Conditions: Cancer
Keywords: cancer colorectal cancer ABT-165 FOLFIRI Bevacizumab bowel cancer metastatic colorectal cancer metastatic colorectal
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 70
Healthy volunteers: no

Brief summary:
A study to evaluate the efficacy and tolerability of ABT-165 plus FOLFIRI compared to bevacizumab plus FOLFIRI in participants with previously treated metastatic adenocarcinoma of the colon or rectum.

Detailed description:

Arms:
arm 1: ABT-165 plus FOLFIRI (irinotecan, leucovorin, fluorouracil). arm 2: Bevacizumab plus FOLFIRI (irinotecan, leucovorin, fluorouracil).

Interventions: intervention 1: Leucovorin intervention 2: Fluorouracil - bolus intervention 3: Bevacizumab intervention 4: Fluorouracil - infusion intervention 5: ABT-165 intervention 6: Irinotecan
Intervention descriptions: intervention 1: Intravenous intervention 2: Intravenous intervention 3: Intravenous intervention 4: Intravenous intervention 5: Intravenous intervention 6: Intravenous

Protocol document:
Prot_SAP_000.pdf: 
NCT03368859


  
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TABLE OF CONTENTS
1
SYNOPSIS
5
2
INTRODUCTION
8
2.1
BACKGROUND AND RATIONALE
8
2.2
BENEFITS AND RISKS TO PATIENTS
9
3
STUDY OBJECTIVES AND ENDPOINTS
10
3.1
OBJECTIVES
10
3.2
PRIMARY ENDPOINT
10
3.3
SECONDARY ENDPOINTS
10
3.4
SAFETY ENDPOINTS
11
3.5
PHARMACOKINETIC ENDPOINTS
11
3.6
BIOMARKER RESEARCH ENDPOINTS
11
4
INVESTIGATIONAL PLAN
12
4.1
OVERALL STUDY DESIGN AND PLAN
12
4.2
DISCUSSION OF STUDY DESIGN
13
5
STUDY ACTIVITIES
14
5.1
ELIGIBILITY CRITERIA
14
5.2
CONTRACEPTION RECOMMENDATIONS
19
5.3
PROHIBITED MEDICATIONS AND THERAPY
20
5.4
PRIOR AND CONCOMITANT THERAPY
20
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
21
5.6
FOLLOW-UP FOR SUBJECT WITHDRAWAL FROM STUDY
22
5.7
STUDY DRUGS
23
5.8
RANDOMIZATION/DRUG ASSIGNMENT
23
5.9
PROTOCOL DEVIATIONS
24
5.10 TUMOR ASSESSMENTS (RADIOLOGIC)
24
6
SAFETY CONSIDERATIONS
25
6.1
COMPLAINTS AND ADVERSE EVENTS
25
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6.2
TOXICITY MANAGEMENT
27
6.3
PRODUCT COMPLAINT
35
7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
35
7.1
STATISTICAL AND ANALYTICAL PLANS
35
7.2
DEFINITION FOR ANALYSIS POPULATIONS
35
7.3
STATISTICAL ANALYSES FOR EFFICACY
36
7.4
STATISTICAL ANALYSES FOR SAFETY
36
7.5
DATA MONITORING COMMITTEE (DMC)
37
8
ETHICS
37
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD (IEC/IRB)
37
8.2
ETHICAL CONDUCT OF THE STUDY
37
8.3
SUBJECT CONFIDENTIALITY
38
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
38
10 DATA QUALITY ASSURANCE
38
11 COMPLETION OF THE STUDY
38
12 REFERENCES
38
LIST OF TABLES
TABLE 1.
FOLFIRI DOSE REDUCTIONS
28
LIST OF FIGURES
FIGURE 1.
STUDY DESIGN
13
LIST OF APPENDICES
APPENDIX A.
STUDY SPECIFIC ABBREVIATIONS AND TERMS
40
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
42
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
43
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APPENDIX D.
ACTIVITY SCHEDULE
44
APPENDIX E.
PROTOCOL SUMMARY OF CHANGES
48
APPENDIX F.
OPERATIONS MANUAL
49
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2 INTRODUCTION
2.1 Background and Rationale
Why Is This Study Being Conducted
Preclinical evidence suggests that a combined blockade of delta-like ligand 4 (DLL4) and vascular 
endothelial growth factor (VEGF), resulting in a potent inhibition of DLL4 mediated Notch-1 activation 
and inhibition of VEGF-stimulated endothelial cell proliferation, could be a promising approach for the 
treatment of subjects with solid, metastatic neoplastic lesions, including metastatic colorectal cancer 
(mCRC).  Current treatment paradigms for mCRC suggest that new treatments are needed to overcome 
intrinsic and acquired resistance against existing anti-VEGF therapies.  AbbVie is developing a first-in 
class humanized recombinant DVD-Ig molecule with a dual specificity for human DLL4 and VEGF, 
ABT-165, which may address the current needs for subjects with mCRC.
ABT-165 binds with nanomolar affinities to DLL4 and VEGF, and blocks DLL4 and VEGF interaction with 
their cognate receptors; this results in potent inhibition of DLL4 mediated Notch-1 activation, and 
inhibition of VEGF-stimulated endothelial cell proliferation.  In preclinical animal studies, combined 
blockade of both DLL4 and VEGF results in increased inhibition of subcutaneous (SC) xenograft growth of 
human tumor cell lines derived from colon, breast, and glioblastoma, relative to blocking either axis 
alone.1,2  ABT-165 also induces tumor regression in vivo in combination with chemotherapy, with 
significantly better efficacy in comparison to anti-VEGF monoclonal antibody (mAb) treatment with 
cytotoxic agents.
Current standard second-line therapy for patients with mCRC includes FOLFIRI (irinotecan/fluorouracil 
[-FU]/leucovorin [Folinic Acid] with bolus and continuous infusion 5-FU).  Fluorouracil (5-FU) is 
commonly administered with leucovorin, which modulates 5-FU activity.  Irinotecan is active in 
advanced colorectal cancer (CRC) and was first approved by the Food and Drug Administration for 
patients with disease refractory to 5-FU/leucovorin.  Initial approval was based on a response rate of 
about 15% and subsequently confirmed with a randomized study demonstrating improved survival for 
patients refractory to 5-FU who were treated with irinotecan compared to best supportive care.3  Two 
combinations of irinotecan/5-FU/leucovorin were compared to 5-FU/leucovorin regimens, 1 with bolus 
5-FU/leucovorin and another with continuous infusion 5-FU.4,5  In both studies, the irinotecan-containing 
combinations conferred a survival advantage.
Three biological agents, and 1 biosimilar agent, targeting the VEGF-pathway have now been approved in 
second-line CRC in combination with FOLFIRI; bevacizumab, ziv-aflibercept, ramucirumab, and a 
bevacizumab biosimilar.  Bevacizumab (Avastin) and bevacizumab biosimilar (MVASI) are both a 
recombinant humanized version of a murine anti-human VEGF mAb that has been clinically evaluated 
both as a single agent and in combination with cytotoxic chemotherapy in multiple metastatic solid 
tumor types.  It is approved for use in the first- and second-line setting for advanced CRC in combination 
with fluorouracil-based chemotherapy.6  In a study comparing irinotecan/5-FU/leucovorin with 
irinotecan/5-FU/leucovorin plus bevacizumab in first-line mCRC, a survival advantage of more than 
4 months was observed in bevacizumab-treated patients.7  In the BICC-C Phase 3 study of irinotecan plus 
infusional, bolus, or oral fluoropyrimidines in first-line mCRC by Fuchs and colleagues, progression-free 
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survival (PFS) and overall survival (OS) were improved in bevacizumab combination versus respective 
chemotherapy only arms.8  With the addition of bevacizumab to FOLFIRI, PFS improved from 7.6 to 
11.2 months and OS from 23.1 to 28 months.8  Bevacizumab does not appear to alter the toxicity profile 
of chemotherapy, although hypertension and proteinuria are commonly seen.  Approximately 3.4% of 
patients receiving bevacizumab suffer arterial thrombotic events. 
In patients who were previously treated with FOLFOX (leucovorin/fluorouracil/oxaliplatin) and 
bevacizumab in first-line therapy, the combination of FOLFIRI/bevacizumab increased median OS from 
9.8 months to 11.2 months, an improvement of 1.4 months (Hazard Ratio [HR] = 0.81; P < 0.0062).9  
Similarly, another agent which binds to VEGF, ziv aflibercept, has been approved in second-line CRC in 
combination with FOLFIRI.10  Aflibercept improved median OS (mOS) from 12.1 months to 13.5 months 
(an improvement of 1.4 months; HR = 0.817; P < 0.0032) in patients who had been previously treated 
with oxaliplatin-based regimens in first-line therapy.11
An antibody targeting the VEGF receptor (ramucirumab) has also been approved in combination with 
FOLFIRI in second-line CRC.12  The combination of FOLFIRI and ramucirumab improved mOS from 11.7 to 
13.3 months (an improvement of 1.6 months; HR = 0.85; P = 0.023) in patients who had previously been 
treated with oxaliplatin/bevacizumab-based regimens in first-line therapy.  VEGF pathway-targeting 
agents provide a small yet statistically significant improvement in mOS but clearly agents that provide a 
greater benefit would be preferred.
Clinical Hypothesis
It is hypothesized that the combination of ABT-165 plus FOLFIRI will prolong PFS in second-line mCRC 
subjects more than the combination of bevacizumab plus FOLFIRI while demonstrating similar safety 
and tolerability.
2.2 Benefits and Risks to Patients
This study proposes to determine if subjects with second-line mCRC have improved PFS through the 
addition of ABT-165 to FOLFIRI chemotherapy compared to bevacizumab plus FOLFIRI.  Preclinical data 
demonstrate that ABT-165 potentiates the anti-tumor activity of irinotecan and in clinical studies the 
combination of ABT-165 plus FOLFIRI appeared safe and tolerable.  The current study is the first study to 
test whether subjects with CRC receiving ABT-165 have improved PFS compared to those receiving 
bevacizumab plus FOLFIRI.
Risks in this study include toxicity from the addition of ABT-165 to standard therapy.  Preliminary safety 
data from a Phase 1 study of the proposed combination suggest a toxicity profile similar to that of 
bevacizumab plus FOLFIRI with potentially higher rates of hypertension and pulmonary hypertension.  
Since gastrointestinal perforation has occurred in subjects treated with ABT-165 on both the Phase 1/1b 
study and the current Phase 2 M14-064, additional exclusion criteria have been implemented in order to 
decrease the risk of this adverse event (AE) which can occur with VEGF inhibition.  Furthermore, 
additional stopping rules based upon toxicity have been implemented.
For further details, please see the ABT-165 Investigator Brochure.13
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3 STUDY OBJECTIVES AND ENDPOINTS
3.1 Objectives
Primary
1.
To estimate the PFS of ABT-165 plus irinotecan, fluorouracil and leucovorin chemotherapy 
regimen (FOLFIRI) compared to bevacizumab plus FOLFIRI, as assessed by blinded independent 
central review, in subjects with previously treated mCRC who have received a regimen 
containing fluoropyrimidine, oxaliplatin, and bevacizumab.
Secondary
2.
To assess OS, objective response rate (ORR), safety, and tolerability of ABT-165 plus FOLFIRI 
compared to bevacizumab plus FOLFIRI.
Exploratory
1.
To evaluate predictive biomarkers for association with efficacy and safety.
2.
To correlate DLL4 expression level with response (PFS, OS, and ORR).
3.
To evaluate the pharmacodynamic effect between the 2 treatment groups to establish 
engagement of DLL-4 in the ABT-165 arm.
4.
To explore safety-exposure and efficacy-exposure relationship in the ABT-165 treatment arm.
3.2 Primary Endpoint
The primary endpoint is PFS.  PFS will be defined as the time from randomization until the 
first occurrence of radiographic progression determined by blinded independent central review or until 
death from any cause.  PFS time for a subject who does not have a PFS event will be censored at the 
time of the last tumor assessment.
3.3 Secondary Endpoints
Secondary Endpoints
1.
Overall Survival (OS):  OS is defined as the time from randomization until death from any cause.  
Duration of survival for subjects who are still alive at the time of analysis will be censored on the 
date of last contact.
2.
Objective Response Rate (ORR):  ORR will be defined as the proportion of subjects with a 
complete response (CR) or partial response (PR) as determined by blinded independent central 
review based on Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1.
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3.4 Safety Endpoints
Safety and tolerability of ABT-165 plus FOLFIRI compared to bevacizumab plus FOLFIRI will be assessed.
Safety evaluations include study drug exposure, AE monitoring, serious adverse event (SAE) monitoring, 
recording of all deaths, clinical laboratory testing, and vital sign assessments as measures of safety and 
tolerability for the entire study duration.
3.5 Pharmacokinetic Endpoints
Serum ABT-165 concentrations will be obtained at the visits as indicated in Appendix D and in Table 1 of 
the operations manual (Appendix F).  Serum concentrations of ABT-165, the presence of anti-drug 
antibodies (ADA) and, as needed, the neutralization effect of the ADA (nAb) will be determined.
Serum concentration, ADA (if applicable), and if available nAb data from this study may be combined 
with data from other studies and analyzed using population pharmacokinetic (PK) methodologies.
3.6 Biomarker Research Endpoints
Samples may be collected to conduct exploratory investigations into known and novel biomarkers.  
Some of these samples will be optional.  The types of biomarkers to be analyzed may include, but are 
not limited to, nucleic acids, proteins, lipids, or metabolites.  Several putative biomarkers of efficacy and 
response may be evaluated in this protocol with the goal of defining the relationship between 
biomarker levels and response.  This research may be exploratory in nature and the results may not be 
included with the clinical study report.  Further details regarding the biomarker research rationale and 
collection time points are listed in Appendix D and the Operations Manual (Appendix F), Section 3.5.
Blood samples collected may be used to assess the effects of ABT-165, including but not limited to 
characterization of gene mutational status or expression of genes, particularly those involved in VEGF-
and Notch-related signaling pathways.  Markers of functional drug exposure such as soluble VEGF, and 
tumor response markers such as carcinoembryonic antigen may be explored in plasma as surrogates of 
drug responsiveness.  Additional analyses may be performed as relevant and associated with response.
Examination of the plasma components of subjects on the ABT-165 clinical trials may reveal patterns of 
cell-free nucleic acids or protein/peptide concentrations that may be further evaluated in future clinical 
studies to determine any prognostic value and any correlation with clinical response.  If warranted, 
circulating tumor-derived nucleic acids may be extracted from plasma and quantitated and/or assessed 
for methylation and mutational status of genes relevant to ABT-165 mechanism of action.
Archival Tissue and Fresh Biopsy Samples
Tissue slides from biopsies may be used to assess molecular characteristics and/or expression of protein, 
nucleic acids, metabolites, and presence of stromal cells such as lymphocytes.  Additionally, these 
samples may be examined for mutations and/or methylation of nucleic acids.  Analysis of relevant 
proteins, including but not limited to DLL4 expression, cancer stem cell marker expression, and/or 
expression of DLL4 downstream pathway genes, may be performed on tumor tissue obtained from each 
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consented subject when feasible.  These analyses might reveal putative stratification and/or resistance 
markers for correlation with efficacy.  If tumor tissue and plasma are available from the same subject, 
the results of studies may be compared to assess correlation of the methodologies.
4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
The schematic of the study is shown in Figure 1.  Further details regarding study procedures are located 
in the Operations Manual (Appendix F).
This is an open-label, randomized, treatment-controlled study to evaluate the efficacy and tolerability of 
ABT-165 plus FOLFIRI compared to bevacizumab plus FOLFIRI in previously treated metastatic 
adenocarcinoma of the colon or rectum, whose primary tumor has been resected.  Subjects will be 
randomized to 1 of 2 therapy groups as follows:
a.
ABT-165 plus FOLFIRI
b.
Bevacizumab plus FOLFIRI
Randomization will be stratified according to the subjects' RAS mutation status (mutation in K-RAS or 
N-RAS exons 2 – 4, yes versus no) and tumor location (right-sided including transverse colon to splenic 
flexure versus left-sided).
For the purposes of this study, protocol therapy will be defined as ABT-165 plus FOLFIRI.  Control 
therapy will be defined as bevacizumab plus FOLFIRI.  One cycle of therapy consists of 14 days.  Subjects 
randomized to either arm will receive FOLFIRI as irinotecan, leucovorin, 5-FU bolus immediately 
followed by 5-FU infusion on Day 1 of each 14-day cycle.  At the discretion of the Investigator, the 5-FU 
bolus or continuous infusion may be reduced or eliminated depending on the subject's tolerability of 
prior treatment.  Subjects should continue to follow the dosing schedule for protocol therapy until 
disease progression or intolerable toxicity.  Subjects who are not able to tolerate the FOLFIRI portion of 
the therapy may continue on either ABT-165 or bevacizumab alone until progression or intolerable 
toxicity.  Subjects unable to tolerate ABT-165 or bevacizumab may continue on FOLFIRI or 5-FU alone 
until progression or intolerable toxicity.  Subjects who have discontinued all study therapy due to 
intolerable toxicity should continue to undergo scheduled tumor assessments until radiographic 
progression is documented.
