S1613, A Randomized Phase II Study of Trastuzumab and Pertuzumab (TP) Compared to Cetuximab and Irinotecan (CETIRI) in Advanced/Metastatic Colorectal Cancer (mCRC) With HER-2 Amplification
Phase: PHASE2
Conditions: Colon Adenocarcinoma, ERBB2 Gene Amplification, Rectal Adenocarcinoma, Recurrent Colon Carcinoma, Recurrent Rectal Carcinoma, Stage III Colon Cancer AJCC v7, Stage III Rectal Cancer AJCC v7, Stage IIIA Colon Cancer AJCC v7, Stage IIIA Rectal Cancer AJCC v7, Stage IIIB Colon Cancer AJCC v7, Stage IIIB Rectal Cancer AJCC v7, Stage IIIC Colon Cancer AJCC v7, Stage IIIC Rectal Cancer AJCC v7, Stage IV Colon Cancer AJCC v7, Stage IV Rectal Cancer AJCC v7, Stage IVA Colon Cancer AJCC v7, Stage IVA Rectal Cancer AJCC v7, Stage IVB Colon Cancer AJCC v7, Stage IVB Rectal Cancer AJCC v7
Sponsor: SWOG Cancer Research Network

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PRIVILEGED COMMUNICATION 
Activation Date: October 9, 2017 
FOR INVESTIGATIONAL USE ONLY 
 
SWOG 
 
TITLE 
A RANDOMIZED PHASE II STUDY OF TRASTUZUMAB AND PERTUZUMAB (TP) COMPARED TO 
CETUXIMAB AND IRINOTECAN (CETIRI) IN ADVANCED/METASTATIC COLORECTAL CANCER 
(MCRC) WITH HER-2 AMPLIFICATION 
 
NCT #03365882 
 
STUDY CHAIRS: 
AGENTS: 
 
Kanwal Raghav, M.D. (Medical Oncology) 
IND-Exempt Agents: 
MD Anderson Cancer Center 
Cetuximab (Erbitux) (NSC-714692) 
1515 Holcombe Blvd, Unit 426 
Irinotecan (CPT-11, Camptosar) (NSC-616348) 
Houston, TX 77030 
 
Phone: 917/733-0356 
SWOG-Held IND Agents: 
FAX: 713/563-0617 
Pertuzumab (Perjeta) (NSC-740102)  
E-mail: kpraghav@mdanderson.org  
 
(IND-132527) 
 
Trastuzumab (Herceptin) (NSC-688097)  
Marwan Fakih, M.D. 
 
(IND-132527) 
(Medical Oncology/NRG investigator) 
 
City of Hope Medical Center        
1500 E. Duarte Road 
 
Duarte, CA 91010 
BIOSTATISTICIANS: 
Phone: 626/471-4673 
  
FAX: 626/301-8233 
Katherine A. Guthrie, Ph.D. 
E-mail: mfakih@coh.org  
Shay Bellasea, M.S. 
 
SWOG Statistics and Data Management Center 
Scott Kopetz, M.D., Ph.D. (Translational Med) 
Fred Hutchinson Cancer Research Center 
MD Anderson Cancer Center 
1100 Fairview Avenue N, M3-C102 
1515 Holcombe Blvd, Unit 426 
P.O. Box 19024 
Houston, TX 77030 
Seattle, WA 98109-1024 
Phone: 713/792-2828 
Phone: 206/667-4623 
FAX: 713/745-1163 
FAX: 206/667-4408 
E-mail: skopetz@mdanderson.org  
E-mail: kguthrie@fredhutch.org  
 
E-mail: sbellasea@fredhutch.org  
 
 
 
NCTN INVESTIGATORS: 
 
 
Benjamin Tan, Jr. M.D. (ALLIANCE) 
 
Washington University 
 
Phone: 314/747-7522 
 
E-mail: btan@wustl.edu     
 
 
 
Crystal Denlinger, M.D., FACP (ECOG-ACRIN) 
 
Fox Chase Cancer Center 
 
333 Cottman Avenue 
 
Philadelphia, PA 19107 
 
Phone: 215/214-1676 
 
Fax: 215/214-3229 
 
E-mail: crystal.denlinger@fccc.edu  
 
 

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ECOG-ACRIN STUDY CHAMPION: 
 
Crystal Denlinger, M.D., FACP (ECOG-ACRIN) 
Fox Chase Cancer Center 
333 Cottman Avenue 
Philadelphia, PA 19107 
Phone: 215/214-1676 
Fax: 215/214-3229 
E-mail: crystal.denlinger@fccc.edu  
 
NRG STUDY CHAMPION: 
 
Marwan Fakih, M.D. (Medical Oncology/NRG) 
 
City of Hope Medical Center 
 
1500 E. Duarte Road 
 
Duarte, CA 91010 
 
Phone: 626/471-4673 
 
FAX: 626/301-8233 
  
E-mail: mfakih@coh.org  
 
ALLIANCE STUDY CHAMPION: 
 
Benjamin Tan, Jr. M.D. (ALLIANCE) 
Washington University 
Phone: 314/747-7522 
E-mail: btan@wustl.edu  
 
 
 

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PARTICIPANTS 
 
ALLIANCE/Alliance for Clinical Trials in Oncology 
ECOG-ACRIN/ECOG-ACRIN Cancer Research Group 
NRG/NRG Oncology 
SWOG/SWOG 
 
 

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TABLE OF CONTENTS 
 
TITLE  ......................................................................................................................................................... 1 
PARTICIPANTS ............................................................................................................................................ 3 
TABLE OF CONTENTS ............................................................................................................................... 4 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION ....................... 6 
SCHEMA ....................................................................................................................................................... 7 
1.0 
OBJECTIVES .................................................................................................................................. 9 
1.1 
Primary Objective ............................................................................................................................. 9 
1.2 
Secondary Objectives ...................................................................................................................... 9 
1.3 
Additional Objectives ........................................................................................................................ 9 
1.4 
Translational Objective..................................................................................................................... 9 
2.0 
BACKGROUND ............................................................................................................................... 9 
3.0 
DRUG INFORMATION .................................................................................................................. 12 
3.1 
Cetuximab (IMC-C225, Erbitux®) (NSC-714692) ........................................................................... 12 
3.2 
Irinotecan (Camptosar ®) (NSC-616348) ...................................................................................... 13 
3.3 
Pertuzumab (Perjeta®, RO4368451) (NSC-740102, IND-132527) ............................................... 14 
3.4 
Trastuzumab (Herceptin®, rhuMAb HER-2/NEU; MoAb HER2/NEU) (NSC-688097, IND 132527)
 ....................................................................................................................................................... 24 
4.0 
STAGING CRITERIA ..................................................................................................................... 34 
5.0 
ELIGIBILITY CRITERIA ................................................................................................................ 34 
5.1 
Step 1 Initial Registration: HER-2 Testing ..................................................................................... 35 
5.2 
Step 2 Randomization .................................................................................................................... 36 
5.3 
Step 3 Crossover Registration (Optional) ...................................................................................... 39 
6.0 
STRATIFICATION FACTORS ....................................................................................................... 40 
7.0 
TREATMENT PLAN ...................................................................................................................... 40 
7.1 
Pre-Medication ............................................................................................................................... 40 
7.2 
General considerations .................................................................................................................. 40 
7.3 
Treatment – Arm 1: Trastuzumab + Pertuzumab (TP) a ................................................................ 43 
7.4 
Treatment – Arm 2: Irinotecan + Cetuximab (CETIRI)................................................................... 43 
7.5 
Crossover Following Disease Progression on CETIRI .................................................................. 44 
7.6 
Criteria for Removal from Protocol Treatment ............................................................................... 44 
7.7 
Discontinuation of Treatment ......................................................................................................... 45 
7.8 
Follow-Up Period ............................................................................................................................ 45 
8.0 
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS .............................................. 45 
8.1 
Two different versions of the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) will be used on this study ........................................................................................... 45 
8.2 
General Considerations ................................................................................................................. 45 
8.3 
Dose Modifications ......................................................................................................................... 45 
8.4 
Dose Modifications and Toxicity Management for TP and CETIRI ............................................... 47 
8.5 
Toxicity Management for TP Only .................................................................................................. 51 
8.6 
Dose Modifications and Toxicity Management for CETIRI Only .................................................... 52 
8.7 
White Blood Cell Growth Factors ................................................................................................... 54 
8.8 
Dose Modifications Contacts ......................................................................................................... 54 
8.9 
Adverse Event Reporting ............................................................................................................... 54 
9.0 
STUDY CALENDAR ...................................................................................................................... 55 
9.1 
Arm 1: Trastuzumab and Pertuzumab (TP) .................................................................................. 55 
9.2 
Arm 2: Cetuximab + Irinotecan (CETIRI) ...................................................................................... 57 
9.3 
Arm 3: Trastuzumab and Pertuzumab (TP) ................................................................................... 59 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS ..................................................... 61 
10.1 
Measurability of Lesions................................................................................................................. 61 
10.2 
Objective Status at Each Disease Evaluation ................................................................................ 62 
10.3 
Best Response ............................................................................................................................... 65 
10.4 
Performance Status: ...................................................................................................................... 65 
10.5 
Progression-Free Survival.............................................................................................................. 66 
10.6 
Time to Death ................................................................................................................................. 66 

