Clinical trial NCT02292758
Conditions: Colorectal Adenocarcinoma RAS Wild Type Stage IV Colorectal Cancer AJCC v7 Stage IVA Colorectal Cancer AJCC v7 Stage IVB Colorectal Cancer AJCC v7
Sponsor: Academic and Community Cancer Research United
Start date: 2014-12-12; Completion date: 2019-09-27
Enrollment: 36 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized phase II trial studies how well irinotecan and cetuximab with or without bevacizumab work in treating patients with RAS wild-type colorectal cancer that has spread to other places in the body (locally advanced/metastatic) and cannot be removed by surgery. Irinotecan may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as cetuximab and bevacizumab, may help the body?s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving irinotecan and cetuximab with or without bevacizumab may work betting in treating patients with colorectal cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To assess and compare the progression-free survival (PFS) of patients receiving irinotecan, cetuximab, and bevacizumab with patients receiving irinotecan, cetuximab and placebo, in the population of patients with RAS wild-type, irinotecan-refractory metastatic colorectal cancer (mCRC) who also previously received bevacizumab in at least one prior line therapy.

SECONDARY OBJECTIVES:

I. To assess the adverse event (AE) profile and safety of the proposed treatment in this population.

II. To assess and compare the overall survival (OS) between treatment arms in this population.

III. To assess and compare the disease control rate (DCR) between treatment arms in this population.

IV. To assess and compare the overall response rate (ORR) between treatment arms in this population.

V. To assess and compare the duration of response between treatment arms in this population.

VI. To assess and compare time to treatment failure between treatment arms in this population.

VII. To assess relative dose intensity of treatment agents between treatment arms in this population.

CORRELATIVE OBJECTIVES:

I. Determine the change in genotype concentrations of prespecified gene mutations in circulating cell-free deoxyribonucleic acid (DNA) (cfDNA) collected serially during protocol treatment.

II. Explore the predictive value of pretreatment mutation status, germline single nucleotide polymorphisms (SNPs), and gene expression signatures for cetuximab sensitivity and resistance.

III. Explore the predictive value of dynamic changes in mutation status and gene expression signatures for cetuximab sensitivity and resistance.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive cetuximab intravenously (IV) over 90-120 minutes, bevacizumab IV over 30-90 minutes, and irinotecan IV over 90 minutes on day 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive cetuximab IV over 90-120 minutes, placebo IV over 30-90 minutes, and irinotecan IV over 90 minutes on day 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for up to 2 years.

Arms: arm 1: Patients receive cetuximab IV over 90-120 minutes, bevacizumab IV over 30-90 minutes, and irinotecan IV over 90 minutes on day 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive cetuximab IV over 90-120 minutes, placebo IV over 30-90 minutes, and irinotecan IV over 90 minutes on day 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Bevacizumab intervention 2: Cetuximab intervention 3: Irinotecan intervention 4: Laboratory Biomarker Analysis intervention 5: Placebo
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV intervention 4: Correlative studies intervention 5: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
RU021302I 
 
Addendum4 
 
Academic and Community Cancer Research United (ACCRU) 
 
BOND-3: A Randomized, Double-blind, Placebo-Controlled Phase II Trial of Irinotecan, Cetuximab, and 
Bevacizumab Compared with Irinotecan, Cetuximab, and Placebo in RAS-Wildtype, Irinotecan-Refractory, 
Metastatic Colorectal Cancer 
 
For any communications regarding this protocol, please contact the person listed on 
the Protocol Resource page. This is a stand-alone document found on the ACCRU 
website (www.ACCRU.org) 
 
 
Study Chairs 
ACCRU: 
Kimmie Ng, M.D., M.P.H. 
 
 
 
 
 
Dana-Farber Cancer Institute 
 
 
 
 
 
Kimmie_Ng@DFCIHARVARD.EDU 
 
  Study Co-chairs: 
 
 
 
 
 
 
 
 
 
      FDA IND Sponsor/Investigator: 
 
 
 
 
 
 
 Correlative Science Chair: 
 
 
 
 
 
 
 
 Statistician:  
 
 
Mayo Clinic 
 
 
 
 
 
 
 
 
 
 
 
Mayo Clinic 
 
 
 
 
 
 
 
√ Study contributor(s) not responsible for patient care. 
 
 
 
 
 
 
Drug Availability 
Commercial Agents: Irinotecan, Cetuximab 
Drug Company Supplied: Bevacizumab 
 
Study Participants – Limited: ACCRU Membership 
 
Research Coordinating Center 
Academic and Community Cancer Research United 
 
 
 
 
 
 
 
Document History 
 
Effective Date 
 
 
 
 
Pre-activation 
 
 
October 10, 2014 
 
 
 
 
Activation Addendum 1 
 
December 12, 2014 
 
 
 
 
Addendum 2 
 
 
May 19, 2017 
 
 
 
 
Addendum 3 
 
 
August 17, 2018 
 
 
 
 
Addendum 4 
 
 
May 24, 2019 
 
 
 
 


RU021302I 
2 
Addendum 3 
 
 
Index 
 
Schema 
1.0 Background 
2.0 Goals 
3.0 Patient Eligibility 
4.0 Test Schedule 
5.0 Stratification Factors 
6.0 Registration/Randomization Procedures 
7.0 Protocol Treatment 
8.0 Dosage Modification Based on Adverse Events 
9.0 Ancillary Treatment/Supportive Care 
10.0 Adverse Event (AE) Reporting and Monitoring 
11.0 Treatment Evaluation Using RECIST Guideline 
12.0 Descriptive Factors 
13.0 Treatment/Follow-up Decision at Evaluation of Patient 
14.0 Body Fluid Biospecimens 
15.0 Drug Information 
16.0 Statistical Considerations and Methodology 
17.0 Pathology Considerations/Tissue Biospecimens 
18.0 Records and Data Collection Procedures 
19.0 Budget 
20.0 References 
 
 
 
 


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3 
Addendum 3 
 
 
Schema 
 
 
 
 
 
 
 
 
1Cycle length = 14 days. 
NOTE: If a patient is deemed ineligible or a cancel, please refer to Section 13.0 for follow-up 
information. 
 
Generic name: Bevacizumab 
Brand Name: Avastin 
Availability: McKesson Specialty Pharmacy, 
Clinical Research Services 
Generic name: Placebo 
Brand Name: NA 
Availability: Commercial supply 
Generic name: Irinotecan 
Brand Name: Camptosar 
Availability: Commercial 
Generic name: Cetuximab 
Brand Name: Erbitux 
Availability: Commercial 
 
Event Monitoring: Is not part of the Active Monitoring phase of a study. It is the time period when the 
participant is no longer following the protocol test schedule. During Event Monitoring, the data collection 
schedule is dictated by the protocol but the visit schedule is determined by clinical practice at each 
participating site. During the Event Monitoring Phase of the study, the participant is being monitored for 
key study events such as progression, new primaries, and death. Participants may not be required to return 
to the consenting site for study-related reasons or be required to have research-related tests performed. 
Samples from biospecimens collected in the course of clinical care may be requested but cannot be 
required of the participant. 
Event 
Monitoring 
Bevacizumab + irinotecan and 
cetuximab each cycle1 
PD, death, or 
unacceptable 
adverse events 
Placebo + irinotecan and 
cetuximab each cycle1 
PD, death, or 
unacceptable 
adverse events 
Randomization 


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4 
Addendum 3 
 
 
1.0 
Background 
 
1.1 
Colorectal Cancer 
 
Colorectal cancer (CRC) is the third most common cancer and the second leading cause 
of cancer death in the U.S. In 2013, an estimated 142,820 cases of CRC will be diagnosed 
and 50,830 people will die from the disease (American Cancer Society, 2013). Fifteen to 
25% of patients with CRC have metastatic disease at the time of diagnosis, and a 
significant proportion of patients who are initially diagnosed with localized disease 
ultimately develop metastases (Kindler and Shulman, 2001). While there have been 
substantive advances in the treatment of metastatic CRC (mCRC) over the past few years, 
median survival for these patients remains at two years, and less than 6% survive for 
more than five years (American Joint Committee on Cancer, 2010). Clearly, there is a 
critical need for new effective treatment regimens to further prolong survival. 
 
1.2 
5-Fluorouracil-Based Chemotherapy 
 
Historically, treatment for CRC was limited to 5-fluorouracil (5-FU) and leucovorin 
(LV), with response rates (RRs) of 23% and median survival time of approximately 10 to 
12 months (Advanced Colorectal Cancer Meta-Analysis Project, 1992). 5-FU is 
incorporated into RNA and DNA and inhibits the enzyme thymidylate synthase (TS), 
thus interfering with the formation of new strands of DNA during replication. LV is a 
reduced folate which, when combined with 5-FU, augments 5-FU cytotoxicity by 
increasing the inhibition of TS by the 5-FU active metabolite FdUMP. Because 5-FU has 
a short half-life, continuous infusion regimens appear to offer a pharmacological benefit, 
with the maximal dose intensity of 5-FU delivery being achieved when the drug is 
administered over 24-48 hours. 
 
In the initial treatment of mCRC, 5-FU/LV is often administered with either irinotecan or 
oxaliplatin. Irinotecan is converted by carboxylesterase to its active metabolite, SN-38, 
which binds and stabilizes topoisomerase I, leading to double-stranded DNA breaks and 
apoptosis. Randomized controlled trials have shown that irinotecan is active both in 
refractory mCRC as a single agent (Cunningham, et al, 1998) and in the first-line setting 
when combined with bolus 5-FU/LV (IFL) (Saltz, et al, 2000) or infusional 5-FU/LV 
(FOLFIRI) (Douillard, et al, 2000). Oxaliplatin is a platinum derivative that leads to the 
formation of DNA adducts, and has been evaluated in combination with both bolus (i.e., 
FLOX) and infusional forms of 5-FU/LV (FOLFOX), as well as capecitabine 
(CAPEOX). All of these studies have found that combination chemotherapy is superior to 
5-FU/LV alone. Indeed, FOLFOX has been shown to be superior to IFL in the first-line 
setting (Goldberg, et al, 2004), but equivalent to FOLFIRI (Tournigand, et al, 2004). 
 
1.3 
Cetuximab 
 
Cetuximab is a chimeric human-murine monoclonal antibody that binds selectively to the 
extracellular region of the epidermal growth factor receptor (EGFR). Binding inhibits 
ligand-induced, tyrosine kinase-dependent phosphorylation of EGFR and leads to 
internalization and degradation of the receptor. A reduction in available EGFR at the cell 
surface subsequently results in reduced activation of downstream signaling pathways. 
 
Cetuximab has been extensively studied in mCRC, with antitumor activity demonstrated 
both as a single agent and in combination with chemotherapy in multiple lines of therapy. 


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5 
Addendum 3 
 
 
The BOND-1 trial randomized 329 patients with EGFR+ mCRC who had progressed 
within three months of an irinotecan-based therapy in a 2:1 ratio to irinotecan + 
cetuximab or cetuximab alone (Cunningham, et al, 2004). Response rate (RR) was 
significantly higher with the combination (23% versus 11%), as were median time-to- 
progression (TTP; 4.1 versus 1.5 months) and median overall survival (OS; 8.6 versus 6.9 
months). Cetuximab monotherapy was compared to best supportive care in the CO.17 
phase III trial, and RR, PFS, and OS were all statistically higher in the treatment arm 
(Jonker, et al, 2007). Cetuximab also demonstrated efficacy in the second-line setting in 
the EPIC study, which randomized 1,298 patients with EGFR+ mCRC who had been 
previously treated with 5-FU- and oxaliplatin-based therapy to irinotecan + cetuximab or 
irinotecan alone (Sobrero, et al, 2008). Although the primary endpoint of OS was not 
statistically different between the arms, both median progression-free survival (PFS) and 
RR were significantly higher in the combination arm (P<0.0001 for both). Finally, the 
CRYSTAL trial randomized 1,198 previously untreated mCRC patients to FOLFIRI + 
cetuximab or FOLFIRI alone, and found a statistically improved median PFS with the 
addition of cetuximab (8.9 versus 8.0 months, P=0.048) (Van Cutsem, et al, 2009). RR 
was also significantly higher in the cetuximab-containing arm (46.9% versus 38.7%, 
P=0.004), but there was no difference in median OS (19.9 versus 18.6 months, P=0.31). 
EGFR positivity was not an inclusion criterion for this trial due to further research that 
concluded that it was not, in fact, a predictive marker of cetuximab efficacy. 
 
Following the discovery that EGFR positivity was not predictive of response to anti- 
EGFR therapy, KRAS exon 2 (codons 12 and 13) mutation status emerged as a true 
biomarker of cetuximab activity. A meta-analysis of 281 irinotecan-refractory patients 
treated with irinotecan-based therapy in combination with cetuximab across seven studies 
showed that among the 35% of patients whose tumors harbored a KRAS mutation in 
codon 12 or 13, there were no complete (CR) or partial responses (PR) compared to 2% 
CR and 41% PR rates among KRAS wild-type patients (Di Fiore, et al, 2008). Moreover, 
median PFS and median OS were significantly worse among KRAS-mutated patients (2.7 
versus 5.4 months and 8.0 versus 13.2 months, respectively). Subsequently, multiple 
subgroup analyses of large phase III trials of first-line mCRC demonstrated the same 
findings, with KRAS wild type status predicting superior efficacy outcomes to anti-EGFR 
therapy, and worse outcomes among KRAS-mutated patients (Tveit, et al, 2012; Adams, 
et al, 2011; Bokemeyer, et al, 2011; Douillard, et al, 2010; Van Cutsem, et al, 2009). 
 
However, not all tumors with wild type KRAS codon 12 and 13 respond to anti-EGFR 
antibodies, and it has now been reported that this resistance could be explained by other 
mutations within KRAS as well as NRAS. For example, in a re-analysis of the PRIME 
phase III trial of FOLFOX +/- panitumumab in first-line metastatic colorectal cancer, 
17% of patients without mutations in exon 2 had other mutations in exons 3 and 4 of 
KRAS and in NRAS exons 2, 3, and 4 (Douilliard, et al, 2013). The presence of these other 
RAS mutations predicted a lack of response to panitumumab, as well as inferior PFS and 
overall survival in patients receiving FOLFOX + panitumumab compared to FOLFOX 
alone. Consequently, the National Comprehensive Cancer Network (NCCN) updated 
their guidelines to restrict use of anti-EGFR antibodies to patients with all-RAS wild type 
tumors only. 
 
 
1.4 
Bevacizumab 
 
Bevacizumab is a fully humanized, monoclonal antibody against the vascular endothelial 
growth factor (VEGF). Although bevacizumab has limited activity as a single agent for 


RU021302I 
6 
Addendum 3 
 
 
treatment of mCRC, the addition of the agent to chemotherapy significantly improves 
patient outcome. The phase III trial that won bevacizumab its FDA approval randomized 
815 patients with previously-untreated mCRC to IFL + bevacizumab versus IFL alone, 
and found statistically significantly superior RR (44.8% versus 34.8%, P=0.004), median 
PFS (10.6 versus 6.2 months, P<0.001), and median OS (20.3 versus 15.6 months, 
P<0.001) in the bevacizumab-containing arm (Hurwitz, et al, 2004). The NO16966 trial 
subsequently confirmed the superiority of adding bevacizumab to an oxaliplatin-based 
chemotherapy backbone such as CAPEOX and FOLFOX in the first-line setting (Saltz, et 
al, 2008). Finally, the E3200 trial reported improved median PFS (7.3 versus 4.7 months) 
and OS (12.9 versus 10.8 months) for previously treated mCRC patients randomized to 
FOLFOX + bevacizumab versus FOLFOX alone (Giantonio, et al, 2007). 
 
1.5 
Study Rationale 
 
Given the multitude of trials reporting a benefit of adding either an anti-VEGF antibody 
or an anti-EGFR antibody to standard chemotherapy in multiple lines of therapy for 
mCRC, there is great interest in exploring the addition of both antibody types 
simultaneously to chemotherapy. Unfortunately, trials in the first-line therapy of mCRC 
suggest no benefit for the combination of chemotherapy with both an anti-EGFR 
antibody and bevacizumab (Hecht, et al, 2009; Tol, et al, 2009). 
 
Nonetheless, in patients with irinotecan-refractory mCRC, a randomized trial does 
suggest a benefit for the combination of irinotecan, cetuximab, and bevacizumab (Saltz, 
et al, 2007). That randomized phase II trial, BOND-2 (N = 83), evaluated the safety and 
efficacy of cetuximab and bevacizumab with or without irinotecan in patients with 
irinotecan-refractory mCRC. The patient population enrolled in the trial had received 
extensive previous treatment with a median number of prior chemotherapy regimens of 
three. Patients in Arm A (n = 43) of the study received cetuximab, bevacizumab, and 
irinotecan. Patients in Arm B (n = 40) received only cetuximab plus bevacizumab. 
Patients receiving cetuximab, bevacizumab, and irinotecan had a TTP of 7.3 months, RR 
of 37%, and an OS of 14.5 months. In comparison, patients receiving cetuximab and 
bevacizumab without irinotecan had a TTP of 4.9 months, RR of 20%, and an OS of 11.4 
months. Of note, BOND-2 only enrolled patients with bevacizumab-naive mCRC. 
 
These response rates compare favorably with those from other studies in patients with 
refractory mCRC (see Table 1 below). In the BOND-1 study described above, patients 
with irinotecan-refractory mCRC treated with cetuximab and irinotecan (n = 218) had a 
median TTP of 4.1 months and a RR of 23% (Cunningham, et al, 2004). These results 
suggest that, in patients with irinotecan-refractory mCRC, the combination of irinotecan, 
cetuximab, and bevacizumab may offer superior efficacy when compared to irinotecan 
and cetuximab. Moreover, the results suggest that, in contrast to first-line therapy, the 
combination of cetuximab and bevacizumab may offer synergy in later lines of therapy. 
More recently, other studies suggest a benefit for continuation of bevacizumab into later 
lines of therapy following progression on first-line chemotherapy and bevacizumab 
(Arnold, et al, 2012). 


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Addendum 3 
 
 
Table 1: Cross-study comparison of efficacy from the BOND-1 and BOND-2 trials 
 
STUDY 
BOND-2 
BOND-1 
INVESTIGATIONAL ARM 
Irinotecan + Cetuximab 
+ Bevacizumab 
Irinotecan + Cetuximab 
RR (%) 
37 
23 
PFS (months) 
7.9 
4.0 
CONTROL ARM 
Cetuximab + 
Bevacizumab 
Cetuximab 
RR (%) 
20 
11 
PFS (months) 
5.6 
1.5 
 
 
Consequently, this study proposes a double-blind, placebo-controlled trial of irinotecan, 
cetuximab, and bevacizumab vs. irinotecan, cetuximab, and placebo in patients with 
RAS-wild-type, irinotecan-refractory mCRC who have also previously received 
bevacizumab in at least one prior line of therapy. Results from this trial could support 
the addition of bevacizumab to the approved combination of irinotecan and cetuximab in 
irinotecan-refractory mCRC. Recent U.S.-wide data suggest that the majority of anti- 
EGFR use is in irinotecan-refractory mCRC (Abrams, et al, 2012). As such, beyond data 
supporting first-line use of bevacizumab and continuation of bevacizumab into second- 
line therapy, results of our proposed trial would support continuation of bevacizumab 
into third-line therapy with irinotecan and cetuximab. 
 
 
2.0 
Goals 
 
2.1 
Primary 
 
2.11 
To assess and compare the progression-free survival (PFS) of patients receiving 
irinotecan, cetuximab, and bevacizumab with patients receiving irinotecan, 
cetuximab and placebo, in the population of patients with RAS-wildtype, 
irinotecan-refractory metastatic colorectal cancer (mCRC) who also previously 
received bevacizumab in at least one prior line therapy. 
 
2.2 
Secondary 
 
2.21 
To assess the adverse event (AE) profile and safety of the proposed treatment in 
this population. 
 
2.22 
To assess and compare the overall survival (OS) between treatment arms in this 
population. 
 
2.23 
To assess and compare the disease control rate (DCR) between treatment arms in 
this population. 
 
2.24 
To assess and compare the overall response rate (ORR) between treatment arms 
in this population. 


RU021302I 
8 
Addendum 3 
 
 
2.25 
To assess and compare the duration of response between treatment arms in this 
population. 
 
2.26 
To assess and compare time to treatment failure between treatment arms in this 
population. 
 
2.27 
To assess relative dose intensity of treatment agents between treatment arms in 
this population. 
 
2.3 
Correlative 
 
2.31 
Determine the change in genotype concentrations of prespecified gene mutations 
in circulating cell-free DNA (cfDNA) collected serially during protocol 
treatment. 
 
2.32 
Explore the predictive value of pretreatment mutation status, germline single 
nucleotide polymorphisms (SNPs), and gene expression signatures for cetuximab 
sensitivity and resistance. 
 
2.33 
Explore the predictive value of dynamic changes in mutation status and gene 
expression signatures for cetuximab sensitivity and resistance. 
 
 
3.0 
Patient Eligibility 
 
3.1 
Inclusion Criteria 
 
3.11 
Metastatic or locally advanced (unresectable) colorectal cancer with histological 
confirmation of adenocarcinoma. 
 
3.12 
Age ≥18 years of age. 
 
3.13 
Measurable disease as defined in Section 11.0. 
 
3.14 
RAS wild-type tumor (Appendix IV). 
 
Note: Evidence of EGFR expression in the tumor is not required. 
 
3.15 
Previous failure of at least one fluoropyrimidine- and irinotecan-containing 
chemotherapy regimen for metastatic disease. 
 
Note: Previous failure is defined as disease progression while receiving 
treatment or within 6 weeks after the last dose of irinotecan. Failure for this 
assessment is defined as any enlargement of measurable or assessable lesion(s) 
or the development of any new lesion. A rising tumor marker alone is not 
sufficient to define failure. Patients can have received irinotecan in any previous 
line of therapy. 
 
3.16 
Treatment with bevacizumab in at least one prior line of therapy for metastatic 
disease. 


RU021302I 
10 
Addendum 3 
 
 
3.17 
Negative serum or urine pregnancy test done ≤7 days prior to registration, 
for women of childbearing potential only. 
 