The study population will consist of subjects with metastatic adenocarcinoma of the colon or rectum 
who have progressed during or after 1 line of prior chemotherapy for their mCRC including 
fluoropyrimidine, oxaliplatin, and bevacizumab, but not irinotecan.  See Section 5.1 for information 
regarding eligibility criteria.
Safety data will be monitored by the Sponsor and documented internally.  Throughout study conduct for 
Study M14-064, individual subject safety data and aggregate safety data will be reviewed by the Safety 
Management Team, the Therapeutic Area Medical Director and the Product Safety Team Therapeutic 
Area Physician with potential safety signals assessed by a cross functional ABT-165 Product Safety Team.  
As part of routine pharmacovigilance, individual case safety reports are reviewed per timelines for 
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regulatory reporting and aggregate safety data reviewed on a quarterly basis by the previously 
referenced AbbVie personnel.  Sites will be informed of any significant findings impacting subject safety 
as they arise.
An administrative interim analysis (AIA) for safety and efficacy will be conducted by an internal Data 
Monitoring Committee (DMC) after approximately 100 subjects are enrolled.  The purpose of the AIA is 
to enable further development activities.  
Figure 1.
Study Design
4.2 Discussion of Study Design
Choice of Control Group
The control group will receive standard of care FOLFIRI plus bevacizumab, which is approved for 
second-line CRC subjects who previously progressed on a fluoropyrimidine/oxaliplatin/bevacizumab-
regimen.
Appropriateness of Measurements
Standard statistical, clinical, and laboratory procedures will be utilized in this study.  All efficacy 
measurements in this study are standard for assessing disease activity in subjects with mCRC.  All clinical 
and laboratory procedures in this study are standard and generally accepted.  Echocardiograms (ECHO) 
will be performed for safety to monitor for potential decrease in ejection fraction or pulmonary 
hypertension.
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Suitability of Subject Population
Subjects with pathologically metastatic adenocarcinoma of the colon or rectum whose primary tumor 
has been resected who have progressed during or after treatment with a fluoropyrimidine and 
oxaliplatin based regimen with bevacizumab will be selected to participate in this study.  The proposed 
eligibility criteria are anticipated to result in a study subject population representative of second-line 
mCRC patients who receive systemic therapy according to current practice guidelines.14
Subjects with second-line mCRC will be treated with FOLFIRI and ABT-165 instead of FOLFIRI in 
combination with bevacizumab, ziv-aflibercept, or ramucirumab (approved biological agents in second 
line CRC).  The rationale for this approach is that the addition of bevacizumab, ziv-aflibercept, or 
ramucirumab provides a marginal improvement in mOS of 1.4 to 1.6 months beyond FOLFIRI alone and 
that ABT-165 through targeting both VEGF and DLL4 may provide an improved benefit compared to the 
approved biologic agents.
However, although ABT-165 can bind to both VEGF and DLL4 as demonstrated in preclinical and clinical 
studies, it is currently unknown if ABT-165 would provide less, similar or more benefit than the 
approved biological agents.  Subjects will be fully informed in the Informed Consent Form, and during 
the consenting process, of the benefit and safety risks of receiving ABT-165 in place of one of the 
approved biological agents.
Selection of Doses in the Study
The dose of ABT-165 (2.5 mg/kg) selected for this study is based on analysis of PK, pharmacodynamic, 
safety, and efficacy data from a Phase 1 dose escalation study (Study M14-006) in subjects with 
advanced solid tumors.  The dose selection is based on the monotherapy dose escalation/expansion 
(doses ranging from 1.25 – 7.5 mg/kg) and the combination of ABT-165 with FOLFIRI (ABT-165 doses 
ranging from 1.25 – 2.5 mg/kg).  Monotherapy anti-tumor efficacy was observed at the lowest dose of 
ABT-165 (1.25 mg/kg) in an ovarian cancer subject.  Monotherapy doses of ABT-165 of 3.75 mg/kg and 
above, although tolerable through the 28-day dose-limiting toxicity window, appeared to have toxicity 
i.e., gastrointestinal perforation and uncontrolled hypertension after further dosing.  ABT-165 at 2.5 
mg/kg plus FOLFIRI was tolerable through multiple cycles with some subjects experiencing stable 
disease or PR.  A dose of ABT-165 of 2.5 mg/kg given intravenously with FOLFIRI every 2 weeks is 
expected to be efficacious with an acceptable safety profile.  The starting dose of ABT-165 should be 
1.25 mg/kg for first 2 cycles if the last dose of bevacizumab is within 6 weeks of ABT-165 treatment 
initiation.  The dose of ABT-165 should then be increased to 2.5 mg/kg after 2 cycles of the 1.25 mg/kg 
dose.
Standard of care FOLFIRI and bevacizumab will be used in this study.
5 STUDY ACTIVITIES
5.1 Eligibility Criteria
Subjects must meet all of the following criteria in order to be included in the study.  Anything other than 
a positive response to the questions below will result in exclusion from study participation.
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Consent
1. Subjects must voluntarily sign and date an informed consent, approved by an Independent 
Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening 
or study-specific procedures.
Demographic and Laboratory Assessments
2. Adult male or female, at least 18 years old.
3. Laboratory values meeting the following criteria within the screening period prior to 
randomization:
•
Bone marrow:
•
Absolute Neutrophil count (ANC) ≥1,250/μL;
•
Platelets ≥ 75,000/mm3; (independent of platelet transfusions within 3 days prior to 
randomization);
•
Hemoglobin ≥ 8.0 g/dL (independent of red blood cell transfusions within 3 days prior to 
randomization).
•
Renal function:
•
Serum creatinine ≤ 1.5 × the institution's upper limit of normal (ULN) range or creatinine 
clearance ≥50 mL/min measured by 24-hour urine collection, or estimated using a 
Cockcroft-Gault calculation;
•
Proteinuria (Grade ≤ 1):  urine dipstick ≤ 1+ (or urinalysis equivalent).  If urine dipstick 
for proteinuria is ≥ 2+ (or urinalysis equivalent), subject is still eligible if a 24-hour urine 
collection has ≤ 1 gm protein.
•
Hepatic function and enzymes:
•
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × the ULN of 
institution's normal range.  Subjects with liver metastases may have an AST and ALT of ≤ 
5.0 × ULN;
•
Bilirubin:  ≤ 1.5 × the ULN of institution's normal range.
•
Coagulation function
•
International normalized ratio (INR) ≤ 1.5 × and a partial thromboplastin time (PTT or 
aPTT) ≤ 1.5 × ULN if not receiving anticoagulation therapy
4. Are willing and able to comply with procedures required in this protocol.
Disease Activity
5. Diagnosis of histologically or cytologically confirmed metastatic adenocarcinoma of the colon 
or rectum.
•
Primary tumor has been resected > 3 months prior to randomization.
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6. Subject meets the following disease activity criteria:
•
At least 1 lesion on a computed tomography (CT) scan (preferred) or magnetic resonance 
imaging (MRI) that is measurable as defined by RECIST, Version 1.1.
•
Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1.
•
Progression following treatment with 1 prior line of therapy in the metastatic setting 
•
Prior therapy in first-line setting should have included a fluoropyrimidine (fluorouracil, 
capecitabine or tegafur), oxaliplatin, and bevacizumab, but not irinotecan or any other 
systemic chemotherapy for first-line treatment of metastatic disease
•
Maintenance therapy after discontinuation of oxaliplatin is considered part of first-
line therapy 
•
Subjects who received a local health authority-approved biosimilar bevacizumab 
antibody in 1L in place of bevacizumab will be eligible
•
PFS in first-line of therapy ≥ 3 months
7. Stratification factors (primary tumor location and RAS status) are known at time of 
randomization.
•
Subject is B-RAF wild type if tested (if B-RAF status is unknown, test is not required)
8. Subject does not have known uncontrolled metastases to the central nervous system (CNS).  
Subjects with treated brain metastases that are radiographically stable (for at least 2 weeks 
after therapy) and have no evidence of cavitation or hemorrhage in the brain lesion(s), are 
eligible provided that they are asymptomatic and do not require systemic corticosteroids 
(subjects must have discontinued systemic steroids specifically for brain metastases at least 
1 week prior to randomization).
•
No history of carcinomatous meningitis or untreated active spinal cord compression.
•
No history of neurosurgical resection of CNS metastasis within 90 days prior to 
randomization.
Subject History
9. No history of Gilbert's syndrome or the following UGT1A1 genotypes if tested:  UGTA1*6/*6, 
UGT1A1*28/*28 or UGT1A1*6/*28 or any other genotype known to increase irinotecan toxicity.
10. No unresolved clinically significant toxicities from prior anticancer therapy, defined as any 
Common Terminology Criteria for Adverse Events (CTCAE) that has not resolved to Grade ≤ 1 
with the exception of peripheral neuropathy which must have resolved to Grade ≤2 and except 
where otherwise noted in the eligibility criteria.
11. No active clinically significant condition(s) that might put the subject at higher risk for anti-
angiogenic therapy: 
•
Symptomatic or persistent, uncontrolled hypertension defined as either systolic blood 
pressure ≥ 150 mmHg and/or diastolic blood pressure ≥ 90 mmHg
•
Subjects may be on up to 2 antihypertensive medications to achieve this level of control.
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•
Combination antihypertensive agents consisting of 2 different medications will be 
considered as 2 antihypertensive medications.
•
Subjects must be on stable doses of antihypertensive medications with stable blood 
pressure in the 7 days prior to randomization.
•
Prior history of clinically significant:  pulmonary hypertension, uncontrolled systemic 
hypertension or hypertensive crisis, symptomatic heart failure (Heart Association class III –
IV), cardiomyopathy, myocardial infarction, unstable/severe angina pectoris, active cardiac 
arrhythmia, coronary/peripheral artery bypass graft, aneurysm or aneurysm repair, 
angioplasty, cerebrovascular accident or transient ischemic attack within 1 year of 
randomization.
•
Left ventricular ejection fraction (LVEF) < 50%.
•
Evidence for pulmonary hypertension as defined by peak tricuspid velocity (TV) > 2.5 m/s on 
Doppler ECHO.
•
Subjects who have inadequate (unmeasurable) tricuspid regurgitation Doppler signal are 
eligible provided they do not have other evidence for pulmonary hypertension.
•
Brain natriuretic peptide (BNP) 2 × above the normal institutional range (i.e., > 200 pg/mL).
•
History of any of the following during first-line therapy with a bevacizumab-containing 
regimen:  arterial thrombotic/thromboembolic event, bowel perforation, Grade 4 
hypertension, Grade 3 proteinuria, or Grade 3 – 4 bleeding event.
•
Non-healed wound, ulcer, or bone fracture.
•
Osteonecrosis of the jaw.
•
Subject has had major surgery, open biopsy, or significant traumatic injury within 28 days 
prior to randomization or is anticipated to have a major surgical procedure during the 
course of the study.
•
Subject had minor surgical procedures, such as fine needle aspirations or core biopsies, 
within 7 days prior to randomization.
•
Subject has radiologic evidence of tumor invading or encasing a major blood vessel.
•
Subject with history of esophageal varices or bleeding peptic ulcer or erosive esophagitis or 
gastritis < 3 months prior to randomization.
•
Subject has history of significant bleeding (Grade ≥ 2) < 3 months prior to randomization.
•
Subject has history of deep venous thrombosis or pulmonary embolism < 3 months prior to 
randomization.
•
Subject may be on maintenance anticoagulation at time of randomization as long as 
they have not had clinically significant bleeding within 14 days prior to randomization.
•
Subject has used nonsteroidal anti-inflammatory agent (within 7 days prior to 
randomization) or aspirin > 325 mg/day or other agents known to irreversibly inhibit platelet 
function (within 14 days prior to randomization) or subject has a condition that requires use 
of high dose steroids or chronic nonsteroidal anti-inflammatory agent administration.
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•
Subject has high risk of gastrointestinal perforation or fistula formation in the judgment of 
the Investigator or Medical Monitor.
•
Subject with active ulcerative colitis, Crohn's disease, or inflammatory bowel disease 
< 1 year prior to randomization.
•
Subject with history of fistula or abdominal irradiation.
•
Subject with clinical (including paralyzed bowel, ileus, or mechanical obstruction) or 
radiographic evidence of partial or complete gastrointestinal obstruction < 3 months 
prior to randomization.
•
Subject with history of gastrointestinal perforation or fistula including tracheo-
esophageal fistula.
•
Subject with clinical history of diverticulitis with evidence of diverticuli by CT scan or 
colonoscopy.
•
Subject with extensive peritoneal carcinomatosis or bulky abdominal disease.
•
Subject has history of ascites requiring paracentesis < 6 months prior to randomization.
12. No history of prior malignancy except for successfully treated Non-Melanoma Skin Cancer, 
localized carcinoma in situ of the cervix, adequately treated Stage I or II cancer from which the 
subject is currently in complete remission, or any other cancer from which the subject has been 
disease free for at least 2 years.
13. No history of clinically significant (per Investigator's judgment) drug or alcohol abuse within 
the last 6 months.
14. No history of clinically significant medical conditions or any other reason that in the opinion 
of the Investigator would interfere with the subject's participation in this study or would make 
the subject an unsuitable candidate to receive study drug.
15. No history of an allergic reaction or significant sensitivity to constituents of the study drugs 
(and its excipients) and/or other products in the same class.
16. No clinically relevant or significant ECG abnormalities.
17. No history of uncontrolled hereditary or acquired bleeding or thrombotic disorders.
18. No history of prior autologous or allogeneic organ or transplantation.
19. No history of active infection requiring parenteral antibiotic, antifungal, or antiviral therapy.
20. No ongoing treatment for active Hepatitis B virus (prophylaxis allowed) or Hepatitis C virus
•
Subject with documented cure after anti-viral therapy may be enrolled.
21. No known human immunodeficiency virus infection or acquired immunodeficiency 
syndrome-related illness.
22. No history of cirrhosis at a level of Child-Pugh B (or worse); or cirrhosis (any degree) and a 
history of hepatic encephalopathy or clinically meaningful ascites resulting from the cirrhosis 
and requiring ongoing treatment with diuretics and/or paracentesis
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Contraception
23. A negative serum pregnancy test for all female subjects (except post-menopausal) at the 
Screening Visit and a negative urine pregnancy test for all female subjects (except post-
menopausal) at baseline prior to the first dose of study drug.
24. If female, subject must be either postmenopausal, OR permanently surgically sterile OR for 
women of childbearing potential (WOCBP) practicing at least 1 protocol-specified method of 
birth control, that is effective from Study Day 1 through at least 6 months after the last dose of 
study drug.
25. If male, and subject is sexually active with female partner(s) of childbearing potential, he 
must agree, from Study Day 1 through 6 months after the last dose of study drug, to practice the 
protocol-specified contraception.
26. Female who is not pregnant, breastfeeding, or considering becoming pregnant during the 
study or for approximately 6 months after the last dose of study drug.
27. Male who is not considering fathering a child or donating sperm during the study or for 
approximately 6 months after the last dose of study drug.
Concomitant Medications
28. Subject must have discontinued prior anticancer therapy at least 21 days prior to 
randomization, with resolution of any toxicity from prior therapy.
•
Palliative radiation therapy for bone or skin metastases or subcutaneous metastatic nodules 
for 10 fractions or less is not subject to a washout period.
29. Subject must not currently be enrolled in another therapeutic clinical study.
30. Subject must not have been treated with any agent known to target DLL4.
31. Subject must not have received any live vaccine within 4 weeks prior to randomization, or 
expected need of live vaccination during study participation including at least 4 weeks after the 
last dose of study drug.
•
Subject may not get inactivated vaccines within a 3-day window of receiving study drug.
5.2 Contraception Recommendations
Contraception Requirements for Females
Postmenopausal is defined as:
•
Age > 55 years with no menses for 12 or more months without an alternative medical cause.
•
Age ≤ 55 years with no menses for 12 or more months without an alternative medical cause 
AND a follicle-stimulating hormone level > 40 IU/L.
If female, subject must be either post-menopausal, permanently surgically sterile (bilateral 
oophorectomy, bilateral salpingectomy or hysterectomy) or a WOCBP and must practice at least 1 of the 
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following methods of birth control, throughout the study including 6 months after the last study drug 
dose is given.