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11.0 
STATISTICAL CONSIDERATIONS .............................................................................................. 66 
11.1 
Sample Size and Primary Analysis ................................................................................................ 66 
11.2 
Other Analyses ............................................................................................................................... 66 
11.3 
Translational Medicine ................................................................................................................... 67 
11.4 
Data and Safety Monitoring ........................................................................................................... 67 
12.0 
DISCIPLINE REVIEW .................................................................................................................... 69 
13.0 
REGISTRATION GUIDELINES ..................................................................................................... 69 
13.1 
Registration Timing ........................................................................................................................ 69 
13.2 
Investigator/Site Registration ......................................................................................................... 69 
13.3 
OPEN Registration Requirements ................................................................................................. 71 
13.4 
Registration Procedures................................................................................................................. 73 
13.5 
Exceptions to SWOG registration policies will not be permitted. ................................................... 73 
14.0 
DATA SUBMISSION SCHEDULE ................................................................................................ 73 
14.1 
Data Submission Requirement ...................................................................................................... 73 
14.2 
Master Forms ................................................................................................................................. 73 
14.3 
Data Submission Procedures ........................................................................................................ 74 
14.4 
Data Submission Overview and Timepoints .................................................................................. 75 
14.5 
Data Submission FOR PATIENTS WHO WILL NOT ENROLL TO STEP 2 RANDOMIZATION: 75 
14.6 
Step 2 Submission (required for patients randomized to a treatment arm) .......................... 75 
15.0 
SPECIAL INSTRUCTIONS............................................................................................................ 78 
15.1 
Specimens for HER-2 testing (required for patients) ..................................................................... 78 
15.2 
Submission of Specimens for Banking (optional for patients registered to Step 2 Randomization)
 ....................................................................................................................................................... 79 
15.3 
Submission of Images for Banking (required for patients on TP [Arm 1] and CETIRI [Arm 2]) ..... 82 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................... 86 
16.1 
Adverse Event Reporting Requirements........................................................................................ 86 
17.0 
BIBLIOGRAPHY ............................................................................................................................ 92 
18.0 
APPENDIX ..................................................................................................................................... 96 
18.1 
New York Heart Association Criteria .............................................................................................. 97 
18.2 
Receipt, Processing, and Distribution Instructions for the SWOG Biospecimen Bank .................. 98 
 
 
 

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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
For regulatory requirements: 
For patient 
enrollments: 
 
For study data submission: 
 
Regulatory documentation can be 
submitted to the CTSU via: 
 
ONLINE: 
Regulatory Submission Portal 
(Sign in at www.ctsu.org, and 
select the Regulatory Submission 
sub-tab under the Regulatory tab.)  
EMAIL: 
CTSURegulatory@ctsu.coccg.org 
(regulatory documentation only) 
FAX:  
215-569-0206 
MAIL:  
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
 
For regulatory questions call the 
CTSU Regulatory Help Desk at 1-
866-651-CTSU 
 
Please refer to the patient 
enrollment section of the 
protocol for instructions on using 
the Oncology Patient Enrollment 
Network (OPEN) which can be 
accessed at 
https://www.ctsu.org/OPEN_SY
STEM/ or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk 
with any OPEN-related 
questions at 
ctsucontact@westat.com. 
 
 
 
Data collection for this study will 
be done exclusively through 
Medidata Rave.  Please see the 
data submission section of the 
protocol for further instructions.  
 
Do not submit study data or 
forms to CTSU Data Operations. 
Do not copy the CTSU on data 
submissions. 
 
Other Tools and Reports: 
Institutions participating through 
the CTSU continue to have 
access to other tools and reports 
available on the SWOG 
Workbench. Access this by using 
your active CTEP-IAM userid 
and password at the following 
url: 
 
https://crawb.crab.org/TXWB/cts
ulogon.aspx  
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at 
https://www.ctsu.org.  Access to the CTSU members’ website is managed through the Cancer Therapy 
and Evaluation Program - Identity and Access Management (CTEP-IAM) registration system and requires 
user log on with CTEP-IAM username and password.  
For patient eligibility questions contact the SWOG Statistics and Data Management Center by phone 
or email: 
206-652-2267 
giquestion@crab.org 
For treatment or toxicity related questions contact the Study PI of the Coordinating Group. 
For questions unrelated to patient eligibility, treatment, or data submission contact the CTSU Help 
Desk by phone or e-mail: 
 
CTSU General Information Line: 
888-823-5923 
ctsucontact@westat.com  
 
All calls and correspondence will be triaged to the appropriate CTSU representative. 
 
The CTSU Web site is located at https://www.ctsu.org 

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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*  Screening prior to progression is permitted 
• Metastatic or locally advanced and unresectable colorectal cancer.* 
• KRAS & NRAS Wild Type (no mutation in exon 2 [codons 12 and 13], exon 3 [codon 59 and 61]; exon 4 [codons 117 and 146]).*  
• No BRAF V600E exon 15 mutation.* 
• No prior treatment with either cetuximab or pertuzumab. 
*Step 1 Registration:  
HER-2 Amplification Screening 
Not HER-2 amplified 
Exclude from study 
HER-2 Amplified 
Step 2 Registration: Randomization # 
Arm 1: Trastuzumab + Pertuzumab (TP) 
Arm 2: Cetuximab + Irinotecan (CETIRI) 
Disease progression 
Disease progression 
Arm 3 Crossover: Trastuzumab 
+ Pertuzumab (TP) 
Off Treatment 
Off Treatment 
Disease progression 
Off Treatment 
Step 3 Registration:  
Optional Crossover 

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#  Randomization can be performed after progression on at least one line (or maximum 2 lines) of chemotherapy. 

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1.0 
OBJECTIVES 
 
1.1 
Primary Objective 
 
a. 
To evaluate the efficacy of trastuzumab and pertuzumab (TP) in HER-2 amplified 
metastatic colorectal cancer (mCRC) by comparing progression-free survival 
(PFS) on TP compared to control arm of cetuximab and irinotecan (CETIRI). 
 
1.2 
Secondary Objectives 
 
a. 
To evaluate the overall response rate (ORR), including confirmed complete and 
partial response per RECIST 1.1, in the TP and CETIRI treatment arms. 
 
b. 
To evaluate the overall survival (OS) in the TP and CETIRI treatment arms. 
 
c. 
To evaluate the safety and toxicity of TP compared to CETIRI. 
 
1.3 
Additional Objectives 
 
a. 
To estimate the rates of PFS, OS, and ORR in patients who crossover to TP after 
disease progression on CETIRI. 
 
b. 
To bank images for future retrospective analysis. 
 
1.4 
Translational Objective 
 
a. 
To evaluate if the following are prognostic of clinical efficacy (PFS and ORR) in 
patients receiving TP or CETIRI: 
 
1. 
HER-2/CEP17 signal ratio 
 
2. 
HER-2 gene copy number (GCN) 
 
b. 
To bank tissue and blood samples for other future correlative studies from patients 
enrolled on the study. 
 
 
2.0 
BACKGROUND 
 
Scope of the Problem: Colorectal cancer (CRC) is a major global burden and accounts for over 
1.36 million new cancer cases and about 700,000 deaths as per 2012 estimates, worldwide. (1) 
Despite advances in systemic therapy, median survival in metastatic disease with current available 
regimens is about 30 months. (2) Options for systemic therapy are limited and include both 
cytotoxics (5-fluorouracil, capecitabine, oxaliplatin and irinotecan) and targeted agents 
(bevacizumab, cetuximab, pertuzumab, aflibercept, ramucirumab and regorafenib). (3) Therefore, 
a large unmet need for novel strategies targeting novel pathways involved in colorectal 
carcinogenesis and therapeutic resistance exists.  The HER-2 (human epidermal growth factor 2) 
pathway is emerging as one such unique potentially drug-targetable pathway in CRC through 
comprehensive molecular characterization and recurrent copy number alterations specifically 
amplifications of HER-2 have been identified. (4,5) 
 
HER-2 Amplification/Overexpression in CRC: HER-2 is amplified and/or overexpressed in a 
small but distinct subset (3-4%) of all unselected cases of mCRC. (6,7,8,9) As is the case with 
breast cancer, strong concordance exists between gene amplification and protein overexpression. 
(10) While low level of gene amplification and protein overexpression suggests that this oncogene 
plays an infrequent role in development and progression of unselected mCRC, recent data has 

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emerged showing enrichment for HER-2 amplification in cetuximab-resistant KRAS wild type 
subset (13.6%) and in quadruple negative (wild type KRAS, NRAS, BRAF and PIK3CA) 
xenopatients (36.4%) demonstrating its key role in a select subset of mCRC and in development 
of resistance to anti-EGFR therapy in mCRC. (11) The largest prospective experience regarding 
the prevalence of HER-2 amplification in mCRC patients comes from the HERACLES study in 
which HER-2 amplification (by IHC and FISH) was seen in 4.8% (total patients with KRAS wild-
type tumors screened = 913). (12) This also forms the basis of HER-2 testing strategy in mCRC. 
(2)  In a retrospective analysis of 1,342 patients in stage IV trials (FOCUS and PICCOLO), HER-2-
overexpression was associated with KRAS/BRAF-wild type status (5.2% in wild type versus 1.0% 
in mutated tumors (P < 0.0001). (13) HER-2 amplification will be tested using the principles of 
ASCO/CAP guidelines for breast cancer and TOGA criterion for gastric cancer. (14,15) Patients 
will be tested for HER-2 using immunohistochemistry (IHC) and dual-probe in-situ hybridization 
(Dual-ISH). The following criteria will be used: 
 
• 
HER-2 IHC 
o 
Patients with HER-2 IHC 0 (no reactivity) and HER-2 IHC 1+ (faint or barely 
perceptible membranous reactivity) will be considered as HER-2 non-amplified. 
o 
Patients with HER-2 IHC 2+/3+ (weak to moderate complete basolateral or lateral 
membranous reactivity in > 10% of cancer cells) will undergo Dual ISH. 
• 
Dual-ISH 
o 
HER-2 amplification testing will then be performed on HER IHC 2+/3+ cases and 
will be considered positive if HER-2/CEP17 ratio ≥ 2.0. These cases will be 
reported as HER-2 amplified. Cases with HER-2/CEP17 ratio < 2.0 will be reported 
as non-amplified. 
 
