory Associate 
prior to submission to their IRB.   
10.8 
Record Retention 
Study documentation includes all eCRFs, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 


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regulatory documents (e.g., protocol and amendments, IRB correspondence and 
approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical 
activities and all reports and records necessary for the evaluation and 
reconstruction of the clinical research study. 
 
Government agency regulations and directives require that all study 
documentation pertaining to the conduct of a clinical trial must be retained by the 
study investigator.  In the case of a study with a drug seeking regulatory approval 
and marketing, these documents shall be retained for at least two years after the 
last approval of marketing application in an International Conference on 
Harmonization (ICH) region.  In all other cases, study documents should be kept 
on file until three years after the completion and final study report of this 
investigational study. 
10.9 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the 
site in accordance with Title 21 of the Code of Federal Regulations and/or the 
Declaration of Helsinki.  The Principal Investigator is responsible for personally 
overseeing the treatment of all study patients.  The Principal Investigator must 
assure that all study site personnel, including sub-investigators and other study 
staff members, adhere to the study protocol and all FDA/GCP/NCI regulations 
and guidelines regarding clinical trials both during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for 
assuring that all the required data will be collected and entered into the eCRFs. 
Periodically, monitoring visits will be conducted and the Principal Investigator 
will provide access to his/her original records to permit verification of proper 
entry of data. At the completion of the study, all eCRFs will be reviewed by the 
Principal Investigator and will require his/her final signature to verify the 
accuracy of the data. 
 
 
 
 
 
 


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11.0 REFERENCES 
 
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Kabbinavar, F.F., et al., Combined analysis of efficacy: the addition of 
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Van Cutsem, E., et al., Cetuximab and chemotherapy as initial treatment for 
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Lievre, A., et al., KRAS mutations as an independent prognostic factor in patients 
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Fuchs, C.S., et al., Phase III comparison of two irinotecan dosing regimens in 
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Van Cutsem, E., et al., A phase II study of irinotecan alternated with five days 
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17. 
Toffoli, G., et al., Genotype-driven phase I study of irinotecan administered in 
combination with fluorouracil/leucovorin in patients with metastatic colorectal 
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Toffoli, G., et al., The role of UGT1A1*28 polymorphism in the 
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Hoskins, J.M., et al., UGT1A1*28 genotype and irinotecan-induced neutropenia: 
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Ramchandani, R.P., et al., The role of SN-38 exposure, UGT1A1*28 
polymorphism, and baseline bilirubin level in predicting severe irinotecan 
toxicity. J Clin Pharmacol, 2007. 47(1): p. 78-86. 
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Innocenti, F., et al., Genetic variants in the UDP-glucuronosyltransferase 1A1 
gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol, 2004. 
22(8): p. 1382-8. 
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Deeken, J.F., R. Slack, and J.L. Marshall, Irinotecan and uridine diphosphate 
glucuronosyltransferase 1A1 pharmacogenetics: to test or not to test, that is the 
question. Cancer, 2008. 113(7): p. 1502-10. 
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Le Tourneau, C., J.J. Lee, and L.L. Siu, Dose escalation methods in phase I 
cancer clinical trials. J Natl Cancer Inst, 2009. 101(10): p. 708-20. 
24. 
Marcuello, E., et al., A genotype-directed phase I-IV dose-finding study of 
irinotecan in combination with fluorouracil/leucovorin as first-line treatment in 
advanced colorectal cancer. Br J Cancer, 2011. 105(1): p. 53-7. 
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Pectasides, D., et al., XELIRI-bevacizumab versus FOLFIRI-bevacizumab as first-
line treatment in patients with metastatic colorectal cancer: a Hellenic 
Cooperative Oncology Group phase III trial with collateral biomarker analysis. 
BMC Cancer, 2012. 12: p. 271. 
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Ducreux, M., et al., Efficacy and safety of bevacizumab-based combination 
regimens in patients with previously untreated metastatic colorectal cancer: final 
results from a randomised phase II study of bevacizumab plus 5-fluorouracil, 
leucovorin plus irinotecan versus bevacizumab plus capecitabine plus irinotecan 
(FNCLCC ACCORD 13/0503 study). Eur J Cancer, 2013. 49(6): p. 1236-45. 
27. 
Sharma M, T.G., Buonadonna A et al, A UGT1A1 genotype-guided dosing study 
of irinotecan in metastatic colorectal cancer (mCRC) patients (pts). ASCO 
Gastrointestinal Cancer Symposium (in press), 2014 (in press). 
28. 
Cheng, L., et al., UGT1A1*6 polymorphisms are correlated with irinotecan-
induced toxicity: a system review and meta-analysis in Asians. Cancer Chemother 
Pharmacol, 2014. 73(3): p. 551-60. 
29. 
Falcone A, C.C., Masi G et al, FOLFOXIRI/bevacizumab (bev) versus 
FOLFIRI/bev as first-line treatment in unresectable metastatic colorectal cancer 
(mCRC) patients (pts): Results of the phase III TRIBE trial by GONO group. J 
Clin ONcol, 2013. 31: p. 3505. 
30. 
Heinemann V, v.W.L., Decker T et al, Randomized comparison of FOLFIRI plus 
cetuximab versus FOLFIRI plus bevacizumab as first-line treatment of KRAS 
wild-type metastatic colorectal cancer: German AIO study KRK-0306 (FIRE-3). J 
Clin Oncol, 2013. 31: p. abstract LBA3506. 