•
Combined (estrogen and progestogen containing) hormonal birth control (oral, intravaginal, 
transdermal) associated with inhibition of ovulation initiated at least 1 month prior to study 
Baseline Day 1.
•
Progestogen-only hormonal birth control (oral, injectable, implantable) associated with 
inhibition of ovulation initiated at least 1 month prior to study Baseline Day 1.
•
Bilateral tubal occlusion/ligation.
•
Intrauterine device (IUD).
•
Intrauterine hormone-releasing system (IUS).
•
Vasectomized sexual partner(s) (the vasectomized partner(s) provided the vasectomized partner 
has received medical assessment of the surgical success and is the sole sexual partner of the 
trial participant).
•
True abstinence:  Refraining from heterosexual intercourse when this is in line with the 
preferred and usual lifestyle of the subject (periodic abstinence [e.g., calendar, ovulation, 
symptothermal, post-ovulation methods] and withdrawal are not acceptable).
Contraception Requirements for Males
Male subjects who are sexually active with a WOCBP, even if the male subject has undergone a 
successful vasectomy, must agree from Study Day 1 through at least 6 months after the last dose of 
study drug to use condoms and his female partner(s) must use at least 1 of the contraceptive measures 
(as defined above for female study subjects of childbearing potential).
5.3 Prohibited Medications and Therapy
During the study any anti-cancer agents, anti-cancer medicinal/herbal remedies, anti-cancer hormonal 
therapy, and other investigational drugs are prohibited.  Cannabinoids are not prohibited for treating 
pain, nausea, anorexia, etc.
Palliative radiation therapy for bone or skin metastases or subcutaneous metastatic nodules for 
10 fractions or less is allowed if the subject is otherwise stable.
Subjects should not receive live vaccines during the study.
5.4 Prior and Concomitant Therapy
Non-steroidal anti-inflammatory drugs such as ibuprofen are allowed but preferably after end of Cycle 1 
and at lowest doses that are needed to achieve desired results.  Use of salicylates such as acetylsalicylic 
acid (Aspirin) > 325 mg/day is discouraged and should be avoided.
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All subjects should be highly encouraged to have excellent bowel care consisting of high fiber diet or 
supplemental fiber and/or stool softeners with adequate oral hydration to reduce diverticulitis or 
constipation.
Any medication or vaccine (including over the counter or prescription medicines, vitamins and/or herbal 
supplements) that the subject is receiving at the time of enrollment or receives during the study must be 
recorded.
Any questions regarding concomitant or prior therapy should be raised to the AbbVie Medical Monitor 
(SPONSOR/Emergency Medical Contact).
Subjects must be able to safely discontinue any prohibited medications 5 half-lives or 2 weeks prior to 
randomization, whichever is longer.  Subjects must be consented for the study prior to discontinuing any 
prohibited medications for the purpose of meeting study eligibility.
5.5 Withdrawal of Subjects and Discontinuation of Study
A subject will be withdrawn from ABT-165/bevacizumab and FOLFIRI treatment at any time for reasons 
including, but not limited to, the following:  
•
The subject experiences radiographic disease progression (as defined by RECIST version 1.1).
•
The subject's response to therapy is unsatisfactory, as evidenced by clinically significant and 
clearly documented progression of disease.
•
The subject requires alternate anti-cancer agents during the study period.
•
Clinically significant abnormal laboratory results or AEs, which rule out continuation of study 
drug(s), as determined by the Investigator or the AbbVie Medical Monitor.
•
The Investigator believes it is in the best interest of the subject.
•
The subject requests withdrawal from the study.
•
Eligibility criteria violation was noted after the subject started study drug and continuation of 
the study drugs would place the subject at risk.
•
Introduction of prohibited medications or dosages and continuation of the study drugs would 
place the subject at risk.
•
The subject becomes pregnant while on study drugs.
•
Subject is significantly non-compliant with study procedures which would put the subject at risk 
for continued participation in the trial.
ABT-165/bevacizumab will be permanently discontinued if any of the following AEs occur but subject 
may remain on FOLFIRI and on study until radiographic progression after resolution of toxicity as 
deemed appropriate by the Investigator:
•
Gastrointestinal perforation or fistula formation involving an internal organ.
•
Serious (Grade ≥ 3) hemorrhage.
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•
Arterial thromboembolic events (e.g., myocardial or cerebral infarction) of any grade.
•
Documented blood pressure in triplicate of systolic ≥ 180 or diastolic ≥ 110 mmHg (either 
systolic or diastolic exceeded on all 3 readings).
•
Hypertensive crisis or hypertensive encephalopathy.
•
Reversible posterior leukoencephalopathy syndrome (RPLS).
•
Nephrotic syndrome (Grade 3 proteinuria).
•
Grade 4 infusion-related reaction (IRR).
•
Necrotizing fasciitis.
•
Class III or IV heart failure (including Grade ≥ 2 congestive heart failure).
•
Acute coronary syndrome (including cardiac ischemia).
•
Drop in LVEF to < 40% or an LVEF of 40% – 45% with a 10% or greater absolute decrease below 
pretreatment values.
•
Pulmonary hypertension Grade 3 or 4
For subjects to be considered lost to follow-up, reasonable attempts must be made to obtain 
information on the final status of the subject.  At a minimum, 2 telephone calls must be made and 
1 certified letter must be sent and documented in the subject's source documentation.
AbbVie may terminate this study prematurely, either in its entirety or at any site.  If AbbVie terminates 
the study for safety reasons, AbbVie will promptly notify the Investigator.  The Investigator may also 
stop the study at his/her site if he/she has safety concerns.
In the event AbbVie is notified in writing that a subject withdraws consent to participate in the clinical 
study, and no longer consent to the biomarker research and/or the optional biomarker research, no new 
biomarker data will be collected for the withdrawn subject or added to the existing data or database(s).  
A subject may withdraw consent for optional biomarker research at any time and remain in the clinical 
study.  Data generated from mandatory and/or optional biomarker research collected before subject 
withdrawal of consent will remain part of the study results.
5.6 Follow-Up for Subject Withdrawal from Study
To minimize missing data for efficacy and safety assessments, subjects who prematurely discontinue 
study treatment but have not progressed radiographically, should continue to be followed by imaging 
until progression, unless subjects have decided to discontinue study participation entirely (withdrawal of 
informed consent).  Subjects should be advised on the continued scientific importance of their data even 
if they discontinue study treatment early.
If a subject prematurely discontinues study participation (withdrawal of informed consent), the 
procedures outlined for the Premature Discontinuation visit (PD visit) should be completed as soon as 
possible, preferably within 2 weeks.  In addition, if subject is willing, a 30/90-day follow-up phone call 
after the last dose of study drug may be completed to ensure all treatment-emergent AEs/SAEs have 
been resolved, unless another anti-cancer therapy is started in the interim.
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All attempts must be made to determine the primary reason for discontinuation of study drug or study 
participation.  The information will be recorded on the appropriate electronic case report form (eCRF) 
page.
5.7 Study Drugs
ABT-165 (2.5 mg/kg or 1.25 mg/kg for the first 2 cycles, see below) plus FOLFIRI (irinotecan –
180 mg/m2; leucovorin (folinic acid) – DL-400 mg/m2 or L-200 mg/m2; fluorouracil – bolus:  400 mg/m2, 
then continuous infusion:  1200 mg/m2/day × 2 days - total of 2400 mg/m2 over 46 – 48 hours) or 
bevacizumab (5 mg/kg) plus FOLFIRI will be administered via intravenous (IV) infusion on Day 1 of each 
14-day cycle.  The Investigator may adjust the suggested FOLFIRI dosing based on Institutional guidelines 
and best medical practice.  The first infusion of ABT-165 or bevacizumab will be administered over 
60 (± 10) minutes.  If the first infusion is tolerated, the second and subsequent infusions will be 
administered over 30 (± 10) minutes as tolerated.  For those subjects who required a 90 minute (or 
longer) infusion of bevacizumab in the first-line setting, the first infusion of ABT-165 or bevacizumab will 
be administered over 90 (± 10) minutes and may be decreased to 60 (± 10) minutes and 
30 (± 10) minutes as tolerated.
The dose of ABT-165/bevacizumab does not need to be adjusted unless the subject's measured weight 
changes by > 10% from baseline or the subject has received bevacizumab within 6 weeks of the first 
dose of ABT-165.  The starting dose of ABT-165 should be 1.25 mg/kg for first 2 cycles if the last dose of 
bevacizumab was within 6 weeks of ABT-165 treatment initiation.  The dose of ABT-165 should then be 
increased to 2.5 mg/kg after 2 cycles of the 1.25 mg/kg dose.
Dosing of bevacizumab may follow site's standard of care guidelines.
ABT-165 will be provided as lyophilized powder and bevacizumab may be provided as solution for IV 
injection.  ABT-165, bevacizumab, and FOLFIRI treatment will be open to investigators and subjects.
Each kit will be labeled per local requirements and this label must remain affixed to the kit.  Upon 
receipt, study drug should be stored as specified on the label and kept in a secure location.  Each kit will 
contain a unique kit number.  This kit number is assigned to a subject via interactive response 
technology (IRT) and encodes the appropriate study drug to be dispensed at the subject's corresponding 
study visit.  Study drug will only be used for the conduct of this study.
Instructions for drug preparation will be provided by AbbVie.
AbbVie will not routinely supply drugs other than ABT-165.  AbbVie may provide Bevacizumab and 
FOLFIRI at some sites depending on operational or regulatory requirements.  Non-investigational 
medicinal product (standard of care) must be obtained commercially.  
5.8 Randomization/Drug Assignment
All subjects will be assigned a unique identification number by the IRT at the screening visit.  For 
subjects who rescreen, the screening number assigned by the IRT at the initial screening visit should be 
used.  The IRT will assign a randomization number that will encode the subject's treatment group 
assignment according to the randomization schedule generated by the statistics department at AbbVie.
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Subjects will be randomized in a 1:1 ratio to ABT-165 plus FOLFIRI or to bevacizumab plus FOLFIRI.  
Randomization will be stratified by subjects' RAS status (mutation in K-RAS or N-RAS yes vs no) and 
tumor location (right-sided vs left-sided).  Permuted block randomization method will be used to 
allocate treatments.  The stratification factors used for the randomization should be the last values on 
or prior to the date of randomization and should be consistent with those on the eCRF.
5.9 Protocol Deviations
The Investigator is responsible for complying with all protocol requirements, written instructions, and 
applicable laws regarding protocol deviations.  Protocol deviations are prohibited except when 
necessary to eliminate an immediate hazard to study subjects.  If a protocol deviation occurs (or is 
identified), the Investigator is responsible for notifying IEC/ IRB, regulatory authorities (as applicable) 
and AbbVie.
5.10 Tumor Assessments (Radiologic)
A CT scan of all areas of metastatic disease (including the chest, abdomen, and pelvis) using RECIST, 
Version 1.1 will be used in the evaluation of tumor responses.  If the subject is unable to undergo a CT 
scan with IV contrast due to allergy or renal insufficiency, a non-contrast CT may be performed.  
Magnetic resonance imaging (MRI) can be conducted instead of CT scans in cases where local 
laws/requirements mandate or when an MRI would be a better tool for tumor assessments.  Subjects 
are to continue monitoring by the same methods unless evidence of tumor metastasis warrants 
otherwise or a medical contraindication is noted.
Baseline tumor assessments must be conducted at Screening within 28 days before randomization.  
Post-baseline tumor assessment will be conducted approximately every 8 weeks from Cycle 1 Day 1 
(C1D1) until radiographic progression.  Scheduled tumor assessments will not be affected by delays in 
therapy and/or drug holidays.  Scheduled tumor assessments should be performed prior to the 
administration of study drug.  Tumor assessments should be performed every 8 weeks until a subject 
has evidence for radiographic progression.  An unscheduled tumor assessment should be performed if 
the subject discontinues from the study for a reason other than radiographic progression (including 
clinical progression), and no scan has been performed within the last 28 days.
Response criteria will be assessed using RECIST, Version 1.1.  Disease progression will be defined as 
radiographic progression of disease by RECIST, Version 1.1.  (Appendix B of the Operations Manual 
(Appendix F)), or clinical progression as determined by the Investigator (in which case every reasonable 
effort must be made to document radiographic progression).
For the purposes of this protocol, complete or PR do not need to be confirmed on a subsequent scan 
following initial documentation of the response.
AbbVie will require that sites electronically transfer copies of all CT or MRI scans used for radiographic 
tumor assessments.  Instructions regarding procedures for transferring scans will be provided in a 
separate manual.
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6 SAFETY CONSIDERATIONS
6.1 Complaints and Adverse Events
Complaints
A complaint is any written, electronic, or oral communication that alleges deficiencies related to the 
physical characteristics, identity, quality, purity, potency, durability, reliability, safety, effectiveness, or 
performance of a product/device.  Complaints associated with any component of this investigational 
product must be reported to AbbVie.
Medical Complaints/Adverse Events and Serious Adverse Events
An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment.  An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not the event is considered causally related to the use of the 
product.
The investigators will monitor each subject for clinical and laboratory evidence of AEs on a routine basis 
throughout the study.  All AEs will be followed to a satisfactory conclusion.
The following standard SAE supplemental case report forms will be available and are to be used as 
applicable:  Investigator SAE Supplemental, SAE Study Drug Information, SAE Supplemental Laboratory, 
SAE Supplemental Microbiology, and SAE Supplemental Procedure.
If an AE meets any of the following criteria, it is to be reported to AbbVie as a SAE within 24 hours of the 
site being made aware of the SAE:
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not been 
taken.  This does not include an event that would have been fatal if it 
had occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any length 
of time or prolongs the subject's hospital stay.  This does not include 
an emergency room visit or admission to an outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that results in 
fetal loss.
Persistent or Significant 
Disability/Incapacity
An event that results in a condition that substantially interferes with 
the activities of daily living of a study subject.  Disability is not 
intended to include experiences of relatively minor medical
significance such as headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle).
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Important Medical Event 
Requiring Medical or Surgical 
Intervention to Prevent 
Serious Outcome
An important medical event that may not be immediately life-
threatening or result in death or hospitalization, but based on 
medical judgment may jeopardize the subject and may require 
medical or surgical intervention to prevent any of the outcomes 
listed above (i.e., death of subject, life threatening, hospitalization, 
prolongation of hospitalization, congenital anomaly, or persistent or 
significant disability/incapacity).  Additionally, any elective or 
spontaneous abortion or stillbirth is considered an important 
medical event.  Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or 
drug abuse.
All adverse events reported from the time of study drug administration until 90 days after 
discontinuation of study treatment will be collected, whether solicited or spontaneously reported by the 
subject.  In addition, protocol-related serious adverse events and nonserious adverse events will be 
collected from the time the subject signs the study-specific informed consent.
AbbVie will be responsible for Suspected Unexpected Serious Adverse Reactions (SUSAR) reporting for 
the Investigational Medicinal Product (IMP) in accordance with global and local guidelines.
Adverse Events of Special Interest
The following AEs of special interest will be monitored during the study:
•
Uncontrolled hypertension:  Grade 4
•
Gastrointestinal perforation:  any Grade
•
Pulmonary hypertension:  ≥ Grade 2
•
Proteinuria:  Grade 3 (nephrotic syndrome)
Adverse Event Severity and Relationship to Study Drug
The investigators will rate the severity of each AE as mild, moderate or severe according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03.  If a reported AE 
increases in severity, the initial AE should be given an outcome date and a new AE must be reported on 
a different onset date than the end date of the previous AE to reflect the change in severity.  The dates 
on the AEs cannot overlap.  For all reported SAEs that increase in severity, the supplemental eCRFs also 
need to be updated to reflect any changes due to the increase in severity.  The investigator will use the 
following definitions to assess the relationship of the AE to the use of study drug:
Reasonable Possibility – After consideration of factors including timing of the event, biologic plausibility, 
clinical judgment, and potential alternative causes, there is sufficient evidence (information) to suggest 
a causal relationship.
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No Reasonable Possibility – After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is insufficient evidence 
(information) to suggest a causal relationship.
Pregnancy
While not an AE, pregnancy in a study subject or in the partner of a study subject must be reported to 
AbbVie within 1 working day of the site becoming aware of the pregnancy.  If a pregnancy occurs in a 
study subject or in the partner of a study subject, information regarding the pregnancy and the outcome 
will be collected.  In the event of pregnancy occurring in a subject's partner during the study, written 
informed consent from the partner must be obtained prior to collection of any such information.  A 
separate consent will be provided by AbbVie for this purpose.  Pregnancies in study subject's partners 
will be collected from the date of the first dose through 6 months following the last dose of study drug.