3.18 
ECOG Performance Status (PS): 0 or 1 (form available on the ACCRU member 
website at 
 
 
3.19 a 
Adequate organ and bone marrow function as defined below (see Section 3.19b) 
3.19b The following laboratory values obtained ≤14 days prior to randomization: 
• 
Total serum bilirubin ≤ institutional upper limit of normal (ULN) 
• 
Absolute neutrophil count (ANC) ≥1500/mm3 
• 
Platelet count ≥100,000/mm3 
• 
Hemoglobin ≥9.0 g/dL (hemoglobin may be supported by transfusion) 
• 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 
x ULN (≤5 x ULN for subjects with liver involvement of their cancer) 
• 
Creatinine within institutional limits of normal 
OR 
creatinine clearance >60 mL/min/1.73 m2 for patients with creatinine levels 
above institutional normal. 
• 
Urinary protein ≤1+ 
 
o Patients discovered to have ≥2+ proteinuria must have a spot urine 
protein:creatinine ratio (UPCR) <1.0 
 
• 
Partial thromboplastin time (PTT) ≤1x institutional ULN and international 
normalized ratio (INR) ≤1.5, unless participant is on full dose 
anticoagulation therapy. Patients on full-dose anticoagulation are eligible if 
the following criteria are met: 
 
o Patient has an in-range INR (usually 2-3) on a stable dose of warfarin or 
other anticoagulant ≤14 days or is on a stable dose of low molecular 
weight heparin 
o Patient has no active bleeding or pathological condition that carries a 
high risk of bleeding (i.e., tumor involving major vessels or known 
varices) 
o Patients receiving anti-platelet agents are eligible. In addition, patients 
who are on daily prophylactic aspirin or anticoagulation for atrial 
fibrillation are eligible. 
 
3.19c 
Life expectancy >3 months 
 
3.19d Provide informed written consent. 
 
3.19e 
Willing to provide blood samples for mandatory correlative and research 
purposes (see Sections 6.0 and 14.0). 
 
3.19f 
Willing to provide tissue and blood samples for mandatory banking purposes (see 
Sections 6.0, 14.0 and 17.0). 


RU021302I 
11 
Addendum 3 
 
 
3.19g Any major surgery or open biopsy completed ≥4 weeks prior to randomization. 
 
3.19h Any minor surgery or core biopsy completed ≥1 week prior to randomization and 
patient must have fully recovered from the procedure. 
 
Note: Insertion of a vascular access device is not considered major or minor 
surgery. 
 
3.2 
Exclusion Criteria 
 
3.21 
Presence of a RAS mutation in exons 2, 3, or 4 of KRAS or NRAS. (Patients with 
mutations in exons 2, 3, or 4 of KRAS and/or NRAS are excluded) 
 
3.22 
Prior treatment with cetuximab or panitumumab. 
 
3.23 
Prior intolerance to irinotecan and/or bevacizumab despite dose reduction. 
 
3.24 
Known or suspected brain or central nervous system (CNS) metastases, or carcinomatous 
meningitis. 
 
3.25 
Active, uncontrolled infection, including hepatitis B, hepatitis C. 
 
3.26 
Concurrent anti-cancer therapy, including chemotherapy agents, targeted agents, or 
biological agents not otherwise specified in this protocol. 
 
3.27 
Anti-cancer therapy ≤14 days prior to randomization. 
 
3.28 
Prior radiotherapy to >25% of bone marrow. 
 
Note: Standard rectal cancer chemoradiation will not exclude subject from study 
protocol. 
 
3.29 a 
Radiation therapy ≤2 weeks prior to randomization. 
 
3.29 b Any of the following, because this study involves agents whose genotoxic, mutagenic and 
teratogenic effects on the developing fetus and newborn are unknown: 
 
• 
Pregnant women 
• 
Nursing women 
• 
Men or women of childbearing potential who are unwilling to employ adequate 
contraception 
 
3.29c 
Co-morbid systemic illnesses or other severe concurrent disease, history of any 
psychiatric or addictive disorder, or laboratory abnormality, which, in the judgment of the 
investigator, would make the patient inappropriate for entry into this study or interfere 
significantly with the proper assessment of safety and toxicity of the prescribed regimens. 
 
3.29d Patients known to be HIV positive 


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12 
Addendum 3 
 
 
3.29e 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, 
symptomatic pulmonary fibrosis or interstitial pneumonitis, or psychiatric illness/social 
situations that, in the opinion of the investigator, may increase the risks associated with 
study participation or study treatment, or may interfere with the conduct of the study or 
the interpretation of the study results. 
 
3.29f 
Receiving any other investigational agent which would be considered as a treatment for 
the primary neoplasm. 
 
3.29g Other active malignancy ≤3 years prior to registration. 
 
EXCEPTIONS: Non-melanoma skin cancer, prostatic intraepithelial neoplasia without 
evidence of prostate cancer, lobular carcinoma in situ in one breast, or carcinoma-in-situ 
of the cervix that has been treated. 
 
3.29h History of prior malignancy for which patient is receiving other specific treatment for 
their cancer. 
 
3.29i 
History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to irinotecan, cetuximab, and/or bevacizumab that led to discontinuation of 
those agents. 
3.29j 
Significant history of bleeding events or pre-existing bleeding diathesis ≤6 months of 
randomization (unless the source of bleeding has been resected) 
 
3.29k History of gastrointestinal perforation ≤12 months prior to randomization. 
 
3.29l 
Predisposing colonic or small bowel disorders in which the symptoms are uncontrolled as 
indicated by baseline pattern of >3 loose stools daily in subjects without a colostomy or 
ileostomy. Subjects with a colostomy or ileostomy may be entered at investigator 
discretion. 
 
3.29m   Arterial thrombotic events ≤6 months prior to randomization 
 
Note: This includes transient ischemic attack (TIA), cerebrovascular accident (CVA), 
unstable angina or angina requiring surgical or medical intervention in the past 6 months, 
or myocardial infarction (MI). 
 
3.29n Clinically significant peripheral artery disease (e.g., claudication with <1 block) or any 
other arterial thrombotic event. 
 
3.29o Serious or non-healing wound, ulcer, or bone fracture. 
 
3.29p History of hypertension not well-controlled (≥160/90) even though on a regimen of anti- 
hypertensive therapy. 
 
3.29q Evidence of Gilbert’s syndrome or known homozygosity for the UGT1A1*28 allele 
(special screening not required). 


RU021302I 
13 
Addendum 3 
 
 
 
4.0 
Test Schedule 
Tests and procedures 
≤14 days 
prior to 
registration 
Cycle 1, Day 
11 
Subsequent 
cycles, Day 1 
End of 
treatment10 
Complete medical history and physical exam, 
weight, vital signs 
X 
X 
Height 
X 
Limited physical exam, including weight and 
vital signs 
X 
X 
ECOG PS 
X 
X 
X 
X 
Concurrent medications 
X 
X 
X 
X 
Adverse event assessment 
X 
X 
X 
X11 
Hematology: 
CBC/differential and platelets 
X 
X2 
X 
X 
Serum chemistry: Sodium, potassium, chloride, 
bicarbonate, BUN, creatinine, glucose, calcium, 
magnesium, total bilirubin, alkaline 
phosphatase, total protein, albumin, SGOT 
(AST), SGPT (ALT) 
X 
X2 
X 
X 
PT, INR, PTT 
X 
Urinalysis3 
X 
X4 
Carcinoembryonic antigen (CEA) 
X 
X2 
X5 
X 
RAS mutation status 
(links for commercially available tests in 
Appendix IV) 
X 
Radiologic imaging/tumor measurement 
 X6
 
 
X6 
X 
B-HCG/serum or urine pregnancy test7 
X 
Mandatory blood samples (see Section 14.0)8,R 
X 
X12 
X 
Mandatory tissue sample (see Section 17.0)9,R 
X 
1. Cycle = 14 days +/- 3 days. 
2. Labs do not have to be repeated on Cycle 1, Day 1 if they were done ≤7 days. 
3. If 2+ protein on urinalysis, obtain additional urine sample for urine protein: creatinine (UPC) ratio – 
if UPC ≥2, obtain 24-hour urine sample for protein. If ≥3+ protein on urinalysis, obtain 24-hour urine 
sample for protein. 
4. Repeated every other cycle starting with cycle 2. 
5. Repeated every 4 cycles (approximately every 8 weeks). 
6. ≤ 28 days prior to registration and then repeated every 4 cycles (approximately every 8 weeks). 
Specify method (e.g., CT, MRI, etc.) Use same imaging throughout the study. Documentation 
(radiologic) must be provided for participants removed from study for progressive disease. 
7. For women of childbearing potential only. Must be done ≤7 days prior to Cycle 1, Day 1. 
8. Mandatory blood samples for future biomarker research. If the sample was not obtained ≤14 days 
prior to registration, it can be obtained on Cycle 1 Day 1 prior to initiation of protocol therapy. 
Cryovials are required for this collection (see Section 14.0). 
9. Mandatory archival tissue for future research. Submit all available archived specimens, if feasible. 
Submit the associated operative and pathology reports ≤60 days of registration. 
10. End of treatment evaluation should occur within 30 days (+/-3 days) after the last dose of study 
treatment. The visit at which a response assessment shows disease progression may be used as the end 
of treatment visit. 


RU021302I 
14 
Addendum 3 
 
 
11. Follow for AE monitoring for a total of 30 days (+/- 3 days) from the last dose of study treatment. 
Participants with an AE that is ongoing at the end of treatment visit should be contacted at least 
monthly until the event has resolved or until the subject begins treatment with a new anti-cancer 
therapy. 
12. At the time of the first restaging (prior to Cycle 5) and second restaging (prior to Cycle 9) 
R Research funded. 
 
 
5.0 
Stratification Factors: 
 
5.1 
Prior chemotherapy regimens for metastatic disease: 1 vs. ≥ 2. 
 
5.2 
Bevacizumab received in the immediate prior treatment regimen: Yes vs. no. 
 
 
6.0 
Registration/Randomization Procedures 
 
6.1 
Registration 
 
6.11 
To register a patient, access the ACCRU web page 
  
go to the Application section and click on "Registration" and enter the 
registration/randomization application. The registration/randomization 
application is available 24 hours a day, 7 days a week. Back up and/or system 
support contact information is available on the Web site. If unable to access the 
Web site, call the Academic and Community Cancer Research United (ACCRU) 
Registration Office at 
 between the hours of 8 a.m. and 4:30 p.m. 
Central Time (Monday through Friday). 
 
The instructions for the registration/randomization application are available on 
the above web page under the Study Resources section, "Application Training." 
Prior to initiation of protocol treatment, this process must be completed in its 
entirety and an ACCRU subject ID number must be available as noted in the 
instructions. It is the responsibility of the individual and institution registering 
the patient to confirm the process has been successfully completed prior to 
release of the study agent. Patient registration via the registration/randomization 
application can be confirmed in any of the following ways: 
 
• 
Contact the ACCRU Registration Office 
. If the patient was 
fully registered, the ACCRU Registration Office staff can access the 
information from the centralized database and confirm the registration. 
• 
Refer to "Application Training" at
: click on 
"Registration, Installation & Entry Instructions". 
 
6.12 
Correlative Research 
 
A mandatory correlative research component is part of this study, the patient will 
be automatically registered onto this component (see Sections 3.19e and 14.11). 
 
6.13 
Documentation of IRB approval must be on file in the Registration Office 
before an investigator may register any patients. Approvals should be 
uploaded using online ACCRU Regulatory Management System 
(ARMS). 
 
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) with ACCRU. Approvals 
should be uploaded using online ACCRU Regulatory Management Systems 


RU021302I 
15 
Addendum 3 
 
(ARMS). If the necessary documentation is not submitted in advance of 
attempting patient registration, the registration will not be accepted and the 
patient may not be enrolled in the protocol until the situation is resolved. 
 
 
Submission of annual IRB approvals is required until the study has been closed   
through your IRB. 
 
6.14 
Prior to accepting the registration/randomization, the registration/randomization 
application will verify the following: 
 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information 
 
6.15 
At the time of registration, the following will be recorded: 
 
• 
Patient has given permission to store and use his/her blood and tissue 
sample(s) for future research to learn about, prevent, or treat cancer. 
• 
Patient has given permission to store and use his/her blood and tissue 
sample(s) for future research to learn, prevent, or treat other health problems 
(for example: diabetes, Alzheimer’s disease, or heart disease). 
• 
Patient has/has not given permission for ACCRU to give his/her blood and 
tissue sample(s) to outside researchers. 
 
6.16 
Treatment on this protocol must commence at an ACCRU institution under the 
supervision of a medical oncologist. 
 
6.17 
Treatment cannot begin prior to registration and must begin ≤14 days after 
registration. 
 
6.18 
Pretreatment tests/procedures (see Section 4.0) must be completed within the 
guidelines specified on the test schedule. 
 
6.19 a 
All required baseline symptoms (see Section 10.5) must be documented and 
graded. 
 
6.19b Study drug is available on site. 
6.19c 
Cryovials available on site. 
6.2 
Randomization Procedures 
 
6.21 
The factors defined in Section 5.0, together with the registering membership, will 
be used as stratification factors. 
 
6.22 
After the patient has been registered into the study, the values of the stratification 
factors will be recorded, and the patient will be assigned to one of the following 
treatment groups using the Pocock and Simon (Pocock and Simon, et al, 1975) 
dynamic allocation procedure which balances the marginal distributions of the 
stratification factors between the treatment groups. 
 
• 
Bevacizumab + irinotecan + cetuximab 
• 
Placebo + irinotecan + cetuximab 
 
 


RU021302I 
16 
Addendum 3 
 
6.3 
Procedures for Double-Blinding the Treatment Assignment 
 
6.31 
After the treatment assignment has been ascertained by the 
registration/randomization application, the registration specialist will notify the 
designated data manager/nurse/pharmacist at the patient’s institution. 
 
The name of this contact person is to be entered in the designated space on the 
eligibility checklist so the Registration Office personnel have it for each patient 
at the time of registration. Make sure this contact person will be available at the 
time of registration so he or she can take a call from the registration specialist if 
necessary. This contact person may not be involved in assessing adverse events 
or any other outcome measure and should not be the same person listed on page 
one of the Eligibility Checklist Form as the person completing the form. The last 
page of the Eligibility Checklist Form should provide the sources of 
communication, either fax or e-mail, and the appropriate contact information. 
The registration specialist will then communicate the treatment assignment 
“active or placebo” to the designated contact at the patient’s institution. 
 
6.32 
The treatment assignment will be to bevacizumab + irinotecan + cetuximab or 
placebo + irinotecan + cetuximab. The bevacizumab/placebo solution will be 
prepared and labeled by the unblinded pharmacist as “Bevacizumab OR Placebo” 
so that the contents are not discernible to the person administering the treatment. 
 
6.33 
The unblinded pharmacist will maintain records that indicate the identity of the 
patient and their corresponding treatment assignment. 
 
 
7.0 
Protocol Treatment 
 
7.1 
Treatment Schedule - Use actual weight or estimated dry weight if fluid retention 
 
17.11 Pretreatment medication 
 
7.111 Pretreatment anti-emetic medications should be administered per 
institutional standard of care. Suggestions for pretreatment include 
ondansetron 16 mg (or similar agent) and dexamethasone 12 mg PO or 
IV, and consideration of fosaprepitant or an aprepitant tri-fold pack. 
Other anti-emetics may be administered as clinically indicated. 
 
7.112 Diphenhydramine 50 mg (or similar agent) IV should be administered 
prior to each dose of cetuximab in an effort to prevent an infusion or 
hypersensitivity reaction. Premedication is recommended prior to 
subsequent doses, but a lower dose may be used based on patient 
tolerance to the previous dose and investigator discretion. Pretreatment 
with acetaminophen may also be used. 


RU021302I 
17 
Addendum 3 
 
 
7.2 
Drug/Placebo Administration 
 
7.21 
Sequence of administration 
 
7.211 Cetuximab should be the first agent delivered, and should be 
administered per institutional standard of care, but the following 
procedure may be considered: 
 
• 
The first dose of cetuximab should be administered after 
diphenhydramine premedication (see above) and infused over 120 
minutes. 
• 
If well-tolerated, subsequent infusions may be administered over 
approximately 90 minutes (not to exceed 10 mg/minute). 
• 
Cetuximab should be administered with the use of a low protein- 
binding 0.22 micron in-line filter, and 0.9% normal saline should be 
used to flush the IV line at the end of the infusion. 
 
7.212 Following cetuximab infusion, bevacizumab/placebo should be given 
according to institutional standard of care, but the following procedure 
may be considered: 
 
• 
The initial dose of bevacizumab/placebo should be infused over 90 
minutes, the second dose over 60 minutes, and all subsequent doses 
over 30 minutes if prior infusions are tolerated without infusion- 
associated adverse events. 
• 
For patients in whom elective surgery is contemplated, 
bevacizumab/placebo should be discontinued for at least 8 weeks 
prior to surgery. 
• 
Bevacizumab/placebo may be resumed after at least 8 weeks 
following surgery. For patients in whom non-elective surgery is 
required, bevacizumab/placebo should be held as long as possible 
prior to surgery and for at least 8 weeks following surgery. Other 
protocol treatment may be given while bevacizumab/placebo is held 
at the discretion of the treating physician. 
 
7.213 Lastly, irinotecan infusion should follow bevacizumab/placebo and 
should be given over 90 minutes or per institutional standard of care. 


RU021302I 
18 
Addendum 3 
 
 
 
7.22 
Protocol treatment administration table 
 
Agent1 
Dose Level 
Route 
Day 
Cetuximab 
500 mg/m2 
IV 
Day 1 of 
each cycle2 
(±3 days) 
Bevacizumab 
OR Placebo 
5 mg/kg 
(bevacizumab) OR 
normal saline in a 
volume equal to 
bevacizumab volume 
Irinotecan 
180 mg/m2 3 
1. Administer cetuximab first, then bevacizumab, then irinotecan (see Section 
7.3). 
2. Cycle = 14 days 
3. If during previous irinotecan chemotherapy the irinotecan dose was reduced 
due to toxicity, this lower tolerated dose should be used as the starting dose. 
 
7.3 
For this protocol, the patient must return to the consenting ACCRU institution for 
evaluation at least every 14 days during treatment and again within 30 days (+/-3 days) 
after the last dose of study treatment. 
 
7.4 
Protocol treatment by a Local Medical Doctor (LMD) is not allowed. 
 
7.5 
Breaking Codes in Double–Blinded Studies 
 
7.51 
The treatment code may not be broken except for emergencies. 
 
7.52 
In the event of an emergency, call the ACCRU Registration Office at (507) 284– 
2753 to break the code on Monday through Friday, 8:00 a.m. to 4:30 p.m. Central 
Time. If the code must be broken after hours, assume the patient was assigned to 
active treatment and treat accordingly. Place a call to the ACCRU Registration 
Office and leave a message informing them of the need to un-blind a patient. 
Provide your contact information so that ACCRU Registration Office personnel 
can return the call the next business day. 


RU021302I 
19 
Addendum 3 
 
 
 
8.0 
Dosage Modification Based on Adverse Events 
 
These modifications should be regarded as guidelines to produce mild-to-moderate, but not 
debilitating, side effects. If multiple adverse events are seen, administer dose based on greatest 
reduction required for any single adverse event observed. Reductions or increases apply to 
treatment given in the preceding cycle and are based on adverse events observed since the prior 
dose. 
 
ALERT: 
ADR reporting may be required for some adverse events (See Section 10) 
 
8.1 
Dose levels (Based on Adverse Events in Tables 8.2, 8.3 and 8.4) 
 
Dose Level 
Bevacizumab / 
Placeboa 
Irinotecan 
Cetuximab 
0* 
5 mg/kg 
180 mg/m2b 
500 mg/m2 
-1 
5 mg/kg 
150 mg/m2 
400 mg/m2 
-2 
5 mg/kg 
120 mg/m2 
300 mg/m2 
-3 
5 mg/kg 
100 mg/m2 
200 mg/m2 
* 
Dose level 0 refers to the starting dose. 
a. Bevacizumab/placebo dose is always 5 mg/kg IV. Bevacizumab may be skipped or 
discontinued, but the dose is not reduced or escalated. 
b. For patients starting out at the maximum irinotecan dose. If starting out at a lower 
dose that was previously tolerated in a prior treatment regimen, further dose 
reductions for adverse events should proceed to the next lower dose level from the 
starting dose. If starting out at a lower dose that was previously tolerated in a prior 
treatment regimen, consideration can be given to escalating the irinotecan dose 
during subsequent protocol therapy after discussion with the Study Chair. 
 
 
Use the following definitions to determine actions in the Action columns of the following tables: 
 
 Omit = Treatment is not given for this cycle 
 Hold/Delay = Treatment can be made up as part of this cycle 
 Discontinue = Treatment is totally stopped 


RU021302I 
20 
Addendum 3 
 
 
 
8.2 
Dose modifications for irinotecan 
 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless otherwise 
specified   
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
ACTION**1 
 
BASED ON INTERVAL ADVERSE EVENT 
Investigations 
Neutrophil count decreased 
Grade 1 (< LLN – 1.5 x 
109/L) 
OR 
Grade 2 (< 1.5 x 109/L - 1.0 x 
109/L) 
Maintain dose level 
Grade 3 (<1.0 x 109/L – 0.5 x 
109/L) 
OR 
Grade 4 (<0.5 x 109/L) 
Hold irinotecan, cetuximab, and bevacizumab/placebo. 
When ANC has recovered to ≤grade 2, resume treatment and 
decrease irinotecan by one dose level. Cetuximab and 
bevacizumab/placebo should continue at the same dose level 
as previous. 
If ANC <1.0 x 109/L after 4 weeks, discontinue irinotecan. 
Continuation of cetuximab and bevacizumab/placebo on 
protocol can be considered at the treating investigator’s 
discretion after discussion with the study chair. 
Platelet count decreased 
Grade 1 (<LLN – 75 x 109/L) Maintain dose level 
Grade 2(<75 x 109/L – 50 x 
109/L) 
OR 
Grade 3 (<50 x 109/L – 25 x 
109/L) 
Hold irinotecan, cetuximab, and bevacizumab/placebo. 
When platelets have recovered to ≤ grade 1, resume 
treatment and decrease irinotecan by one dose level. 
Cetuximab and bevacizumab/placebo should continue at the 
same dose level as previous. 