HER-2 and Anti-EGFR Resistance: Extensive cross-talk between EGFR and HER-2 signaling 
links HER-2 in development of resistance to anti-EGFR therapy (cetuximab or pertuzumab).  
Although, EGFR expression is seen in about 50% of mCRC, anti-EGFR monotherapy results in low 
response rates and minimal clinical benefit even after appropriate selection of patients for RAS 
mutations, the single most important negative predictive biomarker, and other alterations in one or 
more downstream effectors of EGFR pathway (BRAF, AKT, PIK3CA). (16) In a molecularly 
annotated platform of patient derived xenografts, HER-2 amplification was shown to be an 
important mechanism of cetuximab resistance in mCRC patients. (17) This blunted response to 
anti-EGFR therapy was demonstrated clinically in a small retrospective study (N = 170) of mCRC 
patients. (18) In this study 4% patients with HER-2 gene amplification (HER-2/CEP17 ratio ≥ 2) 
compared to non-amplified patients showed poorer progression-free survival (median PFS in 
months: 2.5 vs 6.7; P = 0.0026) and overall survival (median OS in months: 4.2 vs 13.0; P = 0.0002). 
(19) In another cohort (n = 233) of mCRC patients with 13 (5.5%) HER-2 amplified tumors treated 
with cetuximab alone or in combination with chemotherapy, Yoneska et al. showed similar results 
with median PFS for HER-2 amplified patients being 2.9 months (0/23 responses to prior anti-
EGFR therapy) compared to 5.0 months for patients without HER-2 amplification. (20)   
 
HER-2 Inhibition in CRC (Pre-clinical and Clinical Data):  In patient derived xenografts of HER-
2 amplified mCRC, dual inhibition of HER-2 with lapatinib and pertuzumab resulted in significant 
tumor volume reduction. (21) A Phase II study of trastuzumab in combination with irinotecan in 
HER-2 overexpressed mCRC refractory to first-line therapy was performed by Ramanathan et al. 
and showed HER-2 overexpression was present in 11 of 138 (8.0%) of screened tumors. (22) 
Partial responses were seen in 70% cases (5/7 evaluable patients). (23) In another Phase II study 
of trastuzumab and lapatinib in HER-2-amplified, KRAS exon 2 wild-type, mCRC patients (n = 44 
[total screened 913]) resistant to standard therapies (HERACLES Trial) an overall response rate of 
35% (8 of 23 evaluable) was observed. (24) Median time to progression was 5.5 months (95% CL 
3.7-9.8) and toxicity was limited to Grade 2 diarrhea, fatigue, and rash. (25) Preliminary experience 
from the My Pathway study which enrolled 13 HER-2 amplified mCRC patients refractory to 
standard lines of therapy and treated with trastuzumab and pertuzumab, showed partial responses 
in 3 and stable disease in 6 patients of 11 evaluable patients. (26) 
 

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Rationale for Control Arm:  Addition of anti-EGFRab such as Cetuximab to a cytotoxic 
chemotherapy backbone is considered the standard of care for RAS wild-type patients. Irinotecan 
based regimen is considered the standard of care for patients who have progressed on an 
oxaliplatin based regimen. (27) Although both FOLFIRI and irinotecan can be used in patients after 
progression on FOLFOX based therapy, in a meta-analysis, no overall survival benefit of irinotecan 
and fluoropyrimidine treatment over irinotecan alone was seen and therefore both regimens remain 
reasonable options in treating patients with advanced or metastatic CRC, especially in patients who 
have progressed on a prior 5FU based regimen. (28) Since there were higher risks of toxicity 
outcomes Grade 3 or 4 diarrhea and Grade 3 or 4 neutropenia in combination, we choose irinotecan 
as the chemotherapy backbone. (29) The EPIC trial of second line cetuximab and irinotecan after 
oxaliplatin progression showed improved PFS and ORR with combined therapy. (30) Similarly, the 
BOND trial compared irinotecan plus weekly cetuximab versus cetuximab alone in patients with 
irinotecan-refractory mCRC and showed that combined therapy was associated with a significantly 
better response rate and TTP. (31)  
 
Summary: Recognizing that HER-2 amplification adversely influences the clinical response to 
therapy with anti-EGFR-antibody, cetuximab (negative predictor of response to EGFR inhibition), 
and is predictive of response to dual anti-HER-2 therapy (positive predictor of response to HER-2-
targeting agents), in HER-2 amplified mCRC patients, we hypothesize that dual anti-HER-2 
inhibition using monoclonal antibodies, trastuzumab and pertuzumab, will result in enhanced tumor 
suppression in irinotecan-refractory mCRC patients thereby resulting in improved progression-free 
survival outcomes compared to standard of care therapy with cetuximab and irinotecan.   
 
Inclusion of Women and Minorities 
 
This study was designed to include women and minorities, but was not designed to measure 
differences of intervention effects.  The anticipated accrual in the ethnicity/race and sex categories 
is shown in the table below.  
 
Note: We estimate that approximately 296 patients will be screened for HER-2 amplification in order 
to enroll the 62 patients necessary for the study. This table represents only the patients with HER-
2 amplification who register to Step 2 (randomization).  
 
DOMESTIC PLANNED ENROLLMENT REPORT 
Racial 
Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American 
Indian/ Alaska 
Native 
1 
1 
0 
0 
2 
Asian 
2 
2 
0 
1 
5 
Native 
Hawaiian or 
Other Pacific 
Islander 
1 
1 
0 
0 
2 
Black or 
African 
American 
2 
2 
0 
0 
4 
White 
23 
24 
1 
1 
49 
More Than 
One Race 
0 
0 
0 
0 
0 
Total 
29 
30 
1 
2 
62 
 

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3.0 
DRUG INFORMATION 
 
Investigator Brochures  
 
For information regarding Investigator Brochures, please refer to SWOG Policy 15. 
 
For this study, cetuximab and irinotecan are commercially available; therefore, Investigator 
Brochures are not applicable to this/these drug/s.  Information about commercial drugs is publicly 
available in the prescribing information and other resources. 
 
For this study, pertuzumab and trastuzumab are investigational and are being provided under an 
IND held by SWOG.  For INDs filed by SWOG, the protocol serves as the Investigator Brochure for 
the performance of the protocol.  In such instances submission of the protocol to the IRB should 
suffice for providing the IRB with information about the drug.  However, in cases where the IRB 
insists on having the official Investigator Brochure from the company, further information may be 
requested by contacting the SWOG Operations Office at 210/614-8808. 
 
3.1 
Cetuximab (IMC-C225, Erbitux®) (NSC-714692)  
 
a. 
PHARMACOLOGY 
 
Mechanism of Action: Cetuximab, a chimerized antibody of the IgG1 subclass, was 
originally derived from a mouse myeloma cell line.  Cetuximab was genetically 
engineered by cloning the heavy and light chains of cetuximab and adapting them 
for expression together with the constant regions of the human kappa light chain 
and human gamma 1 heavy chain.  The chimerization resulted in an antibody with 
binding affinity to epidermal growth factor receptors (EGFR) greater than the 
natural ligand epidermal growth factor (EGF).  Cetuximab blocks binding of EGF 
and transforming growth factor alpha (TGFα) to EGFR and inhibits ligand-induced 
activation of this tyrosine kinase receptor.  Cetuximab also stimulates EGFR 
internalization, effectively removing the receptor from the cell surface for 
interaction with ligand. 
  
b. 
PHARMACOKINETICS 
 
1. 
Absorption: When cetuximab was administered as monotherapy or in 
combination with chemotherapy or radiation therapy it exhibited nonlinear 
pharmacokinetics.  The area under the concentration time curve (AUC) 
increased in a greater than dose proportional manner while the clearance 
decreased from 0.08 to 0.02 L/h/m2 as the dose increased from 20 to 200 
mg/m2.  The clearance seemed to plateau at doses greater than 200 
mg/m2. 
 
2. 
Distribution: The volume of distribution of cetuximab is independent of the 
dose and is approximately the plasma volume (2 to 3 L/m2).  When 
administered at the recommended dose regimen of 400 mg/m2 initial dose 
followed by 250 mg/m2 weekly dose, the concentration of cetuximab 
reached steady-state levels by the third weekly infusion with mean peak 
and trough concentrations in the range of 168 to 235 and 41 to 85 mcg/mL, 
respectively. 
 
3. 
Metabolism: Cetuximab is eliminated via the EGFR binding/internalization 
on hepatocytes and skin in a saturable manner. 
 

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4. 
Elimination:  At the recommended dose regimen, the mean half-life of 
cetuximab was approximately 112 hours (range 63–230 hours). 
 
3.2 
Irinotecan (Camptosar ®) (NSC-616348) 
 
a. 
PHARMACOLOGY 
 
Mechanism of Action: Irinotecan and its metabolite SN-38 inhibit topoisomerase I. 
Topoisomerase I relieves torsional strain in the DNA helix during replication and 
RNA transcription by inducing single-strand breaks. By binding with the 
topoisomerase I—DNA complex, irinotecan or SN-38 prevents the relegation of 
the single-strand breaks. Irreversible DNA damage occurs when a DNA replication 
fork encounters the irinotecan or SN-38/topoisomerase I complexes resulting in 
double-strand DNA breaks. Camptothecins are highly S-phase specific in their 
activity due the requirement of DNA synthesis. 
 
b. 
PHARMACOKINETICS 
 
1. 
Absorption: N/A 
 
2. 
Distribution: Protein binding of irinotecan is 30-70%, whereas SN-38 
shows a higher protein binding of 95%. Both irinotecan and SN-38 are 
primarily bound to albumin. Volume of distribution of irinotecan is 
approximately 110-234 L/m2. 
 