The medical outcome for either mother or infant, meeting any serious criteria including an elective or 
spontaneous abortion, is considered a SAE and must be reported to AbbVie within 24 hours of the site 
becoming aware of the event.
6.2 Toxicity Management
The management of specific AEs and laboratory parameters is described below.  This includes, but is not 
limited to, AEs of uncontrolled hypertension, gastrointestinal perforation, and pulmonary hypertension.  
This also includes the following laboratory abnormality:  proteinuria.
For observed toxicities, subjects should be assessed for inter-current illness or other causes and treated 
as appropriate.  While Investigator discretion and best medical practice should be used for subject 
management with regards to toxicities, some suggested guidelines are given below and in the sections 
referenced.
General Considerations for Toxicity Management
If a subject experiences AEs during a cycle, the subject will complete the planned activities of the cycle 
as scheduled per the Treatment Period Visit Activities Tables (Section 2.1 of the Operations Manual) 
(i.e., vital signs, labs, radiographic tumor assessment, etc.) before resuming protocol therapy.
If a dose interruption is needed, the subject will continue to have study visits as planned; however, 
pharmacodynamics and/or PK samples will not be collected during this period.  Dose interruptions for 
events that are clearly not related to the protocol therapy (e.g., underlying cancer, planned surgical 
procedures, or acute viral illnesses) should not necessitate a dose reduction for FOLFIRI.  The timing of 
dose resumption should be at the discretion of the Investigator; pharmacodynamics and/or PK sample 
collection should restart as indicated once subjects have resumed dosing.
Best supportive care and treatment will be given as appropriate to each subject e.g., antiemetics, 
antibiotics, transfusions, oxygen therapy, nutritional support, palliative treatment for pain or cough, 
drugs for prevention of skeletal-related events or osteoporosis.  A new cycle of chemotherapy treatment 
in general may not begin until the ANC is ≥ 1,250/mm3, the platelet count is ≥75,000/mm3, and any 
treatment-related gastrointestinal toxicity has resolved to ≤ Grade 1.  For subjects whose blood counts 
do not meet the above standards, the Investigator may use their judgment and clinical best practice 
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standards to determine if it is in the best interest of the subject to continue dosing FOLFIRI, potentially 
at a reduced dose, or hold FOLFIRI until recovery of blood counts.  If the initiation of a new cycle is 
delayed for > 4 weeks, Investigators should contact the Study Designated Physician regarding ongoing 
clinical benefit prior to resumption of protocol therapy.
ABT-165/bevacizumab can be given with FOLFIRI or irinotecan or 5-FU/LV.  ABT-165/bevacizumab can 
be continued even after discontinuation of FOLFIRI.  FOLFIRI or irinotecan or 5-FU/LV can be continued 
even if ABT-165/bevacizumab is discontinued.  No dose reductions of ABT-165/bevacizumab are 
allowed.  General guidance for dose reduction of FOLFIRI is given below; however, Investigators should 
use their judgment and are allowed to follow best medical practice and Institutional standards.
Dose Reductions and Delays for FOLFIRI Toxicity
Dose modification for the current cycle and reduction for subsequent cycles may be carried out as 
shown below (Table 1).  Dose adjustments of irinotecan and 5-FU infusion may be made independently 
based on the specific types of toxicities observed as discussed below.  For the purposes of this study, 
only 3 dose reductions of FOLFIRI are allowed.  If a dose reduction is required beyond dose level –3 for 
irinotecan, discontinue irinotecan use, but continue ABT-165/bevacizumab, 5-FU and leucovorin.  If a 
dose reduction is required beyond dose level –3 for 5-FU, discontinue 5-FU but ABT-165/bevacizumab 
may continue until disease progression or intolerable toxicity.
Note:  The 5-FU bolus can only be skipped or discontinued.
Table 1.
FOLFIRI Dose Reductions
Drug*
Starting Dose
Dose Level –1
Dose Level –2
Dose Level –3
Irinotecan 
180 mg/m2
150 mg/m2
120 mg/m2
100 mg/m2
5-FU Infusion
2400 mg/m2
1920 mg/m2
1600 mg/m2
1360 mg/m2
5-FU Bolus
400 mg/m2
Discontinued
Discontinued
Discontinued
*
Leucovorin (LV) may be administered as DL- 400 mg/m2 or L-200 mg/m2 IV prior to the 5-FU infusion.  However, LV may 
also be administered or omitted per Institutional standards.  If an infusion of 5-FU needs to be skipped, leucovorin must 
also be skipped.
Toxicity Management Guidelines for Protocol Therapy
In addition to AEs of special interest, uncontrolled hypertension, gastrointestinal perforation, pulmonary 
hypertension, and proteinuria, the following AEs are addressed in this section:  hematologic toxicities, 
gastrointestinal toxicities, pulmonary toxicities, cardiovascular toxicities, posterior reversible 
leukoencephalopathy syndrome (RPLS/PRES), wound dehiscence, gastrointestinal perforation, 
intra-abdominal fistula, hypersensitivity, and infusion reactions.
Hematologic Toxicities:
No ABT-165/bevacizumab dose modifications will be made for hematologic toxicity.  Subjects may 
receive ABT-165/bevacizumab while 5-FU infusion and irinotecan are suspended for resolution of 
hematologic toxicity unless they have febrile neutropenia (see below).
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The following dose modifications are recommended for the next treatment cycle based on unresolved 
toxicity experienced during a previous cycle (i.e., after Day 1 of any cycle):
•
Grade 2 neutropenia or thrombocytopenia, discontinue 5-FU bolus.  Reduce 5-FU infusion and 
irinotecan 1 dose level for the next cycle.  For each subsequent cycle, may resume 5-FU infusion 
and irinotecan at the previous dose levels, provided ANC ≥ 1,250/μL and platelets 
≥75,000/mm3.
•
Grade 3 or 4 neutropenia or thrombocytopenia, suspend chemotherapy (FOLFIRI).  If counts 
recover to ANC ≥ 1,250/μL and platelets ≥ 75,000/mm3 within 4 weeks, resume protocol therapy 
with dose reductions as follows:  discontinue 5-FU bolus and continue 5-FU infusion and 
irinotecan at 1 lower dose level.
•
Febrile neutropenia (defined as ANC < 1000/μL and T ≥ 38.5°C), suspend all protocol therapy.  If 
fever resolves, and counts recover to ANC ≥ 1,250/μL and platelets ≥ 75,000/mm3 within 
4 weeks, resume protocol therapy with dose reductions as follows:  discontinue 5-FU bolus and 
continue 5-FU infusion and irinotecan at 1 lower dose level.
Gastrointestinal Toxicities:
Gastrointestinal Perforation or Intra-Abdominal Fistula:  For any grade gastrointestinal perforation, or 
intra-abdominal fistula:  Discontinue ABT-165/bevacizumab.
Diarrhea:  Lacrimation, rhinorrhea, miosis, diaphoresis, hot flashes, flushing, abdominal cramping, 
diarrhea, or other symptoms of early cholinergic syndrome may occur during or shortly after receiving 
irinotecan.  It is strongly suggested that Atropine, 0.25 – 1.0 mg IV or SC be used at the time of 
irinotecan administration to prevent these symptoms.  Additional antidiarrheal measures may be used 
at the discretion of the Investigator.  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 more than 24 hours after irinotecan) should be managed with 
loperamide as described below.
The following concomitant medications and/or dose modifications are based on toxicity experienced 
during a cycle (i.e., after Day 1 of any cycle):
Oral fluoroquinolone treatment should be initiated for any of the following:
•
Diarrhea persisting for more than 24 hours despite loperamide.
•
ANC < 500/μL (even in the absence of diarrhea or fever).
•
Fever with diarrhea (even in the absence of neutropenia).
•
Antibiotic therapy should also be initiated in patients who are hospitalized with prolonged 
diarrhea (even in the absence of neutropenia).
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•
For Grade 2 diarrhea, discontinue 5-FU bolus.  Reduce 5-FU infusion and irinotecan 1 dose level 
for the next cycle.  For each subsequent cycle, resume 5-FU infusion and irinotecan at the 
previous dose levels, provided diarrhea has fully resolved.
•
For Grade 3 or 4 diarrhea, suspend all protocol therapy.  If diarrhea resolves to ≤ Grade 2 within 
4 weeks, resume protocol therapy with dose reductions as follows:  discontinue 5-FU bolus and 
continue 5-FU infusion and irinotecan at 1 lower dose level.
For symptoms of diarrhea and/or abdominal cramping that occur at any time during a treatment cycle 
with irinotecan, subjects will be instructed to begin taking loperamide.  Loperamide should be started at 
the earliest sign of 1) a poorly formed or loose stool or 2) the occurrence of 1 to 2 more bowel 
movements than usual in 1 day or 3) an increase in stool volume or liquidity.  Loperamide should be 
taken in the following manner:  4 mg at the first onset of diarrhea, then 2 mg every 2 hours around the 
clock until diarrhea-free for at least 12 hours.  Subjects may take loperamide 4 mg every 4 hours during 
the night.  The maximum daily dose of loperamide is 16 mg/day.  Subjects should be provided with 
loperamide at the initial treatment visit so that they have sufficient supply on hand in case antidiarrheal 
support is required.  Additional antidiarrheal measures may be used at the discretion of the Investigator.  
Subjects should be instructed to increase fluid intake to help maintain fluid and electrolyte balance 
during episodes of diarrhea.
Mucositis:  The following dose modifications are based on the grade of mucositis seen on the day of 
treatment for any day after Day 1 in any cycle.
•
For Grade 2 mucositis, may discontinue 5-FU bolus.  Reduce 5-FU infusion and irinotecan 1 dose 
level for the next cycle.  For each subsequent cycle, may resume 5-FU infusion and irinotecan at 
the previous dose levels, provided mucositis has fully resolved.
•
For Grade 3 or 4 mucositis, suspend all protocol therapy.  If mucositis resolves to ≤ Grade 2 
within 4 weeks, resume protocol therapy with dose reductions as follows:  discontinue 5-FU 
bolus and continue 5-FU infusion and irinotecan at 1 lower dose level.
Nausea/Vomiting:  The following dose modifications are based on the grade of nausea and vomiting 
occurring during a cycle (i.e., after Day 1 in any cycle).
•
For Grade 3 nausea or vomiting, reduce irinotecan 1 dose level for the next cycle.  For each 
subsequent cycle, may continue irinotecan at previous dose level, provided nausea has resolved 
≤ Grade 2.
•
For Grade 4 nausea or vomiting, discontinue 5-FU bolus and continue 5-FU infusion and 
irinotecan at 1 lower dose level.  These dose reductions for vomiting and/or nausea should be 
made only if they persist/occur despite 2 treatments with adequate (combination) antiemetic 
therapy.  The use of aprepitant is prohibited for those patients receiving FOLFIRI.
Pulmonary Toxicities
•
For ≥ Grade 3 cough, dyspnea, hypoxia, pneumonitis, or pulmonary infiltrates, hold 
ABT-165/bevacizumab and irinotecan until interstitial lung disease is ruled out.  5-FU/leucovorin 
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may be continued based on Investigator judgment.  Discontinue all protocol therapy if 
interstitial lung disease is confirmed.
Dose Delays and Discontinuation for ABT-165/Bevacizumab Toxicity
ABT-165 is always administered at 2.5 mg/kg IV.  ABT-165 may be delayed or discontinued, but the dose 
will not be reduced.
Bevacizumab is always administered at 5 mg/kg IV.  Bevacizumab may be delayed or discontinued, but 
the dose will not be reduced.
For certain toxicities described in the Protocol, ABT-165/bevacizumab will be permanently discontinued 
but subject may remain on FOLFIRI after resolution of toxicity if deemed appropriate by the Investigator.
Pulmonary Hypertension
Subjects with TV of ≥ 3.7 m/s on ECHO must have ABT-165/bevacizumab held.  FOLFIRI dosing may 
continue as tolerated.  A repeat ECHO should be performed every month.  When the TV is ≤ 3.0, dosing 
with ABT-165/bevacizumab may resume with monthly ECHO.  If repeat ECHO shows TV ≥ 3.7, ABT-
165/bevacizumab must be permanently discontinued.
Cardiovascular Toxicities:
Hypertension
The following general guidance is given for Investigators to maintain the majority of blood pressures 
< 150/90 mmHg with the use of antihypertensive medications, dose delays and discontinuation of 
ABT-165/bevacizumab.  In general, antihypertensive therapy should be started or intensified as soon as 
blood pressure is ≥ 150/90 mmHg or systolic blood pressure has increased by 20 mmHg and should be 
titrated promptly to maximum approved doses.  The Principal Investigator may consult with or refer the 
subject to physicians trained in the management of hypertension.  Subjects who have difficulty to 
control hypertension (for example multiple blood pressure readings ≥ 160/100 mmHg) should be 
discussed with the Medical Monitor. Subjects may receive up to 4 different antihypertensive 
medications at any 1 time to control hypertension.
Subjects requiring more than 4 different antihypertensive medications to maintain the majority of their 
blood pressures < 150/90 mmHg will have their dose of ABT-165/bevacizumab held and may be 
resumed once blood pressures is < 150/90 mmHg on the day of dosing and they are on 4 or fewer 
antihypertensive agents.
The preferred usage of antihypertensive medication is as follows:
•
Calcium channel blocker (dihydropyridines)
•
Angiotensin receptor blocker or Angiotensin-converting enzyme (ACE) inhibitor (but not used 
simultaneously)
•
Beta adrenergic blocker (not to be used in subjects with heart rate ≤ 50)
•
Centrally acting sympathetic agonist (i.e., clonidine)
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•
Diuretic
The Investigator should use best medical practice in treating hypertension given the general guidance 
above.
Thrombotic Events
Subjects should be carefully monitored for evidence of thromboembolic disease during treatment.
Venous Thrombotic Events
•
For Grade 3 venous thrombosis or asymptomatic pulmonary embolism:  Skip 
ABT-165/bevacizumab.  If the planned duration of full-dose anticoagulation is < 2 weeks, 
ABT-165/bevacizumab should be held until the full-dose anticoagulation period is over.  If the
planned duration of full-dose anticoagulation is > 2 weeks, ABT-165/bevacizumab may be 
resumed during the period of full-dose anticoagulation if all of the following criteria are met:
•
The patient must have an in-range INR (usually between 2 and 3) on a stable dose of 
warfarin or be on stable dose of low molecular weight heparin prior to restarting ABT-
165/bevacizumab treatment;
•
The patient must not have pathological conditions that carry high risk of bleeding 
(e.g., tumor involving major vessels);
•
The patient must not have had hemorrhagic events (Grade ≥3) while on study.
•
For Grade 4 or for recurrent/worsening venous thromboembolic events after resumption of 
ABT-165/bevacizumab:  Discontinue all protocol therapy.
•
For symptomatic pulmonary embolism, subjects will discontinue all protocol therapy.
Arterial Thrombotic Events
•
For Grade 2 arterial thrombotic events not present at baseline or worsened since the initiation 
of protocol therapy, discontinue ABT-165/bevacizumab.  Subjects may continue other protocol 
therapy.
•
For Grade 3 cerebrovascular ischemia, and/or peripheral or visceral arterial ischemia, 
discontinue ABT-165/bevacizumab.  Subjects may continue other protocol therapy.
•
For Grade 3 cardiac ischemia/infarction, discontinue all protocol therapy.
•
For any Grade 4 arterial thrombotic event, including cerebrovascular ischemia, cardiac 
ischemia/infarction, peripheral or visceral arterial ischemia, discontinue all protocol therapy.
Left Ventricular Dysfunction
•
For Grade 3 left ventricular dysfunction, discontinue ABT-165/bevacizumab.  Subjects may 
continue other protocol therapy.
•
For Grade 4 left ventricular dysfunction, discontinue all protocol therapy.
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Hemorrhage/Bleeding
•
For Grade 3 hemorrhage/bleeding, discontinue ABT-165/bevacizumab and skip other protocol 
therapy; once hemorrhage or bleeding resolves, other protocol therapy may be continued at the 
treating physician's discretion.
•
For Grade 4 hemorrhage/bleeding, discontinue all protocol therapy.
Posterior Reversible Leukoencephalopathy Syndrome (RPLS/PRES)
For signs and symptoms suggestive of RPLS (e.g., confusion, headache, seizures, cortical blindness) skip 
ABT-165/bevacizumab.  Suspected RPLS should be investigated with MRI.  If diagnosis of RPLS is 
confirmed, ABT-165/bevacizumab should be permanently discontinued.
If RPLS is ruled out via MRI, the decision on resuming ABT-165/bevacizumab should be based on the 
nature of the signs/symptoms.  For Grade 4 events with likely relationship to ABT-165/bevacizumab, 
discontinue ABT-165/bevacizumab; for Grade 3 events, ABT-165/bevacizumab may be resumed if 
toxicities completely resolve within 4 weeks.