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31. 
Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer, 2009. 45(2): p. 228-47. 
32. 
Smith, T.J., et al., 2006 update of recommendations for the use of white blood cell 
growth factors: an evidence-based clinical practice guideline. J Clin Oncol, 2006. 
24(19): p. 3187-205. 
33. 
Hay, J.L., et al., Cognitive interviewing of the US National Cancer Institute's 
Patient-Reported Outcomes version of the Common Terminology Criteria for 
Adverse Events (PRO-CTCAE). Qual Life Res, 2014. 23(1): p. 257-69. 
34. 
Basch, E., Systematic collection of patient-reported adverse drug reactions: a 
path to patient-centred pharmacovigilance. Drug Saf, 2013. 36(4): p. 277-8. 
35. 
Basch, E., A. Bennett, and M.C. Pietanza, Use of patient-reported outcomes to 
improve the predictive accuracy of clinician-reported adverse events. J Natl 
Cancer Inst, 2011. 103(24): p. 1808-10. 
36. 
Jensen, R.E., et al., Review of Electronic Patient-Reported Outcomes Systems 
Used in Cancer Clinical Care. J Oncol Pract, 2013. 
 
 
 


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12.0  APPENDICES 
 
12.1 
Appendix A ECOG Performance Status 
 
Grade 
Description 
0 
Fully active, able to carry on all pre-diseases performance without 
restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature (e.g. light housework, office work).  
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours.  
3 
Capable of only limited self-care, confined to bed or chair more than 50% 
of waking hours.  
4 
Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair.  
5 
Death  
 
 
 
 
 


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12.2 
Appendix B List of Prohibited Drugs and Prohibited Juices and Fruits 
The following drugs are prohibited in the 14 days prior to first dose of FOLFIRI 
through end of study therapy. 
 
Strong CYP3A4,5,7 
inhibitors 
CYP3A4 inducers* 
CYP3A4 and UGT1A1 
Inhibitor 
clarithromycin 
avasimibe 
atazanavir 
conivaptan 
barbiturates 
 