3. 
Metabolism: Irinotecan is metabolized primarily in the liver by 
carboxylesterase to SN-38, and via hepatic cytochrome P450 (CYP) 3A4 
to aminopentane carboxylic acid (APC). SN-38 is conjugated to form a 
glucuronide metabolite by the enzyme UDP-glucuronosyl transferase 1A1 
(UGT1A1). Genetic polymorphisms exist in the enzyme UGT1A1, leading 
to different levels of exposure and toxicity among patients.  In addition, 
both irinotecan and SN-38 undergo plasma hydrolysis between their active 
(lactone) and inactive forms (carboxylate). Finally, a small amount of 
irinotecan is metabolized by the intestinal wall. 
 
4. 
Elimination: Approximately 10-25% of irinotecan is recovered unchanged 
in urine whereas only small amounts of SN-38 have been found. 
Clearance is approximately 13.5 L/hr/m2. In addition, irinotecan has 
approximately 25% biliary excretion. 
 
c. 
ADVERSE EFFECTS  
 
1. 
Possible Side Effects of irinotecan: 
Refer to the current FDA-approved package insert for the most 
comprehensive and up to date information on adverse reactions. 
 
Adverse effects reported in >20% to 100% of subjects treated with 
irinotecan include: diarrhea and cholinergic reaction (may be severe), 
constipation, 
nausea, 
vomiting, 
asthenia, 
infection, 
leukopenia, 
neutropenia, alopecia, anorexia, weight loss, anemia, fatigue, fever, pain, 
dizziness, cough, dyspnea, mucositis, rash, thrombocytopenia. 
 
Adverse effects reported in 4% to 20% of subjects include: gastrointestinal 
perforation, 
hypersensitivity 
reaction, 
cardiovascular 
events, 
thromboembolic events, interstitial lung disease. 
 

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2. 
Pregnancy and Lactation: Pregnancy Category D. It is not known whether 
irinotecan or its derivatives are excreted in human milk. Women should 
avoid pregnancy while taking irinotecan (in combination with cetuximab) 
and for at least 6 months after the last dose and men should avoid potential 
partner’s pregnancy for at least 3 months after the last dose. 
 
3. 
Drug Interactions: Irinotecan and its active metabolite SN-38 may be 
substrates 
for 
CYP3A4, 
CYP2B6, 
OATP1B1/SCLO1B1, 
P-
glycoprotein/ABCB1 and UGT1A1. Inducers or inhibitors may affect serum 
concentrations of irinotecan. Due to potential drug interactions, a complete 
patient medication list, including irinotecan, should be screened prior to 
initiation of and during treatment with irinotecan. Refer to the current FDA-
approved package insert. See Section 8.0 Toxicities to be Monitored and 
Dosage Modifications. 
 
d. 
DOSING & ADMINISTRATION 
 
See Section 7.0 Treatment Plan  
 
e. 
HOW SUPPLIED  
 
Irinotecan is commercially available and will not be supplied. Refer to the current 
FDA-approved package insert for the most comprehensive and up to date 
information. 
 
3.3 
Pertuzumab (Perjeta®, RO4368451) (NSC-740102, IND-132527) 
 
a. 
PHARMACOLOGY 
 
Mechanism of Action: Pertuzumab is a HER2/neu receptor antagonist that blocks 
ligand-dependent heterodimerization of HER2 with other HER family members, 
including EGFR, HER3, and HER4. As a result, pertuzumab inhibits ligand-initiated 
intracellular signaling through two major signal pathways, mitogen-activated 
protein (MAP) kinase, and phosphoinositide 3-kinase (PI3K). Inhibition of these 
signaling pathways can result in cell growth arrest and apoptosis, respectively. In 
addition, pertuzumab mediates antibody-dependent cell-mediated cytotoxicity 
(ADCC). 
 
Description: Pertuzumab is a recombinant humanized monoclonal antibody that 
targets the extracellular dimerization domain (Subdomain II) of the human 
epidermal growth factor receptor 2 protein (HER2). Pertuzumab is produced by 
recombinant DNA technology in a mammalian cell (Chinese Hamster Ovary) 
culture. M.W.: 148 kDa. 
 
b. 
PHARMACOKINETICS 
 
1. 
Absorption: steady state concentration is reached after the first 
maintenance dose 
 
2. 
Distribution: two-compartment linear model 
 
3. 
Metabolism: Does not appear to undergo renal or hepatic metabolism 
 
4. 
Elimination: first-order elimination; total body clearance 0.24 L/day; 
elimination half-life 18 days. 
 
 

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c. 
ADVERSE EFFECTS: Pertuzumab (Perjeta) (NSC-740102, IND 132527) 
 
1. 
Adverse Effects: 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
For Pertuzumab (NSC 740102) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) 
provides a single list of reported and/or potential adverse events (AE) 
associated with an agent using a uniform presentation of events by body 
system. In addition to the comprehensive list, a subset, the Specific 
Protocol Exceptions to Expedited Reporting (SPEER), appears in a 
separate column and is identified with bold and italicized text. This subset 
of AEs (SPEER) is a list of events that are protocol specific exceptions to 
expedited reporting to NCI (except as noted below).  Refer to the 'CTEP, 
NCI 
Guidelines: 
Adverse 
Event 
Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
aeguidelines.pdf for further clarification. Frequency is provided based on 
9575 patients. Below is the CAEPR for Pertuzumab. 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted 
in parentheses next to the AE in the SPEER.  If this CAEPR is part of a 
combination protocol using multiple investigational agents and has an AE 
listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
 
NOTE: Frequencies of AEs on this CAEPR are based on pooled clinical 
data from treatment arms, pivotal clinical trials using pertuzumab in 
combination with trastuzumab and docetaxel in patients with MBC 
(metastatic breast cancer), and pertuzumab in combination with 
trastuzumab and chemotherapy in patients with EBC (early stage breast 
cancer).   
 
Version 2.4, July 6, 20191 
 
 Adverse Events with Possible  
 Relationship to Pertuzumab 
 (CTCAE 5.0 Term) 
[n= 9575] 
 
 Specific 
Protocol 
Exceptions to 
Expedited 
Reporting 
(SPEER) 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but 
Serious (<3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
 
Anemia 
 
Anemia (Gr 3) 
 
Febrile 
neutronpenia 
 
Febrile 
neutropenia  
(Gr 2) 
CARDIAC DISORDERS 
 
 
 
Heart failure 
 
EYE DISORDERS 
 
 
Watering eyes  
 
GASTROINTESTINAL DISORDERS 
 
 
Abdominal 
pain 
 
 
 
Constipation 
 
Constipation  

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 Adverse Events with Possible  
 Relationship to Pertuzumab 
 (CTCAE 5.0 Term) 
[n= 9575] 
 
 Specific 
Protocol 
Exceptions to 
Expedited 
Reporting 
(SPEER) 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but 
Serious (<3%) 
(Gr 2) 
Diarrhea 
 
 
Diarrhea (Gr 3) 
 
Dyspepsia 
 
 
 
Mucositis oral  
Mucositis oral 
(Gr 2) 
Nausea 
 
 
Nausea (Gr 3) 
Vomiting 
 
 
Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION 
SITE CONDITIONS 
 
 
Edema limbs  
Edema limbs 
 (Gr 2) 
Fatigue 
 
 
Fatigue (Gr 2) 
 
Fever 
 
Fever (Gr 2) 
 
General 
disorders and 
administration 
site conditions 
- Other 
(mucosal 
inflammation) 
 
 
IMMUNE SYSTEM DISORDERS 
 
 
Allergic 
reaction2 
 
Allergic reaction2 
(Gr 2) 
 
 
Anaphylaxis2 
 
INFECTIONS AND INFESTATIONS 
 
 Infection3 
 
 
Infection3 (Gr 3) 
INJURY, POISONING AND PROCEDURAL 
COMPLICATIONS 
 
 
Dermatitis 
radiation 
 
 
 
Infusion 
related 
reaction4 
 
Infusion related 
reaction4 (Gr 2) 
INVESTIGATIONS 
 
 
Alanine 
aminotransfer
ase increased 
 
 
 
Aspartate 
aminotransfer
ase increased 
 
 
 
 
Ejection fraction 
decreased 
 
Neutrophil count 
decreased 
 
 
Neutrophil count 
decreased (Gr 2) 
 
White blood 
cell decreased 
 
White blood cell 
decreased (Gr 2) 

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 Adverse Events with Possible  
 Relationship to Pertuzumab 
 (CTCAE 5.0 Term) 
[n= 9575] 
 
 Specific 
Protocol 
Exceptions to 
Expedited 
Reporting 
(SPEER) 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but 
Serious (<3%) 
METABOLISM AND NUTRITION DISORDERS 
 
 
Anorexia 
 
Anorexia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE 
DISORDERS 
 
 
Arthralgia 
 
Arthralgia (Gr 2) 
 
Back pain 
 
 
 
Myalgia 
 
Myalgia (Gr 2) 
 
Pain in 
extremity 
 
 
NERVOUS SYSTEM DISORDERS 
 
 
Dizziness 
 
Dizziness (Gr 2) 
 
Dysgeusia 
 
Dysgeusia (Gr 2) 
 
Headache 
 
Headache (Gr 2) 
 
Paresthesia 
 
 
 
Peripheral 
motor 
neuropathy 
 
 
 
Peripheral 
sensory 
neuropathy 
 
 
PSYCHIATRIC DISORDERS 
 
 
Insomnia 
 
Insomnia (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS 
 
 
Cough 
 
 
 
Dyspnea 
 
Dyspnea (Gr 2) 
 
Epistaxis 
 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
Alopecia 
 
 
Alopecia (Gr 2) 
 
Dry skin 
 
 
 
Nail changes  
Nail changes (Gr 
2) 
 
Palmar-
plantar 
erythrodysest
hesia 
syndrome 
 
 
 
Pruritus 
 
Pruritus (Gr 2) 
 
Rash5 
 
Rash5 (Gr 2) 
VASCULAR DISORDERS 
 
 
Hot flashes 
 
 
1 
This table will be updated as the toxicity profile of the agent is revised.  
Updates will be distributed to all Principal Investigators at the time of 
revision.  The current version can be obtained by contacting 

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PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, 
the protocol and the agent should be included in the e-mail. 
2 
Symptoms of allergic reaction and anaphylaxis may include 
bronchospasm. 
 