Other protocol therapy may be continued at the discretion of the Investigator.
Proteinuria
Moderate to severe proteinuria pending further evaluation
•
Subjects with a 2+ urine protein dipstick (or urinalysis equivalent) reading may receive their 
scheduled dose of ABT-165/bevacizumab and, if they continue to have 2+ urine dipstick (or 
urinalysis) on repeat analysis, should have a 24-hour urine protein measured prior to the next 
scheduled dose of ABT-165/bevacizumab.
•
Subjects with a 3+ or greater urine protein dipstick (or urinalysis equivalent) reading may have 
their protein dipstick (or urinalysis) repeated and if still 3+ or greater should not receive their 
scheduled dose of ABT-165/bevacizumab until the results of a 24-hour urine protein analysis are 
available.
•
Suspend ABT-165/bevacizumab administration for ≥ 2 grams of protein/24 hours and resume 
when proteinuria is < 2 grams/24 hours (if urine protein decreases to ≤ 1 gm/24 hours, may 
resume monitoring with dipstick).
•
Permanently discontinue ABT-165/bevacizumab if subject develops nephrotic syndrome 
(Grade 3 proteinuria).
Sites that monitor urine protein measured by laboratory urinalysis (i.e., 30 mg/dL) may convert 
numerical terms to + terms and follow the protocol as generally outlined above or their Institutional 
standard of care.
Wound Dehiscence
•
For wound dehiscence requiring medical or surgical intervention:  Discontinue 
ABT-165/bevacizumab.
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Hypersensitivity and Infusion Reactions
Note that the NCI CTCAE defines these reactions differently:  "Cytokine release syndromes/acute 
infusion reactions are different from allergic/hypersensitivity reactions, although some of the 
manifestations are common to both AEs.  An acute infusion reaction may occur with an agent that 
causes cytokine release (e.g., mAbs or other biological agents).  Signs and symptoms usually develop 
during or shortly after drug infusion and generally resolve completely within 24 hours of completion of 
infusion."  See the "Syndromes" section of the CTCAE version 4.0 for a complete list of signs and 
symptoms of "Cytokine release syndrome/acute infusion reaction;" and see the "Allergy/Immunology" 
section for a description of hypersensitivity.
ABT-165/Bevacizumab Dose Modifications for Infusion Reactions
The initial ABT-165/bevacizumab dose should be administered over a minimum of 60 ± 10 minutes.  If 
no adverse reactions occur, the second and subsequent doses should be administered over a minimum 
of 30 minutes.  If infusion-related adverse reactions occur, subsequent infusions should be administered 
over the shortest period that is well tolerated.  Patients may receive premedication with 
diphenhydramine 25 to 50 mg intravenously or orally 30 minutes prior to ABT-165/bevacizumab if they 
have previously experienced mild infusion reactions.  Acetaminophen premedication may also be used.
Infusion Modifications for Hypersensitivity Reactions
•
For Grade 1 hypersensitivity reactions (transient rash, drug fever < 38°C):  Decrease the infusion 
rate by 50% until symptoms resolve, then resume at the initial planned rate.
•
For Grade 2 hypersensitivity reactions (urticaria, drug fever ≥ 38°C and/or asymptomatic 
bronchospasm):  Stop infusion.  Administer H1 and/or H2 blockers, and/or steroids according to 
institutional policy.  Restart the infusion when symptoms resolve and pretreat before all 
subsequent doses.  Treat according to institutional policy.
•
For Grade 3 or Grade 4 hypersensitivity reactions:  Stop the infusion.  Discontinue all protocol 
treatment and notify the Study Designated Physician.
Other Non-Hematologic Toxicities
•
For all other ≥ Grade 3 clinically significant non-hematologic toxicities not described above, hold 
all protocol therapy and monitor toxicity at least weekly.  If toxicity resolves to ≤ Grade 1 or 
baseline within 4 weeks, protocol therapy may be resumed.  Dose modification of FOLFIRI and 
dosing delays of ABT-165/bevacizumab will be at the discretion of the Investigator.
For allowed study drug interruption, the following rules apply:
1.
Some types of elective surgery will be allowed during this study (i.e., cataract surgery) but only 
after consultation with the Medical Monitor.  For elective surgery, the following guidelines have 
to be followed:  Discontinue treatment with ABT-165/bevacizumab at least 28 days prior to 
elective surgery.  Do not initiate ABT-165/bevacizumab for at least 28 days after surgery and 
until the surgical wound is fully healed.
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2.
If the subject must undergo emergency surgery, the study drug should be interrupted at the 
time of the surgery.  After emergency surgery, reintroduction of study drug is allowed 28 days 
after surgery provided that it is safe to do so and once the physician has examined the surgical 
site and determined that it has healed and there is no sign of infection.
6.3 Product Complaint
A product complaint is any complaint related to the biologic or drug component of the product or to the 
medical device component(s).
For a product this may include, but is not limited to, damaged/broken product or packaging, product 
appearance whose color/markings do not match the labeling, labeling discrepancies/inadequacies in the 
labeling/instructions (e.g., printing illegible), missing components/product, device not working properly, 
or packaging issues.
Product complaints concerning the investigational product and/or device must be reported to AbbVie 
within 1 business day of the study site's knowledge of the event.  Product complaints occurring during 
the study will be followed up to a satisfactory conclusion.
7 STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
7.1 Statistical and Analytical Plans
The primary efficacy analysis will be conducted when approximately 60 PFS events are accrued.  Based 
on the assumption of median PFS of 5.7 months in control arm, 
 
Complete and specific details of the statistical analysis will be described and fully documented in the 
Statistical Analysis Plan (SAP).  The SAP will be finalized prior to the database lock.  The statistical 
analyses will be performed using SAS (SAS Institute Inc., Cary, North Carolina, USA).
7.2 Definition for Analysis Populations
The intent to treat (ITT) population includes all randomized subjects.  The ITT will be used for all efficacy 
and baseline analyses.  Subjects will be grouped according to treatment as randomized.  The Per-
Protocol Analysis Set represents a subset of the ITT who received at least 1 dose of study drug and 
without any major violations.  Definitions of major protocol violations will be detailed in the SAP.  
Additional analysis may be conducted on the Per-Protocol Analysis Set, in order to evaluate the impact 
of major protocol violations.
The Safety Analysis Set consists of all subjects who received at least 1 dose of study drug.  For the Safety 
Analysis Set, subjects are assigned to a treatment group based on the treatment actually received, 
regardless of the treatment randomized.
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7.3 Statistical Analyses for Efficacy
Primary Analysis
Analysis of the primary endpoint (PFS) will be conducted on the ITT population.
The HR of PFS of ABT-165 plus FOLFIRI compared to bevacizumab plus FOLFIRI will be estimated using 
the stratified Cox model.  Progression free survival will be defined as the time from randomization until 
the first occurrence of radiographic progression, as determined by a blinded independent central 
review, or death from any cause.  Progression free survival time for subjects without PFS events will be 
censored at the time of last tumor assessment.  The stratification factors for the stratified Cox model 
will be the stratification variables used in the randomization.  This primary analysis will include a 90% 
confidence interval (CI) for the estimated stratified HR for PFS.  Kaplan-Meier methodology will also be 
used to estimate the PFS curve, median PFS and its associated 90% CI in each treatment arm.  Results 
from a stratified and unstratified log-rank test will also be presented.
Sensitivity analysis of the primary endpoint (PFS) will be conducted on the Per-Protocol Analysis 
population.
Secondary Analysis
Overall Survival (OS):  Duration of OS is defined as the time from randomization until death from any 
cause.  Duration of survival for subjects who are still alive at the time of analysis will be censored on the 
date of last contact.  The same method used in the PFS analysis will be used for the OS analysis.
Objective Response Rate (ORR):  ORR will be defined as the proportion of subjects with a CR or PR as 
determined by blinded independent central review based on RECIST, Version 1.1.  The ORR will be 
estimated in each treatment arm.  The 90% CI of the estimated ORR will be provided.
Details on the primary and other efficacy analyses are provided in the SAP.
Sample Size Estimation
The planned total sample size of approximately 100 subjects for this study is based upon the precision of 
estimating the HR for PFS with a total of 60 PFS events.  The median PFS of subjects in second-line mCRC 
treated with bevacizumab plus FOLFIRI is 5.7 months.  Based on a minimum of 60 PFS events, if a HR of 
0.74 (or an increase in median PFS from 5.7 to 7.7 months assuming exponential PFS) is observed, the 
approximate 90% CI for the HR would be (0.48, 1.13).  An observed HR of 0.66 (median PFS increases 
from 5.7 to 8.6 months) would have the approximate 90% CI of (0.43, 1.01).  This study is intended to be 
hypothesis-generating.
7.4 Statistical Analyses for Safety
Safety will be assessed by evaluating study drug exposure, AEs, SAEs, all deaths, as well as changes in 
laboratory data and vital signs.  Subjects who are randomized but do not receive study drug (ABT-165) 
or bevacizumab will not be included in the analyses of safety.  Safety analysis results will be presented 
by treatment group.  Subjects will be grouped according to the actual treatment received.
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Details on the safety analyses are provided in the SAP.
7.5 Data Monitoring Committee (DMC)
An internal DMC comprised of persons independent of the AbbVie study team and with relevant 
expertise in their field will be established to review unblinded safety data initially approximately 
6 months after the first subject is enrolled and approximately every 3 months thereafter.  Furthermore, 
the DMC will also review the available efficacy data approximately every 3 months.  The efficacy portion 
of the analysis for the DMC review will be based on investigator assessment.  The purpose of the review 
of efficacy data in addition to safety is to ensure an adequate benefit to risk ratio is being maintained 
and to enable further development activities.
Gastrointestinal perforation is 1 of the AEs of special interest and as such, the DMC is required to 
monitor this event closely.  If the observed rate of gastrointestinal perforation meets both of the 
following conditions at any time, the DMC may recommend stopping the study:
•
90% lower bound of the observed gastrointestinal perforation rate in the ABT-165 arm is > 5%.
•
The observed gastrointestinal perforation rate in the ABT-165 arm is statistically significantly 
higher than the observed gastrointestinal perforation rate in the bevacizumab arm (P < 0.10).
A separate DMC charter will be prepared outside of the protocol and will describe the roles and 
responsibilities of the DMC members, frequency of data reviews and relevant safety data to be 
assessed.
8 ETHICS
8.1 Independent Ethics Committee/Institutional Review Board 
(IEC/IRB)
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IEC/IRB for review and approval.  Approval of both the protocol and the informed 
consent form(s) must be obtained before any participant is enrolled.  Any amendment to the protocol 
will require review and approval by the IEC/IRB before the changes are implemented to the study.  In 
addition, all changes to the consent form(s) will be IEC/IRB approved.
8.2 Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, Operations Manual (Appendix F), 
International Council for Harmonisation (ICH) guidelines, applicable regulations and guidelines governing 
clinical study conduct and the ethical principles that have their origin in the Declaration of Helsinki.  
Responsibilities of the Investigator are specified in Appendix B.
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8.3 Subject Confidentiality
To protect subjects' confidentiality, all subjects and their associated samples will be assigned numerical 
study identifiers or "codes."  No identifiable information will be provided to AbbVie.
9 SOURCE DOCUMENTS AND CASE REPORT FORM 
COMPLETION
The Investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported.  All source documents should be attributable, legible, contemporaneous, original, 
accurate, and complete to ensure accurate interpretation of data.  Clinical site monitoring is conducted 
to ensure that the rights and well-being of human subjects are protected, that the reported trial data 
are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with the 
currently approved protocol, ICH Good Clinical Practice (GCP), and applicable local regulatory 
requirement(s).
10 DATA QUALITY ASSURANCE
AbbVie will ensure that the clinical trial is conducted and data are generated, documented and reported 
in compliance with the protocol, ICH GCP and applicable regulatory requirements.
11 COMPLETION OF THE STUDY
The end-of-study is defined as the date of last subject's last survival follow-up contact.  The sponsor may 
also end the study at any time.
12 REFERENCES
1.
Ridgway J, Zhang G, Wu Y, et al.  Inhibition of Dll4 signalling inhibits tumour growth by 
deregulating angiogenesis.  Nature.  2006;444(7122):1083-7.
2.
Li JL, Harris AL.  Crosstalk of VEGF and Notch pathways in tumour angiogenesis:  therapeutic 
implications.  Front Biosci (Landmark Ed).  2009;14:3094-110.
3.
Cunningham D, Pyrhönen S, James RD, et al.  Randomised trial of irinotecan plus supportive care 
versus supportive care alone after fluorouracil failure for patients with metastatic colorectal 
cancer.  Lancet.  1998;352(9138):1413-8.
4.
Saltz LB, Cox JV, Blanke C, et al.  Irinotecan plus fluorouracil and leucovorin for metastatic 
colorectal cancer.  Irinotecan Study Group.  N Engl J Med.  2000;343(13):905-14.
5.
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 randomized 
randomized trial.  Lancet.  2000;355(9209):1041 7.
6.
Avastin® (bevacizumab) [package insert].  South San Francisco, CA; Genentech, Inc.  March 2013.
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7.
Mendelsohn J.  Targeting the epidermal growth factor receptor for cancer therapy.  J Clin Oncol.  
2002;20 (18 Suppl):1S-13S.
8.
Fuchs CS, Marshall J, Mitchell E, et al.  Randomized, controlled trial of irinotecan plus infusional, 
bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer:  results 
from the BICC-C Study.  J Clin Oncol.  2007;25(30):4779-86.
9.
Bennouna J, Sastre J, Arnold D, et al.  Continuation of bevacizumab after first progression in 
metastatic colorectal cancer (ML18147):  a randomized Phase 3 trial.  Lancet Oncol.  
2013;14(1):29-37.
10. ZALTRAP® (ziv-aflibercept) [package insert].  Bridgewater, NJ; Sanofi-Aventis US LLC.  August 
2012.
11. Van Cutsem EV, Tabernero J, Lakomy R, et al.  Addition of aflibercept to fluorouracil, leucovorin, 
and irinotecan improves survival in a Phase III randomized trial in patients with metastatic 
colorectal cancer previously treated with an oxaliplatin based regimen.  J Clin Oncol.  
2012;30(28):3499-506.
12. CYRAMZA® (ramucirumab) [package insert].  Indianapolis, IN; Eli Lilly and Company, 2015.
13. AbbVie.  ABT-165 Investigator's Brochure Edition 4.  30 September 2016.
14. National Comprehensive Cancer Network.  NCCN Guidelines Version 3.  2014, Colon Cancer.  
Available from:  http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#colon.  
Accessed on:  2014 April 16.
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CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX A. STUDY SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
ADA
Anti-Drug Antibody
AE
Adverse Event
AIA
Administrative Interim Analysis
ANC
Absolute Neutrophil Count
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
BNP
Brain Natriuretic Peptide
C1D1
Cycle 1 Day 1
CI
Confidence Interval
CNS
Central Nervous System
CR
Complete Response
CRC
Colorectal Cancer
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
DLL4
Delta-Like Ligand 4
DMC
Data Monitoring Committee
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
ECG
Electrocardiogram
5-FU
Fluorouracil
FOLFIRI
Irinotecan/Fluorouracil (5-FU)/Leucovorin (Folinic Acid) with bolus and continuous 
infusion 5-FU
FOLFOX
Leucovorin/Fluorouracil/Oxaliplatin
GCP
Good Clinical Practice
HR
Hazard Ratio
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
INR
International Normalized Ratio
IRB
Institutional Review Board
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STUDY M14-064  |  Version 3.0  / EudraCT 2017-003669-87
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IRR
Infusion-Related Reaction
IRT
Interactive Response Technology
ITT
Intent To Treat
IUD
Intrauterine Device
IUS
Intrauterine Hormone-Releasing System
IV
Intravenous
LVEF
Left Ventricular Ejection Fraction
mAb
Monoclonal Antibody
mCRC
Metastatic Colorectal Cancer
mOS
Median Overall Survival
MRI
Magnetic Resonance Imaging
nAb
Neutralization effect of the ADA
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
OS
Overall Survival
ORR
Objective Response Rate
PFS
Progression-Free Survival
PK
Pharmacokinetic(s)
PR
Partial Response
PTT
Partial Thromboblastin Time
RECIST
Response Evaluation Criteria in Solid Tumors
RPLS
Reversible posterior Leukoencephalopathy Syndrome
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SC
Subcutaneous
SUSAR
Suspected Unexpected Serious Adverse Reactions
TV
Tricuspid Velocity
ULN
Upper Limit of Normal
WOCBP
Woman of Childbearing Potential
VEGF
Vascular Endothelial Growth Factor
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STUDY M14-064  |  Version 3.0  / EudraCT 2017-003669-87
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M14-064:  ABT-165 plus FOLFIRI vs Bevacizumab plus FOLFIRI in mCRC Previously Treated with 
Fluoropyrimidine, Oxaliplatin and Bevacizumab
Protocol Date:  07 February 2019
Clinical research studies sponsored by AbbVie are subject to the International Council for Harmonisation 
(ICH) Good Clinical Practices (GCP) and local regulations and guidelines governing the study at the site 
location.  In signing the Investigator Agreement, the investigator is agreeing to the following:
1.