RU021302I 
21 
Addendum 3 
 
 
 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless otherwise 
specified   
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
ACTION**1 
 
BASED ON INTERVAL ADVERSE EVENT 
 
Grade 4 (<25 x 109/L) 
Hold irinotecan, cetuximab, and bevacizumab/placebo. 
When platelets have recovered to ≤grade 1, resume 
treatment and decrease irinotecan by two dose levels (if only 
one dose level remaining, decrease by one dose level). 
Cetuximab and bevacizumab/placebo should continue at the 
same dose level as previous. 
If platelets <75 x 109/L after 4 weeks, discontinue irinotecan. 
Continuation of cetuximab and bevacizumab/placebo on 
protocol can be considered at the treating investigator’s 
discretion after discussion with the study chair. 
Blood and lymphatic 
system disorders 
Febrile neutropenia 2,3 
Grade 3 (ANC <1.0 x 109/L 
with single temperature 
>38.3ºC [101° F], or 
sustained temperature ≥ 38ºC 
[100.4° F] for >1 hour) 
OR 
Grade 4 (life-threatening 
consequences; urgent 
intervention indicated) 
Hold irinotecan, cetuximab, and bevacizumab/placebo. 
When ANC has recovered to >1.0 x 109/L, fever resolved, 
and any infection under control, resume treatment and 
decrease irinotecan by one dose level. Cetuximab and 
bevacizumab/placebo should continue at the same dose level 
as previous. 
If ANC <1.0 x 109/L after 4 weeks, and/or fever or infection 
not resolved after 4 weeks, discontinue protocol therapy. 


RU021302I 
22 
Addendum 3 
 
 
 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless otherwise 
specified   
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
ACTION**1 
 
BASED ON INTERVAL ADVERSE EVENT 
Gastrointestinal disorders 
Diarrhea 
Lacrimation, rhinorrhea, 
miosis, diaphoresis, hot 
flashes, flushing, abdominal 
cramping, diarrhea, or other 
symptoms of early 
cholinergic syndrome 
occurring during or shortly 
after receiving irinotecan 
Follow institutional standard of care, such as administering 
atropine 0.25-1 mg IV or SC. In patients with troublesome 
or recurrent symptoms, prophylactic administration of 
atropine shortly before irinotecan therapy may be 
considered. Additional antidiarrheal measures may be used 
at the discretion of the treating physician. Combination 
anticholinergic medications containing barbiturates or other 
agents (e.g., Donnatal) should not be used because these 
may affect irinotecan metabolism. Anticholinergics should 
be used with caution in patients with potential 
contraindications (e.g., obstructive uropathy, glaucoma, 
tachycardia, etc.). 
Late Diarrhea (e.g., 
developing >24 hours after 
irinotecan) 
Grade 1 (increase of <4 
stools/day over baseline; 
mild increase in ostomy 
output compared to baseline) 
Maintain dose level 
Grade 2 (increase of 4-6 
stools/day over baseline; 
moderate increase in ostomy 
output compared to baseline) 
Maintain dose level if resolved to ≤grade 1 by Day 1. If 
≥grade 2 diarrhea present on Day 1 of cycle despite optimal 
anti-diarrheal therapy, decrease irinotecan by one dose level. 
Cetuximab and bevacizumab/placebo should continue at the 
same dose level as previous. 


RU021302I 
23 
Addendum 3 
 
 
 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless otherwise 
specified   
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
ACTION**1 
 
BASED ON INTERVAL ADVERSE EVENT 
 
Grade 3 (increase of ≥7 
stools/day over baseline; 
incontinence; hospitalization 
indicated; severe increase in 
ostomy output compared to 
baseline; limiting self care 
ADL) 
Or 
Grade 4 
Decrease irinotecan by one dose level if resolved to ≤grade 2 
by Day 1. If ≥grade 3 diarrhea present on Day 1 of cycle 
despite optimal anti-diarrheal therapy, hold irinotecan and 
check weekly, then treat based on interval toxicity. 
Cetuximab and bevacizumab/placebo may continue at the 
same dose level as previous at the treating investigator’s 
discretion. 
If ≥grade 3 diarrhea after 4 weeks despite optimal anti- 
diarrheal therapy, discontinue irinotecan permanently. 
Continuation of cetuximab and bevacizumab/placebo on 
protocol can be considered at the treating investigator’s 
discretion after discussion with the lead PI. 
Gastrointestinal disorders 
(continued) 
Nausea or Vomiting 
Grade 1 
Maintain dose level 
Grade 2 
Maintain dose level if resolved to ≤grade 1 by Day 1. If ≥ 
grade 2 vomiting present on Day 1 of cycle despite optimal 
anti-emetic therapy, decrease irinotecan by one dose level. 
Cetuximab and bevacizumab/placebo should continue at the 
same dose level as previous. 
Grade 3 
Or 
Grade 4 
Decrease irinotecan by one dose level if resolved to ≤grade 2 
by Day 1. If ≥ grade 3 vomiting present on Day 1 of cycle 
despite optimal anti-emetic therapy, hold irinotecan and 
check weekly, then treat based on interval toxicity. 
Cetuximab and bevacizumab/placebo may continue at the 
same dose level as previous at the treating investigator’s 
discretion. 
If ≥grade 3 vomiting after 4 weeks despite optimal anti- 
emetic therapy, discontinue irinotecan permanently. 
Continuation of cetuximab and bevacizumab/placebo on 
protocol can be considered at the treating investigator’s 
discretion after discussion with the study chair. 


RU021302I 
24 
Addendum 3 
 
 
 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless otherwise 
specified   
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
ACTION**1 
 
BASED ON INTERVAL ADVERSE EVENT 
Other 
Other irinotecan-related, 
clinically significant, non- 
hematologic toxicities 
Grade 1 
Or 
Grade 2 
Maintain dose level 
Grade 3 
Or 
Grade 4 
Decrease irinotecan by one dose level if resolved to ≤grade 1 
by Day 1. If ≥grade 2 on Day 1 of cycle despite optimal 
medical management, hold irinotecan and check weekly, 
then treat based on interval toxicity. Cetuximab and 
bevacizumab/placebo may continue at the same dose level as 
previous at the treating investigator’s discretion. 
If ≥grade 2 after 4 weeks despite optimal medical 
management, discontinue irinotecan permanently. 
Continuation of cetuximab and bevacizumab/placebo on 
protocol can be considered at the treating investigator’s 
discretion after discussion with the study chair. 
Footnotes follow on next page 


RU021302I 
25 
Addendum 3 
 
 
 
* 
Located  at http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
**  Use the following definitions to describe actions in the Action column: 
 Omit = Treatment is not given for this cycle 
 Hold/Delay = Treatment can be made up as part of this cycle 
 Discontinue = Treatment is totally stopped 
 
1. Refers to dose used in next cycle 
2. At the treating physician’s discretion, GCSF or pegylated GCSF should be used, and considered for use 
in subsequent cycles, according to standard of care, the most recent version of the product label, and all 
applicable guidelines. 
3. In case of febrile neutropenia or grade ≥2 infection at any time, GCSF should be used according to all 
applicable guidelines. 
 
NOTE: If the patient experiences a significant adverse event requiring a dose reduction at the start of 
the next cycle, then the dose will remain lowered for that entire subsequent cycle. If that cycle is 
completed with no further adverse events > Grade 2, then the dose may be increased, at the 
investigator’s discretion, one level at a time, in subsequent cycles. 
 
NOTE: Adverse events requiring a dose-reduction step for any or all drugs beyond the three dose- 
reduction steps (levels –1,–2, and −3) will be at the discretion of the treating physician, if the decision 
is made for the patient to be kept on study. These dose reductions must be clearly recorded in the 
reported clinical data. 


RU021302I 
26 
Addendum 3 
 
 
 
8.3 
Dose modifications for cetuximab 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless otherwise 
specified   
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
ACTION**1 
BASED ON INTERVAL ADVERSE EVENT 
Skin and subcutaneous 
tissue disorders 
Rash acneiform 
OR 
Rash maculopapular 
OR 
Nail disorders 
Grade 1 
OR 
Grade 2 
Maintain dose level. Initiate symptom management with topical 
and/or oral antibiotics (e.g., minocycline, topical clindamycin, 
topical silver sulfadiazine, hydroxyzine) according to institutional 
standard of care. 
Grade 3 
Hold cetuximab for up to 4 weeks and assess weekly. Initiate 
symptom management with topical and/or oral antibiotics (e.g., 
minocycline, topical clindamycin, topical silver sulfadiazine, 
hydroxyzine) according to institutional standard of care. Upon 
recovery to ≤grade 2, resume cetuximab at same previous dose. 
For subsequent occurrences, hold cetuximab again for up to 4 
weeks and assess weekly. Upon recovery to ≤grade 2, resume 
treatment and decrease cetuximab by one dose level. If subsequent 
recurrence of ≥grade 3 rash while patient is already at lowest dose 
level, discontinue cetuximab permanently. Irinotecan and 
bevacizumab/placebo may continue at the same dose level as 
previous at the treating investigator’s discretion after discussion 
with the study chair. 
Grade 4 
Discontinue cetuximab permanently. Irinotecan and 
bevacizumab/placebo may continue at the same dose level as 
previous at the treating investigator’s discretion after discussion 
with the study chair. 
If ≥grade 3 after 4 consecutive weeks despite optimal medical 
management, discontinue cetuximab permanently. Continuation of 
irinotecan and bevacizumab/placebo on protocol can be 
considered at the treating investigator’s discretion after discussion 
with the study chair. 


RU021302I 
27 
Addendum 3 
 
 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless otherwise 
specified   
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
ACTION**1 
BASED ON INTERVAL ADVERSE EVENT 
General disorders and 
administration site 
conditions 
Immune system 
disorders 
Infusion related 
reaction / cytokine 
release syndrome 
Allergic reaction 
Grade 1 
Decrease cetuximab infusion rate by 50%. All subsequent 
infusions should be administered at this lower rate. 
Grade 2 
Immediately stop cetuximab infusion and provide supportive care 
according to institutional standards. Upon recovery to ≤grade 1, 
may resume cetuximab infusion on the same day at 50% lower 
rate with close monitoring at the treating investigator’s discretion. 
Use lower rate and administer premedication for all subsequent 
infusions. If recurrence despite premedication and slower rate, 
discontinue cetuximab. 
Grade 3 
Or 
Grade 4 
Immediately stop infusion and provide supportive care according 
to institutional standards. Discontinue cetuximab and notify the 
study chair. 
Metabolism and 
nutrition disorders 
Hypomagnesemia 
All grades 
Provide intravenous magnesium supplementation per institutional 
standard of care. No dose adjustment of cetuximab required; 
however, continue careful monitoring. 


RU021302I 
28 
Addendum 3 
 
 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless otherwise 
specified   
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
ACTION**1 
BASED ON INTERVAL ADVERSE EVENT 
Other 
Other cetuximab- 
related, clinically 
significant, non- 
hematologic toxicities 
Grade 1 
Or 
Grade 2 
Maintain dose level 
Grade 3 
Or 
Grade 4 
Decrease cetuximab by one dose level if resolved to ≤grade 1 by 
Day 1. If ≥grade 2 on Day 1 of cycle despite optimal medical 
management, hold cetuximab and check weekly, then treat based 
on interval toxicity. Irinotecan and bevacizumab/placebo may 
continue at the same dose level as previous at the treating 
investigator’s discretion. 
If ≥grade 2 after 4 weeks despite optimal medical management, 
discontinue cetuximab permanently. Continuation of irinotecan 
and bevacizumab/placebo on protocol can be considered at the 
treating investigator’s discretion after discussion with the study 
chair. 
* 
Located  
 
** Use the following to describe actions in the Action column: 
 Omit = Treatment is not given for this cycle 
 Hold/Delay = Treatment can be made up as part of this cycle 
 Discontinue = Treatment is totally stopped 
1.   Refers to dose used in next cycle 
 
NOTE: If the patient experiences a significant adverse event requiring a dose reduction at the 
start of the next cycle, then the dose will remain lowered for that entire subsequent cycle. If that 
cycle is completed with no further adverse events > Grade 2, then the dose may be increased, at 
the investigator’s discretion, one level at a time, in subsequent cycles. 
 
NOTE: Adverse events requiring a dose-reduction step for any or all drugs beyond the three 
dose-reduction steps (levels –1, –2, and −3) will be at the discretion of the treating physician, if 
the decision is made for the patient to be kept on study. These dose reductions must be clearly 
recorded in the reported clinical data. 


RU021302I 
29 
Addendum 3 
 
 
 
 
8.4 
Dose modifications for bevacizumab/placebo 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless otherwise 
specified   
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
ACTION**1 
 
BASED ON INTERVAL ADVERSE EVENT 
General disorders and 
administration site 
conditions 
Infusion related reaction / 
cytokine release syndrome 
Grade 1 
Continue bevacizumab/placebo infusion and monitor vital 
signs, administer supportive care per institutional standards 
and treating investigator’s discretion. May reduce rate of 
infusion by 50% at investigator discretion. 
Grade 2 
0BImmediately interrupt infusion and provide supportive care 
according to institutional standards. Upon recovery, may 
resume infusion on the same day at reduced rate with close 
monitoring at treating investigator’s discretion. 
Premedication for subsequent infusions is recommended. If 
second occurrence, discontinue bevacizumab/placebo. 
Grade 3 
Or 
Grade 4 
Immediately interrupt infusion and provide supportive care 
according to institutional standards. Discontinue 
bevacizumab/placebo and notify the study chair. 
Renal and urinary 
disorders 
Proteinuria 
1BGrade 1: 1+ proteinuria 
(30 - < 100 mg/dL); urinary 
protein < 1 g/24 hours 
Continue bevacizumab/placebo 
2BGrade 2: 2+ proteinuria 
(>100-< 500 mg/dL); urinary 
protein 1-3.4 g/24 hours 
3BContinue bevacizumab/placebo. Obtain additional urine 
sample for urine protein: creatinine (UPC) ratio2 
• 
4BUPC ratio ≤ 1.9: Continue bevacizumab/placebo. 
• 
5BUPC ratio ≥ 2: Hold bevacizumab/placebo and collect 
a 24-hour urine sample for urinary protein prior to next 
visit. May resume bevacizumab/placebo when urine 
protein is <2.0 g/24 hours. 


RU021302I 
30 
Addendum 3 
 
 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless otherwise 
specified   
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
ACTION**1 
 
BASED ON INTERVAL ADVERSE EVENT 
 
Grade 3: Urinary protein ≥3.5 
g/24 hours 
6BHold bevacizumab/placebo. Collect a 24-hour urine sample 
for urinary protein. May resume when urinary protein is 
<2.0 g/24 hours. Consider nephrology consult. 
If urine protein >2.0 g/24 hours after 4 weeks despite 
optimal medical management, discontinue 
bevacizumab/placebo permanently. Continuation of 
irinotecan and cetuximab on protocol can be considered at 
the treating investigator’s discretion after discussion with 
the study chair. 
Discontinue bevacizumab/placebo permanently. Consider 
nephrology consult. Continuation of irinotecan and 
cetuximab on protocol can be considered at the treating 
investigator’s discretion after discussion with the study 
chair. 
 
Nephrotic syndrome 
7BDiscontinue protocol therapy. Consider nephrology consult. 
Vascular disorders 
Hypertension 
Grade 1 
(Prehypertension: systolic BP 
120-139 mmHg or diastolic BP 
80-89 mmHg) 
Continue bevacizumab/placebo 
Grade 2 
(Stage 1 hypertension: systolic 
BP 140-159 mmHg or diastolic 
BP 90-99 mmHg; medical 
intervention indicated; recurrent 
or persistent [≥24 hours]; 
symptomatic increase by >20 
mmHg [diastolic] or to >140/90 
mmHg if previously WNL; 
monotherapy indicated) 
Continue bevacizumab/placebo. Initiate antihypertensive 
medication (e.g., DHP calcium channel blocker such as 
amlodipine). 


RU021302I 
31 
Addendum 3 
 
 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless otherwise 
specified   
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
ACTION**1 
 
BASED ON INTERVAL ADVERSE EVENT 
 
Grade 3 
(Stage 2 hypertension: systolic 
BP ≥160 mmHg or diastolic 
≥100 mmHg; medical 
intervention indicated; more than 
one drug or more intensive 
therapy than previously used 
indicated) 
Hold bevacizumab/placebo. Add additional antihypertensive 
medication according to institutional standard of care or 
treating investigator’s discretion (e.g., ACE inhibitor or 
angiotensin receptor blocker). Other protocol therapy may 
be continued at treating investigator’s discretion. When BP 
controlled to ≤ grade 2, resume bevacizumab/placebo at full 
dose. 
If ≥ grade 3 after 4 weeks despite optimal medical 
management, discontinue bevacizumab/placebo 
permanently. Continuation of irinotecan and cetuximab on 
protocol can be considered at the treating investigator’s 
discretion after discussion with the study chair. 
Grade 4 
(life-threatening consequences 
[e.g., malignant hypertension, 
transient or permanent 
neurologic deficit, hypertensive 
crisis]; urgent intervention 
indicated) 
Discontinue bevacizumab/placebo permanently. 
Continuation of irinotecan and cetuximab on protocol can be 
considered at the treating investigator’s discretion after 
discussion with the study chair. 
Vascular disorders 
Thromboembolic event 
Grade 1: Venous thrombosis 
(e.g., superficial thrombosis) 
OR 
8BGrade 2: Venous thrombosis 
(e.g., uncomplicated deep vein 
thrombosis), medical 
intervention indicated 
Continue bevacizumab/placebo at treating investigator’s 
discretion. Medical intervention as clinically indicated per 
institutional standards and treating investigator’s discretion. 


RU021302I 
32 
Addendum 3 
 
 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless otherwise 
specified   
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
ACTION**1 
 
BASED ON INTERVAL ADVERSE EVENT 
 
Grade 3: Thrombosis (e.g., 
uncomplicated pulmonary 
embolism [venous], non-embolic 
cardiac mural [arterial] 
thrombosis), medical 
intervention indicated 
9BHold bevacizumab/placebo. Other protocol therapy may be 
continued at treating investigator’s discretion. Resume when 
medically stable and on stable dose of anticoagulation. 
10BGrade 4: Life-threatening 
(e.g., pulmonary embolism, 
cerebrovascular event, arterial 
insufficiency); hemodynamic or 
neurologic instability; urgent 
intervention indicated 
Discontinue bevacizumab/placebo permanently. 
Continuation of irinotecan and cetuximab on protocol can be 
considered at the treating investigator’s discretion after 
discussion with the study chair. 
Cardiac disorders 
 
Vascular disorders 
 
Nervous system 
disorders 
Arterial thrombotic events 
(e.g., acute coronary 
syndrome, myocardial 
infarction, peripheral 
ischemia, visceral arterial 
ischemia, ischemia 
cerebrovascular) 
Grade 2 
OR 
Grade 3 
OR 
Grade 4 
Discontinue bevacizumab/placebo permanently. 
Continuation of irinotecan and cetuximab on protocol can be 
considered at the treating investigator’s discretion after 
discussion with the study chair. 


RU021302I 
33 
Addendum 3 
 
 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless otherwise 
specified   
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
ACTION**1 
 
BASED ON INTERVAL ADVERSE EVENT 
Nervous system 
disorders 
Reversible posterior 
leukoencephalopathy 
syndrome (RPLS) 
For signs and symptoms suggestive of RPLS (e.g., 
confusion, headache, seizures, cortical blindness), hold 
bevacizumab/placebo. Suspected RPLS should be 
investigated with MRI. If diagnosis of RPLS is confirmed, 
bevacizumab/placebo should be permanently discontinued. 
If RPLS is ruled out via MRI, the decision on resuming 
bevacizumab/placebo should be based on the nature of the 
signs/symptoms. For grade 4 events with likely relationship 
to bevacizumab/placebo, discontinue bevacizumab/placebo; 
for grade 3 events, bevacizumab/placebo may be resumed if 
toxicities completely resolve within 4 weeks. 
Other protocol therapy may be continued at the discretion of 
the treating physician after discussion with the study chair. 
Cardiac disorders 
Left ventricular systolic 
dysfunction 
Grade 3 
Or 
Grade 4 
Discontinue bevacizumab/placebo permanently. 
Continuation of irinotecan and cetuximab on protocol can be 
considered at the treating investigator’s discretion after 
discussion with the study chair. 
Gastrointestinal 
disorders 
Intra-abdominal fistula or 
perforation 
Any grade 
Discontinue bevacizumab/placebo permanently. 
Continuation of irinotecan and cetuximab on protocol can be 
considered at the treating investigator’s discretion after 
discussion with the study chair. 


RU021302I 
34 
Addendum 3 
 
 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless otherwise 
specified   
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
ACTION**1 
 
BASED ON INTERVAL ADVERSE EVENT 
Other 
Hemorrhage / Bleeding 
Grade 1 
Or 
Grade 2 
Continue bevacizumab/placebo at treating investigator’s 
discretion. Initiate wound care and medical therapy 
according to institutional standard of care. 
Grade 3 
Or 
Grade 4 
Discontinue bevacizumab/placebo permanently. 
Continuation of irinotecan and cetuximab on protocol can be 
considered at the treating investigator’s discretion after 
discussion with the study chair. 
Injury, poisoning, and 
procedural 
complications 
Wound dehiscence 
Grade 1 
Or 
Grade 2 
Continue bevacizumab/placebo at treating investigator’s 
discretion. Initiate wound care and medical therapy 
according to institutional standard of care. 
Grade 3 
Or 
Grade 4 
Discontinue bevacizumab/placebo permanently. 
Continuation of irinotecan and cetuximab on protocol can be 
considered at the treating investigator’s discretion after 
discussion with the study chair. 
Other 
Other bevacizumab/placebo- 
related, clinically significant, 
non-hematologic toxicities 
Grade 1 
Or 
Grade 2 
Continue bevacizumab/placebo 


RU021302I 
35 
Addendum 3 
 
 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless otherwise 
specified   
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
ACTION**1 
 
BASED ON INTERVAL ADVERSE EVENT 
 
Grade 3 
Or 
Grade 4 
Hold bevacizumab/placebo and restart at full dose if 
resolved to ≤grade 1 by Day 1. If ≥grade 2 on Day 1 of 
cycle despite optimal medical management, continue to hold 
bevacizumab/placebo and check weekly, then treat based on 
interval toxicity. Irinotecan and cetuximab may continue at 
the same dose level as previous at the treating investigator’s 
discretion. 
If ≥grade 2 after 4 weeks despite optimal medical 
management, discontinue bevacizumab/placebo 
permanently. Continuation of irinotecan and cetuximab on 
protocol can be considered at the treating investigator’s 
discretion after discussion with the study chair. 
* 
Located  at 
 
** Use the following to describe actions in the Action column: 
 Omit = Treatment is not given for this cycle 
 Hold/Delay = Treatment can be made up as part of this cycle 
 Discontinue = Treatment is totally stopped 
 
1. Refers do dose used in previous cycles. 
2. Obtain at least 4 ml of a random urine sample. Determine spot urine protein concentration (mg/dL) 
and spot urine creatinine concentration (mg/dL) quantitatively (i.e., not by urine dipstick). Divide 
results of protein concentration by creatinine concentration to obtain the UPC ratio 
 
NOTE: 
Adverse events requiring a dose-reduction step for any or all drugs beyond the three dose- 
reduction steps (levels –1, –2, and -3) will be at the discretion of the treating physician after 
discussion with the overall PI, if the decision is made for the patient to be kept on study. These 
dose reductions must be clearly recorded in the reported clinical data. 
 