indinavir 
bosentan 
 
itraconazole 
carbamazepine 
 
ketoconazole 
efavirenz 
 
lopinavir 
etravirine 
 
mibefradil 
modafenil 
 
nefazodone 
nafcillin 
 
nelfinavir 
nevirapine 
 
posaconazole 
oxcarbazepine 
 
ritonavir 
phenobarbital 
 
saquinavir 
phenytoin 
 
telithromycin 
pioglitazone  
 
troleandomycin 
rifabutin 
 
voriconazole 
rifapentine 
 
 
rifampin 
 
 
St. John's wort 
 
 
talviraline 
 
 
tipranavir 
 
 
topiramate 
 
 
troglitazone  
 
This database of CYP inhibitors was compiled from the Indiana University School of Medicine’s 
“Clinically Relevant” Table and from the University of Washington’s Drug Interaction Database based 
on in vitro studies.  This database of CYP inducers was compiled from the FDA’s “Guidance for 
Industry, Drug Interaction Studies;” from the Indiana University School of Medicine’s “Clinically 
Relevant” Table; and from Pursche et al. 2008  Curr Clin Pharm. 3:198-203. 
 
*Systemic glucocorticoids eliminated from list of prohibited CYP3A4 inducers as dexamethasone does 
not appear to alter the pharmacokinetics of irinotecan (see pfizer.com, Camptosar® prescribing 
information). 
 
All juices/fruits listed are prohibited in the 7 days prior to first dose of FOLFIRI: 
grapefruits, grapefruit juices, grapefruit hybrids, Seville oranges, pummelos, 
and exotic citrus fruits 
 
 


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12.3 Appendix C New York Heart Association Functional Classification 
 
Class 
NYHA Functional Classification 
I 
Subjects have cardiac disease but without the resulting limitations of physical 
activity. Ordinary physical activity does not cause undue fatigue, palpitation, 
dyspnea, or anginal pain. 
II 
Subjects have cardiac disease resulting in slight limitation of physical activity. 
They are comfortable at rest. Ordinary physical activity results in fatigue, 
palpitation, dyspnea, or anginal pain. 
III 
Subjects have cardiac disease resulting in marked limitation of physical 
activity. They are comfortable at rest. Less than ordinary physical activity 
causes fatigue, palpitation, dyspnea, or anginal pain. 
IV 
Subjects have cardiac disease resulting in inability to carry on any physical 
activity without discomfort. Symptoms of cardiac insufficiency or of the 
anginal syndrome may be present even at rest. If any physical activity is 
undertaken, discomfort is increased. 
 
 


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12.4 Appendix D List of Drugs to be Used with Caution 
 
Moderate CYP3A4,5,7 inhibitors 
amprenavir 
aprepitant 
atazanavir 
cimetidine 
ciprofloxacin 
darunavir 
diltiazem 
elvitegravir 
erythromycin 
fluconazole 
fosamprenavir 
imatinib 
tipranavir 
tofisopam 
verapamil 
This database of CYP inhibitors was compiled from the 
Indiana University School of Medicine’s “Clinically 
Relevant” Table and from the University of 
Washington’s Drug Interaction Database based on in 
vitro studies.   
 
 
 
 


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12.5 
Appendix E Dietetic and pharmacologic guidelines for the treatment of drug 
induced diarrhea 
Patients receiving iriontecan are at risk of developing diarrhea and should be managed 
early and appropriately to avoid potential escalation in severity, duration or complications 
as well as treatment delays or dose reductions. Patients should be educated about the risks 
of developing diarrhea, and encouraged to contact the site to report and discuss the severity 
of diarrhea including the appropriate course of treatment. 
The following recommendations are based on available guidelines for the management of 
cancer treatment induced diarrhea (Wadler et al 1998, Kornblau et al. 2000, Benson et al. 
2004).  
Table 1               NCI CTCAE (Version 4) grading of diarrhea  
Grade 
Definition 
1 
increase of < 4 stools/day over baseline; mild increase in ostomy output 
compared to baseline 
2 
Increase of 4-6 stools/day over baseline, moderate increase in ostomy output 
compared to baseline 
3 
increase of ≥7 stools/day over baseline; incontinence; hospitalization indicated; 
severe increase in ostomy output compared to baseline; limiting self-care ADL 
4 
Life threatening consequences; urgent intervention indicated 
Management 
Evaluate diarrhea 
• Obtain history of onset and duration of diarrhea including a description of the number 
of stools and stool composition (e.g. watery, blood or mucus in stool) 
• Assess patient for fever, abdominal pain/cramps, distension, bloating, nausea, 
vomiting, dizziness, weakness (i.e., rule out risk for sepsis, bowel obstruction, 
dehydration) 
• Determine if diarrhea is complicated vs. uncomplicated  
• Obtain medication and dietary profile (i.e. to identify any diarrheogenic agents) 
 