Conducting the study in accordance with ICH GCP, the applicable regulatory requirements, 
current protocol and operations manual (Appendix F), and making changes to a protocol only 
after notifying AbbVie and the appropriate Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC), except when necessary to protect the subject from immediate harm.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed consent and 
ethics committees (e.g., IEC or IRB) review and approval of the protocol and its amendments.
4.
Reporting complaints that occur in the course of the investigation(s) to AbbVie.
5.
Reading the information in the Investigator's Brochure/safety material provided, including the 
instructions for use and the potential risks and side effects of the investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the study about 
their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making those records 
available for inspection by representatives of AbbVie and/or the appropriate regulatory agency, 
and retaining all study-related documents until notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and approved the initial 
clinical protocol and all of its amendments.
9.
Reporting promptly, all changes in the research activity and all unanticipated problems involving 
risks to human subjects or others, to the appropriate individuals (e.g., coordinating investigator, 
institution director) and/or directly to the ethics committees and AbbVie.
10. Providing direct access to source data documents for study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s).
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
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APPENDIX C. LIST OF PROTOCOL SIGNATORIES
Name
Title
Functional Area
Clinical Program Development
Clinical Program Development
Bioanalysis
Clinical Oncology
Clinical Pharmacology/Clinical PK
Data and Statistical Sciences
Medical Writing
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CONFIDENTIAL INFORMATION
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APPENDIX E. PROTOCOL SUMMARY OF CHANGES
Previous Protocol Versions
Protocol
Date
Version 1.0
26 September 2017
Version 2.0
24 October 2018
The purpose of this Version is to modify ABT-165 dosing guidelines, edit eligibility criteria, and add 
stopping rules based upon occurrence of gastrointestinal perforation events, including the following:
•
Updated Introduction
Rationale:  To reflect the approval of a bevacizumab biosimilar (MVASI)
•
Added modified dosing guidelines to the protocol and operations manual for subjects who 
received bevacizumab within 6 weeks of ABT-165 treatment initiation
Rationale: To reduce risk of gastrointestinal perforation
•
Clarified that primary tumor must be resected > 3 months prior to randomization
Rationale: To reduce risk of gastrointestinal perforation
•
Modified eligibility criteria to exclude subjects who have conditions that require use of high 
dose steroids or chronic nonsteroidal anti-inflammatory agents
Rationale: To reduce risk of gastrointestinal perforation
•
Modified eligibility criteria to exclude subjects who have any history of fistula, abdominal 
irradiation, or diverticulitis
Rationale: To reduce risk of gastrointestinal perforation
•
Modified and clarified medications and therapy that are prohibited on study.
Rationale:  For consistency with the Phase 1 study of ABT-165.
•
Added guidance for bowel care while on study
Rationale:  To reduce risk of gastrointestinal perforation
•
Increased the frequency of DMC reviews of safety and efficacy data to every 3 months following 
the initial 6 month review
Rationale: To more closely monitor safety events during the study and to ensure an adequate 
benefit to risk ratio is being maintained
•
Introduced stopping rules for gastrointestinal perforation events
Rationale: To ensure subject safety
In addition, minor clerical errors were corrected and edits for consistency within the document were 
made.
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APPENDIX F. OPERATIONS MANUAL
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M14-064 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
1 CONTACTS
Sponsor/
Emergency 
Contact
 
Sr. Medical Director, Oncology
AbbVie 
1500 Seaport Blvd.
Redwood City, CA 94063
Email:  
EMERGENCY 24 hour Number:  
Office:
Mobile:
Fax:
Safety Concerns
Oncology Group Safety Management
1 North Waukegan Road
North Chicago, IL  60064
Phone:
Email:
SAE Reporting 
outside of RAVE
Email:
Fax:
Protocol 
Deviations
Medical Director
AbbVie Inc.
1500 Seaport Blvd.
Redwood City, CA  94063
Study Project Manager
AbbVie Inc.
1500 Seaport Blvd.
Redwood City, CA  94063
Phone:
Fax:
Email:
Phone:
Fax:
Email:
Certified Clinical 
Lab
COVANCE CENTRAL LABORATORY SERVICES 
L.P.
8211 SciCor Drive
Indianapolis, IN
46214-2985 USA
Phone:
+1 (317) 271 1200
Fax:
+1 (317) 273 4030
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M14-064 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
TABLE OF CONTENTS
1
CONTACTS
2
2
INVESTIGATION PLAN
5
2.1
INDIVIDUAL TREATMENT PERIOD VISIT ACTIVITIES
5
2.2
INDIVIDUAL POST-TREATMENT PERIOD VISIT ACTIVITIES
12
3
STUDY PROCEDURES
12
3.1
SUBJECT INFORMATION AND INFORMED CONSENT
12
3.2
MEDICAL/CANCER HISTORY
13
3.3
ADVERSE EVENT ASSESSMENT
13
3.4
PHARMACOKINETIC SAMPLING
13
3.5
BIOMARKER RESEARCH SAMPLING
14
3.6
12-LEAD ELECTROCARDIOGRAM
17
3.7
CARDIAC ECHO
17
3.8
HEIGHT AND WEIGHT
18
3.9
VITAL SIGNS
18
3.10 PHYSICAL EXAMINATION
19
3.11 ADMINISTRATION OF STUDY DRUGS
19
3.12 TUMOR ASSESSMENTS
21
3.13 CLINICAL LABORATORY TESTS
21
4
SAFETY MANUAL
24
4.1
METHODS AND TIMING OF SAFETY ASSESSMENT
24
4.2
RECORDING DATA AND ANALYSES OF SAFETY FINDINGS
25
4.3
DEFINITION OF ADVERSE EVENT
26
4.4
ADVERSE EVENTS COMMONLY ASSOCIATED WITH MCRC STUDY POPULATION AND/OR PROGRESSION OF MCRC
27
4.5
ADVERSE EVENTS EXPECTED DUE TO STUDY-RELATED ENDPOINTS
27
4.6
REPORTING ADVERSE EVENTS AND INTERCURRENT ILLNESSES
28
5
STUDY DRUG
29
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M14-064 Version 3.0
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5.1
TREATMENTS ADMINISTERED
29
5.2
PACKAGING AND LABELING
29
5.3
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS
30
5.4
SELECTION AND TIMING OF DOSE FOR EACH SUBJECT
30
LIST OF TABLES
TABLE 1.
SCHEDULE OF STUDY M14-064 STUDY PK AND BIOMARKER SAMPLES (FOR SUBJECTS ON BOTH 
ARMS)
16
TABLE 2.
CLINICAL LABORATORY TESTS
23
LIST OF APPENDICES
APPENDIX A.
STUDY SPECIFIC ABBREVIATIONS AND TERMS
31
APPENDIX B.
RECIST (VERSION 1.1) CRITERIA FOR TUMOR RESPONSE
33
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M14-064 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
subject's medical record.  An entry must also be made in the subject's dated source documents to 
confirm that informed consent was obtained prior to any study-related procedures and that the subject 
received a signed copy.
Information regarding benefits for subjects and information regarding provisions for treating and/or 
compensating subjects who are harmed as a consequence of participation in the study can be found in 
the informed consent form.
Samples for optional pharmacogenetic analyses will only be collected if the subject has voluntarily 
signed and dated a separate written consent form for pharmacogenetic testing that has been approved 
by an IRB/IEC, after the nature of the testing has been explained and the subject has had an opportunity 
to ask questions.  The separate written consent may be part of the main consent form.  If the subject 
does not consent to the pharmacogenetic testing, it will not impact the subject's participation in the 
study.
3.2 Medical/Cancer History
A complete medical history including history of tobacco, alcohol, and drug use will be taken at screening.  
The subject's medical history will be updated at the Study Day 1 visit.  This updated medical history will 
serve as the baseline for clinical assessment. A detailed oncology history will also be collected including:  
histology, date of diagnosis of metastatic colorectal cancer (mCRC), stage and grade of mCRC, RAS 
status, primary tumor location, any surgical procedures, treatments administered (including dates and 
type of modality), and any other cancers besides mCRC.
On Cycle 1 Day 1, any additional medical history observed after signing of the informed consent but 
prior to initial study drug administration and not considered related to study-required procedures will 
be recorded in the subject's medical history.
3.3 Adverse Event Assessment
Please refer to Section 4.2 on page 23.
3.4 Pharmacokinetic Sampling
Blood samples for subjects on both arms will be collected for analysis of serum concentrations.  Blood 
samples will be collected throughout the treatment period on the study and the time points specified in 
Table 1, and processed as outlined in the most current version of the Study M14-064 laboratory manual.
Serum concentrations of ABT-165, the presence of antidrug antibodies (ADA) and, as needed, the 
neutralization effect of the ADA (nAb), will be determined using validated methods by or under 
supervision of the bioanalysis department at AbbVie.  Serum samples collected for ABT-165 and ABT-165 
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M14-064 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
ADA analysis may be used for future assay development or validation activities.  Testing for serum 
samples collected for bevacizumab may be performed as needed.
3.5 Biomarker Research Sampling
Biomarker samples for subjects on both arms will be collected throughout the treatment period on the 
study and the time points specified in Table 1, and processed as outlined in the most current version of 
the Study M14-064 laboratory manual.
Exploratory biomarker assessments may include (but are not limited to) pathway(s) targeted by ABT-165 
and those believed to be related to colorectal cancer, the disease being studied.  The types of 
biomarkers studied may include nucleic acids, proteins, lipids, or metabolites.  Samples may also be used 
to develop new diagnostic tests, therapies, research methods, or technologies.  The analyses are 
exploratory in nature, may be conducted in non-Good Laboratory Practice (GLP) laboratories, and the 
results may not be included with the clinical study report.  AbbVie (or people or companies working with 
AbbVie) will store the samples and data in a secure storage space with adequate measures to protect 
confidentiality.  Biomarker samples may be stored for up to 20 years, while research on ABT-165 (or 
drugs of this class) or colorectal cancer and related conditions continues.
Blood Samples
Peripheral blood samples may be collected to conduct exploratory analyses to identify potential 
prognostic, predictive, or surrogate biomarker signatures, including (but not limited to) the following:
•
Circulating nucleic acids in the peripheral blood may be analyzed at baseline and subsequent 
time points on therapy to assess tumor-related genetic alterations and to determine the effect 
of therapy.
•
Expression levels (ribonucleic acid [RNA] or protein) of molecules may be assessed 
(e.g., molecules involved in the angiogenesis pathway) and evaluated for correlations with 
efficacy.
Tumor Tissue Collection
Archived or Fresh Tissue Biopsy.  All subjects should provide a tumor sample prior to enrollment in the 
study.  Availability of archival tissue (most recent sample is preferred) needs to be confirmed prior to 
enrollment in the study.  If no archived tissue is available, a fresh pre-treatment biopsy should be 
collected from subjects as per Institutional guidelines, if it is deemed safe to do so in the judgment of 
the Investigator.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M14-064 Version 3.0
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Pharmacogenetic deoxyribonucleic acid (DNA) Sample (Optional)
Whole blood samples for pharmacogenetic exploratory research (DNA) will be collected from subjects 
who consent.  DNA samples may be analyzed for genetic factors contributing to the subject's response 
to ABT-165, or other study treatment, in terms of pharmacokinetics (PK), pharmacodynamics, efficacy, 
tolerability, and safety.  The samples may be analyzed as part of a multi-study assessment of genetic 
factors involved in the response to ABT-165 or drugs of this class.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M14-064 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
3.6 12-Lead Electrocardiogram
A 12-lead electrocardiogram (ECG) will be performed at the designated study visits as specified in 
Section 2.1.  The ECG should be performed prior to blood collection.
The ECGs will be evaluated by an appropriately trained physician at the site ("local reader").  The local 
reader from the site will sign and date all ECG tracings and will provide his/her global interpretation as a 
written comment on the tracing using the following categories:
•
Normal ECG
•
Abnormal ECG – not clinically significant
•
Abnormal ECG – clinically significant
Only the local reader's evaluation of the ECG will be collected and documented in the subject's source 
folder.  The automatic machine reading (i.e., machine-generated measurements and interpretation that 
are automatically printed on the ECG tracing) will not be collected.
3.7 Cardiac ECHO
Echocardiogram (ECHO) will be performed at screening and approximately every 8 weeks from Cycle 1 
Day 1 as specified in Section 2.1.  It is preferred that the same operator, machine and calculation 
algorithm be used throughout the course of the study.
At Screening, ECHO will be performed to determine if any findings outside normal physiological variation 
are clinically significant, including but not limited to left ventricular ejection fraction and peak tricuspid 
velocity.  Any clinically significant findings outside normal physiological variation will be documented on 
the appropriate electronic case report form (eCRF).  For subsequent ECHOs performed every 4 cycles, 
any significant changes from baseline or evaluations performed while on study should be documented.  
Any clinically significant changes, including pulmonary hypertension and decrease in left ventricular 
ejection fraction, from baseline will be evaluated by the Investigator and Medical Monitor prior to 
further dosing.
The assessment performed at Screening will serve as the baseline for future comparisons.  Additional 
cardiac assessments and studies may be performed at the discretion of the Investigator after 
consultation with the Medical Monitor.
All study reports will be retained as source documentation in the subject's records at the study site.  Any 
abnormal study reports, including the screening reports, in subjects who have been dosed with ABT-165
will be forwarded to the Sponsor for further evaluation.  The Sponsor may also choose to have ECHO 
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M14-064 Version 3.0
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scans/reports reviewed by an independent central radiographic institution at any time during or after 
the study.
3.8 Height and Weight
Height will be measured at screening only.  Body weight will be measured at scheduled visits as specified 
in Section 2.1.  The subject will wear lightweight clothing and no shoes during weighing.  Ideal, total or 
adjusted weight will not be used.
3.9 Vital Signs
Vital sign determinations of systolic and diastolic blood pressure in triplicate, pulse rate, and body 
temperature will be obtained at visits as specified in Section 2.1.
In general, blood pressure (BP) measurements should follow the most current guidelines of the 
American Heart Association with the following considerations.  Blood pressure and heart rate 
measurements should be performed prior to scheduled blood collections.  At each office visit, BP will be 
measured in triplicate approximately 5 minutes apart.  Blood pressure and pulse rate will be measured 
after the subject has been sitting comfortably in a chair with legs uncrossed and back supported.  The 
arm used for BP measurements should be supported for at least 5 minutes.  Triplicate BP measurements 
may be repeated if there were any disruptions during the measurements (i.e., blood draws, exams etc.) 
or if Investigator/Staff consider BP readings are not accurate due to anxiety (i.e., "white coat 
hypertension") or other issues unrelated to study drug.
Home Blood Pressure Monitoring
Since hypertension is expected, the Sponsor will provide each subject with a BP monitor capable of 
recording BPs for the duration of the subject's participation in the study.  The subject (or their caretaker) 
will measure the subject's BP daily (or more often if needed to manage hypertension), starting after 
dosing on Cycle 1 Day 1 and lasting to the end of Cycle 2.  Subjects and/or their caretakers will be 
trained on the proper methods to measure BP at home and will be instructed to contact the 
Investigator/Site Staff for management of BP readings ≥160/100.  Beginning with Cycle 3, subjects with 
well controlled hypertension as assessed by the Investigator, may measure their BP at home less 
frequently (approximately 3 times/week) but should still be instructed to contact Investigator/Site Staff 
for management of BP readings ≥ 160/100.
Subjects will be instructed to bring their home monitoring equipment and diary with them to each clinic 
visit.  Data from home BP monitoring may be used to adjust antihypertensive medications in between 
clinic visits as needed to maintain the majority of BPs < 150/90.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M14-064 Version 3.0
CONFIDENTIAL INFORMATION
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3.10 Physical Examination
A complete physical examination will be performed at the designated study visits as specified in 
Section 2.1. The physical examination performed on Study Day 1 will serve as the baseline physical 
examination for the entire study.  Any significant physical examination findings after the first dose will 
be recorded as adverse events (AEs).  All findings, whether related to an AE or part of each subject's 
medical history, will be captured on the appropriate eCRF page.
At any time, a symptom-directed physical examination can be performed as deemed necessary by the 
Investigator.
3.11 Administration of Study Drugs
Study drug will be administered to subjects as specified in Section 2.1.  The first dose of study drug will 
be administered after all other baseline (Day 1) procedures are completed.