 
9.0 
Ancillary Treatment/Supportive Care 
 
9.1 
Antiemetics may be used at the discretion of the attending physician. 
 
9.2 
Blood products and growth factors should be utilized as clinically warranted and 
following institutional policies and recommendations. The use of growth factors should 
follow published guidelines of the American Society of Clinical Oncology (ASCO) 
Update of Recommendations for the Use of White Blood Cell Growth Factors: An 
Evidence-Based Clinical Practice Guideline. J Clin Oncol 2006;24:3187-3205. 


RU021302I 
36 
Addendum 3 
 
 
 
9.3 
Patients should receive full supportive care while on this study. This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or 
concurrent medical conditions. All blood products and concomitant medications such as 
antidiarrheals, analgesics, and/or antiemetics received from the first day of study 
treatment administration until 30 days after the final dose will be recorded in the medical 
records. 
 
9.4 
Diarrhea: This could be managed conservatively with loperamide. The recommended 
dose of loperamide is 4 mg at first onset, followed by 2 mg every 2-4 hours until diarrhea 
free (maximum 16 mg/day). 
 
In the event of grade 3 or 4 diarrhea, supportive measures and antidiarrheal medication 
should be initiated as soon as possible. If fever or neutropenia is present, consider 
hospitalization and antibiotic therapy. 
 
If diarrhea is severe (requiring intravenous rehydration) and/or associated with fever or 
severe neutropenia (grade 3 or 4), broad-spectrum antibiotics must be prescribed. Patients 
with severe diarrhea or any diarrhea associated with severe nausea or vomiting should be 
hospitalized for intravenous hydration and correction of electrolyte imbalances. 
 
 
10.0 
Adverse Event (AE) Reporting and Monitoring 
 
The site principal investigator is responsible for reporting any/all serious adverse events to the 
sponsor as described within the protocol, regardless of attribution to study agent or treatment 
procedure. 
 
The sponsor/sponsor-investigator is responsible for notifying FDA and all participating 
investigators in a written safety report of any of the following: 
 
• 
Any suspected adverse reaction that is both serious and unexpected. 
• 
Any findings from laboratory animal or in vitro testing that suggest a significant risk for 
human subjects, including reports of mutagenicity, teratogenicity, or carcinogenicity. 
• 
Any findings from epidemiological studies, pooled analysis of multiple studies, or 
clinical studies, whether or not conducted under an IND and whether or not conducted by 
the sponsor, that suggest a significant risk in humans exposed to the drug. 
• 
Any clinically important increase in the rate of a serious suspected adverse reaction over 
the rate stated in the protocol or Investigator’s Brochure (IB). 
 
Definitions 
 
Adverse Event 
Any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related. 
 
Suspected Adverse Reaction 
Any adverse event for which there is a reasonable possibility that the drug caused the 
adverse event. 


RU021302I 
37 
Addendum 3 
 
 
Expedited Reporting 
Events reported to sponsor within 24 hours, 5 days or 10 days of study team becoming 
aware of the event. 
 
Routine Reporting 
Events reported to sponsor via case report forms 
 
Events of Interest 
Events that would not typically be considered to meet the criteria for expedited reporting, 
but that for a specific protocol are being reported via expedited means in order to 
facilitate the review of safety data (may be requested by the FDA or the sponsor). 
 
10.1 
Adverse Event Reporting Period 
 
CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site: 
 
 
10.11 Adverse event monitoring and reporting is a routine part of every clinical trial. 
 
10.12 Identify and grade the severity of the event using the CTCAE version 4.0. 
 
10.13 Determine whether the event is expected or unexpected (see Section 10.2). 
 
10.14 Determine if the adverse event is related to the study intervention (agent, medical 
treatment, or procedure) (see Section 10.3). 
 
10.15 Determine whether the event must be reported as an expedited report. If yes, 
determine the timeframe/mechanism (see Section 10.4). 
 
10.16 All AEs reported via expedited mechanisms must also be reported via the routine 
data reporting mechanisms defined by the protocol (see Sections 10.5 and 18.0). 
 
Each CTCAE term in the current version is a unique representation of a specific event 
used for medical documentation and scientific analysis and is a single MedDRA Lowest 
Level Term (LLT). 
 
NOTE: A severe AE, as defined by the above grading scale, is NOT the same as serious 
AE which is defined in the table in Section 10.4. 
 
10.2 
Expected vs. Unexpected Events 
 
Expected events - are those described within the Section 15.0 of the protocol, the study 
specific consent form, package insert (if applicable), and/or the investigator brochure, (if 
an investigator brochure is not required, otherwise described in the general 
investigational plan). 


RU021302I 
38 
Addendum 3 
 
 
 
Unexpected adverse events or suspected adverse reactions are those not listed in Section 
15.0 of the protocol, the study specific consent form, package insert (if applicable), or in 
the investigator brochure (or are not listed at the specificity or severity that has been 
observed); if an investigator brochure is not required or available, is not consistent with 
the risk information described in the general investigational plan. 
 
Unexpected also refers to adverse events or suspected adverse reactions that are 
mentioned in the investigator brochure as occurring with a class of drugs but have not 
been observed with the drug under investigation. 
 
Unanticipated Adverse Device Event (UADE) 
Any serious adverse effect on health or safety or any life-threatening problem or death 
caused by, or associated with, a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the investigational plan 
or application (including a supplementary plan or application), or any other unanticipated 
serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects. 
 
10.3 
Assessment of Attribution 
 
When assessing whether an adverse event is related to a medical treatment or procedure, 
the following attribution categories are utilized: 
 
Definite - The adverse event is clearly related to the agent(s). 
Probable - The adverse event is likely related to the agent(s). 
Possible - The adverse event may be related to the agent(s). 
Unlikely - The adverse event is doubtfully related to the agent(s). 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
 
Events determined to be possibly, probably or definitely attributed to a medical 
treatment suggest there is evidence to indicate a causal relationship between the 
drug and the adverse event. 
 
10.31 AEs Experienced Utilizing Investigational Agent(s) and Commercial Agent(s) on 
SEPARATE Arms 
 
• 
An AE that occurs on an arm using an investigational agent /intervention 
under an IND/IDE must be assessed in accordance with the guidelines in the 
appropriate IND/IDE Reporting Table in Section 10.4. 
 
• 
An AE that occurs on an arm using a commercial agent on a separate 
treatment arm must be assessed as specified in the protocol. Refer to 
Commercial Reporting Table in Section 10.4. 
 
10.32 AEs Experienced Utilizing Investigational Agents and Commercial Agent(s) on 
the SAME Arm 
 
When a commercial agent is used on the same treatment arm as the 
investigational agent/intervention (also, investigational drug, biologic, 
cellular product, or other investigational therapy under an IND), the 
entire combination (arm) is then considered an investigational 


RU021302I 
39 
Addendum 3 
 
 
 
intervention for reporting. These AEs should be assessed as specified 
in the appropriate IND/IDE reporting guidelines in Section 10.4. 
 
10.33 EXPECTED Serious Adverse Events: Protocol-Specific Exceptions to 
Expedited Reporting 
 
For this protocol only, the following Adverse Events/Grades are expected to 
occur within this population and do not require Expedited Reporting. These 
events must still be reported via Routine Reporting (see Section 10.6). * 
 
System Organ Class 
(SOC) 
Adverse event/ Symptoms 
CTCAE Grade at which 
the event will not be 
expeditiously reported. 
Vascular Disorders 
Hypertension 
≤ grade 3 
Arterial thromboembolic 
events 
Any grade 
Venous thromboembolic 
events 
≤ grade 3 
Renal and urinary 
disorders 
Proteinuria 
≤ grade 3 
Gastrointestinal 
disorders 
Gastric perforation, 
abscesses 
Any grade 
Gastric fistula 
Any grade 
Injury, poisoning 
and procedural 
complications 
Wound complication 
≤ grade 3 
Respiratory, thoracic 
and mediastinal 
disorders 
Bronchopulmonary 
hemorrhage 
≤ grade 3 
Nervous system 
disorders 
Reversible posterior 
leukoencephalopathy 
syndrome 
Any grade 
Intracranial hemorrhage 
≤ grade 2 
Cardiac disorder 
Heart failure 
≤ grade 3 
 
Specific protocol exceptions to expedited reporting should be reported 
expeditiously by investigators ONLY if they exceed the expected grade of the 
event regardless of hospitalization. 
 
* 
Report any clinically important increase in the rate of a serious suspected 
adverse reaction (at your study site) over that which is listed in the protocol 
or investigator brochure as an expedited event. 
 
* 
Report an expected event that is greater in severity or specificity than 
expected as an expedited event. 
 
* 
An investigational agent/intervention might exacerbate the expected AEs 
associated with a commercial agent.  Therefore, if an expected AE (for the 


RU021302I 
40 
Addendum 3 
 
 
 
commercial agent) occurs with a higher degree of severity or specificity, 
expedited reporting is required. 
 
A list of known/expected AEs is reported in the investigator brochure, package 
insert or the literature, including AEs resulting from a drug overdose. 
 
10.331 
Death 
 
• 
Any death occurring within 30 days of the last dose, regardless of 
attribution to an agent/intervention under an IND/IDE requires 
expedited  reporting  within 24-hours. 
 
• 
Any death occurring greater than 30 days with an attribution of 
possible, probable, or definite to an agent/intervention under an 
IND/IDE requires  expedited  reporting within 24-hours. 
 
• 
Reportable categories of  Death 
 
• 
Death attributable to a CTCAE  term. 
 
• 
Death NOS: A cessation of life that cannot be attributed to a 
CTCAE term associated with Grade  5. 
 
• 
Sudden death NOS: A sudden (defined as instant or within 
one hour of the onset of symptoms) or an unobserved 
cessation of life that cannot be attributed to a CTCAE term 
associated with Grade  5. 
 
• 
Death due to progressive disease should be reported as 
Grade 5 “Neoplasms benign, malignant and unspecified 
(including cysts and polyps) – Other (Progressive 
Disease)” under the system organ class (SOC) of the same 
name. Evidence that the death was a manifestation of 
underlying disease (e.g., radiological changes suggesting 
tumor growth or progression: clinical deterioration 
associated with a disease process) should be submitted. 
 
10.332 
Secondary Malignancy 
 
• 
A secondary malignancy is a cancer caused by treatment for a 
previous malignancy (e.g., treatment with investigational 
agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
• 
All secondary malignancies that occur following treatment with an 
agent under an IND/IDE to be reported. Three options are available 
to describe the event: 


RU021302I 
41 
Addendum 3 
 
 
 
o Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myeloctyic Leukemia [AML]) 
 
o Myelodysplastic syndrome (MDS) 
 
o Treatment-related  secondary malignancy 
• 
Any malignancy possibly related to cancer treatment (including 
AML/MDS) should also be reported via the routine reporting 
mechanisms outlined in each protocol. 
 
10.333 
Second Malignancy 
 
• 
A second malignancy is one unrelated to the treatment of a prior 
malignancy (and is NOT a metastasis from the initial malignancy). 
Second malignancies require ONLY routine reporting. 
 
10.334 
Pregnancy 
 
Prior to obtaining private information about a pregnant woman and her 
infant, the investigator must obtain consent from the pregnant woman 
and the newborn infant’s parent or legal guardian before any data 
collection can occur. A consent form will need to be submitted to the 
IRB for these subjects if a pregnancy occurs. If informed consent is not 
obtained, no information may be collected. 
 
In cases of fetal death, miscarriage, or abortion the mother is the 
patient. In cases where the child/fetus experiences a serious adverse 
event other than fetal death, the child/fetus is the patient. 
 
NOTE: When submitting ACCRU Adverse Event Report reports for 
“Pregnancy”, “Pregnancy loss”, or “Neonatal loss”, the potential risk 
of exposure of the fetus to the investigational agent(s) or chemotherapy 
agent(s) should be documented in the “Description of Event” section. 
Include any available medical documentation. 


RU021302I 
42 
Addendum 3 
 
 
 
10.4 
Expedited Adverse Event Reporting Requirements for IND/IDE Agents 
 
10.41 Expedited Reporting via the ACCRU Adverse Event Expedited Report Form 
for Adverse Events That Occur Within 30 Days1 of the Last Dose of the 
Investigational Agent 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether 
or not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes: 
1) Death 
2) 
A life-threatening adverse event 
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours 
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions 
5) 
A congenital anomaly/birth defect. 
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found in 
Section 10.33 of the protocol. 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the 
sponsor within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization ≥ 24 
hrs 
7 Calendar Days 
24-Hour; 3 
Calendar Days 
Not resulting in 
Hospitalization ≥ 24 
hrs 
Not required 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 3 Calendar Days” - The AE must initially be reported within 24 hours of learning of the 
AE, followed by a complete expedited report within 3 calendar days of the initial 24-hour report. 
o 
“7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar 
days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as 
follows: 
Expedited 24-hour notification followed by complete report within 3 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive 
half-lives, rounded UP to the nearest whole day, after the agent/intervention was last administered. 
Footnote “1” above applies after this reporting period. 
Effective Date: May 5, 2011 


RU021302I 
43 
Addendum 3 
 
 
 
Additional Instructions: 
 
1. Any event that results in persistent or significant disability/incapacity, 
congenital anomaly, or birth defect must be reported via expedited 
mechanisms if the event occurs following treatment on a trial under an IND. 
 
2. Use the ACCRU protocol number and the protocol-specific patient ID 
provided during trial registration on all reports. 
 
The above expedited reports (24-hour and 3 or 7 day) must be submitted via 
the ACCRU Adverse Event Expedited Report Form. Submit reports to the 
ACCRU SAE Coordinator via fax 
 
 
3. Once the ACCRU SAE Coordinator receives the report via fax, the ACCRU 
SAE Coordinator will forward a copy of the above expedited reports to: 
 
• The ACCRU IND Coordinator who will notify the FDA as warranted by 
the event and stipulated in the U.S. Code of Federal Regulations. 
 
• Genentech: Genentech will be informed in writing of any SAE within 24 
hours/1 business day of receipt of the fax. The fax will be sent by the 
ACCRU SAE Coordinator to Genentech Drug Safety at: 
 
 
 
o The ACCRU SAE Coordinator will provide relevant follow-up 
information to Genentech Drug Safety as soon as it becomes available. 
 
o Serious AE reports that are related to the bevacizumab and AEs of 
Special Interest (regardless of causality) will be transmitted to Genentech 
within fifteen (15) calendar days of the Awareness Date. 
 
o Serious AE reports that are unrelated to the bevacizumab will be 
transmitted to Genentech within thirty (30) calendar days of the 
Awareness Date. 
 
o Additional Reporting Requirements to Genentech (from ACCRU) 
include the following: 
 
 Any reports of pregnancy following the start of administration with 
bevacizumab will be transmitted to Genentech within thirty (30) 
calendar days of the Awareness Date. 
 
 All Non-serious Adverse Events originating from the Study will be 
forwarded in a quarterly report to Genentech (from ACCRU). 
 
 Special situation reports 
 
 In addition to all SAEs, pregnancy reports and AESIs, the 
following Special Situations Reports should be collected even in 
the absence of an Adverse Even and transmitted to Genentech 
within (30) calendar days: 
 Data related to the Product usage during pregnancy or 
breastfeeding 
 Data related to overdose, abuse, off-label use, misuse, 
inadvertent/erroneous administration, medication error (including 
potentially exposed in case of medication errors or intercepted 


RU021302I 
44 
Addendum 3 
 
medication errors) or occupational exposure, with or without 
association with an AE/SAE unless otherwise specified in the 
protocol 
 Lack of therapeutic efficacy 
 Drug interaction 
Use of a medicinal Product in an Elderly population (in addition, 
reasonable attempts should be made to obtain and submit the age 
or age group of the patient, in order to be able to identify potential 
safety signals specific to a particular population) 
Occasionally Genentech may contact ACCRU for additional 
information, clarification, or current status of the patient for whom 
an adverse event was reported, 
 
 
10.424 
Pregnancy 
 
If a female subject becomes pregnant while receiving investigational 
therapy or within 90 days after the last dose of study drug, a report 
should be completed and expeditiously submitted to Genentech, Inc. 
Follow-up to obtain the outcome of the pregnancy should also occur. 
 
Abortion, whether accidental, therapeutic, or spontaneous, should 
always be classified as serious, and expeditiously reported as an 
SAE. 
 
Similarly, any congenital anomaly/birth defect in a child born to 
a female subject exposed to the bevacizumab should be reported 
as an SAE. 
 
 
10.425  
Post-Study Adverse Events 
 
The investigator should expeditiously report any SAE occurring 
after a subject has completed or discontinued study participation 
if attributed to prior {study drug} exposure. If the investigator 
should become aware of the development of cancer or a 
congenital anomaly in a subsequently conceived offspring of a 
female subject, including, pregnancy occurring in the partner of 
a male study subject] who participated in the study, the should 
be reported as an SAE adequately to Genentech drug Safety 
during follow up period. 
 
 


RU021302I 
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Addendum 3 
 
 
10.5 
Other Required Reporting 
 
10.51 Baseline and Adverse Events Evaluations 
 
Pre-treatment symptoms/conditions to be graded at baseline and adverse 
events to be graded at each evaluation are stated in the table below*: 
 
System Organ 
Class 
Adverse/Event Symptoms 
Baseline 
Each 
Evaluation 
Investigations 
Neutrophil count decreased 
X 
Platelet count decreased 
X 
Gastrointestinal 
disorders 
# Stools per day 
X 
Diarrhea 
X 
Vascular disorders 
Hypertension 
X 
X 
Skin and 
subcutaneous 
tissue disorders 
Rash acneiform 
X 
Rash maculo-papular 
X 
Metabolism and 
nutrition disorders 
Hypomagnesemia 
X 
* 
Grading is per CTCAE v4.0 unless otherwise specified. 
 
10.52 Case Report Forms 
 
Submit via appropriate Academic and Community Cancer Research 
United (ACCRU) Case Report Forms (i.e., paper or electronic, as 
applicable) the following AEs experienced by a patient and not 
specified in Section 10.5: 
 
10.521 
Grade 2 AEs deemed possibly, probably, or definitely related to 
the study treatment or procedure. 
 
10.522 
Grade 3 and 4 AEs regardless of attribution to the study 
treatment or procedure. 
 
10.523 
Grade 5 AEs (Deaths) 
 
10.5231 
Any death within 30 days of the patient’s last 
study treatment or procedure regardless of 
attribution to the study treatment or procedure. 
 
10.5232 
Any death more than 30 days after the patient’s last 
study treatment or procedure that is felt to be at least 
possibly treatment related must also be submitted as a 
Grade 5 AE, with a CTCAE type and attribution 
assigned. 
 
10.53 Genentech AEs of Special Interest 
 
AEs of Special Interest for bevacizumab are defined by Genentech as a potential 
safety problem identified as a result of ongoing safety monitoring of their 
product. As such, surveillance AEs in Appendix II MUST be undertaken at 
each treatment evaluation. Development of one of these AEs (≥ grade 1 
unless otherwise noted) MUST be reported on the AE case report forms in 
terms of CTCAE v4.0 grade and attribution. 
 
10.531 
Reconciliation: ACCRU agrees to conduct reconciliation for the 


RU021302I 
46 
Addendum 3 
 
product. Genentech and the Sponsor will agree to the reconciliation 
periodicity and format but agree at a minimum to exchange quarterly 
line listings of cases received by the other party. The periodic line-
listing will be exchanged within seven (7) calendar days of the end of 
the agreed time period. Confirmation of receipt should be received 
within the time period mutually agreed upon. 
 
 
 
Following Case Transmission Verification, single case reports which 
have not been received by Genentech shall be forwarded by ACRRU 
to Genentech within five (5) calendar days from request by 
Genentech 
 
 
 
If discrepancies are identified, (ACCRU) and Genentech will 
cooperate in resolving the discrepancies. The responsible individuals 
for each party shall handle the matter on a case-by-case basis until 
satisfactory resolution. 
 
 
 
At the end of the study, a final cumulative Case Transmission 
Verification report will be sent to Genentech. 
 
10.532 
Study Close-out: Any study report submitted to the FDA by the 
Sponsor-Investigator should be copied to Genentech. This includes all 
IND annual reports and the Clinical Study Report (final study report). 
Additionally, any literature articles that are a result of the study 
should be sent to Genentech by ACCRU. Copies of such reports 
should be mailed to the assigned Clinical Operations contact for the 
study and to Genentech Drug Safety CTV oversight mail box at: 
 
 
Email:
 
. 
 
 
and 
Email: 
  
 
 
11.0 
Treatment Evaluation Using RECIST Guideline 
 
Note: This study uses protocol RECIST v1.1 template dated 2/16/2011. See the footnote 
for the table regarding measureable disease in Section 11.44, as it pertains to data 
collection and analysis. 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guidelines (version 1.1) (Eisenhauer, et al, 2009). Changes in the largest diameter 
(unidimensional measurement) of the tumor lesions and the short axis measurements in the case 
of lymph nodes are used in the RECIST guideline. 
 