 
 
 
 
 
 
 
 


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Table 2              Uncomplicated vs. complicated diarrhea 
Uncomplicated 
Complicated 
Grade 1-2 diarrhea with 
no complicating signs and 
symptoms  
Grade 3-4 diarrhea  
Grade 1-2 with the following complicating signs or symptoms: 
Moderate to severe cramping 
Grade ≥ 2 nausea/vomiting 
Decreased performance status 
Fever 
Sepsis 
Neutropenia 
Frank bleeding 
Dehydration 
Rule out other or concomitant causes 
Other or concomitant causes of diarrhea such as medications (e.g. stool softeners, laxatives, 
antacids), infections (e.g. C difficile, Candida species), partial bowel obstruction, 
malabsorption, fecal impaction, short bowel syndrome, endocrine dysfunction, dietary 
factors (high fiber diet, lactulose, etc.) should be ruled out. Consider appropriate tests and 
diarrhea work up as outlined below. 
General recommendations 
• Stop all lactose-containing products, alcohol 
• Stop laxatives, bulk fiber (Metamucil®, Procter & Gamble), and stool softeners 
(docusate sodium; Colace®, Roberts) 
• Stop high-osmolar food supplements such as Ensure® Plus and Jevity® Plus (with 
fiber) 
• Drink 8 to 10 large glasses of clear liquids per day [water, Pedialyte® (Ross), 
Gatorade® (Quaker), broth] 
• Eat frequent small meals (bananas, rice, applesauce, Ensure®, toast) 
It is further recommended that patients be provided loperamide tablets (or prescription) 
with the start of study treatment. When provided with loperamide, it is mandatory that 
patients are instructed on the correct use in order to manage signs or symptoms of diarrhea 
at home (e.g. initial administration of 4 mg, then 2 mg every 4 hours at the first sign of 
loose stool or symptoms of abdominal pain; do not exceed 16 mg/day). At each study visit, 
each patient should be specifically questioned regarding any experience of diarrhea or 
diarrhea related symptoms. If symptoms were experienced, then the healthcare provider 
should question the patient regarding the actions taken for these symptoms. Note that high 
dose loperamide can result in paralytic ileus. 


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Medications 
Loperamide is usually indicated for Grade 1 and 2 diarrhea. The standard dose is 4 mg 
followed by 2 mg every 4 hrs or after each unformed stool (maximum 16 mg/day). This 
dose may be increased in patients with mild to moderate diarrhea (Grade 1 or 2) that persists 
for more than 24 hours (“high dose loperamide”). The dose is 4 mg to start, followed by 2 
mg every 2 hours (maximum 16 mg/day). Loperamide should be discontinued after a 12 
hour diarrhea-free interval. 
Diphenoxylate hydrochloride and atropine sulfate may be used in place of loperamide 
as first-line treatment for diarrhea at the discretion of the treating physician. It may not be 
expected that this would be sufficient for the management of Grade 3 or 4 diarrhea. 
Octreotide may be considered for unresolved Grade 1-2 after 24 hours high-dose 
loperamide +/- diphenoxylate/atropine (48 hrs. total treatment with loperamide) or Grade 
3-4 diarrhea. These patients usually require hospitalization.  
Opiates may be considered as second-line treatment option for unresolved Grade 1 to 2 or 
Grade 3 to 4 diarrhea such as Opium tincture (deodorized tincture of opium or opium 10% 
tincture) or Paregoric (Camphorated Tincture of Opium®). Note that due to the differences 
in morphine content, special care must be taken to avoid potential overdose. Opium tincture 
is 25 times more concentrated (at 10 mg/mL of morphine) than Paregoric (at 0.4 mg/mL). 
Opioids should be stopped 24h after resolution of diarrhea. If opium tincture is not 
available, administration of codeine phosphate can be considered as an alternative. 
Antibiotics (e.g. fluoroquinolones) should be considered (prophylactically or 
concomitantly), particularly in the case of persistent diarrhea, severe neutropenia or fever. 
Treatment of uncomplicated grade 1or 2 diarrhea 
The recommended algorithm for management of uncomplicated grade 1 or 2 diarrhea is 
summarized in the following table: 