ABT-165 or bevacizumab will be administered as an intravenous (IV) infusion on Day 1 of every 14-day 
dosing cycle.  Blood pressure will be measured in triplicate prior to each dose of ABT-165/bevazicumab 
and if all three measurements have either systolic ≥ 150 or diastolic ≥ 90 mmHg (either systolic or 
diastolic exceeded on all 3 readings), the subject cannot receive the dose of ABT-165/bevacizumab.
The dose of ABT-165/bevacizumab does not need to be adjusted unless the subject's measured weight 
changes by > 10% from baseline.  Site standard of care for bevacizumab dosing will supersede guidelines 
given in this protocol.
Subjects will not be pre-medicated for prophylaxis of infusion-related reactions (IRRs) prior to the first 
infusion of ABT-165/bevacizumab.  The first dose of ABT-165/bevacizumab will be given intravenously 
over 60 ± 10 minutes.  Subjects will be closely monitored for IRRs (chills, fever, rigors, hypertension, rash 
or other acute toxicities) during the infusion and the post-infusion observation period (30 – 45 minutes).  
If the first infusion is tolerated, the second and subsequent infusions of ABT-165/bevacizumab may be 
administered over 30 ± 10 minutes provided that subjects have not experienced IRRs.  For those 
subjects who required a 90 minute infusion of bevacizumab in the first-line setting, the first infusion of 
ABT-165 or bevacizumab will be administered over 90 (± 10) minutes and may be decreased to 60 (± 10) 
minutes and 30 (± 10) minutes as tolerated.  Subjects who had a history of infusion reactions with 
bevacizumab may be premedicated to prophylax IRRs at the discretion of the Investigator if they are 
receiving bevacizumab or ABT-165.
After the first infusion, direct observation is not required; however, pre-infusion and post-infusion (30 to 
45 minutes) vital signs should still be taken.  Longer observation periods and more frequent vital sign 
checks may be required in subjects who experience IRRs or elevations in BP.  Subjects who experience 
acute elevations of BP during or in the observation period following a dose, should be monitored in 
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M14-064 Version 3.0
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clinic until BP is < 150/90 mmHg for at least 1 hour with or without medication after which time they 
may be monitored and treated in the outpatient setting as medically appropriate.
For subjects experiencing an acute IRR, immediately interrupt ABT-165/bevacizumab infusion and 
administer appropriate medical therapy such as acetaminophen/paracetamol, diphenhydramine, 
H2-blockers, or steroids per Institutional standard of care.  Subjects who have had a Grade 1 or 2 IRR 
may be treated prophylactically prior to subsequent doses at the Investigator's discretion.
Folinic acid, fluorouracil, and irinotecan (FOLFIRI) will be administered per Institutional guidelines and 
best medical practice (Protocol suggested dosing guidelines are given below).  Modifications of FOLFIRI 
therapy, both the initial dose (depending on tolerance of prior therapy) and subsequent doses, are 
allowed at the discretion of the Investigator following prescribing information, Institutional guidelines, 
or best medical practice.  Subjects receiving ABT-165/bevacizumab and FOLFIRI should receive full 
supportive care including any standard pre-medications and monitoring associated with administration 
of Standard of Care agents.  Any toxicity associated with FOLFIRI should be managed utilizing best 
medical practice which may include symptomatic treatment and/or reduction or modification of FOLFIRI 
therapy.
Administration of Irinotecan
For the purposes of this protocol, the suggested dosing of irinotecan is 180 mg/m2 administered as a 
90 (± 15) minute IV infusion on Day 1 of each 14-day cycle.  Investigators should evaluate subjects for 
irinotecan treatment per the locally approved product label, local practice, or applicable Summary of 
Product Characteristics (SmPC).
Administration of Leucovorin (LV; folinic acid)
For the purposes of this protocol, the suggested dosing of leucovorin is DL-400 mg/m2 or L-200 mg/m2 
administered as a 90 (± 15) minute IV infusion concurrent with irinotecan on Day 1 of each 14-day cycle.  
Irinotecan and leucovorin may be administered sequentially in accordance with local practice.  
Investigators should evaluate subjects for leucovorin treatment per the locally approved product label, 
local practice, or applicable SmPC.
Administration of Fluorouracil (5-FU) Bolus
For the purposes of this protocol, a suggested 5-FU 400 mg/m2 bolus (up to 15 minutes) will be 
administered followed by the 5-FU infusion.  Investigators should evaluate subjects for 5-FU treatment 
per the locally approved product label, local practice, or applicable SmPC.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M14-064 Version 3.0
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Administration of Fluorouracil (5-FU) Infusion
For the purposes of this protocol, the suggested dosing of 5-FU is 2400 mg/m2 administered as a 
46-hour (± 2 hours) IV infusion on Day 1 of each 14-day cycle.  Investigators should evaluate subjects for 
5-FU treatment per the locally approved product label, local practice, or applicable SmPC.
At the discretion of the Investigator, the 5-FU bolus or continuous infusion may be reduced or 
eliminated depending on the subject's tolerability of prior treatment.  
Order of Administration
Protocol therapy will be administered in the following order:  ABT-165/bevacizumab followed by
FOLFIRI as irinotecan concurrent with leucovorin followed by a 5-FU bolus followed by 5-FU infusion.  
For the purposes of this protocol, ABT-165/bevacizumab should always be given first.
Irinotecan and leucovorin may be administered sequentially in accordance with local treatment practice.
3.12 Tumor Assessments
Baseline radiographic tumor assessment must be performed within 28 days prior to Cycle 1 Day 1 and 
will consist of computed tomography (CT) (or magnetic resonance imaging [MRI] where clinically 
indicated) of the chest, abdomen, and pelvis (and other tumor involved regions as clinically indicated).  
Imaging will be repeated every 8 weeks from Cycle 1 Day 1.  Imaging will also be performed at the Final 
Visit if a subject discontinues from the study for a reason other than radiographic progression and no 
scan has been performed within the last 4 weeks.  Imaging may also be performed at other times if the 
Investigator suspects tumor progression.  Imaging of the brain for metastatic disease will only be
performed if clinically indicated.  The same imaging technique should be used throughout the study if 
possible.  The tumor assessment performed at Screening will serve as the baseline for clinical 
assessment.  Changes in measurable lesions over the course of therapy will be assessed using Response 
Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as described in Appendix B.  Radiographic 
images will be evaluated both by the site and by a blinded, independent central radiographic institution.
3.13 Clinical Laboratory Tests
All subjects will have laboratory analyses performed as outlined in Table 2.  The baseline laboratory test 
results for clinical assessment for a particular test will be defined as the last measurement prior to the 
initial dose of study drug.
A certified laboratory will be utilized to process and provide results for the clinical laboratory tests.  
Laboratory reference ranges will be obtained prior to the initiation of the study.  A local reference 
laboratory will perform chemistry, hematology, coagulation, and urinalysis tests for subject treatment 
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management and eligibility; however, split or concurrent samples must be drawn and sent to the central 
laboratory for analysis (applies to scheduled and unscheduled labs).
The Central laboratory tests may include hematology, chemistry, urinalysis, coagulation, 
carcinoembryonic antigen (CEA), or brain natriuretic peptide (BNP) depending on the study visit.  Central 
laboratory chemistry, hematology, coagulation, and urinalysis tests will be performed at the same study 
visit as the local laboratory tests.  Central laboratory BNP and CEA will be performed at odd numbered 
study visits and at the final study visit.  The central laboratory data will be used for safety analysis and 
any other related analysis.
**If there is a discrepancy between the local and central laboratory results, the site must enter the 
relevant local laboratory results that were used for eligibility or treatment decisions on the appropriate 
eCRF along with reference ranges.**
Instructions regarding the collection, processing, and shipping of these samples will be provided by the 
central laboratory and sent to the following certified laboratory addresses depending on the location of 
the site:
COVANCE CENTRAL LABORATORY SERVICES L.P.
8211 SciCor Drive 
Indianapolis, IN 
46214-2985 USA 
Tel (317) 271 1200 (local calls) 
Fax (317) 273 4030 
COVANCE CENTRAL LABORATORY SERVICES SÀRL 
Rue Moïse-Marcinhes 7 
CH - 1217 Meyrin/Genève 
Switzerland 
Tel +41 58 822 7901 
Fax +41 58 822 7521
Covance (Asia) Pte. Limited 
1, International Business Park 
#01-01 The Synergy 
Singapore 609917 
Tel +65 6560 8793 
Fax +65 6565 5901
If a laboratory test value is outside the reference range and the investigator considers the laboratory 
result to be clinically significant, the investigator will:
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•
repeat the test to verify the out-of-range value if needed;
•
follow the out-of-range value to a satisfactory clinical resolution; or
•
discontinue the subject from the study or require the subject to receive treatment; in this case, 
the laboratory result will be recorded as an AE.
Table 2.
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Coagulation Tests
Hematocrit
Hemoglobin
Red Blood Cell (RBC) count
White Blood Cell (WBC) count
Neutrophils
Bands 
Lymphocytes
Monocytes
Basophils
Eosinophils
Platelet count (estimate not
acceptable)
Blood Urea Nitrogen (BUN)
Creatinine
Total bilirubin
Albumin
Alanine transaminase (SGPT/ALT) 
Aspartate transaminase (SGOT/AST) 
Gamma-Glutamyl Transferase (GGT)
Alkaline phosphatase****
Sodium
Potassium
Calcium
Inorganic phosphorus****
Uric acid****
Cholesterol****
Total protein
Glucose
Triglycerides****
Lactate dehydrogenase (LDH) ****
Magnesium****
Bicarbonate/CO2
Chloride 
Creatinine clearance
Prothrombin time (PT)
Activated partial thromboplastin 
time (aPTT)
International normalized ratio (INR)
Cardiac
BNP
Urinalysis
Tumor Marker
Specific gravity
Ketones
pH
Protein*
Blood
Glucose
Carcinoembryonic antigen (CEA)**
Pregnancy Tests
Serum or Urine
Human Chorionic Gonadotropin 
(hCG)***
*
For proteinuria of ≥ 2+, confirm total urine protein with a 24-hour urine collection.
**
CEA tests will be performed at the central laboratory.  Sites may do their own CEA testing but should not discontinue 
subjects based on rising CEA alone unless clinically warranted.
*** 
At Screening and at any time point in which pregnancy is suspected or following a positive urine pregnancy test.
****
Optional local laboratory tests
Pregnancy Tests (Serum and Urine)
A serum pregnancy test will be performed at Screening and a serum or quantitative urine pregnancy test 
will be performed monthly on Study Day 1 of each odd treatment cycle for all women of child-bearing 
potential (WOCBP) subjects.
If the serum pregnancy test is positive, the subject is considered a screen failure.  If the serum 
pregnancy test is borderline, it should be repeated 2 days later to determine eligibility.
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If the repeat serum pregnancy test is:
•
Positive, the subject is considered a screen failure;
•
Negative, the subject can be enrolled into the trial;
•
Still borderline, the AbbVie Therapeutic Area Medical Director will be consulted.
Determination of postmenopausal status will be made during the screening period based on the 
subject's history.
A pregnant or breastfeeding female will not be eligible for participation or continuation in this study.
Additional urine pregnancy tests will be performed at visits indicated in Section 2.1.
If the urine pregnancy test (which is performed at the site) is negative, begin or continue dosing.  If urine 
pregnancy test is positive, withhold dosing and perform a serum pregnancy test.  Pregnant subjects 
must discontinue from the study.
Monthly pregnancy tests will be continued after the last treatment cycle for 6 months for all WOCBP 
subjects.
Chemistry
No fasting is required for the collection of blood samples for serum chemistry tests.
4 SAFETY MANUAL
4.1 Methods and Timing of Safety Assessment
All protocol-related serious adverse events (SAEs) as well as nonserious AEs will be collected from the 
time the subject signed the study-specific informed consent until study drug administration.  From the 
time of study drug administration until 90 days after discontinuation of study drug administration or 
start of another anti-cancer therapy, whichever occurs sooner, all AEs and SAEs will be collected 
whether solicited or spontaneously reported by the subject.
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*
Only if considered by the investigator to be causally related to study required procedures.
4.2 Recording Data and Analyses of Safety Findings
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  The 
number and percentage of subjects with treatment-emergent adverse events (i.e., any event that begins 
or worsens in severity after initiation of study drug through 90 days post-study drug dosing) will be 
tabulated by primary MedDRA System Organ Class (SOC) and preferred term (PT) and compared 
between arms using Fisher's exact test.  The tabulation of the number of subjects with treatment 
emergent adverse events by severity grade and relationship to study drug will also be provided.  
Subjects reporting more than 1 AE for a given MedDRA preferred term will be counted only once for 
that term using the most severe grade according to the severity grade table and the most related 
according to the relationship to study drug tables.  Subjects reporting more than 1 type of event within a 
SOC will be counted only once for that SOC.
Safety data will be monitored by the Sponsor and documented internally.  Throughout study conduct for 
Study M14-064, individual subject safety data and aggregate safety data will be reviewed by the Safety 
Management Team, the Therapeutic Area Medical Director and the Product Safety Team Therapeutic 
Area Physician with potential safety signals assessed by a cross functional ABT-165 Product Safety Team.  
As part of routine pharmacovigilance, individual case safety reports are reviewed per timelines for 
regulatory reporting and aggregate safety data reviewed on a quarterly basis by the previously 
referenced AbbVie personnel.  Within this context, critical safety related data points such as AEs, vital 
signs and laboratory data will be reviewed on an ongoing basis in accordance with the Study M14-064 
safety review plan (SRP).  Annually, in conjunction with the update of the Investigator Brochure, an 
aggregate review of the safety data across all study cohorts will be conducted and will include 
frequencies of treatment-emergent serious adverse events (SAEs) and non-serious AEs by MedDRA SOC 
and PT tables, deaths, SAEs, and AEs of special interest.  Sites will be informed of any significant findings 
impacting subject safety as they arise.
An internal Data Monitoring Committee (DMC) comprised of persons independent of the AbbVie study 
team and with relevant expertise in their field will be established to review unblinded safety data 
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initially approximately 6 months after the first subject is enrolled and approximately every 3 months 
thereafter.  Furthermore, the DMC will also review the available efficacy data approximately every 
3 months.
4.3 Definition of Adverse Event
An AE can result from use of the drug as stipulated in the protocol or labeling, as well as from accidental 
or intentional overdose.  Any worsening of a pre-existing condition or illness is considered an AE.  
Worsening in severity of an AE should be reported as a new AE.  Laboratory abnormalities and changes 
in vital signs are considered to be AEs only if they result in discontinuation from the study, necessitate 
therapeutic medical intervention, meet protocol specified criteria (see Section 6.2 in protocol regarding 
toxicity management), and/or if the investigator considers them to be AEs.
The investigator will monitor each subject for clinical and laboratory evidence of AEs on a routine basis 
throughout the study.  The investigator will assess and record any AE in detail including the date of 
onset, event diagnosis (if known), or sign/symptom, severity, time course (end date, ongoing, 
intermittent), relationship of the AE to study drug, and any action(s) taken.  For SAEs considered as 
having "no reasonable possibility" of being associated with study drug, the investigator will assign 
"other" as the cause of the event.  For AEs to be considered intermittent, the events must be of similar 
nature and severity.  AEs, whether in response to a query, observed by site personnel, or reported 
spontaneously by the subject, will be recorded.
All AEs will be followed to a satisfactory conclusion.
Disease progression and signs, symptoms or test abnormalities that, in the opinion of the investigator, 
are unequivocally due to disease progression should not be reported as AEs, even if serious or fatal (see 
also Section 4.4 and Section 4.5).
An elective surgery/procedure scheduled to occur during a study will not be considered an AE if the 
surgery/procedure is being performed for a pre-existing condition and the surgery/procedure was 
preplanned before study entry.  However, if the pre-existing condition deteriorates unexpectedly during 
the study (e.g., surgery performed earlier than planned) then the deterioration of the condition for 
which the elective surgery/procedure is being done will be considered an AE.  Hospitalization of a 
subject who is in Post Treatment Follow-Up or Survival, following discontinuation of study drug, for 
subsequent line of therapy will not be captured as an SAE.  A treatment-emergent AE is defined as any 
AE reported by a subject with onset or worsening from the time that the first dose of study drug is 
administered until 90 days have elapsed following discontinuation of study drug administration.
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4.4 Adverse Events Commonly Associated with mCRC Study Population 
and/or Progression of mCRC
Certain AEs are anticipated to occur in the study population at some frequency independent of drug 
exposure.  Such events include known consequences of mCRC (e.g., symptoms, disease progression) and 
events unlikely to be related to the underlying disease under investigation but common in the study 
population independent of drug therapy (e.g., cardiovascular events in an elderly population).