11.1 
Schedule of Evaluations 
 
For the purposes of this study, patients should be reevaluated every 8 weeks (e.g. 4 
cycles). 
 
11.2 
Definitions of Measurable and Non-Measurable Disease 
 
11.21 Measurable Disease 
 
11.211 
A non-nodal lesion is considered measurable if its longest diameter can 
be accurately measured as ≥2.0 cm with chest x-ray, or as ≥1.0 cm 
with CT scan, CT component of a PET/CT, or MRI. 


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A d de n d u m 3  
 
 
1 1. 2 1 2  
A s u perficial n o n- n o dal lesi o n is meas ura ble if its l o n gest dia meter is  ≥ 
1. 0 c m i n dia meter as assesse d usi n g cali pers (e. g. s ki n n o d ules) or 
i ma gi n g. I n t he case of s ki n lesi o ns, d oc u me ntati o n b y c ol or 
p h ot o gra p h y, i ncl u di n g a r uler t o esti mate t he size of t he lesi o n, is 
rec o m me n de d. 
 
1 1. 2 1 3  
A mali g na nt l y m p h n o de is c o nsi dere d meas ura ble if its s h ort a xis is 
> 1. 5 c m w he n assesse d b y C T sca n ( C T sca n slice t hic k ness 
rec o m me n de d t o be n o greater t ha n 5 m m). 
 
N O T E: A lesi o n i n a pre vi o usl y irra diate d area is n ot eli gi ble f or 
meas ura ble disease u nless t here is o bj ecti ve e vi de nce of pr o gressi o n of 
t he lesi o n pri or t o st u d y e nr oll me nt. Lesi o ns i n pre vi o usl y irra diate d 
areas m ust be clearl y i de ntifie d as s uc h.  
 
1 1. 2 2  N o n -Meas ura ble  Disease  
 
1 1. 2 2 1 
All ot her lesi o ns ( or sites of disease) are  c o nsi dere d  n o n -meas ura ble 
disease, i ncl u di n g pat h ol o gical n o des (t h ose wit h a s h ort a xis ≥1. 0  t o 
< 1. 5 c m). B o ne lesi o ns, le pt o me ni n geal disease, ascites, 
ple ural/ pericar dial eff usi o ns, l y m p ha n gitis c utis/ p ul m o nis, 
i nfla m mat or y breast disease, a n d a b d o mi nal masses ( n ot f oll o we d b y 
C T or M RI), are c o nsi dere d as n o n -meas ura ble as well.  
 
N O T E : ‘ C ystic lesi o ns’ t h ou g ht t o re prese nt c ystic metastases ca n be 
c o nsi dere d as meas ura ble lesi o ns, if t he y meet t he defi niti o n of 
meas ura bilit y descri be d a b o ve. H o we ver, if n o n -c ystic lesi o ns are 
prese nt i n t he sa me patie nt, t hese are preferre d f or selecti o n as tar get 
lesi o ns. I n a d diti o n, l y m p h n o des t hat ha ve a s h ort a xis < 1. 0 c m are 
c o nsi dere d n o n- pat h ol o gical (i.e., n or mal) a n d s h o ul d n ot be rec or de d 
or f oll o we d. 
 
1 1. 3  
G ui deli nes f or E val uati o n of Meas ura ble  Disease  
 
1 1. 3 1  Meas ure me nt  Met h o ds: 
 
 All meas ure me nts s h o ul d be rec or de d i n metric n otati o n (i.e., deci mal 
fracti o ns of ce nti meters) usi n g a r uler or cali pers. 
 
 T he sa me met h o d of assess me nt a n d t he sa me tec h ni q ue m ust be use d t o 
c haracterize eac h i de ntifie d a n d re p orte d lesi o n at baseli ne a n d d uri n g 
f oll o w- u p. F or patie nts ha vi n g o nl y lesi o ns meas uri n g at least 1 c m t o  less 
t ha n 2 c m m ust use C T i ma gi n g f or b ot h pre- a n d p ost-treat me nt t u m or 
assess me nts. 
 
 I ma gi n g- base d e val uati o n is preferre d t o e val uati o n b y cli nical e xa mi nati o n 
w he n b ot h met h o ds ha ve bee n use d at t he sa me e val uati o n t o assess t he 
a ntit u m or effect of a treat me nt. 
 
1 1. 3 2  Acce pta ble M o dalities f or Meas ura ble  Disease:  
 
 C o n ve nti o nal C T a n d M RI : T his g ui deli ne has defi ne d meas ura bilit y of 
lesi o ns o n C T sca n base d o n t he ass u m pti o n t hat C T slice t hic k ness is 5 m m 
or less. If C T sca ns ha ve slice t hic k ness greater t ha n 5 m m, t he mi ni m u m 
size f or a meas ura ble lesi o n s h o ul d be t wice t he slice t hic k ness. 
 


R U 0 2 1 3 0 2I  
4 8  
A d de n d u m 3  
 
 As wit h C T, if a n M RI is perf or me d, t he tec h nical s pecificati o ns of t he 
sca n ni n g se q ue nces use d s h o ul d be o pti mize d f or t he e val uati o n of t he t y pe 
a n d site of disease. T he lesi o ns s h o ul d be meas ure d o n t he sa me p ulse 
se q ue nce. I deall y, t he sa me t y pe of sca n ner s h o ul d be use d a n d t he i ma ge 
ac q uisiti o n pr ot oc ol s h o ul d be f oll o we d as cl osel y as p ossi ble t o pri or sca ns. 
B o d y sca ns s h o u l d be perf or me d wit h breat h- h ol d sca n ni n g tec h ni q ues, if 
p ossi ble.  
 
 P E T -C T : If t he site ca n d oc u me nt t hat t he C T perf or me d as part of a P E T -C T 
is of i de ntical dia g n ostic q ualit y t o a dia g n ostic C T ( wit h I V a n d oral 
c o ntrast), t he n t he C T p orti o n of t he P E T-C T ca n be use d f or R E CI S T 
meas ure me nts a n d ca n be use d i nterc ha n gea bl y wit h c o n ve nti o nal C T i n 
acc uratel y meas uri n g ca ncer lesi o ns o ver  ti me. 
 
 C hest X -ra y: Lesi o ns o n c hest x-ra y are acce pta ble as meas ura ble lesi o ns 
w he n t he y are clearl y defi ne d a n d s urr o u n de d b y aerate d l u n g. H o we ver, C T 
sca ns are prefera ble.  
 
 P h ysical E xa mi nati o n : F or s u perficial n o n- n o dal lesi o ns, p h ysical 
e xa mi nati o n is acce pta ble, b ut i ma gi n g is prefera ble, if b ot h ca n be d o ne. I n 
t he case of s ki n lesi o ns, d oc u me ntati o n b y c ol or p h ot o gra p h y, i ncl u di n g a 
r uler t o esti mate t he size of t he lesi o n, is rec o m me n de d. 
 
•  
F D G -P E T : F D G- P E T sca n ni n g is all o we d t o c o m ple me nt C T sca n ni n g i n 
assess me nt of pr o gressi ve disease [ P D] a n d partic ularl y p ossi ble ' ne w' 
disease. A ‘ p ositi ve’ F D G -P E T sca n n e d lesi o n is defi ne d as o ne w hic h is 
F D G a vi d wit h a n u p date greater t ha n t wice t hat of t he s urr o u n di n g tiss ue o n 
t he atte n uati o n c orrecte d i ma ge; ot her wise, a n F D G-P E T sca n ne d lesi o n is 
c o nsi dere d ‘ ne gati ve.’ Ne w lesi o ns o n t he basis of F D G- P E T i ma gi n g ca n be 
i de ntifie d acc or di n g t o t he f oll o wi n g al g orit h m: 
 
a. Ne gati ve F D G -P E T at baseli ne wit h a p ositi ve F D G - P E T at f oll o w- u p is 
a si g n of P D base d o n a ne w lesi o n. 
 
b.  N o F D G -P E T at baseli ne a n d a p ositi ve F D G -P E T at  f oll o w- u p: 
 
i. 
If t he p ositi ve F D G-P E T at f oll o w- u p c orres p o n ds t o a ne w site of 
disease c o nfir me d b y C T, t his is  P D.  
 
ii. If t he p ositi ve F D G-P E T at f oll o w -u p is n ot c o nfir me d as a ne w site 
of disease o n C T at t he sa me e val uati o n, a d diti o nal f oll o w - u p C T 
sca ns (i.e., a d diti o nal f oll o w-u p sca ns at lea st 4 wee ks later) are 
nee de d t o deter mi ne if t here is tr ul y pr o gressi o n occ urri n g at t hat 
site. I n t his sit uati o n, t he date of P D will be t he date of t he i nitial 
a b n or mal P D G-P E T  sca n. 
 
iii. If t he p ositi ve F D G-P E T at f oll o w -u p c orres p o n ds t o a pre -e xisti n g 
site of disease o n C T t hat is n ot pr o gressi n g o n t he basis of t he 
a nat o mic i ma ges, it is n ot classifie d as  P D.  
 
1 1. 3 3  Meas ure me nt at F oll o w - u p E val uati o n: 
 
 I n t he case of sta ble disease ( S D), f oll o w-u p meas ure me nts m ust ha ve met 
t he S D criteria at least o nce after st u d y e ntr y at a mi ni m u m i nter val of 6 
wee ks (see Secti o n  1 1. 4 4). 
 
 T he c yt ol o gical c o nfir mati o n of t he ne o plastic ori gi n of a n y eff usi o n t hat 


R U 0 2 1 3 0 2I  
4 9  
A d de n d u m 3  
 
a p pears or w orse ns d uri n g treat me nt w he n t he meas ura ble t u m or has met 
criteria f or res p o nse or sta ble disease is m a n dat or y t o differe ntiate bet wee n 
res p o nse or sta ble disease (a n eff usi o n ma y be a si de effect of t he treat me nt) 
a n d pr o gressi ve disease.  
 
 C yt ol o gic  a n d hist ol o gic tec h ni q ues ca n be use d t o differe ntiate bet wee n P R 
a n d C R i n rare cases (e. g., resi d ual lesi o ns i n t u m or t y pes s uc h as ger m cell 
t u m ors, w here k n o w n resi d ual be ni g n t u m ors ca n re mai n.) 
 
1 1. 4  
Meas ure me nt of  Effect  
 
1 1. 4 1  T ar get Lesi o ns & T ar get L y m p h  N o des 
 
•  
Meas ura ble lesi o ns (as defi ne d i n Secti o n 1 1. 2 1) u p t o a ma xi m u m of 5 
lesi o ns, re prese ntati ve of all i n v ol ve d or ga ns, s h o ul d be i de ntifie d as “ Tar get 
Lesi o ns” a n d rec or de d a n d meas ure d at baseli ne. T hese lesi o ns ca n be n o n - 
n o dal or n o dal (as defi ne d i n 1 1. 2 1), w here n o m ore t ha n 2 lesi o ns are fr o m 
t he sa me or ga n a n d n o m ore t ha n 2 mali g na nt n o dal lesi o ns are selecte d. 
 
N O T E: If fe wer t ha n 5 tar get lesi o ns a n d tar get l y m p h n o des are i de ntifie d 
(as t here ofte n will be), t here is n o reas o n t o perf or m ad diti o nal st u dies 
be y o n d t h ose s pecifie d i n t he pr ot oc ol t o disc o ver ne w lesi o ns. 
 
 T ar get lesi o ns a n d tar get l y m p h n o des s h o ul d be selecte d o n t he basis 
of t heir size, be re prese ntati ve of all i n v ol ve d sites of disease, b ut i n 
a d diti o n s h o ul d be t h ose t hat le n d t he msel ves t o re pr o d uci ble 
re peate d meas ure me nts. It ma y be t he case t hat, o n occasi o n, t he 
lar gest lesi o n ( or mali g na nt l y m p h n o de) d oes n ot le n d itself t o 
re pr o d uci ble meas ure me nts i n w hic h circ u msta nce t he ne xt lar gest 
lesi o n ( or mali g na nt l y m p h no de) w hic h ca n be meas ure d 
re pr o d uci bl y s h o ul d be selecte d. 
 
 Baseli ne S u m of Di me nsi o ns ( B S D): A s u m of t he l o n gest dia meter f or all 
tar get lesi o ns pl us t he s u m of t he s h ort a xis of all t he tar get l y m p h n o des will 
be calc ulate d a n d re p orte d as t he baseli ne  s u m of di me nsi o ns ( B S D). T he 
B S D will be use d as refere nce t o f urt her c haracterize a n y o bjecti ve t u m or 
res p o nse i n t he meas ura ble di me nsi o n of t he disease.  
 
 P ost -Baseli ne S u m of t he Di me nsi o ns ( P B S D): A s u m of t he l o n gest 
dia meter f or all tar get lesi o ns p l us t he s u m of t he s h ort a xis of all t he tar get 
l y m p h n o des will be calc ulate d a n d re p orte d as t he p ost-baseli ne s u m of 
di me nsi o ns ( P B S D). If t he ra di ol o gist is a ble t o pr o vi de a n act ual meas ure 
f or t he tar get lesi o n ( or tar get l y m p h n o de), t hat s h o ul d be rec or de d, e ve n if it 
is bel o w 0. 5 c m. If t he tar get lesi o n ( or tar get l y m p h n o de) is belie ve d t o be 
prese nt a n d is fai ntl y see n b ut t o o s mall t o meas ure, a defa ult val ue of 0. 5 c m 
s h o ul d be assi g ne d. If it is t he o pi ni o n of t he ra di ol o gist t hat t he tar get lesi o n 
or tar get l y m p h n o de has li kel y disa p peare d, t he meas ure me nt s h o ul d be 
rec or de d as 0 c m. 
 
 T he mi ni m u m s u m of t he di me nsi o ns ( M S D) is t he mi ni m u m of t he B S D a n d 
t he P B S D.  
 
1 1. 4 2  N o n -T ar get Lesi o ns & N o n - T ar get L y m p h N o des 
 
N o n -meas ura ble sites of disease ( Secti o n 1 1. 2 2) are classifie d as n o n - tar get 
lesi o ns or n o n-tar get l y m p h n o des a n d s h o ul d als o be rec or de d at baseli ne. 
T hese lesi o ns a n d l y m p h n o des s h o ul d be f oll o we d i n acc or d wit h 1 1. 4 3 3. 


RU021302I 
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Addendum 3 
 
 
11.43 Response Criteria 
 
11.431 
All target lesions and target lymph nodes followed by CT/MRI/PET- 
CT/Chest X-ray/physical examination must be measured on re- 
evaluation at evaluation times specified in Section 11.1. Specifically, a 
change in objective status to either a PR or CR cannot be done without 
re-measuring target lesions and target lymph nodes. 
 
NOTE: Non-target lesions and non-target lymph nodes should be 
evaluated at each assessment, especially in the case of first response or 
confirmation of response. In selected circumstances, certain non-target 
organs may be evaluated less frequently. For example, bone scans may 
need to be repeated only when complete response is identified in target 
disease or when progression in bone is suspected. 
 
11.432 
Evaluation of Target Lesions 
 
• 
Complete Response (CR): 
 
All of the following must be true: 
 
a. Disappearance of all target lesions. 
 
b. Each target lymph node must have reduction in short axis to 
<1.0 cm. 
 
c. Normalization of tumor biomarkers (i.e., CEA). 
 
• 
Partial Response (PR): 
 
At least a 30% decrease in PBSD (sum of the longest diameter for 
all target lesions plus the sum of the short axis of all the target 
lymph nodes at current evaluation) taking as reference the BSD 
(see Section 11.41). 
 
• 
Progression (PD): 
 
At least one of the following must be true: 
 
a. At least one new malignant lesion, which also includes any 
lymph node that was normal at baseline (< 1.0 cm short axis) 
and increased to ≥ 1.0 cm short axis during follow-up. 
 
b. At least a 20% increase in PBSD (sum of the longest diameter 
for all target lesions plus the sum of the short axis of all the 
target lymph nodes at current evaluation) taking as reference 
the MSD (Section 11.41). In addition, the PBSD must also 
demonstrate an absolute increase of at least 0.5 cm from the 
MSD. 
 
c. See Section 11.32 for details in regards to the requirements for 
PD via FDG-PET imaging. 
 
• 
Stable Disease (SD): 
 
Neither sufficient shrinkage to qualify for PR, nor sufficient 


RU021302I 
51 
Addendum 3 
 
increase to qualify for PD taking as reference the MSD 
 
11.433 
Evaluation of Non-Target Lesions & Non-target Lymph Nodes 
 
• 
Complete Response (CR): 
 
All of the following must be true: 
 
a. Disappearance of all non-target lesions. 
 
b. Each non-target lymph node must have a reduction in short 
axis to <1.0 cm. 
 
• 
Non-CR/Non-PD: 
 
Persistence of one or more non-target lesions or non-target lymph 
nodes. 
 
• 
Progression (PD): 
 
At least one of the following must be true: 
 
a. At least one new malignant lesion, which also includes any 
lymph node that was normal at baseline (<1.0 cm short axis) 
and increased to ≥1.0 cm short axis during follow-up. 
 
b. Unequivocal progression of existing non-target lesions and 
non-target lymph nodes. (NOTE: Unequivocal progression 
should not normally trump target lesion and target lymph node 
status. It must be representative of overall disease status 
change.). 
 
c. See Section 11.32 for details in regards to the requirements for 
PD via FDG-PET imaging. 
 
11.44 Overall Objective Status 
 
The overall objective status for an evaluation is determined by combining 
the patient’s status on target lesions, target lymph nodes, non-target lesions, 
non- target lymph nodes, and new disease as defined in the following table: 
 
For Patients with Measurable Disease 
 
Target Lesions & 
Target Lymph 
Nodes 
Non-Target Lesions & 
Non-Target Lymph 
Nodes 
New 
Sites of 
Disease 
Overall 
Objective 
Status 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
CR 
Non-CR/Non-PD 
No 
PR 
CR/PR 
Not All Evaluated* 
No 
PR** 
SD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
SD 
Not all Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
Not Evaluated 
(NE) 


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A d de n d u m 3  
 
P D  
U ne q ui v ocal P D 
C R  
N o n -C R/ N o n -P D  
N ot All E val uate d *  
Yes or N o  
P D  
C R/ P R/ S D/ P D/ N o  
t all E val uate d 
U ne q ui v ocal P D  
Yes or N o  
P D  
C R/ P R/ S D/ P D/    
N o t all 
E val uate d  
C R  
N o n -C R/ N o n -P D 
N ot All E val uate d *  
Yes  
P D  
* 
See Secti o n  1 1. 4 3 1 
* * N O T E : T his st u d y uses t he pr ot oc ol R E CI S T v 1. 1 te m plate date d 2/ 1 6/ 2 0 1 1. 
F or data c ollecti o n a n d a nal ysis p ur p oses t he o bjecti ve stat us c ha n ge d fr o m 
S D t o P R i n t he A C C R U pr ot oc ol R E CI S T v 1. 1 te m plate as of 2/ 1 6/ 2 0 1 1 
a n d t o matc h R E CI S T v 1. 1 re q uire me nts. 
 
1 1. 4 5  S y m pt o matic Deteri orati o n: Patie nts wit h gl o bal deteri orati o n  of healt h stat us 
re q uiri n g disc o nti n uati o n of treat me nt wit h o ut o bjecti ve e vi de nce of disease 
pr o gressi o n at t hat ti me, a n d n ot eit her relate d t o st u d y treat me nt or ot her 
me dical c o n diti o ns, s h o ul d be re p orte d as P D d ue t o “s y m pt o matic 
deteri orati o n.” E ve r y eff ort s h o ul d be ma de t o d oc u me nt t he o bjecti ve 
pr o gressi o n e ve n after disc o nti n uati o n of treat me nt d ue t o s y m pt o matic 
deteri orati o n. A patie nt is classifie d as ha vi n g P D d ue t o “s y m pt o matic 
deteri orati o n” if a n y of t he f oll o wi n g occ ur t hat are n ot eit h er relate d t o st u d y 
treat me nt or ot her me dical c o n diti o ns: 
 
 Wei g ht l oss > 1 0 % of b o d y wei g ht.  
 W orse ni n g of t u m or- relate d s y m pt o ms. 
 Decli ne i n perf or ma nce stat us of > 1 le vel o n E C O G  scale. 
 
1 2. 0 
Descri pti ve  F act ors:  
 
N o ne 
 
 
1 3. 0  
Tre at me nt/ F oll o w – u p Decisi o n at E v al u ati o n of P atie nt  
 
1 3. 1  
Patie nts w h o are C R, P R, or S D will c o nti n ue treat me nt per pr ot oc ol. 
 
1 3. 2  
Patie nts w h o de vel o p P D w hile recei vi n g t hera p y will g o t o t he e ve nt- m o nit ori n g p hase.  
 
1 3. 3  
Patie nts w h o g o off pr ot oc ol treat me nt f or reas o ns ot her t ha n P D will g o t o t he e ve nt- 
m o nit ori n g p hase per Secti o n 1 8. 0. 
 
1 3. 4  
Patie nts w h o de vel o p ne w C N S disease o nl y will be c o nsi dere d t o ha ve P D a n d will g o t o 
E ve nt  M o nit ori n g.  
 
1 3. 5  
Patie nts w h o de vel o p P D at a n y ti me s h o ul d g o t o E ve nt M o nit ori n g. T hese patie nts ca n 
be treate d wit h alter nati ve treat me nt o pti o ns at t he treati n g i n vesti gat or’s discreti o n if 
t heir cli nical stat us is g o o d e n o u g h t o all o w f urt her t hera p y. 
 
1 3. 6  
A patie nt is dee me d i neli gi ble if after re gistrati o n, it is deter mi ne d t hat at t he ti me of 
re gistrati o n, t he patie nt di d n ot satisf y eac h a n d e ver y eli gi bilit y criteria f or st u d y e ntr y. 
T he patie nt ma y c o nti n ue treat me nt off- pr ot oc ol at t he discreti o n of t he p h ysicia n as l o n g 
as t here are n o safet y c o ncer ns, a n d t he patie nt was pr o perl y re gistere d. T he patie nt will 
g o di rectl y t o t he e ve nt- m o nit ori n g p hase of t he st u d y. 
 