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Table 3               Treatment of uncomplicated grade 1 or 2 diarrhea  
Timeline 
Treatment 
Initial Treatment 
Standard dose of loperamide (initial administration 4 mg, then 2 mg every 
4 hours or after each unformed stool; max 16 mg/day) 
 
NOTE: Diphenoxylate hydrochloride and atropine sulfate may be used 
in place of loperamide as first-line treatment for diarrhea. 
Re-assessment 
12-24 hours after 
initial onset of 
diarrhea 
If diarrhea 
resolved 
Continue instructions for dietary modification and gradually add solid 
foods to diet 
 Discontinue loperamide after 12-hours diarrhea-free interval 
If diarrhea 
unresolved 
 
Diarrhea Grade 1-2 (uncomplicated) 
Escalate to high dose loperamide (2 mg every 2 hours or after each 
unformed stool; max 16 mg/day) 
Monitor patient condition (to rule out dehydration, sepsis, ileus) 
Observe patient for response to antidiarrheal treatment and reassess 12 
to 24 hours later 
Consider oral antibiotics 
 
Progression to complicated Grade 1-2 (e.g. presence of fever, 
dehydration, neutropenia) or Grade 3-4 with or without symptoms 
See  below for treatment guidance. 
Re-assessment 
24-48 hours after 
the initial onset of 
diarrhea 
If diarrhea 
resolved 
Continue instructions for dietary modification and gradually add solid 
foods to diet 
Discontinue loperamide and/or other treatment after 12-hours diarrhea-
free interval 
 
NOTE: Use of high-dose loperamide can result in paralytic ileus 
If diarrhea 
unresolved  
Unresolved Grade 1-2 after 24 hours high-dose loperamide (48 hrs total 
treatment with loperamide) or progression to Grade 3-4 
Evaluate patient in an office/outpatient center for a medical/laboratory 
check and selected workup (see ‘Diarrhea workup’ within this section for 
additional recommended tests); Hospitalization may need to be 
considered 
Replace fluids and electrolytes as appropriate 
Discontinue loperamide and begin a second-line agent which can be an 
opiate or octreotide acetate 
Opiates 
Opium tincture (deodorized tincture of opium or opium 10% tincture) or 
Paregoric (Camphorated Tincture of Opium®)  
NOTE: Due to the differences in morphine content, special care must be 
taken to avoid potential overdose. Opium tincture is 25 times more 
concentrated (at 10 mg/mL of morphine) than Paregoric (at 0.4 mg/mL). 
Opioids should be stopped 24h after resolution of diarrhea. 
If opium tincture is not available administration of codeine phosphate can 
be considered as an alternative. 
Octreotide 
Recommended dose of octreotide is 100-150 μg SC TID (every 8 hours). 
Treatment should be administered until patient is free of symptoms for 
24 hours. 