3 
Infection may include any of the 75 infection sites under the 
INFECTIONS AND INFESTATIONS SOC and may be due to 
concomitant chemotherapy. 
4 
In pivotal studies adverse events that occurred during or within 24 
hours after study drug administration and were judged to be related to 
the infusion of study drug were captured as associated signs and 
symptoms, not as a diagnosis (e.g., “infusion-related reaction”). 
5 
Rash includes the terms rash, exfoliative rash, rash papular, rash 
maculo-papular. 
 
Adverse events reported on pertuzumab trials, but for which there is 
insufficient evidence to suggest that there was a reasonable 
possibility that pertuzumab caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Bone marrow 
hypocellular; Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Chest pain - cardiac; Left 
ventricular systolic dysfunction; Pericardial effusion 
EYE DISORDERS - Blurred vision; Dry eye; Eye disorders - Other 
(diplopia) 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Dry 
mouth; Esophagitis; Gastroesophageal reflux disease; Hemorrhoids 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - 
Chills; Death NOS; Flu like symptoms; Generalized edema; Non-cardiac 
chest pain; Pain 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatobiliary disorders - 
Other (hepatitis fulminant); Hepatobiliary disorders - Other (hepatocellular 
injury) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - 
Fracture; Injury, poisoning and procedural complications - Other (post-
procedural inflammation); Injury, poisoning and procedural complications 
- Other (procedural pain); Injury, poisoning and procedural complications 
- Other (skin toxicity); Wound complication; Wound dehiscence 
INVESTIGATIONS - Alkaline phosphatase increased; Blood bilirubin 
increased; Creatinine increased; GGT increased; Investigations - Other 
(granulocytopenia); Lymphocyte count decreased; Platelet count 
decreased; Weight gain; Weight loss 
METABOLISM 
AND 
NUTRITION 
DISORDERS 
- 
Dehydration; 
Hyperglycemia; Hypoglycemia; Hypokalemia; Hypomagnesemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - 
Bone pain; Muscle cramp; Musculoskeletal and connective tissue disorder 
- Other (dermatomyositis syndrome); Musculoskeletal and connective 
tissue disorder - Other (spinal pain) 
NERVOUS SYSTEM DISORDERS - Amnesia; Dysarthria; Lethargy; 
Nervous system disorders - Other (osmotic demyelination syndrome); 
Somnolence; Syncope 
PSYCHIATRIC DISORDERS - Anxiety; Depression 
RENAL AND URINARY DISORDERS - Acute kidney injury; Dysuria; 
Urinary frequency 

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REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Amenorrhea; 
Breast pain; Irregular menstruation; Reproductive system and breast 
disorders - Other (metrorrhagia); Vaginal dryness 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - 
Bronchospasm4; Nasal congestion; Oropharyngeal pain; Pleural effusion; 
Pneumonitis; Postnasal drip; Respiratory failure; Respiratory, thoracic and 
mediastinal disorders - Other (painful respiration); Rhinorrhea 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Erythema 
multiforme; Erythroderma; Hyperhidrosis; Nail discoloration; Pain of skin; 
Rash acneiform; Skin and subcutaneous tissue disorders - Other 
(onycholysis); Skin and subcutaneous tissue disorders - Other 
(onychomadesis); Skin hyperpigmentation; Urticaria 
VASCULAR DISORDERS - Flushing; Hypertension; Hypotension; 
Lymphedema; Thromboembolic event; Vascular disorders - Other 
(hyperemia) 
 
Note: Pertuzumab in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the 
other agent, or the combination may result in events never previously 
associated with either agent. 
 
2. 
Pregnancy and Lactation: Pregnancy Category D 
 
Based on its mechanism of action and findings in animal studies, Perjeta 
can cause fetal harm when administered to a pregnant woman. No studies 
of Perjeta use during pregnancy have been performed. Cases of 
oligohydramnios 
and 
oligohydramnios 
sequence 
manifesting 
as 
pulmonary hypoplasia, skeletal abnormalities, and neonatal death have 
been reported with use of Herceptin during pregnancy. Monitor women 
who received Perjeta and Herceptin during pregnancy or within 7 months 
prior to conception for oligohydramnios.  If oligohydramnios occurs, 
perform fetal testing that is appropriate for gestational age and is 
consistent with community standards of care. 
 
Additional information on any pertuzumab- and/or trastuzumab-exposed 
pregnancy and infant will be requested by Roche Drug Safety at specific 
time points until 12 months of the infant’s life. In case of a report of a 
congenital abnormality, a guided questionnaire will be sent out by Roche 
Drug Safety. 
 
It is unknown whether pertuzumab is excreted into human milk. Published 
literature suggests human IgG is present in all milk, but does not enter the 
neonatal and infant circulation in substantial amounts. However, due to 
the potential for adverse effects on the infant from nursing, it is advisable 
to discontinue breast-feeding during treatment with pertuzumab (in 
combination with trastuzumab) and for 7 months after the last dose. 
 
3. 
Drug Interactions: No drug-drug interactions were observed between 
pertuzumab and trastuzumab, or between pertuzumab and docetaxel. 
 
d. 
DOSING & ADMINISTRATION 
 
See Section 7.0 Treatment Plan 
 
• Route of Administration: intravenous. 
Method of Administration: The initial pertuzumab dose is administered as 

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a 60-minute intravenous infusion.  Subsequent doses are administered by 
intravenous infusion over 30 or 60 minutes, depending on how the initial 
dose was tolerated. 
 
e. 
HOW SUPPLIED 
 
Pertuzumab is supplied by Genentech, Inc. and distributed by Biologics, Inc.  
Pertuzumab is a sterile, clear to slightly opalescent, colorless to pale brown liquid 
for intravenous infusion.  Each single use vial contains 420 mg of pertuzumab at a 
concentration of 30 mg/mL (14mL) in 20 mM L-histidine acetate (pH 6.0), 120 mM 
sucrose and 0.02% polysorbate 20. 
 
f. 
STORAGE, PREPARATION & STABILITY 
 
1. 
Storage: 
• Keep vials in the outer carton in order to protect from light. 
• Store vials in a refrigerator at 2˚C to 8˚C (36˚F to 46˚F) until time of use. 
• Contact supplier for temperature excursion information. 
• Do not freeze. 
• Do not shake. 
 
2. 
Stability: 
 
If the diluted infusion solution is not used immediately, it can be stored at 
2ºC to 8ºC for up to 24 hours.  Dilute with 0.9% Sodium Chloride 
injection only.  
 
Diluted pertuzumab has been shown to be stable for up to 24 hours at a 
temperature up to 30°C. However, since diluted pertuzumab contains no 
preservative, the diluted solution should be stored refrigerated (2°C–8°C). 
 
3. 
Preparation: 
 
Administer as an intravenous infusion only. Do not administer as an 
intravenous push or bolus. Do not mix pertuzumab with other drugs.  
 
Prepare the solution for infusion, using aseptic technique, as follows:  
• 
Parenteral drug products should be inspected visually for 
particulates and discoloration prior to administration.  
• 
Withdraw the appropriate volume of pertuzumab solution from 
the vial(s).  
• 
Dilute into a 250 mL 0.9% sodium chloride PVC or non-PVC 
polyolefin infusion bag.  
• 
Mix diluted solution by gentle inversion. Do not shake.  
• 
Administer immediately once prepared. 
 
4. 
Compatibility: 
• 
0.9% sodium chloride only. 
• 
Do not use dextrose (5%) solution. 
 
g. 
DRUG ORDERING & ACCOUNTABILITY 
 

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1. 
Drug ordering and shipping 
 
a. 
Pertuzumab may be requested by the principal investigator (or 
their authorized designee) at each participating site by completing 
the Biologics Drug Order Request Form for S1613 once the 
patient has been randomized and faxing to the number listed on 
the order form. Authorized and completed orders will be 
processed and shipped “same day” of receipt if received before 
2:00 p.m. EST Monday through Thursday. Authorized and 
completed orders received after 2:00pm EST Monday through 
Thursday or on Friday will be processed and shipped the next 
business morning. All drug orders are shipped via FedEx Priority 
Overnight delivery.  Biologics distribution team monitors packages 
throughout duration of transit via FedEx One Call Solution (live 
support) and delivery exceptions are managed at the highest level 
of urgency to ensure therapy start date adherence. Packing slips 
with the shipment tracking number included will be faxed to the 
designated site coordinator.  
 
Drug deliveries are restricted during weekends and holidays. 
Biologics, Inc. observes the following holidays: New Year’s Day, 
Memorial Day, Independence Day, Labor Day, Thanksgiving Day, 
the Friday following Thanksgiving Day, Christmas Eve, and 
Christmas Day. Sites should plan ahead to accommodate patients 
being treated during restricted times. 
 
Sites must allow up to 5 business days for study drug to arrive 
once the Drug Order Request Form is submitted to Biologics. The 
Drug Order Request Form should be faxed to 919-256-0794. 
 
b. 
Once a patient is randomized, the site will fax a completed Drug 
Order Request Form to Biologics at 919-256-0794. Upon receipt 
of completed and faxed Drug Order Request Form, Biologics Inc. 
will: 
 
• 
Check to confirm site has an active registration and approval 
for shipment. 
 
• 
Place a call or email to the site confirming the Drug Order 
Request Form was received, while providing the estimated 
day and time of arrival for the study drug.  
 