•  
If t he patie nt recei ve d treat me nt, all data u p u ntil t he p oi nt of c o nfir mati o n of 


RU021302I 
53 
Addendum 3 
 
ineligibility must be submitted. Event monitoring will be required per Section 18.0 of 
the protocol. 
 
• 
If the patient never received treatment, on-study material must be submitted. Event 
monitoring will be required per Section 18.0 of the protocol. 
 
13.7 
A patient is deemed a major violation, if protocol requirements regarding treatment in 
cycle 1 of the initial therapy are severely violated that evaluability for primary end point 
is questionable. All data up until the point of confirmation of a major violation must be 
submitted. The patient will go directly to the event-monitoring phase of the study. The 
patient may continue treatment off-protocol at the discretion of the physician as long as 
there are no safety concerns, and the patient was properly registered. Event monitoring 
will be required per Section 18.0 of the protocol. 
 
13.8 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given. On-study material and the End of Active Treatment/Cancel 
Notification Form must be submitted. The patient will go directly to the event-monitoring 
phase of the study, and event monitoring will be required per Section 18.0 of the 
protocol. 


RU021302I 
54 
Addendum 3 
 
 
14.0 
Body Fluid Biospecimens 
 
14.1 
Body Fluid Biospecimen Submission 
 
14.11 Summary Table of Body Fluid Biospecimens for This Protocol 
Type of 
biospecimen 
to submit 
Mandatory 
or optional 
When to 
submit 
Reason for submission 
(background / 
methodology section) 
Where to find 
specific details 
for specimen 
submission 
Blood/blood 
products 
Mandatory 
Quarterly 
(Section 
14.252) 
Future biomarkers 
research and banking 
(Section 14.2) 
Section 14.2 
Blood/blood 
products 
Mandatory 
Banking (Section 14.2) 
Section 14.2 
 
14.2 
Blood/Blood Products Handling 
 
14.21 Kits are not required for this study; however cryovials will be supplied. 
 
14.211 The requisition form and processing instructions will be found on the 
ACCRU study-specific web page, under Forms. Cryovials should be 
requested by each site that is participating on the study prior to first 
enrollment and as needed throughout the course of the study. To request 
cryovials, please contact: 
 
                    
 
 
 
 
  
 
 
 
 
 
Cryovials will not be sent via rush delivery service unless the 
participating institution provides their own FedEx® account number or 
alternate billing number for express service. ACCRU will not cover 
the cost for rush delivery of cryovials. 
 
14.22 All samples should be collected Monday-Friday. 
 
14.23 Collect and process all blood/blood products according to the directions below 
 
14.231 
Time period from blood draw to freezing of plasma must be less than 4 
hours. Tubes can be kept at room temperature until processing. Please 
accurately record time of blood draw and time of processing. 
 
14.232 
Draw venous blood into one 10 mL EDTA tube labeled cfDNA and 
immediately gently invert the tubes 8-10 times. Write the protocol 
number, patient ID number, and draw date number on the tube. 


RU021302I 
55 
Addendum 3 
 
 
 
14.233 
Immediately centrifuge for 10 minutes at 1500 (+\- 150) x g. NOTE: 
Brake switch must be off so the cell/plasma interface is not disturbed. 
 
14.234 
Pipette the plasma layer (top clear layer) into a new 15 mL tube labeled 
“cfDNA/patient ID number”. Do not ship. NOTE: Do not dip the tip of 
the pipette into the plasma/cell interface. Leave a thin plasma layer 
intact over the interface. 
 
14.235 
Centrifuge the 15 mL tube containing the plasma only for 10 minutes 
at 3000 (+/- 150) x g. 
 
14.236 
Transfer using a fresh pipette, the supernatant into a second 15 mL 
tube labeled “cfDNA super.do not ship”. NOTE: Leave about 0.3 mL 
of supernatant in the centrifuged 15 mL tube. This leftover 0.3 mL 
contains cellular debris. 
 
14.237 
Using a fresh pipette, transfer 1 mL of plasma from the “super.do not 
ship” tube into max four (4) 2 mL cryovials labeled 
“cfDNA.ship.patient ID number/protocol number/date of blood draw.” 
 
14.238 
Freeze immediately upright at -70ºC or colder until shipping. 
 
14.239 
Ship the frozen samples quarterly to the address on the requisition 
form.
 
See the instructions for the FedEx account 
number to use to ship the samples priority overnight. 
 
14.24 Summary Table of Research Blood/Blood Products to Be Collected for This 
Protocol 
 
Indicate if 
specimen is 
mandatory 
or optional 
Collection tube 
description 
and/or additive 
(color of tube 
top) 
Volume to 
collect per 
tube (number 
of tubes 
to be 
collected) 
Blood product 
being processed 
and submitted by 
participating site 
Baseline / 
Before 
Treatment 
At time of 
1st and 
2nd 
restaging 
At   
Treatment 
Discontinu 
ation 
Additional 
processing 
required at 
site after 
blood draw? 
Storage / 
shipping 
conditions1 
 
Mandatory 
EDTA (purple) 
10 mL 
(1) 
Plasma and buffy 
coat for future 
research 
X 
X 
X 
Yes 
Freeze 
immediately 
upright at ≤ - 
70° C 
1. After all samples have been processed according to instructions, ship all specimens according to 
shipping instructions (see Section 14.25 for detailed shipping instructions). 
 
14.25 Shipping 
 
14.251 
Verify ALL sections of the Blood Specimen Submission Form (see 
Forms Packet), [BAP Requisition Form and processing instructions 
(see Forms Packet)], and specimen collection labels are completed and 
filled in correctly. 


RU021302I 
56 
Addendum 3 
 
 
14.252 
Specimens will be shipped in batches on a quarterly basis. 
 
14.253 
Ship specimens and requisition forms used to log recording time of 
blood draw and processing via Priority Overnight service, Monday – 
Friday, to BAP Freezer according to instructions. Do not send 
samples on weekends or just prior to federal holidays. 
 
 
 
 
 
14.254 
BAP Freezer will receive the samples and immediately forward the 
specimens to the 
 
 
 
14.3 
Study Methodology and Storage Information 
 
14.31 Blood/blood product samples will be collected for future biomarker studies. 
Analysis will be completed when funding is secured. 
 
We will address the following questions as part of the hypothesis generation 
stage: 
 
14.311 
Identify predictive and prognostic markers (DNA, cfDNA, RNA, 
cfRNA) and assess their associations with toxicity, prognostic value, 
and response to treatment. 
 
14.312 
Define key molecular subtypes and assess their associations with 
toxicity, prognostic value, and response to treatment. 
 
14.313 
Determine the prognostic and predictive values of immune signatures. 
 
13.314 
Investigate stem cell signatures and their association with RR, PFS, OS 
and dependent on location/Braf/MSI. 
 
14.32 Use of Circulating Cell-Free DNA (cfDNA) to Monitor Response and Determine 
Mechanisms of Resistance to Cetuximab 
 
Predictors of clinical benefit from and markers of resistance to EGFR antibodies 
are urgently needed in order to better select patients for treatment and identify 
those unlikely to respond. In addition, mechanisms of acquired resistance remain 
unclear and need to be understood if effective new therapies are to be developed 
for patients who have progressed. Given the procedural risks, cost, and patient 
inconvenience of post-treatment tumor biopsies, the analysis of cfDNA obtained 
from plasma may provide a non-invasive means of interrogating the biology 
underlying response and resistance to EGFR inhibition. Indeed, recent years have 
witnessed several high profile publications demonstrating the potential power of 


RU021302I 
57 
Addendum 3 
 
 
 
cfDNA genotyping. Studies on cfDNA specimens from 24 colon cancer patients 
demonstrated that resistance arose via point mutations in KRAS. (Diaz LA, Jr., 
Williams RT, Wu J, et al. The molecular evolution of acquired resistance to 
targeted EGFR blockade in colorectal cancers. Nature 2012;486:537-40.) In a 
second study, these same mutations were found in two of two patient biopsy 
samples after progression on EGFR inhibitors and cfDNA detection appeared to 
predict resistance to treatment up to 10 months prior to radiographic progression. 
(Misale S, Yaeger R, Hobor S, et al. Emergence of KRAS mutations and 
acquired resistance to anti-EGFR therapy in colorectal cancer. Nature 
2012;486:532-6.) 
 
We have developed a new technology for non-invasive quantification of specific 
tumor mutations in cfDNA isolated from plasma specimens by droplet digital 
PCR (ddPCR). ddPCR emulsifies input DNA into ~20,000 droplets that are PCR 
amplified and fluorescently labeled, and then read in an automated droplet flow 
cytometer. Each droplet is individually assigned a positive or negative value 
based on the fluorescent intensity. The number of positive and negative droplets 
is read by a flow cytometer and is used to calculate the concentration of an allele. 
To gauge feasibility, we studied serial plasma specimens from patients with 
genotype-defined lung cancer or melanoma to determine whether changes in 
cfDNA were representative of tumor biology (Figure 1). In a patient with EGFR- 
mutant NSCLC receiving chemotherapy after failing erlotinib (Figure 1A), an 
increase in plasma L858R and T790M was seen with development of new brain 
metastases, followed by decreased plasma levels when treatment on a clinical 
trial was initiated. In a second case of EGFR-mutant NSCLC receiving 
chemotherapy (Figure 1B), plasma L858R decreased as the patient’s pleural 
drainage resolved, though CT imaging of the non-measurable disease showed 
disease stability. In a patient with KRAS-mutant NSCLC and bone metastases 
(Figure 1C), chemotherapy caused a decrease in plasma G12C levels concordant 
with improved pain control and decreased opiate requirement. Lastly, a patient 
with BRAF-mutant melanoma had progression on experimental immune therapy 
followed by response to vemurafenib (Figure 1D), seen in the rise and fall of 
plasma V600E levels. This pilot experience suggests cfDNA genotyping has 
value for serial assessment of disease status, even in patients without objectively 
measurable disease on CT. 
 
This data also suggests that such a non-invasive assay could be used to 
characterize the biology of resistance. For the colorectal cancer patients enrolled 
in this study, genotype concentrations of KRAS, NRAS, and BRAF mutations will 
be evaluated initially. As more ddPCR assays are validated and new knowledge 
about resistance mechanisms emerges, the mutations to be studied can be 
broadened to include genes such as PIK3CA, PTEN, EGFR, among others. 
Remaining plasma will be banked for this purpose of future research. 


RU021302I 
58 
Addendum 3 
 
 
 
 
 
Figure 1. Serial measurement of plasma genotype for disease monitoring. A wide dynamic range 
is seen in some cases (A, B). Decreases in plasma genotype can be seen both in cases of objective 
tumor shrinkage (A, D) and in cases of symptomatic response with no measurable disease (B, C). 
Concurrent EGFR L858R (A, solid line) and T790M (A, dashed line) mutations trend in parallel. 
 
 
14.33 Droplet Digital PCR (ddPCR) 
 
ddPCR involves dilution of DNA molecules into an aqueous/oil suspension 
containing the necessary reagents for PCR. After disturbance of the suspension, 
thousands of aqueous compartments (or “droplets”) within the oil emulsion are 
formed, and PCR reactions are cycled and quantified using a flow cytometer. We 
have built our ddPCR so that standard TaqMan reagents can be used. In brief, 
TaqMan PCR reaction mixtures will be assembled from a 2× ddPCR Mastermix 
(Bio-Rad) and custom 40x TaqMan probes/primers made specific for each assay. 
Nineteen uL of assembled ddPCR reaction mixture plus 6 μL of ultra pure 
distilled water will be loaded into sample wells of an eight-channel disposable 
droplet generator cartridge (Bio-Rad). An additional seventy uL of droplet 
generation oil (Bio-Rad) will be loaded into the oil well for each channel. 
Droplets will be transferred to a 96-well PCR plate and amplified to end-point by 
conventional PCR .After PCR, the 96-well PCR plate will be read on the QX-100 
droplet reader (Bio-Rad) and analyzed by the QuantaSoft analysis software suite 
(Bio-Rad) that accompanies the droplet reader. Each plasma sample will be 
analyzed in triplicate with an increasing quantity of input DNA (e.g. 1 μL , 2 μL , 
and 4 μL ). Results will be normalized to the mean concentration of mutant 
alleles per μL DNA input, and reported as copies of mutant allele per 100 μL of 
DNA. 


RU021302I 
59 
Addendum 3 
 
 
 
14.4 
Return of Genetic Testing Research Results 
 
Because the results generated by the genetic testing included in this section are not 
currently anticipated to have clinical relevance to the patient or their family members, the 
genetic results will not be disclosed to the patients or their physicians. 
 
If at any time, genetic results are obtained that may have clinical relevance, IRB review 
and approval will be sought regarding the most appropriate manner of disclosure and 
whether or not validation in a CLIA-certified setting will be required. Sharing of research 
data with individual patients should only occur when data have been validated by 
multiple studies and testing has been done in CLIA-approved laboratories. 
 
15.0 
Drug Information 
 
15.1 
Bevacizumab (Avastin) 
 
Investigator brochure will be available on the ACCRU website. 
 
15.11 Background: Bevacizumab is classified as an Anti-VEGF Monoclonal Antibody 
and a Vascular Endothelial Growth Factor (VEGF) Inhibitor. Bevacizumab is a 
recombinant, humanized monoclonal immunoglobulin G1 (IgG1) antibody which 
binds to, and neutralizes, vascular endothelial growth factor (VEGF), preventing 
its association with endothelial receptors, Flt-1 and KDR. VEGF binding initiates 
angiogenesis (endothelial proliferation and the formation of new blood vessels). 
The inhibition of microvascular growth is believed to retard the growth of all 
tissues (including metastatic tissue). 
 
15.12 Formulation: Bevacizumab is manufactured by recombinant DNA technology, 
using a genetically engineered Chinese hamster ovary (CHO) cell line. The 
protein is purified from the cell culture medium by routine methods of column 
chromatography and filtration. The final product is tested for quality, identity, 
safety, purity, potency, strength, and excipient/chemical composition according 
to International Conference on Harmonisation (ICH) guidelines. The purity of 
bevacizumab is >95%. 
 
Bevacizumab is supplied in 100 mg (4 mL) and 400 mg (16 mL) glass vials, each 
with a concentration of 25 mg/mL. Vials contain bevacizumab with phosphate, 
trehalose, polysorbate 20, and sterile water for injection (SWFI), USP. Vials 
contain no preservative and are suitable for single use only. 
 
15.13 Preparation and storage: Bevacizumab vials should be stored in a refrigerator 
at 2°C-8°C. Keep vial in the outer carton due to light sensitivity. DO NOT 
FREEZE. DO NOT SHAKE. 
 
Chemical and physical in-use stability has been demonstrated for 48 hours at 
2°C-30°C in 0.9% sodium chloride solution. Do not administer or mix with 
dextrose solution. From a microbiological point of view, the product should be 
used immediately. If not used immediately, in-use storage times and conditions 
are the responsibility of the user and would normally not be longer than 24 hours 


RU021302I 
60 
Addendum 3 
 
 
 
at 2°C to 8°C, unless dilution has taken place in controlled and validated aseptic 
conditions. 
 
Withdraw the necessary amount of bevacizumab and dilute to the required 
administration volume with 0.9% sodium chloride solution. The concentration of 
the final bevacizumab solution should be kept within the range of 1.4 - 16.5 
mg/mL. Discard any unused portion left in a vial, as the product contains no 
preservatives. Parenteral drug products should be inspected visually for 
particulate matter and discoloration prior to administration. 
 
15.14 Administration: Do not administer as an intravenous push or bolus. Administer 
only as an intravenous (IV) infusion. Do not initiate bevacizumab for 28 days 
following major surgery and until surgical wound is fully healed. 
 
Refer to Section 7 for protocol-specific administration instructions. Guidelines 
recommended by the manufacturer are included for reference. 
 
First infusion: Administer infusion over 90 minutes. Subsequent infusions: 
Administer second infusion over 60 minutes if first infusion is tolerated; 
administer all subsequent infusions over 30 minutes if infusion over 60 minutes 
is tolerated. 
 
15.15 Pharmacokinetic information: 
Distribution: Vd: 46 mL/kg (limited extravascular distribution) 
Half-life elimination: ~20 days (range: 11-50 days) 
Clearance: 2.75-5 mL/kg/day. A low serum albumin and high tumor burden 
increase clearance by 30% and 7% respectively. Clearance increases with 
increasing body weight, and is 15% slower in women than men. 
Time to steady state: 100 days 
 
15.16 Potential Drug Interactions: 
Overall the results from the drug-drug PK interaction investigations 
showed no interaction between bevacizumab and the anti-cancer agents 
tested. Co-administration of bevacizumab with various chemotherapeutic 
and other anti-cancer agents resulted in similar values of CL and Vc for 
bevacizumab, suggesting that the exposure of bevacizumab are not 
affected by concomitant dosing with doxorubicin, capecitabine, 
capecitabine/oxaliplatin (XELOX), 5-FU/leucovorin, 5- 
FU/leucovorin/irinotecan (IFL), 5- FU/leucovorin/oxaliplatin (FOLFOX4), 
erlotinib, carboplatin, cisplatin, oxaliplatin, paclitaxel, gemcitabine, 
temozolomide or interferon-α2a. 
 
The effect of bevacizumab on the disposition of several agents 
(doxorubicin, 5-FU, irinotecan [and its active metabolite SN38], 
capecitabine, oxaliplatin, carboplatin, cisplatin, paclitaxel, gemcitabine, 
erlotinib, temozolomide and interferon alfa-2a) has been investigated. 
Accumulating data do not suggest that bevacizumab affects disposition of 
anti-neoplastic agents. 
 
Increased Effect/Toxicity: Bevacizumab may enhance the cardiotoxic effect of 
Antineoplastic Agents (Anthracycline, Systemic). Bevacizumab may also 


RU021302I 
61 
Addendum 3 
 
 
 
enhance the adverse/toxic effect of Irinotecan, Sorafenib, and Sunitinib. Sunitinib 
may enhance the adverse/toxic effect of Bevacizumab. Specifically, the risk for a 
specific form of anemia, microangiopathic hemolytic anemia (MAHA), may be 
increased. 
 
15.17 Known potential adverse events: Consult the investigator’s brochure and 
package insert for the most current and complete information. U.S. Boxed 
Warnings include severe or fatal hemorrhage, including hemoptysis, 
gastrointestinal bleeding, central nervous system hemorrhage, epistaxis, and 
vaginal bleeding. Avoid use in patients with serious hemorrhage or recent 
hemoptysis. Percentages reported as Monotherapy and as part of combination 
chemotherapy regimens. 
 
Common known potential toxicities, >10%: 
Cardiovascular: Hypertension, venous thromboembolism, peripheral 
edema, hypotension, arterial thrombosis 
Central nervous system: Pain, headache, dizziness, fatigue, taste 
disorder, peripheral sensory neuropathy, anxiety 
Dermatologic: Alopecia, palmar-plantar erythrodysesthesia, exfoliative 
dermatitis, xeroderma. 
Endocrine & metabolic: Ovarian failure, hyperglycemia, 
hypomagnesemia, weight loss, hyponatremia, hypoalbuminemia 
Gastrointestinal: Abdominal pain, anorexia, constipation, diarrhea, 
stomatitis, gastrointestinal hemorrhage, dyspepsia, decreased appetite, 
nausea, vomiting 
Genitourinary: Proteinuria, urinary tract infection, pelvic pain 
Hematologic & oncologic: Hemorrhage, neutropenia, leukopenia 
pulmonary hemorrhage, lymphocytopenia 
Infection: Pneumonia, catheter infection, or wound infection 
Neuromuscular & skeletal: Myalgia, back pain. 
Renal: Increased serum creatinine 
Respiratory: Upper respiratory tract infection, epistaxis, dyspnea, rhinitis 
Miscellaneous: Postoperative wound complication (including 
dehiscence) 
 
Less common known potential toxicities, 1% - 10%: 
Cardiovascular: Thrombosis, deep vein thrombosis, syncope, 
intra-abdominal venous thrombosis, left ventricular dysfunction, 
pulmonary embolism 
Central Nervous System: Voice disorder 
Dermatologic: Acne vulgaris, dermal ulcer, cellulitis 
Endocrine & metabolic: Dehydration, hypokalemia 
Gastrointestinal: Xerostomia, rectal pain, colitis, intestinal 
obstruction, gingivitis, gastrointestinal fistula, gastroesophageal 
reflux disease, gastrointestinal perforation, oral mucosa ulcer, 
gastritis, gingival pain, gingival hemorrhage 
Genitourinary: Vaginal hemorrhage 
Hematologic & oncologic: Febrile neutropenia, neutropenic 
infection, thrombocytopenia, hemorrhage 
Infection: Tooth abscess 
Neuromuscular & skeletal: Weakness, dysarthria 


RU021302I 
62 
Addendum 3 
 
 
 
Ophthalmic: Blurred vision 
Otic: Tinnitus, deafness 
Respiratory: Pneumonitis 
Miscellaneous: Gastrointestinal-vaginal fistula, anal fistula, 
infusion-related reaction 
 
Rare known potential toxicities, <1% (Limited to important 
or life-threatening): 
Angina pectoris, antibody development (anti-bevacizumab and 
neutralizing), bladder fistula, bronchopleural fistula, cerebral 
infarction, conjunctival hemorrhage, endophthalmitis (infectious 
and sterile), fistula of bile duct, fulminant necrotizing fasciitis, 
gallbladder perforation, gastrointestinal ulcer, hemolytic anemia 
(microangiopathic; when used in combination with sunitinib), 
hemoptysis, hemorrhagic stroke, hypersensitivity, hypertensive 
crises, hypertensive encephalopathy, increased intraocular 
pressure, intestinal necrosis, intraocular inflammation (iritis, 
vitritis), mesenteric thrombosis, myocardial infarction, nasal 
septum perforation, ocular hyperemia, osteonecrosis of the jaw, 
ovarian failure, pancytopenia, polyserositis, pulmonary 
hypertension, rectal fistula, renal failure, renal fistula, renal 
thrombotic microangiopathy, retinal detachment, retinal 
hemorrhage, reversible posterior leukoencephalopathy 
syndrome, sepsis, tracheoesophageal fistula, vaginal fistula, 
vitreous hemorrhage, vitreous opacity 
 
15.18 Drug procurement: Genentech will supply commercial drug labeled for 
investigational use toMcKesson. Each participating ACCRU treating location 
will order the drug fromMcKesson. Fax the Drug Order Request Form (found in 
the Forms Packet) request to: 
 
 
 
 
Each participating ACCRU treating location will be responsible for monitoring 
the supply of bevacizumab and will use the Drug Order Request Form to order 
additional supplies as needed. 
 