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Treatment of grade 3-4 or complicated diarrhea regardless of grade 
Severe diarrhea Grade 3 or 4 or complicated Grade 1 or 2 diarrhea may require 
hospitalization, and assessment of CBC, electrolytes and stool workup (e.g. cultures to 
exclude infectious causes) are recommended. Octreotide is the preferred anti-diarrheogenic 
agent (100-150 µg SC TID – every 8 hours; up to 500 µg TID). High dose loperamide 
(initial 4 mg, then 2 mg every 2 hours; maximum 16 mg/d) or opioids (e.g. opium tincture 
or dihydrocodeine tartrate tablets/injections) or atropine/diphenoxylate may be considered; 
however, they may not be sufficient for persistent, complicated or Grade 3 to 4 diarrhea. 
Thus, patients should be assessed for effectiveness of the anti-diarrheal therapy closely and 
switched to octreotide as indicated. Start IV fluids and antibiotics as clinically indicated 
with monitoring of the patient’s condition.  
Treatment of diarrhea grade 3/4 or complicated diarrhea grade 1-2 
• 
Admit to hospital 
• 
Administer IV fluids and electrolytes as needed 
• 
Administer SC octreotide acetate (100-150 µg TID – every 8 hours) 
• 
Stop loperamide and opiates if not already stopped 
• 
If there is no improvement in the diarrhea after 24 hrs, dose escalate octreotide acetate 
up to 500 µg TID SC until diarrhea is controlled 
• 
Medical/laboratory check and selected workup if patient does not need hospitalization 
(see ‘Diarrhea workup’ within this section for additional recommended tests) 
• 
Monitor/Continue IV fluids and antibiotics as needed. Treatment should be 
discontinued within 24 hours after the resolution of diarrhea  
• 
For study drug dose adjustment/delay see the respective protocol section 
Diarrhea workup 
If applicable and as necessary, appropriate tests should be performed (AGA Technical 
Review 1999). 
Spot stool analysis 
• Collect stool separating it from urine (special containers, analyze immediately, 
exceptionally freeze samples) 
• Blood 
• Fecal leukocytes (Wright's staining and microscopy) or 
• Clostridium difficile toxin 
• Fecal cultures including Salmonella spp., Campylobacter spp., Giardia, Entamoeba, 
Cryptosporidium (which can lead to opportunistic infections in immonunosuppressed 
patients), plus Shigella and pathogenic E. coli - enterotoxigenic, enterohemorrhagic 
etc., possibly Aeromonas, Pleisiomonas (if suspected exposure to contaminated water) 


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Endoscopic examinations 
Endoscopic examinations may be considered only if absolutely necessary. The bowel is 
likely to be fragile with evidence of colitis and thus great care and caution must be 
exercised in undertaking these invasive procedures. 
• Gastroscopy to obtain jejunal fluid - re. bacterial overgrowth for cultures and biopsy of 
proximal jejunum to assess extent of inflammatory jejunitis 
• Sigmoidoscopy - reassessment of colitis  
References  
AGA Technical Review on the Evaluation and Management of Chronic Diarrhea 
(1999) Gastroenterol; 116: 1464-1486. 
Benson AB, Ajani JA, Catalano RB, et al. Recommended guidelines for the 
treatment of cancer treatment-induced diarrhea (2004) Journal of Clinical 
Oncology; 22: 2918-2926. 
Kornblau S, Bensen AB, Catalano R, et al (2000) Management of Cancer 
Treatment–Related Diarrhea: Issues and Therapeutic Strategies. Journal of Pain and 
Symptom Management 19:118-129. 
Wadler S, Bensen AB, Engelking C, et al (1998) Recommended guidelines for the 
treatment of chemotherapy induced diarrhea. Journal of Clinical Oncology; 16: 
3169-3178. 
 
 
 
 


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12.6 
Appendix F:  Patient Handout: Prohibited Medications or Those to be used 
with Caution 
 
One of the medications you are receiving during this clinical trial is irinotecan.   
Irinotecan interacts with some drugs that are processed by your liver. Because of 
this, it is very important to tell your study doctors about all of your medicines 
before you start this study. It is also very important to tell them if you stop taking 
any regular medicine, or if you start taking a new medicine while you take part in 
this study. When you talk about your medicine with your study doctor, include 
medicine you buy without a prescription at the drug store (over-the-counter 
remedy), or anything that you buy from the health food store or grocery store 
(herbal supplement). Many health care prescribers can write prescriptions. You 
must also tell your other prescribers (doctors, physicians’ assistants or nurse 
practitioners) that you are taking part in a clinical trial. Bring this paper with 
you.  
 