• 
Prepare an initial shipment supply for the patient’s loading 
dose and subsequent 4 cycles.  
 
• 
Each vial of pertuzumab is 420 mg.  Drug will be labeled by 
Genentech for Investigational Use Only. Drug supply will be 
dispensed by Biologics with patient-specific labeling.  
 
o 
Initial shipments will include approximately 6 vials of 
pertuzumab to complete a loading dose of 840 mg and 4 
subsequent cycles at 420 mg. 
 

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c. 
If additional drug is required, the site will fax a completed Drug 
Order Request Form to Biologics at 919-256-0794. 
 
• Check to confirm site has an active registration and approval 
for shipment. 
 
• Place a call or email to the site confirming the Drug Order 
Request Form was received, while providing the estimated 
day and time of arrival for the study drug.  
 
• Prepare a subsequent shipment supply for the patient’s 
subsequent 4 cycles.  
 
• Drug will be labeled by Genentech for Investigational Use 
Only. Drug supply will be dispensed by Biologics with patient-
specific labeling.  
 
o 
Subsequent shipments will include approximately 4 vials 
of pertuzumab to complete 4 subsequent cycles at 420 
mg. 
 
d. 
Each shipment includes a patient-specific label on the outer 
packaging with the following information: 
 
• 
Study Number and Date Dispensed 
• 
Drug Identification, Lot number, Expiration Date 
• 
Patient ID Number 
• 
Patient Initials 
• 
Storage Instructions 
• 
Dosing Instructions 
• 
IND Caution statement  
 
e. 
Drug Accountability: The investigator, or a responsible party 
designated by the investigator, must maintain a careful record of 
the receipt, disposition, and return or disposal of all drugs received 
from the supplier using the NCI Drug Accountability Record Form 
(DARF) available at http://ctep.cancer.gov. 
 
f. 
Electronic logs are allowed as long as a print version of the log 
process is the exact same appearance as the current NCI DARF. 
If the trial is a placebo control trial – indicate that separate DARFs 
are needed for each patient to also include the placebo drug 
supply. 
 
2. 
Drug return and/or disposition instruction (include forms if needed) 
 
a. 
Drug Returns: Unused drug supplies should NOT be returned. 
Unused drug should be disposed of per local institutional 
guidelines. 
 
b. 
Drug expiration:  Indicate drug expiration date on the DARF under 
Manufacturer and Lot # and use the drug lots with shorter 
expiration date first. 
 

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3. 
Contact Information 
 
 
Questions about drug orders, transfers, returns, or accountability should 
be addressed to Clinical Research Services at Biologics, Inc. at 800-693-
4906 or clinicaltrials@biologicsinc.com.  
 
 

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3.4 
Trastuzumab (Herceptin®, rhuMAb HER-2/NEU; MoAb HER2/NEU) (NSC-688097, IND 
132527) 
 
a. 
PHARMACOLOGY 
 
Mechanism of Action: Trastuzumab is a monoclonal antibody. The HER2 (or c-
erbB2) proto-oncogene encodes a transmembrane receptor protein of 185 kDa, 
which is structurally related to the epidermal growth factor receptor. Herceptin has 
been shown, in both in vitro assays and in animals, to inhibit the proliferation of 
human tumor cells that overexpress HER2. Herceptin is a mediator of antibody-
dependent cellular cytotoxicity (ADCC). In vitro, Herceptin-mediated ADCC has 
been shown to be preferentially exerted on HER2 overexpressing cancer cells 
compared with cancer cells that do not overexpress HER2. 
 
Description: Herceptin (trastuzumab) is a humanized IgG1 kappa monoclonal 
antibody that selectively binds with high affinity to the extracellular domain of the 
human epidermal growth factor receptor 2 protein, HER2. Trastuzumab is 
produced by recombinant DNA technology in a mammalian cell (Chinese Hamster 
Ovary) culture containing the antibiotic gentamicin. Gentamicin is not detectable in 
the final product. 
 
b. 
PHARMACOKINETICS 
 
1. 
Absorption: Time to steady state is 9 weeks in patients with metastatic 
gastric cancer and 12 weeks in patients with breast cancer 
 
2. 
Distribution: Distributed in tissues and fluids; Vd: 44 mL/kg 
 
3. 
Metabolism: Does not undergo renal or hepatic metabolism 
 
4. 
Elimination:  clearance increases with decreasing concentrations due to 
parallel linear and non-linear elimination pathways; elimination half-life 5.8 
days 
 
c. 
ADVERSE EFFECTS  
 
1. 
Adverse Effects: 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) For 
Trastuzumab (Herceptin, NSC 688097 and Herceptin HylectaTM (SQ 
trastuzumab, NSC 827797) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) 
provides a single list of reported and/or potential adverse events (AE) 
associated with an agent using a uniform presentation of events by body 
system. In addition to the comprehensive list, a subset, the Specific 
Protocol Exceptions to Expedited Reporting (SPEER), appears in a 
separate column and is identified with bold and italicized text. This subset 
of AEs (SPEER) is a list of events that are protocol specific exceptions to 
expedited reporting to NCI (except as noted below).  Refer to the 'CTEP, 
NCI 
Guidelines: 
Adverse 
Event 
Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
aeguidelines.pdf for further clarification. Frequency is provided based on 

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4407 patients. Below is the CAEPR for Trastuzumab (Herceptin) and 
Herceptin HylectaTM (SQ trastuzumab) 
 
 
 

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NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted 
in parentheses next to the AE in the SPEER.  If this CAEPR is part of a 
combination protocol using multiple investigational agents and has an AE 
listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
 
 
Version 2.6, December 14, 20211 
 
 Adverse Events with Possible  
 Relationship to Trastuzumab (Herceptin) 
 (CTCAE 5.0 Term) 
[n= 4407] 
 
 
 Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but Serious 
(<3%) 
Expected 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
 
Anemia 
 
Anemia (Gr 3) 
 
Febrile 
neutropenia2 
 
 
CARDIAC DISORDERS 
 
 
Heart failure 
 
 
 
Left ventricular 
systolic 
dysfunction 
 
Left ventricular 
systolic dysfunction 
(Gr 3) 
 
Palpitations 
 
 
 
Pericardial 
effusion 
 
 
 
Pericarditis 
 
 
 
Restrictive 
cardiomyopath
y 
 
 
 
Sinus 
tachycardia3 
 
Sinus tachycardia 
(Gr 2) 
 
Supraventricula
r tachycardia3 
 
 
EYE DISORDERS 
 
 
Watering eyes  
 
GASTROINTESTINAL DISORDERS 
 
 
Abdominal pain  
Abdominal pain (Gr 
2) 
 
Diarrhea 
 
Diarrhea (Gr 3) 
 
Mucositis oral 
 
Mucositis oral (Gr 2) 
 
Nausea 
 
Nausea (Gr 3) 
 
 
Pancreatitis 
 
 
Vomiting 
 
Vomiting (Gr 3)  
GENERAL DISORDERS AND ADMINISTRATION SITE 
CONDITIONS 
 
 
Chills3 
 
Chills3 (Gr 2) 
 
Edema limbs 
 
 
Fatigue 
 
 
Fatigue (Gr 3) 
 
Fever3 
 
Fever3 (Gr 2) 
 
Flu like 
symptoms 
 
Flu like symptoms 
(Gr 2) 

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 Adverse Events with Possible  
 Relationship to Trastuzumab (Herceptin) 
 (CTCAE 5.0 Term) 
[n= 4407] 
 
 
 Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but Serious 
(<3%) 
Expected 
 
Injection site 
reaction4 
 
Injection site 
reaction4 Gr 2) 
 
Non-cardiac 
chest pain 
 
Non-cardiac chest 
pain (Gr 2)  
 
Pain 
 
Pain (Gr 2) 
IMMUNE SYSTEM DISORDERS 
 
 
 
Anaphylaxis 
 
 
 
Allergic reaction5 
 
INFECTIONS AND INFESTATIONS 
 
 
Infection6 
 
Infection6 (Gr 3) 
INJURY, POISONING AND PROCEDURAL 
COMPLICATIONS 
 
 
Infusion related 
reaction7 
 
Infusion related 
reaction7 (Gr 2) 
INVESTIGATIONS 
 
 
Alkaline 
phosphatase 
increased 
 
Alkaline 
phosphatase 
increased (Gr 2) 
 
Aspartate 
aminotransfera
se increased 
 
Aspartate 
aminotransferase 
increased (Gr 2) 
 
Cardiac 
troponin I 
increased 
 
 
 
 
Ejection fraction 
decreased 
Ejection fraction 
decreased (Gr 3)  
 
GGT increased  
GGT increased (Gr 
2) 
 
Neutrophil 
count 
decreased2 
 
Neutrophil count 
decreased2 (Gr 4) 
 
Weight loss 
 
 
METABOLISM AND NUTRITION DISORDERS 
 
 
Anorexia 
 
Anorexia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE 
DISORDERS 
 
 
Arthralgia 
 
Arthralgia (Gr 2) 
 
Back pain 
 
Back pain (Gr 2)  
 
Bone pain 
 
Bone pain (Gr 2) 
 
Muscle cramp  
 
 
Myalgia 
 
Myalgia (Gr 2) 
 
Pain in 
extremity 
 
 
NEOPLASMS BENIGN, MALIGNANT AND 
UNSPECIFIED (INCL CYSTS AND POLYPS) 
 
 
Tumor Pain 
 
Tumor pain (Gr 2) 

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 Adverse Events with Possible  
 Relationship to Trastuzumab (Herceptin) 
 (CTCAE 5.0 Term) 
[n= 4407] 
 
 
 Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but Serious 
(<3%) 
Expected 
NERVOUS SYSTEM DISORDERS 
 
 
Dizziness 
 
 
 
Dysgeusia 
 
 
 