Outdated or remaining drug is to be destroyed on-site according to procedures in 
place at each institution. 
 
15.19 Suggested nursing guidelines: 
 
15.191 
Monitor patients closely for infusion type reactions, including fever, 
chills, myalgias, rigors, or other allergic reactions. While this is less 
likely given that bevacizumab is a humanized antibody, there still 
exists the potential for severe allergic reactions. If these signs or 
symptoms occur, stop the infusion immediately and contact MD. Have 
emergency equipment nearby and be prepared to administer emergency 
treatment as ordered by MD. 


RU021302I 
63 
Addendum 3 
 
 
 
 
15.192 
Monitor urine dipstick or UPC as required by the test schedule. 
 
15.193 
Evaluate IV site regularly for signs of infiltration. 
 
15.194 
Bleeding in the absence of thrombocytopenia is a dose-limiting 
toxicity. Monitor patient closely for hemorrhagic events, including 
CNS hemorrhage, epistaxis, hematemesis and hemoptysis. Most cases 
of bleeding have occurred at the tumor site. Advise patient about the 
potential for bleeding or thrombosis. 
 
15.195 
In patients receiving treatment for lung cancer, hemoptysis and 
pulmonary hemorrhage occurred in up to 10% of patients in one study. 
Monitor these patients especially close. 
 
15.196 
Patients may experience Grade 1-2 nausea, however vomiting is 
uncommon. Medicate as ordered and monitor for effectiveness. 
 
15.197 
Monitor for skin rash, instruct patient to report to MD. 
 
15.198 
Monitor blood pressure. Administer antihypertensives as ordered by 
MD. 
 
15.199a Monitor for signs and symptoms of deep vein thrombosis (DVT) or 
pulmonary embolism (PE), or myocardial infarction (MI) including 
new or worsening angina. These have been reported with therapy. 
Instruct patient to report any calf pain, chest pain or shortness of breath 
to MD immediately. 
 
15.199b Asthenia and headache were reported commonly during therapy (in up 
to 70% and 50% of patients respectively). Administer acetaminophen 
as needed. Monitor for its effectiveness. Avoid the use of aspirin, or 
ibuprofen as this may interfere with the coagulation cascade and 
further add to the risk of bleeding. 
 
15.199c Monitor CBC, including platelets. Instruct patient to report signs and 
symptoms of infection, unusual bruising or bleeding to the MD. 
 
15.199d Patients receiving warfarin therapy for thrombosis should have their 
PT or INR monitored weekly until two stable therapeutic levels are 
attained. For patients on warfarin for venous access prophylaxis, 
routine monitoring is satisfactory. 
 
15.199e   A rare but serious complication of bevacizumab is wound dehiscence. 
Patients who have had recent surgery or have other open wounds 
should be monitored carefully. 
 
15.199f  Gastrointestinal perforation with or without abdominal abscess is rare 
but possible. This may present itself as vague abdominal pain 
associated with constipation and vomiting. Instruct patient to report 
abdominal pain to the MD. 
 
15.199g Reversible Posterior Leukoencephalopathy Syndrome (RPLS) is a rare 
(<1%) but serious condition. Presenting symptoms may include 
changes in mental status, visual disturbance, seizure, or other CNS 


RU021302I 
64 
Addendum 3 
 
 
 
changes. Patients with this syndrome generally had HTN as well, 
therefore BP monitoring is important. Instruct patient to report any 
mental status changes, visual changes, seizures, or other CNS changes 
to the MD immediately. These may be a sign of RPLS or more serious 
condition, such as hemorrhagic event in the CNS. 
 
15.199h  Warn female patients of the possibility of ovarian failure and 
subsequent infertility. Vaginal hemorrhage is also possible. Instruct 
patients to report any heavy or unusual vaginal bleeding to health care 
team. 
15.199i    Warn female patients of the risk of rectovaginal fistula.  
 
15 199j 
Agent may cause increased cardiotoxic effects of anthracyclines as 
well as toxic effects of irinotecan, sorafenib, and sunitinib. Patients 
who on are on dual therapy with these agents should be monitored 
closely. 
 
15.2 
Irinotecan (Camptosar®, CPT11) 
 
15.21 Background: Irinotecan and its active metabolite (SN-38) bind reversibly 
to topoisomerase I-DNA complex preventing relegation of the cleaved 
DNA strand. This results in the accumulation of cleavable complexes and 
double-strand DNA breaks. As mammalian cells cannot efficiently repair 
these breaks, cell death consistent with S-phase cell cycle specificity 
occurs, leading to termination of cellular replication. 
 
15.22 Formulation: Commercially available for injection 20 mg/mL (2 mL, 5 
mL, 25 mL) [contains sorbitol 45 mg/mL; do not use in patients with 
hereditary fructose intolerance]. 
 
15.23 Preparation, storage, and stability: Store intact vials at room 
temperature (15 to 30ºC or 59 to 86ºF) and protect from light. Doses 
should be diluted in 250-500 mL D5W or 0.9% NaCl to a final 
concentration of 0.12-2.8 mg/mL. Solutions diluted in D5W are stable for 
24 hours at room temperature or 48 hours under refrigeration at 2ºC to 
8ºC. Solutions diluted in 0.9% NaCl may precipitate if refrigerated. Do not 
freeze. 
 
15.24 Administration: Administer by I.V. infusion, usually over 90 minutes. 
 
15.25 Pharmacokinetic 
information: 
Distribution: Vd: 33-150 
L/m2 
 
Protein binding, plasma: Predominantly albumin; Parent drug: 30% to 68%, 
SN-38 (active metabolite): ~95% 
Metabolism: Primarily hepatic to SN-38 (active metabolite) by carboxylesterase 
enzymes; SN-38 undergoes conjugation by UDP- glucuronosyl transferase 1A1 
(UGT1A1) to form a glucuronide metabolite. Conversion of Irinotecan to SN-38 


RU021302I 
65 
Addendum 3 
 
 
 
is decreased and glucoronidation of SN-38 is increased in patients who smoke 
cigarettes, resulting in lower levels of the metabolite and overall decreased 
systemic exposure. SN-38 is increased by UGT1A1*28 polymorphism (10% of 
North Americans are homozygous for UGT1A1*28 allele). Patients homozygous 
for the UGT1A1*28 allele are at increased risk of neutropenia; initial one-level 
dose reduction should be considered for both single-agent and combination 
regimens. The lactones of both Irinotecan and SN-38 undergo hydrolysis to 
inactive hydroxyl acid forms. 
Half-life elimination: SN-38: Mean terminal: 10-20 hours 
Time to peak: SN-38: Following 90-minute infusion: ~1 hour 
Excretion: Within 24 hours: urine: Irinotecan (11% to 20%), metabolites (SN-38 
<1%, SN-38 glucuronide, 3%) 
 
15.26 Potential Drug Interactions: 
 
Cytochrome P450 Effect: Substrate (major) of CYP2B6, 3A4, P- 
glycoprotein, SLCO1B1 and UGT1A1 
Increased Effect/Toxicity: CYP2B6 and CYP3A4 inhibitors may increase the 
levels/effects of irinotecan. Bevacizumab may increase the adverse effects of 
irinotecan (e.g., diarrhea, neutropenia). Ketoconazole increases the levels/effects 
of Irinotecan and active metabolite; discontinue ketoconzaole 1 week prior to 
irinotecan therapy; concurrent use is contraindicated. 
Decreased Effect: CYP2B6 and CYP3A4 inducers may decrease the 
levels/effects of irinotecan. 
Ethanol/Nutrition/Herb Interactions Herb/Nutraceutical: St John’s wort 
decreases therapeutic effect of irinotecan; discontinue ≥2 weeks prior to 
irinotecan therapy; concurrent use is contraindicated. 
 
 
15.27 Known potential adverse events: Consult the package insert for the 
most current and complete information including U.S. Boxed Warnings 
pertaining to severe diarrhea and severe myelosuppression. 
 
Common known potential toxicities, >10%: 
Cardiovascular: Vasodilation 
Central nervous system: Cholinergic toxicity (includes rhinitis, 
increased salivation, miosis, lacrimation, diaphoresis, flushing 
and intestinal hyperperistalsis); fever, pain, dizziness, insomnia, 
headache, chills 
Dermatologic: Alopecia, rash 
Endocrine & metabolic: Dehydration 
Gastrointestinal: Late onset diarrhea, early onset diarrhea, 
nausea, abdominal pain, vomiting, cramps, anorexia, 
constipation, mucositis, weight loss, flatulence, stomatitis 
Hematologic: Anemia, leukopenia, thrombocytopenia, 
neutropenia 
Hepatic: Bilirubin increased, alkaline phosphatase increased 
Neuromuscular & skeletal: Weakness, back pain 
Respiratory: Dyspnea, cough, rhinitis 
Miscellaneous: Diaphoresis, infection 


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Addendum 3 
 
 
 
Less common known potential toxicities, 1% - 10%: 
Cardiovascular: Edema, hypotension, thromboembolic events 
Central nervous system: Somnolence, confusion 
Gastrointestinal: Abdominal fullness, dyspepsia 
Hematologic: Neutropenic fever, hemorrhage, neutropenic 
infection 
Hepatic: AST increased, ascites and/or jaundice 
Respiratory: Pneumonia 
 
Rare known potential toxicities, <1% (Limited to important 
or life-threatening): 
ALT increased, amylase increased, anaphylactoid reaction, 
anaphylaxis, angina, arterial thrombosis, bleeding, bradycardia, 
cardiac arrest, cerebral infarct, cerebrovascular accident, 
circulatory failure, colitis, dysrhythmia, embolus, 
gastrointestinal bleeding, gastrointestinal obstruction, 
hepatomegaly, hyperglycemia, hypersensitivity, hyponatremia, 
ileus, interstitial pulmonary disease (IPD), intestinal perforation, 
ischemic colitis, lipase increased, lymphocytopenia, megacolon, 
MI, myocardial ischemia, neutropenic typhylitis, pancreatitis, 
paresthesia, peripheral vascular disorder, pulmonary embolus, 
pulmonary toxicity (dyspnea, fever, reticulnodular infiltrates on 
chest x-ray), renal failure (acute), renal impairment, syncope, 
thrombophlebitis, thrombosis, typhlitis, ulceration, ulcerative 
colitis, 
 
15.28 Drug procurement: Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler. 
 
15.29 Suggested nursing guidelines: 
 
15.291 
If possible, check for any history of hypersensitivity reaction to any 
previous drug formulated with polysorbate 80. 
 
15.292 
Cholinergic symptoms of lacrimation, nasal congestion, diaphoresis, 
flushing, abdominal cramping, and diarrhea can occur at the beginning, 
during, or immediately after the CPT-11 infusion. It is suggested that 
the patient remain in the treatment area for a minimum of one hour 
following the completion of the very first CPT-11 infusion. If diarrhea 
occurs within one hour of infusion, refer to Section 9.2 or 15.16 for 
management. 
 
15.293 
Patient education is extremely important. Impress on the patient the 
importance of compliance with treatment of diarrhea management (see 
Section 9.4). Stress the need for prompt recognition and early 
intervention. Motivate the patient to report any complications 
immediately. The cholera-like syndrome can be unresponsive to 
conventional antidiarrheals and can result in severe dehydration. 
 
15.294 
Ondanestron and diphenhydramine should provide good relief from the 
nausea/vomiting/cramping. Avoid prochlorperazine on the day of 


RU021302I 
67 
Addendum 3 
 
 
 
treatment due to its association with akathisia (motor restlessness). 
Prochlorperazine may be taken between treatments. 
 
15.295 
Advise avoidance of excess caffeine, a GI stimulant. Avoid 
magnesium-based antacids such as Mylanta, Maalox, Rolaids, MOM, 
Mag-Ox 400, and Tylenol with antacid. 
 
15.296 
The pulmonary toxicity seen is usually manifested by dyspnea 
beginning 42-175 days after treatment and occurs at a cumulative dose 
ranging from 400-1000 mg/m (median 750). Instruct patient to report 
any cough or SOB. 
 
15.297 
Patients are at risk for developing eosinophilia and will improve on 
steroid therapy. 
 
15.298 
Hepatic enzyme elevations have been transient and did not require 
intervention. 
 
15.299 a Monitor CBC closely. Leukopenia occurs primarily as neutropenia but 
can be severe and dose limiting. The simultaneous occurrence of grade 
4 diarrhea and grade 4 neutropenia is rare but may render the patient 
more susceptible to polymicrobial sepsis and potentially death. 
 
15.299b   Advise patients of probable hair loss. 
 
15.3 
Cetuximab (Erbitux®) 
 
15.31 Background: Cetuximab is a recombinant human/mouse chimeric monoclonal 
antibody which binds specifically to the epidermal growth factor receptor 
(EGFR, HER1, c-ErbB-1) and competitively inhibits the binding of epidermal 
growth factor (EGF) and other ligands. Binding to the EGFR blocks 
phosphorylation and activation of receptor-associated kinases, resulting in 
inhibition of cell growth, induction of apoptosis, and decreased matrix 
metalloproteinase and vascular endothelial growth factor production. EGFR 
signal transduction results in KRAS wild-type activation; cells with KRAS 
mutations appear to be unaffected by EGFR inhibition. 
 
15.32 Formulation: Commercially available for injection 2 mg/mL (50 mL, 100 mL). 
 
15.33 Preparation, storage, and stability: Refer to package insert for complete 
preparation and dispensing instructions. Store intact vials at refrigeration 
temperature (2 to 8ºC 38 to 46ºF), do not freeze or shake. Reconstitution is not 
required. Appropriate dose should be added to empty sterile container; do not 
shake or dilute. Preparations in infusion containers are stable for up to 12 hours 
under refrigeration (2 to 8ºC 38 to 46ºF) and up to 8 hours at room temperature 
(20 to 36ºC or 68 to 77ºF). 
 
15.34 Administration: Administer via I.V. infusion; loading dose over 2 hours; weekly 
maintenance dose over 1 hour. Do not administer as I.V. push or bolus. Do not 
shake or dilute. Premedication with antihistamines is recommended. The 
maximum infusion rate is 10 mg/minute. Administer through a low protein- 


RU021302I 
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Addendum 3 
 
 
 
binding 0.22 micrometer in-line filter. Use 0.9% NaCl to flush line at the end of 
infusion. For biweekly administration (unlabeled frequency and dose), the initial 
dose was infused over 120 minutes and subsequent doses infused over 60 
minutes. 
 
15.35 Pharmacokinetic information: 
Distribution: Vd: ~2-3 L/m2 
Half-life elimination: ~112 hours (range: 63-230 hours) 
 
15.36 Potential Drug Interactions: 
There are no known interactions where it is recommended to avoid concomitant 
use. 
 
15.37 Known potential adverse events: Consult the package insert for the most 
current and complete information. Refer to the package insert pertaining to the 
following boxed warnings: Severe infusion reactions and cardiopulmonary arrest. 
Cetuximab is contraindicated in patients with known severe reactions to 
Cetuximab. 
 
Common known potential toxicities, >10%: 
Central nervous system: Fatigue, pain, peripheral sensory 
neuropathy, headache, insomnia, fever, confusion, anxiety, 
chills, depression 
Dermatologic: Skin rash, acneiform, eruption, xeroderma, 
pruritus, nail disease 
Endocrine & metabolic: Hypomagnesemia, dehydration 
Gastrointestinal: Nausea, abdominal pain, constipation, diarrhea, 
vomiting, stomatitis, xerostomia 
Neuromuscular & skeletal: Ostealgia, arthralgia 
Respiratory: Dyspnea, cough 
Miscellaneous: Fever, infusion-related reactions 
 
Less common known potential toxicities, 1% - 10%: 
Cardiovascular: Cardiopulmonary arrest 
Central nervous system: Taste disorder 
Dermatologic: Alopecia, skin disorder 
 
Immunologic: Antibody development 
Infection: Sepsis 
Renal: Renal failure 
 
Rare known potential toxicities, <1% (Limited to important 
or life-threatening): 
Abscess, aseptic meningitis, blepharitis, cardiac arrest, cardiac 
arrhythmia, cellulitis, cheilitis, conjunctivitis, corneal ulcer, 
hypertrichosis, hypotension, interstitial pulmonary disease, 
increased eosinophils (a type of white blood cell) in the blood 
with or without scarring or inflammation of the lungs, keratitis, 
leukopenia, loss of consciousness, MI, pulmonary embolism, 
radiation dermatitis, shock, skin fissure, skin infection, stridor 


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Addendum 3 
 
 
 
15.38 Drug procurement: Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler. 
 
15.39 Suggested nursing guidelines: 
 
15.391 
Patients should be closely monitored during the infusion for signs of 
anaphylaxis and standard resuscitative medications should be available 
during and for one hour following the cetuximab infusion. 
 
CAUTION: Infusion reactions may occur during or following 
cetuximab administration. Most infusion reactions occur with the first 
infusion of cetuximab, but some patients’ first infusion reactions have 
been reported following subsequent doses (as far out as the 8th dose). 
The infusion reaction may occur during the infusion, or be delayed 
until any time after the infusion. A nurse should be present in the 
immediate treatment area throughout the infusion and observation 
period. A physician should be in close proximity to the patient 
treatment area. Should an infusion reaction occur, the patient should be 
treated according to institutional guidelines. Patient should be 
instructed to report any delayed reactions to the investigator 
immediately. Patients who have had severe reactions should not 
receive further doses of Cetuximab. 
 
15.392 
Vital signs should be taken prior to, during, post and 1-hour post 
infusion. 
 
15.393 
Patient should be observed for 1 hour following the loading dose and 
each maintenance dose. 
 
 
15.394 
Premedicate with 50 mg of IV diphenhydramine, or other specific 
premedications called for in the protocol, prior to each dose. 
 
15.395 
Patients should be taught to wear sunscreen and hats and limit sun 
exposure while receiving treatment. 
 
15.396 
Recommend that all infusions be run on a volumetric pump. Infusion 
rate MUST NEVER EXCEED 10MG/MINUTE (5 ML/MINUTE). 
 
15.397 
Monitor CBC and instruct patient to report any signs or symptoms of 
infection, unusual bruising, or bleeding to the health care team. 
 
15.398 
Monitor LFTs. 
15.399 a  Fever and chills may occur. Discuss with MD about premedication 
with an antipyretic. 
 
15.399b  Monitor for signs and symptoms of gastrointestinal side effects, 
including nausea, constipation, diarrhea and vomiting. Administer 
antiemetics and antidiarrheals as indicated and evaluate their 
effectiveness. 


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70 
Addendum 3 
 
 
 
15.399c   Instruct patient to report rash. 
 
15.399d  Hypomagnesemia is a complication of cetuximab therapy. Instruct 
patients to report any of the following signs or symptoms as these may 
be signs of the disorder: 
 
Neuromuscular: muscle weakness, muscle cramps, painful 
swallowing 
CNS: Irritability, combativeness, disorientation, psychosis, 
vertigo, seizures 
Cardiac: irregular and/or fast heartbeat 
 
Any or all of the symptoms may or may not be present in the patient 
with this condition. If patients present with any of these symptoms, 
inform MD and a magnesium level should be checked. 
 
15.399e  Sensory neuropathy has been seen. Assess and inform the physician if 
this develops. 
 
15.4 
Placebo 
 
15.41 Each institution will use 100ml bags of normal saline as the placebo 
agent. 
A volume of normal saline equal to the volume of bevacizumab will be added to 
the 100 mL bag of normal saline. The initial placebo dose will be given by IV 
over 90 minutes, the second dose over 60 minutes, and all subsequent doses over 
30 minutes. Each institution will use normal saline from their commercial 
inventory. The ACCRU Research Base Pharmacy will not provide normal saline 
to the ACCRU sites. 
 
15.42 Label as directed in Section 6.32. 
 
16.0 
Statistical Considerations and Methodology 
 
16.1 
Study Design Overview 
 
This randomized Phase II trial is designed to primarily compare progression-free survival 
(PFS) in patients with RAS wild-type, irinotecan-refractory metastatic colorectal cancer 
who have also previously received bevacizumab in at least one prior line of therapy, who 
receive irinotecan and cetuximab plus bevacizumab (experimental arm) versus irinotecan 
and cetuximab plus placebo (control arm). The BOND-1 study (Cunningham, et al, 2004) 
reported a median time to progression of 4.1 months in patients with irinotecan-refractory 
metastatic colorectal cancer who received irinotecan plus cetuximab. The BOND-2 study 
(Saltz, et al, 2007) randomized irinotecan-refractory mCRC patients to bevacizumab and 
cetuximab with or without irinotecan. They reported a median time to progression of 7.3 
in patients who received irinotecan, cetuximab and bevacizumab. Therefore, to design the 
current trial, we assumed median PFS of 4.1 months in the control arm. 


RU021302I 
71 
Addendum 3 
 
 
 
16.2 
Sample Size, Accrual Rate, and Study Duration 
 
16.21 Sample Size: The study design to be utilized is fully described in Section 16.3. 
There will be 30 patients randomized to each treatment group of the study (total 
of 60 patients). 
 
16.22 Accrual Rate and Accrual Duration: We anticipate accruing 4 patients per month. 
With a minimal follow-up of 6 months, we anticipate that the study will take 
approximately 15 months to accrue if there are no major issues of patient safety. 
 
16.23 Primary Endpoint Completion Date for Clinical Trials.gov Reporting: For 
purpose of ClinicalTrial.gov reporting, the primary endpoint completion date for 
this study is the time the last patient registered has been followed for at least 6 
months. 
 