• Irinotecan is processed by a certain enzyme in the liver called CYP3A4.  
Drugs that increase the activity of this enzyme are called “inducers,” and 
drugs that decrease the activity of this enzyme are called “inhibitors.”  
Irinotecan must be used very carefully with other medicines that are 
inducers or inhibitors of CYP3A4.   
• You and healthcare providers who prescribe drugs for you must be careful 
about adding or removing any drug in this category. 
• Before you start the study, your study doctor will work with your regular 
prescriber to switch the prohibited medications listed on the next page if 
you are taking them. 
• Your regular prescribers should look at this web site: 
http://medicine.iupui.edu/clinpharm/ddis/ [1] to see if any medicine they 
want to prescribe is on a list of drugs to avoid.  Your study doctor may 
also have a list of medications for you to show your regular prescribers 
instead of, or in addition to, this website.   
• If you drink grapefruit juice or eat grapefruit, Seville oranges, pummelos 
or exotic citrus fruits you should avoid these until the study is over.  
• Other medicines can be a problem with your study drugs. 
o You should check with your doctor or pharmacist whenever you 
need to use an over-the-counter medicine or herbal supplement. 
o Your regular prescriber should check a medical reference or call 
your study doctor before prescribing any new medicine for you. 
Your study doctor’s name is _______________ and he or she can 
be contacted at _______________________. 
 
 
 
 


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Prohibited Drugs 
atazanavir 
phenobarbital 
avasimibe 
phenytoin 
barbiturates 
pioglitazone  
bosentan 
posaconazole 
carbamazepine 
rifabutin 
clarithromycin 
rifapentine 
conivaptan 
rifampin 
efavirenz 
ritonavir 
etravirine 
saquinavir 
indinavir 
St. John's wort 
itraconazole 
talviraline 
ketoconazole 
tipranavir 
lopinavir 
topiramate 
mibefradil 
telithromycin 
modafenil 
troglitazone 
nafcillin 
troleandomycin 
nefazodone 
voriconazole 
nelfinavir 
 
nevirapine 
 
oxcarbazepine 
 
 
References 
1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. 
Indiana University School of Medicine (2007). 
"http://medicine.iupui.edu/clinpharm/ddis/clinical-table/"  
 


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12.7 
Appendix G:  Subset of PRO-CTCAE Questions 
 
See next page 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


LCCC-1317 PRO-CTCAE Patient Form.  Patient initials____     Study Id____   Date of completion_________ 
 
68 
 
1. In the last 14 days, how OFTEN did you have LOOSE OR WATERY STOOLS 
(DIARRHEA): 
• 
Never / Rarely / Occasionally / Frequently / Almost constantly 
 
2. In the last 14 days, what was the SEVERITY of your CONSTIPATION at its 
WORST: 
• 
None / Mild / Moderate / Severe / Very severe 
 
3. In the last 14 days, what was the SEVERITY of your DIFFICULTY 
SWALLOWING at its WORST: 
• 
None / Mild / Moderate / Severe / Very severe 
 
4. In the last 14 days, what was the SEVERITY of your MOUTH OR THROAT 
SORES at their WORST: 
• 
None / Mild / Moderate / Severe / Very severe 
 
5. In the last 14 days, how much did MOUTH OR THROAT SORES INTERFERE 
with your usual or daily activities: 
• 
Not at all / A little bit / Somewhat / Quite a bit / Very much 
 
6. In the last 14 days, what was the SEVERITY of your FATIGUE, TIREDNESS, OR 
LACK OF ENERGY at its WORST: 
• 
None / Mild / Moderate / Severe / Very severe 
 
7. In the last 14 days, how much did FATIGUE, TIREDNESS, OR LACK OF 
ENERGY INTERFERE with your usual or daily activities: 
• 
Not at all / A little bit / Somewhat / Quite a bit / Very much 
 