Headache 
 
Headache (Gr 2) 
 
Peripheral 
sensory 
neuropathy 
 
 
PSYCHIATRIC DISORDERS 
 
 
Depression 
 
 
 
Insomnia 
 
 
RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS 
 
 
 
Adult respiratory 
distress 
syndrome3,5 
 
 
Allergic rhinitis  
Allergic rhinitis (Gr 
2) 
 
 
Bronchospasm 
 
 
Cough 
 
Cough (Gr 2) 
 
Dyspnea3,5 
 
Dyspnea (Gr 3) 
 
Hypoxia5 
 
Hypoxia (Gr 2) 
 
 
Pneumonitis5 
 
 
 
Pulmonary edema5  
 
 
Pulmonary fibrosis  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
 
Alopecia 
 
 
 
Nail changes 
 
 
 
Nail loss 
 
 
 
Rash acneiform  
Rash acneiform (Gr 
2) 
 
Rash maculo-
papular 
 
Rash maculo-
papular (Gr 2) 
 
Urticaria3 
 
Urticaria3 (Gr 2) 
VASCULAR DISORDERS 
 
 
Hot flashes 
 
 
 
Hypertension3  
 
 
Hypotension3 
 
 
 
Lymphedema 
 
 
 
Vascular 
disorders - 
Other 
(vasodilation) 
 
 
 
1 
This table will be updated as the toxicity profile of the agent is revised. 
Updates will be distributed to all Principal Investigators at the time of 
revision. The current version can be obtained by contacting 

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PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, 
the protocol and the agent should be included in the e-mail. 
2 
Fatal event when given in combination with Xeloda® (capecitabine) 
and Taxotere® (docetaxel). 
3 
Associated with infusion-related reactions or administration-related 
reactions (ARRs).  
4 
Injection site reaction was observed primarily in subjectes treated with 
Herceptin HylectaTM SC formuation. 
5 
Severe 
hypersensitivity 
reactions 
including 
angioedema 
and 
pulmonary adverse events (e.g., hypoxia, dyspnea, pulmonary 
infiltrates, pleural effusion, intersitial lung disease, wheezing, and 
acute respiratory distress syndrome) have been reported. 
6 
Infection may include any of the 75 sites of infection under the 
INFECTIONS AND INFESTATIONS SOC. 
7 
Infusion related reaction was obseved primarily subjects treated with 
the trastuzumab IV formulation. 
 
Adverse events reported on trastuzumab (Herceptin) and/or 
Herceptin HylectaTM (SQ trastuzumab) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable 
possibility that trastuzumab (Herceptin) and/or Herceptin HylectaTM 
(SQ trastuzumab) caused the adverse event: 
 
CARDIAC DISORDERS - Asystole; Atrial fibrillation; Atrial flutter; Chest 
pain - cardiac; Myocardial infarction; Myocarditis; Sinus bradycardia; 
Ventricular arrhythmia; Ventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Hearing impaired; Vertigo 
EYE DISORDERS - Dry eye; Extraocular muscle paresis 
GASTROINTESTINAL DISORDERS - Ascites; Colitis; Constipation; 
Duodenal 
ulcer; 
Dyspepsia; 
Enterocolitis; 
Esophagitis; 
Gastric 
hemorrhage; Gastritis; Gastrointestinal pain; Small intestinal perforation; 
Typhlitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - 
Generalized edema; Sudden death NOS 
HEPATOBILIARY DISORDERs - Cholecystitis 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - 
Dermatitis radiation; Fracture; Injury, poisoning and procedural 
complications - Other (incision site pain); Injury, poisoning and procedural 
complications - Other (procedural pain) 
INVESTIGATIONS - Alanine aminotransferase increased; Creatinine 
increased; Weight gain; White blood cell decreased 
METABOLISM 
AND 
NUTRITION 
DISORDERS 
- 
Dehydration; 
Hyperkalemia; 
Hypoalbuminemia; 
Hypokalemia; 
Hyponatremia; 
Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - 
Arthritis; Chest wall pain; Flank pain; Generalized muscle weakness; Neck 
pain 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL 
CYSTS AND POLYPS) - Leukemia secondary to oncology chemotherapy; 
Treatment related secondary malignancy 
NERVOUS SYSTEM DISORDERS - Amnesia; Depressed level of 
consciousness; 
Encephalopathy; 
Leukoencephalopathy; 
Muscle 
weakness left-sided; Paresthesia; Seizure; Syncope 

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PSYCHIATRIC DISORDERS - Anxiety; Confusion 
RENAL AND URINARY DISORDERS - Acute kidney injury; Proteinuria 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Amenorrhea 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - 
Epistaxis; Nasal congestion; Oropharyngeal pain; Pharyngolaryngeal 
pain; Pleural effusion4; Pulmonary hypertension; Respiratory failure; 
Wheezing4 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Eczema; 
Erythema multiforme; Hyperhidrosis; Palmar-plantar erythrodysesthesia 
syndrome; Pruritus; Skin hyperpigmentation; Stevens-Johnson syndrome 
VASCULAR DISORDERS - Hematoma; Thromboembolic event 
 
Note: Trastuzumab (Herceptin) in combination with other agents could 
cause an exacerbation of any adverse event currently known to be caused 
by the other agent, or the combination may result in events never 
previously associated with either agent 
 
2. 
Pregnancy and Lactation: Exposure to trastuzumab during pregnancy can 
result in oligohydramnios and oligohydramnios sequence manifesting as 
pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Use 
effective contraception during treatment and for 7 months following the last 
dose of trastuzumab. 
 
It is unknown whether trastuzumab is excreted into human milk. Published 
literature suggests human IgG is present in all milk, but does not enter the 
neonatal and infant circulation in substantial amounts. Trastuzumab was 
present in the milk of lactating Cynomolgus monkeys but not associated 
with neonatal toxicity. However, due to the potential for adverse effects on 
the infant from nursing, it is advisable to discontinue breast-feeding during 
treatment with trastuzumab and for 7 months after the last dose of 
trastuzumab 3. Drug Interactions:  
 
Avoid concomitant anthracycline-based therapy and use with caution for 7 
months after stopping trastuzumab due to increased risk of cardiac 
dysfunction. 
 
d. 
DOSING & ADMINISTRATION 
 
See Section 7.0 Treatment Plan 
 
Route of Administration: intravenous infusion. 
 
Method of Administration: Trastuzumab is given by slow intravenous infusion only.  
The typical dosing schedule is 4mg/kg as a loading dose, followed by weekly doses 
of 2mg/kg. The loading dose is infused over 90 minutes. If this is well tolerated, 
subsequent infusions may be given over 30 minutes.  Please consult the protocol 
document for specific dosing/schedule instructions as doses/schedules may be 
different between tumor types. 
 
Drug-Drug Interactions: The mean serum trough concentration of trastuzumab was 
consistently elevated approximately 1.5-fold, when administered in combination 
with paclitaxel as compared to trough concentrations of trastuzumab when 
administered in combination with an anthracycline and cyclophosphamide. In other 
pharmacokinetic studies, where Herceptin was administered in combination with 
paclitaxel, docetaxel, carboplatin, or doxorubicin, Herceptin did not alter the 

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plasma concentrations of these chemotherapeutic agents, or the metabolites that 
were analyzed. In a drug interaction substudy conducted in patients, the 
pharmacokinetics of cisplatin, capecitabine and their metabolites were not altered 
when administered in combination with Herceptin. 
 
e. 
HOW SUPPLIED 
 
Trastuzumab (Herceptin) will be supplied free of charge. It will be provided by 
Genentech and distributed by McKesson Specialty Pharmacy, LP in a 150 mg/vial 
in a single-dose vial as a lyophilized sterile powder, under vacuum.  
 
f. 
STORAGE, PREPARATION & STABILITY 
 
1. 
Storage: 
• Store at 2°C to 8°C (36°F to 46°F) prior to reconstitution 
• Contact supplier for temperature excursion information 
 
2. 
Preparation: 
  
Reconstitute each 150 mg vial of trastuzumab with 7.4 mL of Sterile Water 
for Injection (SWFI) (not supplied) to yield a single-dose solution 
containing 21 mg/mL trastuzumab that delivers 7.15 mL (150 mg 
trastuzumab). 
 
 

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Reconstitution: Use appropriate aseptic technique when performing the 
following reconstitution steps: 
• 
Using a sterile syringe, slowly inject 7.4 mL of Sterile Water for 
Injection (SWFI) into the vial containing the lyophilized powder of 
Herceptin. The stream of SWFI should be directed into the 
lyophilized powder.   The reconstituted vial yields a solution for 
single use, containing 21 mg/ml trastuzumab. 
• 
Swirl the vial gently to aid reconstitution. DO NOT SHAKE. 
• 
Slight foaming of the product may be present upon reconstitution. 
Allow the vial to stand undisturbed for approximately 5 minutes. 
• 
Parenteral drug products should be inspected visually for 
particulate matter and discoloration prior to administration, 
whenever solution and container permit. Inspect visually for 
particulates and discoloration. The solution should be free of 
visible particulates, clear to slightly opalescent and colorless to 
pale yellow. 
• 
Use the Herceptin solution immediately following reconstitution 
with SWFI, as it contains no preservative and is intended for 
single-dose only. If not used immediately, store the reconstituted 
Herceptin solution for up to 24 hours at 2○C to 8○C (36○F to 46○F); 
discard any unused Herceptin after 24 hours. Do not freeze.  
 
Dilution:  
• 
Determine the dose (mg) of Herceptin. Calculate the volume of 
the 21 mg/mL reconstituted Herceptin solution needed, withdraw 
this amount from the vial and add it to an infusion bag containing 
250 mL of 0.9% Sodium Chloride Injection, USP. DO NOT USE 
DEXTROSE (5%) SOLUTION. 
• 
Gently invert the bag to mix the solution. 
 