These AEs may occur alone or in various combinations and are considered expected for reporting 
purposes for this protocol.
4.5 Adverse Events Expected Due to Study-Related Endpoints
Deaths
Deaths that occur during the protocol-specified AE reporting period that are attributed by the 
investigator solely to progression of mCRC should be recorded only on the study completion eCRF with 
disease progression as the reason for discontinuation and not on the AE eCRF.  All other on-study 
deaths, regardless of relationship to study drug, must be recorded on the AE eCRF and immediately 
reported to the sponsor.
Death should be considered an outcome and not a distinct event.  The event or condition that caused or 
contributed to the fatal outcome should be recorded as the single medical concept on the AE eCRF.  
Generally, only 1 such event should be reported.  The term "sudden death" should be used only for the 
occurrence of an abrupt and unexpected death because of presumed cardiac causes in a subject with or 
without pre-existing heart disease within 1 hour after the onset of acute symptoms or, in the case of an 
unwitnessed death, within 24 hours after the subject was last seen alive and stable.  If the cause of 
death is unknown and cannot be ascertained at the time of reporting, "unexplained death" should be 
recorded on the AE eCRF.  If the cause of death later becomes available (e.g., after autopsy), 
"unexplained death" should be replaced by the established cause of death.  During survival follow-up, 
deaths attributed to progression of mCRC should be recorded only on the survival eCRF.
Lack of Efficacy or Worsening of Disease
Events that are clearly consistent with the expected pattern of progression of the underlying disease, 
including transformation to a more aggressive histology, are also considered an expected outcome for 
this study and will NOT be recorded as AEs.  These data will be captured as efficacy assessment data 
only.  If there is any uncertainty as to whether an event is due to disease progression, the event should 
be reported as an AE.
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The sponsor will be responsible for Suspected Unexpected Serious Adverse Reactions (SUSAR) reporting 
for the Investigational Medicinal Product (IMP) in accordance with Directive 2001/20/EC.  The reference 
document used for SUSAR reporting in the European Union countries will be the most current version of 
the Investigator's Brochure.
5 STUDY DRUG
5.1 Treatments Administered
The study drug (ABT-165), comparator (bevacizumab), and back-bone (irinotecan, leucovorin, and 5-FU) 
will be dispensed in the form of an IV infusion at the visits listed in Section 2.1.
ABT-165 will be provided by AbbVie as lyophilized powder in vials containing 200 mg each.  For 
bevacizumab, irinotecan, leucovorin, and 5-FU refer to country-approved package insert or SmPC.
ABT-165 (2.5 mg/kg or 1.25 mg/kg for the first 2 cycles, see below) or bevacizumab (5 mg/kg) with 
irinotecan (180 mg/m2), leucovorin (DL-400 mg/m2 or L-200 mg/ m2), and 5-FU (bolus:  400 mg/m2; then 
continuous infusion:  1200 mg/m2/day × 2 days - total of 2400 mg/m2 over 46 – 48 hours) will be 
administered intravenously on Day 1 of each 14-day cycle.  The Investigator may adjust the suggested 
FOLFIRI dosing based on Institutional guidelines and best medical practice.
The starting dose of ABT-165 should be 1.25 mg/kg for first 2 cycles if the last dose of bevacizumab is 
within 6 weeks of ABT-165 treatment initiation.  The dose of ABT-165 should then be increased to 
2.5 mg/kg after 2 cycles of the 1.25 mg/kg dose.
Study drug must not be dispensed without contacting the Interactive Response Technology (IRT) system.  
Study drug may only be dispensed to subjects enrolled in the study through the IRT system.  At the end 
of the Treatment Period or at the Premature Discontinuation visit, the site will contact the IRT system to 
provide visit date information and study drug return information for each kit.
If any planned study drug (ABT-165/bevacizumab or FOLFIRI) of a cycle is not given, site will register the 
information in IRT and EDC and indicate as "not given."
5.2 Packaging and Labeling
All study drugs will be supplied in vials.
Each vial will be labeled as required per country requirements.
The labels must remain affixed to the vials.
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Storage and Disposition of Study Drug
ABT-165 and bevacizumab must be refrigerated (2 to 8°C) for storage.  For irinotecan, leucovorin, and 
5-FU refer to country-approved package insert or SmPC.
All temperature excursions lasting longer than 30 minutes must be reported to AbbVie.  Study drug 
should be physically quarantined (status of drug in IRT should not be changed to "quarantined" unless 
instructed by the Sponsor study team).  Study drug that has experienced a temperature excursion 
should not be dispensed until AbbVie (or temperature excursion management system) deems drug as 
acceptable.
The investigational products are for investigational use only and are to be used only within the context 
of this study.  The study drug supplied for this study must be maintained under adequate security and 
stored under the conditions specified on the label until dispensed for subject use or destroyed on site as 
appropriate.
5.3 Method of Assigning Subjects to Treatment Groups
This is an open-label, randomized, 2-arm study.  All eligible subjects will receive ABT-165 (2.5 mg/kg) 
plus FOLFIRI (irinotecan – 180 mg/m2; leucovorin – DL-400 mg/m2 or L-200 mg/m2; 5-FU – bolus:  
400 mg/m2, infusion:  2400 mg/m2) or bevacizumab (5 mg/kg) plus FOLFIRI on Day 1 of each 14-day cycle 
until disease progression or study discontinuation.
At the screening visit, all subjects will be assigned a unique subject number through the use of the IRT.  
For subjects who do not meet the study selection criteria, the site personnel must contact the IRT 
system and identify the subject as a screen failure.
Subjects who are enrolled will retain their subject number assigned at the screening visit throughout the 
study.  Upon receipt of study drug, the site will acknowledge receipt in the IRT system.
Contact information and user guidelines for IRT use will be provided to each site.
5.4 Selection and Timing of Dose for Each Subject
During the randomization process, subjects will be randomized in a 1:1 ratio to either ABT-165 
2.5 mg/kg IV plus FOLFIRI or bevacizumab 5 mg/kg IV plus FOLFIRI.
The starting dose of ABT-165 should be 1.25 mg/kg for first 2 cycles if the last dose of bevacizumab is 
within 6 weeks of ABT-165 treatment initiation.  The dose of ABT-165 should then be increased to 
2.5 mg/kg after 2 cycles of 1.25 mg/kg dose.
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APPENDIX A. STUDY SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
ADA
Antidrug Antibody
AE
Adverse event
ALT
Alanine aminotransferase
aPTT
activated Partial Thromboplastin Time
AST
Aspartate aminotransferase
BP
Blood Pressure
BNP
Brain Natriuretic Peptide
BUN
Blood urea nitrogen
CEA
Carcinoembryonic Antigen
CR
Complete Response
CT
Computed Tomography
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic Acid
EC
Ethics Committee
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EDC
Electronic data capture
5-FU
Fluorouracil
FFPE
Formalin-Fixed Paraffin-Embedded
FOLFIRI
Folinic Acid, Fluorouracil, and Irinotecan
hCG
Human Chorionic Gonadotropin
IV
Intravenous
IEC
Independent ethics committee
IMP
Investigational Medical Product
INR
International normalized ratio
IRB
Institutional Review Board
IRR
Infusion-Related Reaction
IRT
Interactive Response Technology
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LDH
Lactate dehydrogenase
LV
Leucovorin
mCRC
Metastatic Colorectal Cancer
MedDRA
Medical Dictionary for Regulatory Activities
mL
Milliliter
MRI
Magnetic Resonance Imaging
nAb
Neutralization effect of the ADA
PK
Pharmacokinetic
PR
Partial Response
PT
Prothrombin Time
RBC
Red blood cells
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic Acid
RPLS/PRES
Posterior Reversible Leukoencephalopathy Syndrome
SAE
Serious adverse event
SGPT
Alanine transaminase
SGOT
Aspartate transaminase
SmPC
Summary of Product Characteristics
SOC
System Organ Class
SUSAR
Suspected Unexpected Serious Adverse Reaction
WOCBP
Women of Child-Bearing Potential
WBC
White Blood Cell
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APPENDIX B. RECIST (VERSION 1.1) CRITERIA FOR TUMOR 
RESPONSE
Response criteria will be assessed using RECIST (version 1.1).  Changes in the measurable lesions over 
the course of therapy must be evaluated using the criteria listed below.
Eligibility
Subjects with measurable disease at Baseline can have objective tumor response evaluated by RECIST 
criteria.  Measurable disease is defined by the presence of at least one measurable lesion.  If the 
measurable disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by 
cytology/histology if possible.
Measurability
Measurable Lesions
Lesions accurately measured in at least 1 dimension with a minimum 
size of:
•
longest diameter ≥ 10 mm (CT scan slice thickness no greater 
than 5 mm)
•
10 mm caliper measurement by clinical exam
Non-Measurable Lesions
All other lesions, including small lesions (longest diameter < 10 mm) as 
well as truly non-measurable lesions.  Lesions considered truly non-
measurable include:  leptomeningeal disease, ascites, 
pleural/pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung and also abdominal masses that are not 
confirmed and followed by imaging techniques.
Measurable Malignant 
Lymph Nodes
To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm).  At baseline 
and in follow-up, only the short axis will be measured and followed.
Non-Measurable 
Malignant Lymph Nodes
Pathological lymph nodes with ≥ 10 to < 15 mm short axis.
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Special Considerations 
Regarding Lesion 
Measurability
Bone lesions
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft 
tissue components, that can be evaluated by cross sectional imaging 
techniques such as CT can be considered as measurable lesions if the 
soft tissue component meets the definition of measurability described 
above.
Blastic bone lesions are non-measurable.
Cystic lesions
Lesions that meet the criteria for radiographically defined simple cysts
should not be considered as malignant lesions (neither measurable nor 
non measurable) since they are, by definition, simple cysts.
'Cystic lesions' thought to represent cystic metastases can be 
considered as measurable lesions, if they meet the definition of 
measurability described above.  However, if noncystic lesions are 
present in the same subject, these are preferred for selection as target 
lesions.
Lesions with prior local treatment
Tumor lesions situated in a previously irradiated area, or in an area
subjected to other loco-regional therapy, are usually not considered 
measurable unless there has been demonstrated progression in the 
lesion.
All measurements should be taken and recorded in metric notation, using calipers if clinically assessed.  
All baseline evaluations should be performed as closely as possible to the beginning of treatment and 
not more than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize each identified 
and reported lesion at Baseline and during follow-up.
Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules and 
palpable lymph nodes) and ≥ 10 mm diameter as assessed using calipers.  For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
recommended.
Methods of Measurement
Conventional CT should be performed with cuts of 5 mm or less in slice thickness contiguously.  This 
applies to tumors of the chest and abdomen.  A scale should be incorporated into all radiographic 
measurements.
If prior to enrollment, it is known a subject is not able to undergo CT scans with IV contrast due to 
allergy or renal insufficiency, the decision as to whether a non-contrast CT or MRI should be used to 
evaluate the subject at Baseline and follow-up should be guided by the tumor type under investigation 
and the anatomic location of the disease.  For subjects who develop contraindications to contrast after 
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baseline contrast CT is done, the decision as to whether non-contrast CT or MRI should be made based 
upon discussion with the AbbVie Medical Monitor.
For accurate objective response evaluation, ultrasound should not be used to measure tumor lesions.
The utilization of endoscopy and laparoscopy for objective tumor evaluation is not advised.  However, 
such techniques can be useful in confirming complete pathological response when biopsies are 
obtained.
Cytology and histology can be used to differentiate between partial response (PR) and complete 
response (CR) in rare cases.
Baseline Documentation of "Target" and "Non-Target" Lesions
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of 
all involved organs should be identified as target lesions and recorded and measured at Baseline.  Tumor 
lesions situated in a previously irradiated area, or in an area subjected to other loco-regional therapy, 
are usually not considered measurable unless there has been demonstrated progression in the lesion.
Lymph nodes merit special mention since they are normal anatomical structures which may be visible by 
imaging even if not involved by tumor.  Pathological nodes which are defined as measurable and may be 
identified as target lesions must meet the criterion of a short axis of ≥ 15 mm by CT scan.  Only the short 
axis of these nodes will contribute to the baseline sum.  The short axis of the node is the diameter 
normally used by radiologists to judge if a node is involved by solid tumor.  Nodal size is normally 
reported as two dimensions in the plane in which the image is obtained (for CT scan this is almost 
always the axial plane).  The smaller of these measures is the short axis.  For example, an abdominal 
node which is reported as being 20 mm × 30 mm has a short axis of 20 mm and qualifies as a malignant, 
measurable node.  In this example, 20 mm should be recorded as the node measurement.  All other 
pathological nodes (those with short axis ≥ 10 mm but < 15 mm) should be considered non-target 
lesions.  Nodes that have a short axis < 10 mm are considered non-pathological and should not be 
recorded or followed.
A sum of diameters for all target lesions will be calculated and reported as the baseline sum of 
diameters.  If lymph nodes are to be included in the sum, then as noted above, only the short axis is 
added into the sum.  The baseline sum diameters will be used as reference by which to characterize the 
objective tumor response.
All other lesions (or sites of disease) including pathological lymph nodes should be identified as non-
target lesions and should also be recorded at Baseline.  Measurements of these lesions are not required, 
but the presence (stable, increasing or decreasing) or absence of each should be noted throughout 
follow-up.
Evaluation of Target Lesions
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M14-064 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Complete Response (CR):
The disappearance of all target lesions.  Any pathological lymph nodes (whether target or non-target) 
must have reduction in short axis to < 10 mm.
Partial Response (PR):
At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum 
diameters.
Progressive Disease:
At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest 
sum of diameters recorded since the treatment started (baseline or after) or the appearance of one or 
more new lesions.  In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm.
Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, 
taking as reference the smallest sum of diameters since the treatment started (baseline or after).
Assessment of Target Lesions:
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded (measured in the same anatomical plane as the baseline examination), even if the nodes 
regress to below 10 mm on study.  This means that when lymph nodes are included as target lesions, 
the 'sum' of lesions may not be zero even if CR criteria are met, since a normal lymph node is defined as 
having a short axis of < 10 mm.  For PR, SD and progressive disease, the actual short axis measurement 
of the nodes is to be included in the sum of target lesions.
All lesions (nodal and non-nodal) recorded at Baseline should have their actual measurements recorded 
at each subsequent evaluation, even when very small (< 5 mm).  However, sometimes target lesions or 
lymph nodes become too small to measure.  If it is in the opinion of the radiologist that the lesion has 
likely disappeared, the measurement should be recorded as 0 mm.  If the lesion is believed to be 
present, but too small to measure, a default value of 5 mm should be assigned (as derived from the 
5 mm CT slice thickness).  The measurement of these lesions is potentially non-reproducible; therefore 
providing this default value will prevent false responses or progression based upon measurement error.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M14-064 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Evaluation of Non-Target Lesions
Complete Response (CR):
The disappearance of all non-target lesions and normalization of tumor marker level.  All lymph nodes 
must be non-pathological in size (< 10 mm short axis).
Non-CR/Non-Progressive Disease:
Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the 
normal limits.
Progressive Disease:
Unequivocal progression of existing non-target lesions.
In this setting, to achieve 'unequivocal progression' on the basis of non-target disease, there must be an 
overall level of substantial worsening in non-target disease such that, even in the presence of SD or PR in 
target disease, the overall tumor burden has increased sufficiently to merit discontinuation of therapy.  
A modest 'increase' in the size of one or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status.  The designation of overall progression solely on the basis of change in 
non-target disease in the face of SD or PR of target disease will therefore be extremely rare.
Note:  If the subject discontinues treatment for symptomatic deterioration, every effort should be made 
to document objective progression even after discontinuation of treatment.
New Lesions
The appearance of new malignant lesions denotes disease progression.  While there are no specific 
criteria for the identification of new radiographic lesions, the findings of a new lesion should be 
unequivocal, i.e., not attributable to differences in scanning technique, timing of scanning, phase of 
contrast administration, change in imaging modality or finding thought to represent something other 
than tumor (e.g., some 'new' bone lesions may be simply healing or flare of pre-existing lesions).  A 
lesion identified on a follow-up study in an anatomical location that was not scanned at Baseline is 
considered a new lesion and will indicate disease progression.  An example of this is the subject who has 
visceral disease at Baseline and while on study has a CT or MRI brain ordered which reveals metastases.  
The subject's brain metastases are considered evidence of progressive disease even if he/she did not 
have brain imaging at Baseline.
If a new lesion is equivocal (i.e., too small to measure), continued therapy and follow-up evaluation will 
clarify if it represents truly new disease.  If repeat scans confirm there is a new lesion, then progression 
should be declared using the date of the initial scan.
In all cases, confirmation of response is not required.
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