8. In the last 14 days, what was the SEVERITY of your DECREASED APPETITE at 
its WORST: 
• 
None / Mild / Moderate / Severe / Very severe 
 
9. In the last 14 days, how much did DECREASED APPETITE INTERFERE with your 
usual or daily activities: 
• 
Not at all / A little bit / Somewhat / Quite a bit / Very much 
 
10. In the last 14 days, what was the SEVERITY of your SHORTNESS OF BREATH 
at its WORST: 
• 
None / Mild / Moderate / Severe / Very severe 
 
11. In the last 14 days, how much did SHORTNESS OF BREATH INTERFERE with 
your usual or daily activities: 
• 
Not at all / A little bit / Somewhat / Quite a bit / Very much 
 
12. In the last 14 days, what was the SEVERITY of your INSOMNIA (INCLUDING 
DIFFICULTY FALLING ASLEEP, STAYING ASLEEP, OR WAKING UP 
EARLY) at its WORST: 
• 
None / Mild / Moderate / Severe / Very severe 
 
13. In the last 14 days, how much did INSOMNIA (INCLUDING DIFFICULTY 
FALLING ASLEEP, STAYING ASLEEP, OR WAKING UP EARLY) INTERFERE 
with your usual daily activities: 
• 
Not at all / A little bit / Somewhat / Quite a bit / Very much 
 
14. In the last 14 days, how OFTEN did you have NAUSEA: 


LCCC-1317 PRO-CTCAE Patient Form.  Patient initials____     Study Id____   Date of completion_________ 
 
69 
 
• 
Never / Rarely / Occasionally / Frequently / Almost constantly 
 
15. In the last 14 days, what was the SEVERITY of your NAUSEA at its WORST: 
• 
None / Mild / Moderate / Severe / Very severe 
 
16. In the last 14 days, how OFTEN did you have VOMITING: 
• 
Never / Rarely / Occasionally / Frequently / Almost constantly 
 
17. In the last 14 days, what was the SEVERITY of your VOMITING at its WORST: 
• 
None / Mild / Moderate / Severe / Very severe 
 
18. In the last 14 days, how OFTEN did you have PAIN: 
• 
Never / Rarely / Occasionally / Frequently / Almost constantly 
 
19. In the last 14 days, what was the SEVERITY of your PAIN at its WORST: 
• 
None / Mild / Moderate / Severe / Very severe 
 
20. In the last 14 days, how much did PAIN INTERFERE with your usual or daily 
activities: 
• 
Not at all / A little bit / Somewhat / Quite a bit / Very much 
 
21. In the last 14 days, how OFTEN did you have PAIN IN THE ABDOMEN (BELLY 
AREA):  
• 
Never / Rarely / Occasionally / Frequently / Almost constantly 
 
22. In the last 14 days, what was the SEVERITY of your PAIN IN THE ABDOMEN 
(BELLY AREA) at its WORST: 
• 
None / Mild / Moderate / Severe / Very severe 
 
23. In the last 14 days, how much did PAIN IN THE ABDOMEN (BELLY AREA) 
INTEFERE with your usual or daily activities: 
• 
Not at all / A little bit / Somewhat / Quite a bit / Very much 
 
24. In the last 14 days, how OFTEN did you have a HEADACHE: 
• 
Never / Rarely / Occasionally / Frequently / Almost constantly  
 
25. In the last 14 days, what was the SEVERITY of your HEADACHE at its WORST: 
• 
None / Mild / Moderate / Severe / Very severe 
 
26. In the last 14 days, how much did your HEADACHE INTERFERE with your usual 
or daily activities: 
• 
Not at all / A little bit / Somewhat / Quite a bit / Very much 
 
 
 
 
 
 
 


LCCC-1317 PRO-CTCAE Clinician Form.  Patient initials____     Study Id____   Date of completion_________  
Clinician Name________________    
 
70 
 
12.8 
Appendix H:  PRO-CTCAE Clinician Form 
 
See next page