16.3 
Statistical Design and Analysis for the Primary Endpoint 
 
16.31 Primary Endpoint: 
 
The primary endpoint is progression-free survival (PFS), defined as time from 
the date of randomization to the date of 1st documented disease progression or 
death due to any cause, whichever occurs first. For patients who died without 
documented progressive disease, if the date of last disease evaluation which 
shows progression-free status is within 6 months before death date, PFS will be 
coded as event occurs at the death date. Otherwise PFS will be censored at the 
last disease evaluation date. 
 
For patients who are alive and progression-free at the time of primary efficacy 
analysis, the following censoring rules will be implemented: 
 
• 
Primary rule – PFS will be censored at the date of last disease evaluation 
which shows progression-free status. 
• 
Secondary rule for sensitivity analysis – PFS will be censored at the earlier 
date of 
 
o Last disease evaluation which shows progression-free status 
o Protocol-specified treatment discontinuation due to severe toxicity 
o Start of alternative treatment due to reasons other than progressive 
disease or severe toxicity 
 
The primary endpoint analysis will be conducted based on the intent-to-treat 
(ITT) population. Sensitivity analysis will be conducted based on the per- 
protocol (PP) population and applying the secondary rule for determining the 
censoring time. 
 
The followings are the definitions of the various analysis populations: 
 
• 
Intent-to-Treat (ITT) population: All randomized patients regardless of 
whether they received any treatment and regardless of their final eligibility 
status. Patients will be analyzed in the group to which they were randomized. 


RU021302I 
72 
Addendum 3 
 
 
 
• 
Per-Protocol (PP) population: All randomized patients meeting the eligibility 
criteria who received at least one dose of the treatment and did not have any 
major treatment violations. Patients will be included in the analysis in the 
group closest in principle to the initial treatment they actually received. 
• 
Safety Analysis (SA) population: All patients who received any quantity of 
study treatment. Patients will be grouped according to treatment received. 
 
16.32 Statistical Design: 
 
A total of 55 events will provide 80% power to detect a treatment effect of 
hazard ratio (HR) = 0.562 (corresponding to median PFS of 4.1 and 7.3months in 
control and experimental arm, respectively) with a one-sided log-rank test, at the 
significance level of 0.10. With the assumptions of accruing 4 patients per month 
and minimal follow up of 6 months, total of 60 patients (30 per arm) will be 
randomized. The sample size calculation was conducted using EAST v6.4. There 
is no interim analysis is planned. 
 
Decision Rules: The primary efficacy analysis will be conducted when there are 
at least 55 events observed for PFS (approximately 28 months after the first 
patient has accrued). At the conclusion of the trial, the experimental regimen will 
be concluded to be superior to the control regimen, if the p-value of log-rank test 
is less than 0.1 (equivalent to HR < 0.708). 
 
16.33 Study Operating Characteristics: 
 
The table below shows the study operating characteristics assuming the time-to- 
event endpoint of PFS follows exponential survival function. The proportion of 
times that the study would conclude that the experimental regimen is superior to 
the control regimen is tabulated by the various true HRs. 
 
If the true 
HR is 
1.00 
0.89 
0.78 
0.67 
0.56 
Then the 
probability of 
declaring the 
experiment 
regimen is 
superior to 
control 
regimen is … 
0.1010 
0.2082 
0.3554 
0.5705 
0.7911 
 
16.34 Analysis Plan: 
 
The distribution of PFS by group will be estimated using the method of Kaplan- 
Meier. Six and 12 month PFS rates by treatment group with confidence intervals 
will be estimated based on Kaplan-Meier curves. The HR with confidence 
interval will be estimated based on stratified Cox models (stratified by levels of 
stratification factors), without and with adjusting for baseline 
clinical/pathological factors. 


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73 
Addendum 3 
 
 
 
16.4 
Supplementary Analysis Plans (Secondary Endpoints): 
 
All analyses of secondary endpoints will be conducted in the ITT population, with the 
exception of safety endpoints, which will be conducted in the Safety population, or 
otherwise specified. 
 
16.41 Adverse events: Adverse events: The maximum grade of each adverse event and 
its attribution will be recorded for each patient. The frequency tables will be 
reviewed to evaluate for patterns of toxicity. The overall adverse event rates for 
Grade 3 or higher adverse events will be compared between the two treatment 
groups using Chi-square test (or Fisher’s exact test if the data in the contingency 
table is sparse) 
 
16.42 Overall survival (OS): OS is defined as time from randomization to the date of 
death due to any cause. The distribution of OS by group will be estimated using 
the method of Kaplan-Meier. Twelve, 18- and 24-month survival rates by 
treatment group with confidence intervals will be estimated based on Kaplan- 
Meier curves. The HR with confidence interval will be estimated based on 
stratified Cox models (stratified by levels of stratification factors), without and 
with adjusting for baseline clinical/pathological factors. 
 
16.43 Disease control rate (DCR): Disease control status will be determined using 
tumor assessment data collected from date of initiation of the treatment to the 
date of treatment discontinuation. Disease control is defined as maintaining CR 
or PR or SD as the tumor assessment result during the defined time window. 
DCR is defined as number of patients with success of disease control divided by 
total number of patients in the analysis population, excluding patients who refuse 
treatment before the initiation of any treatment. DCR will be compared between 
two treatment groups using Chi-square test (or Fisher’s exact test if the data in 
the contingency table is sparse). Logistic regression models will be used to 
estimate the odds ratio (OR) and confidence interval without and with adjusting 
for baseline clinical/pathological factors. 
 
16.44 Overall response rate (ORR): Overall response rate (ORR): Overall response 
status will be determined using tumor assessment data collected from date of 
initiation of the treatment to the date of treatment discontinuation. Overall 
response is defined as achieving CR or PR as the best tumor assessment result 
during the defined time window. ORR is defined as number of patients with CR 
or PR as the best overall response divided by the total number of patients in the 
analysis population, excluding patients who refuse treatment before the initiation 
of any treatment. ORR will be compared between the two treatment groups using 
Chi-square test (or Fisher’s exact test if the data in the contingency table is 
sparse). Logistic regression models will be used to estimate the odds ratio (OR) 
and confidence interval without and with adjusting for baseline 
clinical/pathological factors. 
 
16.45 Duration of response (DOR): DOR is defined as time from the date of first tumor 
assessment with the response status being CR or PR to the date of 1st 
documented progressive disease. If a patient never achieves CR or PR during 
treatment, the DOR will be censored with zero DOR time. If a patient is off 
protocol treatment due to severe AE or other non-PD reasons, the DOR time will 


RU021302I 
74 
Addendum 3 
 
 
 
be censored at the date of treatment discontinuation. The distribution of DOR by 
treatment group will be estimated using the method of Kaplan-Meier. Six and 12 
month durable response (i.e. maintaining CR or PR without PD) rates by 
treatment group with confidence intervals will be estimated based on Kaplan- 
Meier curves. The HR with confidence interval will be estimated based on 
stratified Cox models (stratified by levels of stratification factors), without and 
with adjusting for baseline clinical/pathological factors. 
 
16.46 Time to treatment failure (TTF): TTF is defined as time from the date of 
randomization to the date of treatment discontinuation due to PD, death, or 
severe AE. If a patient discontinues protocol treatment for reasons other than PD, 
he/she will be censored at the date of treatment discontinuation. The distribution 
of TTF by treatment group will be estimated using the method of Kaplan-Meier. 
Six month event-free rates by treatment group with confidence intervals will be 
estimated based on Kaplan-Meier curves. The HR with confidence interval will 
be estimated based on stratified Cox models (stratified by levels of stratification 
factors), without and with adjusting for baseline clinical/pathological factors. 
 
16.47 Relative dose intensity (RDI): RDI is defined as the total dose of protocol 
therapy a patient actually received (i.e., summation of actually received dose at 
each cycle) divided by the total planned dose (i.e., summation of planned dose 
level at each cycle). Separate RDIs will be calculated for irinotecan and 
cetuximab. Agent-specific RDI will be summarized by means, 25th percentiles, 
medians, 75th percentiles, and min and max values, all of which will be 
compared between the two treatment groups by the Wilcoxon Rank sum test. 
 
16.48 Correlative: One of the objectives of this correlative study is to determine the 
change in genotype concentrations of pre-specified gene mutations in circulating 
cfDNA collected serially from baseline to treatment with cetuximab to 
progression. We plan to estimate the mean and median change in mutation 
concentration for each pre-specified gene, and provide the corresponding 95% 
confidence intervals. With a total of 60 patients, we have 80% power to detect an 
average change in the concentration of RAS mutations equaling at least 0.62 
times the standard deviation using a one-sided t-test and 5% type I error. 
 
We plan to estimate the distribution of progression-free survival (PFS) and 
overall survival (OS) using the Kaplan-Meier method and calculate confidence 
limits using the Greenwood formula. We will apply Cox proportional hazards 
models to explore the predictive value of pretreatment mutation status for 
cetuximab sensitivity and resistance, using PFS and OS as the outcome variables. 
 
We will also explore the dynamic change in mutation concentration while the 
patient is receiving cetuximab treatment. We will use scatter plots and box plots 
to illustrate such change. 


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75 
Addendum 3 
 
 
 
16.5 
Monitoring the Study 
 
16.51 Adverse Event Stopping Rule: 
 
The stopping rule specified below is based on the knowledge available at study 
development. We note that the Adverse Event Stopping Rule may be adjusted in 
the event of either (1) the study re-opening to accrual or (2) at any time during 
the conduct of the trial and in consideration of newly acquired information 
regarding the adverse event profile of the treatment(s) under investigation. The 
study team may choose to suspend accrual because of unexpected adverse event 
profiles that have not crossed the specified rule below. 
 
Accrual will be temporarily suspended to this study if at any time we observe 
events considered to be clinically relevant and at least possibly related to study 
treatment (i.e., an adverse event with attribute specified as “possible”, 
“probable”, or “definite”), in either treatment group, that satisfy the following: 
 
If 5 or more patients in the first 20 treated patients (or 25% of all patients after 20 
are accrued) experience a grade 4 or higher non-hematologic adverse event. 
 
We note that we will review grade 4 and 5 adverse events deemed “unrelated” or 
“unlikely to be related”, to verify their attribution and to monitor the emergence 
of a previously unrecognized treatment-related adverse event. 
 
16.6 
Study Reporting; 
 
16.61 This study will be monitored by the Mayo Clinic Data Safety Monitoring Board 
(DSMB). Reports containing patient characteristics, toxicity and administrative 
information will be provided to the DSMB every 3 or six months, with the first 
report due at the first reporting period after study initiation 
 
16.62 Results Reporting on ClinicalTrials.gov: At study activation, this study will have 
been registered within the “ClincialTrails.gov” web site. The Primary and 
Secondary Endpoints (i.e., “Outcome Measures”) along with other required 
information for this study will be reported on ClinicalTrials.gov. 
 
16.7 
Minorities Distributions (sex, race, ethnicity): 
 
This study will be available to all eligible patients, regardless of race, gender, or ethnic 
origin. 
 
There is no information currently available regarding differential effects of this regimen 
in subsets defined by race, gender, or ethnicity, and there is no reason to expect such 
differences to exist. Therefore, although the planned analysis will, as always, look for 
differences in treatment effect based on racial and gender groupings, the sample size is 
not increased in order to provide additional power for subset analyses. 
 
We expect about 8% of patients will be classified as minorities by race and about 40% of 
patients will be women. Expected sizes of racial by gender subsets for patients registered 
to this study are shown in the following table. 


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76 
Addendum 3 
 
 
 
 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
0 
2 
2 
Not Hispanic or Latino 
24 
34 
58 
Ethnic Category: Total of all subjects 
24 
36 
60 
Racial Category 
American Indian or Alaskan Native 
1 
1 
2 
Asian 
0 
0 
0 
Black or African American 
1 
2 
3 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
22 
33 
55 
Racial Category: Total of all subjects 
24 
36 
60 
 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
 
11BNot Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific 
Islanders in previous data collection strategies.) 
 
Black or African American – a person having origins in any of the black racial 
groups of Africa. Terms such as “Haitian” or “Negro” can be used in addition to 
“Black or African American.” 
 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 


RU021302I 
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Addendum 3 
 
 
 
17.0 Pathology Considerations/Tissue Biospecimens 
 
17.1 
Tissue Biospecimen Submission 
 
17.11 Summary Table of Tissue Biospecimens for This Protocol 
Type of tissue 
biospecimen to 
submit 
Mandatory 
or optional 
When to submit 
Reason for submission 
(background/methodology 
section) 
Where to find 
specific 
details for 
biospecimen 
submission 
Formalin-fixed 
paraffin- 
embedded (FFPE) 
tissue block with 
corresponding 
H&E (OR 15 
unstained slides 
with 
corresponding 
H&E)* 
Mandatory* ≤60 days after 
registration 
Banking (Section 17.5) 
Section 17.3 
 
17.2 
All Diagnostic Slides from Original and/or Recurrent Tissue: 
None 
17.3 
Paraffin Embedded Tissue Blocks/Slides 
 
17.31 Submit one formalin fixed paraffin-embedded (FFPE) tumor tissue block with 
largest amount of invasive tumor (at least 1 cm of tumor for cases of surgical 
resection) from original and/or recurrent) surgery or biopsy. A corresponding 
H&E slide for each submitted block must be provided. 
 
17.32 The FFPE tissue block is preferred; however, if an institution is unable to 
provide a tissue block, cut 15 five micron sections and mount on charged glass 
slides. Label the slides with ACCRU patient ID number, accession number, 
and order of sections. H&E stain every tenth slide (i.e., slides labeled 1, 11, 21, 
etc.). The remaining unstained slides will be processed as described in 17.38. For 
samples containing less than 1 square millimeter of tumor tissue, multiple 
sections should be mounted onto each slide to ensure that the appropriate amount 
of tumor tissue is available. Ideally, each slide must have a minimum of 75% 
tumor tissue on the slide to be deemed adequate for study. Do not bake, or place 
covers slips on the slides. Please do not use sticky labels on the slides. 
 
17.33 The following materials below are mandatory (unless indicated otherwise) and 
required for shipment: 
 
• Paraffin embedded tissue block with corresponding H&E slide (OR 15 
unstained slides with corresponding H&E(s)). 


RU021302I 
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Addendum 3 
 
 
 
 
• Research Tissue Specimen Submission Form 
• Surgical Pathology Report 
• Operative Report (optional) 
 
Note: Please include the ACCRU patient ID number on all materials listed 
above. 
 
17.34 The block/slides must be appropriately packed to prevent damage (e.g., slides 
should be placed in appropriate slide container) and placed in an individual 
plastic bag. Label the bag with the protocol number, ACCRU patient ID number, 
and patient initials. 
 
17.35 Tissue specimens must be shipped ≤60 days after registration. 
 
17.36 Verify that the appropriate sections of the Research Tissue Specimen Submission 
Form are completed and filled in correctly. Enter information from the Research 
Tissue Specimen Submission Form into the remote data entry system on the same 
day the specimen is submitted (see Forms Packet). 
 
17.37 Ship all block/slide tissue specimens and accompanying materials to the ACCRU 
Research Base: 
 
 
 
 
 
17.4 
Frozen Tumor tissue: 
None 
17.5 
Study Methodology and Storage Information 
 
17.51 Banking of tumor tissue, according to the patient consent permission, is for future 
research. As protocols are developed, they will be presented for ACCRU and 
IRB review and approval. (This collection is part of a general strategy of 
investigation for ACCRU colorectal cancer studies.) 
 
 
17.52 The institutional pathologist will be notified by the ACCRU Operations Office 
(Pathology Coordinator) if the block may be depleted. 
 
17.53 Blocks requested to accommodate individual patient management will be 
returned promptly upon request. 
 
17.54 Return of Genetic Testing Research Results: 
 
For this study, DNA and/or RNA specimens are only being banked and no 
specific genetic testing is being performed.  If, at any time, genetic results are 


RU021302I 
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Addendum 3 
 
 
 
obtained that may have clinical relevance, IRB review and approval will be 
sought regarding the most appropriate manner of disclosure and whether or not 
validation in a CLIA certified setting will be required. Sharing of research data 
with individual patients should only occur when data have been validated by 
multiple studies and testing has been done in CLIA-approved laboratories. 
 
18.0 
Records and Data Collection Procedures 
 
18.1 
Submission Timetable 
 
Initial Material(s) 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
On-Study Form 
≤2 weeks after registration 
Baseline Adverse Event Form 
RECIST Measurement Form-Baseline 
Research Blood Submission Form (see Section 
14.0) 
Baseline Research Tissue Submission Form (see 
Section 17.0) 
OP and Path Reports (see Section 17.0)1 
End of Active Treatment/Cancel Notification 
Form 
Submit ≤2 weeks after registration if 
withdrawal/refusal occurs prior to beginning protocol 
therapy 
1. Submit copy to the ACCRU Ops Office, Attn. QAS for RU021302I. This is in addition to the 
pathology material requirements for tissue submission (Section 17.0). 


RU021302I 
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Addendum 3 
 
 
 
 
Test Schedule Material(s) 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
At each evaluation during 
treatment 
At end of treatment 
Evaluation/Treatment Form 
X 
X 
Adverse Event Form 
X 
X 
RECIST Measurement Form1 
X 
X 
Research Blood Submission Form 
X(see Section 14.0) 
X 
End of Active Treatment/Cancel Notification 
Form 
X 
Notification Form – Grade 4 or 5 Non-AER 
Reportable Events/Hospitalization Form 
At each occurrence 
(see Section 10.0) 
ADR/AER 
At each occurrence 
(see Section 10.0) 
1.  Submit copy of documentation of response or progression to the 
 
 
 
 
Follow-up Material(s) 
CRF 
q. 3 
months 
until PD 
After 
PD q. 3 
mos. 
Death 
New Primary 
Event Monitoring Form1,2 
X 
X 
X 
At each occurrence 
1. Submit copy of documentation of response or progression to 
 
 
2. Until24mos. after the last patient was enrolled. 


RU021302I 
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Addendum 3 
 
 
19.0 
Budget 
 
19.1 
Costs charged to patient: Routine clinical care costs will be the responsibility of the 
patient and/or the patient’s insurance company. This includes costs associated with the 
administration of the study drugs. Cetuximab and irinotecan will be obtained through 
commercial suppliers. 
 
19.2 
Other budget concerns: Bevacizumab will be provided by Genentech at no charge. 
 
19.3 
Tests to be research funded: 
 
19.31 Mandatory blood samples for future research. 
 
19.32 Mandatory archival tissue samples for future research. 
 
19.4 
Each site should review the test schedule (Section 4.0), taking into account local and 
regional coverage policies to determine which items are considered standard of care 
versus research at their site. Refer to the payment synopsis for funding provided per 
accrual to cover study costs, as well as any additional invoiceables that may be allowed. 
 
20.0 
References 
 
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Adams RA, Meade AM, Seymour MT, et al. Intermittent versus continuous oxaliplatin and 
fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal 
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Advanced Colorectal Cancer Meta-Analysis Project. Modulation of fluorouracil by leucovorin in 
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American Cancer Society. Cancer Facts & Figures 2013. Atlanta: American Cancer Society; 
2013. 
 
American Joint Committee on Cancer. AJCC Cancer Staging Handbook, 7th edition. New York, 
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Arnold D, Andre T, Bennouna J, et al, J Clin Oncol; 30(suppl): abstract #3503, 2012. 
 
Bokemeyer C, Bondarenko I, Hartmann JT, et al. Efficacy according to biomarker status of 
cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: The OPUS 
study. Ann Oncol; 22(7): 1535-46, 2011. 
 
Cunningham D, Pyrhonen S, James RD, et al. Randomised trial of irinotecan plus supportive care 
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Addendum 3 
 
Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus 
irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med; 351(4): 337-45, 
2004. 
 
Di Fiore F, Van Cutsem E, Laurent-Puig P, et al. Role of KRAS mutation in predicting response, 
progression-free survival, and overall survival in irinotecan-refractory patients treatment with 
cetuximab plus irinotecan for a metastatic colorectal cancer: Analysis of 281 individual data from 
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Douilliard JY, Oliner KS, Siena S, et al. Panitumumab-FOLFOX4 treatment and RAS mutations 
in colorectal cancer. N Engl J Med; 369(11): 1023-34, 2013. 
 
Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared 
with fluorouracil alone as first-line treatment for metastatic colorectal cancer: A multicentre 
randomised trial. Lancet; 355(9209): 1041-47, 2011. 
 
Douillard JY, Siena S, Cassidy J, et al. Randomized, phase III trial of panitumumab with 
infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first- 
line treatment in patients with previously untreated metastatic colorectal cancer: The PRIME 
study. J Clin Oncol; 28(31):4697-4705, 2010. 
 
Eisenhauer EA, Therasse P, Bogaert J, et al. New response evaluation criteria in solid tumors: 
revised RECIST guideline (version 1.1). Eur J Cancer 45(2): 228-247, 2009. 
 
Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, 
fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: 
Results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol; 25(12): 1539- 
44, 2007. 
 
Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled trial of fluorouracil plus 
leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated 
metastatic colorectal cancer. J Clin Oncol; 22(1): 23-30, 2004. 
 
Hecht JR, Mitchell E, Chidiac T, et al. A randomized phase IIIB trial of chemotherapy, 
bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for 
metastatic colorectal cancer. J Clin Oncol; 27(5): 672-80, 2009. 
 
Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and 
leucovorin for metastatic colorectal cancer. N Engl J Med; 350(23): 2335-42, 2004. 
 
Jonker DJ, O’Callaghan CJ, Karapetis CS, et al. Cetuximab for the treatment of colorectal cancer. 
N Engl J Med; 357(20): 2040-48, 2007. 
 
Kindler HL, Shulman KL. Metastatic Colorectal Cancer. Curr Treat Options Oncol; 2: 459-71, 
2001. 
 
Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic factors in the 
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Saltz LB, Clarke S, Diaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based 
chemotherapy as first-line therapy in metastatic colorectal cancer: A randomized phase III study. 
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after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin 
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Tol J, Koopman M, Cats A, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic 
colorectal cancer. N Engl J Med; 360(6): 563-72, 2009. 
 
Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse 
sequence in advanced colorectal cancer: A randomized GERCOR study. J Clin Oncol; 22(2): 
229-37, 2004. 
 
Tveit KM, Guren T, Glimelius B, et al. Phase III trial of cetuximab with continuous or 
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1755-62, 2012. 
 
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