3. 
Stability:  
 
The solution of Herceptin for infusion diluted in polyvinylchloride or 
polyethylene bags containing 0.9% Sodium Chloride Injection, USP, 
should be stored at 2°C to 8°C (36°F to 46°F) for no more than 24 hours 
prior to use. Discard after 24 hours. This storage time is additional to the 
time allowed for the reconstituted vials. Do not freeze.    
 
g. 
DRUG ORDERING & ACCOUNTABILITY 
 
1. 
Drug order and shipping 
 
a. 
Trastuzumab may be requested by the principal investigator (or 
their authorized designee) at each participating site by completing 
the Biologics Drug Order Request Form for S1613 once the 
patient has been randomized and faxing to the number listed on 
the order form. Authorized and completed orders will be 
processed and shipped “same day” of receipt if received before 
2:00 p.m. EST Monday through Thursday. Authorized and 
completed orders received after 2:00pm EST Monday through 
Thursday or on Friday will be processed and shipped the next 
business morning. All drug orders are shipped via FedEx Priority 
Overnight delivery.  Biologics distribution team monitors packages 
throughout duration of transit via FedEx One Call Solution (live 

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support) and delivery exceptions are managed at the highest level 
of urgency to ensure therapy start date adherence. Packing slips 
with the shipment tracking number included will be faxed to the 
designated site coordinator.  
 
Drug deliveries are restricted during weekends and holidays. 
Biologics, Inc. observes the following holidays: New Year’s Day, 
Memorial Day, Independence Day, Labor Day, Thanksgiving Day, 
the Friday following Thanksgiving Day, Christmas Eve, and 
Christmas Day. Sites should plan ahead to accommodate patients 
being treated during restricted times. 
 
Sites must allow up to 5 business days for study drug to arrive 
once the Drug Order Request Form is submitted to Biologics. The 
Drug Order Request Form should be faxed to 919-256-0794.  
 
b. 
Once a patient is randomized, the site will fax a completed Drug 
Order Request Form to Biologics at 919-256-0794. Upon receipt 
of completed and faxed Drug Order Request Form, Biologics Inc. 
will: 
 
• Check to confirm site has an active registration and approval 
for shipment. 
 
• Place a call or email to the site confirming the Drug Order 
Request Form was received, while providing the estimated day 
and time of arrival for the study drug.  
 
• Prepare an initial shipment supply for the patient’s loading dose 
and subsequent 4 cycles.  
 
• 
Each vial of trastuzumab is 150 mg.  Drug will be labeled by 
Genentech for Investigational Use Only. Drug supply will be 
dispensed by Biologics with patient-specific labeling.  
 
o 
Initial shipments will include approximately 16 vials of 
trastuzumab to complete a loading dose of 8 mg/kg and 4 
cycles at 6 mg/kg.  
 
c. 
If additional drug is required, the site will fax a completed Drug 
Order Request Form to Biologics at 919-256-0794. 
 
• 
Check to confirm site has an active registration and approval 
for shipment. 
 
• 
Place a call or email to the site confirming the Drug Order 
Request Form was received, while providing the estimated 
day and time of arrival for the study drug.  
 
• 
Prepare a subsequent shipment supply for the patient’s 
subsequent 4 cycles.  
 
• 
Each vial of trastuzumab is 150 mg.  Drug will be labeled by 
Genentech for Investigational Use Only. Drug supply will be 
dispensed by Biologics with patient-specific labeling. 
 

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o 
Subsequent shipments will include approximately 12 vials 
of trastuzumab to complete 4 subsequent cycles at 6 
mg/kg.  
 
d. 
Each shipment includes a patient-specific label on the outer 
packaging with the following information: 
 
• 
Study Number and Date Dispensed 
• 
Drug Identification, Lot number, Expiration Date 
• 
Patient ID Number 
• 
Patient Initials 
• 
Storage Instructions 
• 
Dosing Instructions 
• 
IND Caution statement  
 
2. 
Drug Handling and Accountability  
 
a. 
Drug Accountability: The investigator, or a responsible party 
designated by the investigator, must maintain a careful record of 
the receipt, disposition, and return or disposal of all drugs received 
from the supplier using the NCI Drug Accountability Record Form 
(DARF) available at http://ctep.cancer.gov. 
 
b. 
Electronic logs are allowed as long as a print version of the log 
process is the exact same appearance as the current NCI DARF. 
If the trial is a placebo control trial – indicate that separate DARFs 
are needed for each patient to also include the placebo drug 
supply. 
 
3. 
Drug return and/or disposition instruction  
 
a. 
Drug Returns: Unused drug supplies should NOT be returned. 
Unused drug should be disposed of per local institutional 
guidelines. 
 
b. 
Drug expiration:  If packaging has expiration date, indicate drug 
expiration date on the DARF under Manufacturer and Lot # and 
use the drug lots with shorter expiration date first. 
 
4. 
Contact Information 
 
Questions about drug orders, transfers, returns, or accountability should 
be addressed to Clinical Research Services at Biologics, Inc. at 800-693-
4906 or clinicaltrials@biologicsinc.com. 
 
 
4.0 
STAGING CRITERIA 
 
Staging criteria are not applicable to this study. 
 
 
5.0 
ELIGIBILITY CRITERIA 
 
Each of the criteria in the following section must be met in order for a patient to be considered 
eligible for registration. Section 5.1 must be met prior to initial registration for HER-2 testing, while 
Section 5.2 must be met prior to randomization.  Consider all criteria before enrolling a patient to 

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Step 1.  Section 5.3 must be met prior to crossover registration (optional). For each criterion 
requiring test results and dates, please record this information on the Onstudy Form and submit 
via Medidata Rave® (see Section 14.0).  Any potential eligibility issues should be addressed to the 
SWOG Statistics and Data Management Center in Seattle at 206/652-2267 or giquestion@crab.org 
prior to registration. 
 
In calculating days of tests and measurements, the day a test or measurement is done is 
considered Day 0.  Therefore, if a test is done on a Monday, the Monday 4 weeks later would be 
considered Day 28.  This allows for efficient patient scheduling without exceeding the guidelines.  
If Day 14, 28, 30, or 60 falls on a weekend or holiday, the limit may be extended to the next 
working day. 
 
5.1 
Step 1 Initial Registration: HER-2 Testing 
 
Disease Related Criteria 
 
a. 
Patients must have histologically or cytologically documented adenocarcinoma of 
the colon or rectum that is metastatic or locally advanced and unresectable. 
 
b. 
Mutation results: 
 
1. 
All patients must have molecular testing performed in a CLIA certified lab 
which includes KRAS and NRAS gene and exon 15 of BRAF gene (BRAF 
V600E mutation). Patients with any known activating mutation in exon 2 
[codons 12 and 13], exon 3 [codons 59 and 61] and exon 4 [codons 117 
and 146]) of KRAS/NRAS genes and in exon 15 (BRAFV600E mutation) 
of BRAF gene are not eligible. 
 
Prior/Concurrent Therapy Criteria 
 
c. 
Patients must not have been treated with any of the following prior to Step 1 Initial 
Registration: 
 
• 
Cetuximab, or any other monoclonal antibody against EGFR or inhibitor of 
EGFR. 
• 
HER-2 targeting for treatment of colorectal cancer. Patients who have received 
prior trastuzumab or pertuzumab for other indications such as prior history of 
adjuvant or neoadjuvant breast cancer treatment prior to the development of 
advanced colorectal cancer are eligible.  
 
d. 
Patients must not have had history of severe toxicity and intolerance to or 
hypersensitivity to irinotecan or any other study drug. Patients must not have had 
a severe infusion-related reaction during any prior therapy with pertuzumab or 
trastuzumab. 
 
Specimen and Data Submission Criteria 
 
e. 
Patients must have tumor slides available for submission for HER-2 testing as 
described in Section 15.1. HER-2 testing must be completed by the central lab 
prior to Step 2 Randomization. The central lab will perform HER-2 tests in 
accordance with instructions provided separately. 
 
Regulatory Criteria 
 
f. 
Patients must be informed of the investigational nature of this study and must sign 
and give informed consent in accordance with institutional and federal guidelines. 

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For Step 1 Initial Registration, the appropriate consent form is the Step 1 Consent 
Form.  
 
g. 
As a part of the OPEN registration process (see Section 13.4 for OPEN access 
instructions) the treating institution's identity is provided in order to ensure that the 
current (within 365 days) date of institutional review board approval for this study 
has been entered in the system. 
 
5.2 
Step 2 Randomization 
 
Results of HER-2 testing will be available on the SWOG Specimen Tracking Website and 
sites will be notified by e-mail within 14 calendar days from submission of the tissue 
specimen to the central lab.  
 
 
Disease Related Criteria 
 
a. 
Patients must have HER-2 amplification as determined by central testing (3+ or 2+ 
by immunohistochemistry and HER-2 gene amplification by in situ hybridization 
with a ratio of HER-2 gene signals to centromere 17 signals ≥ 2.0). 
 
b. 
Patients must have measurable disease that is metastatic or locally advanced and 
unresectable. Imaging used to assess all disease per RECIST 1.1 must have been 
completed within 28 days prior to Step 2 Randomization. All disease must be 
assessed and documented on the Baseline Tumor Assessment Form. 
 
Prior/Concurrent Therapy Criteria 
 
c. 
Patients must have had at least one prior regimen of systemic chemotherapy for 
metastatic or locally advanced, unresectable disease. Patients must have 
progressed following the most recent therapy. Prior treatment with irinotecan is 
allowed. For patients that received adjuvant chemotherapy: Prior treatment for 
metastatic disease is not required for patient who experienced disease recurrence 
during or within 6 months of completion of adjuvant chemotherapy. If the patient 
received one line of adjuvant treatment and had disease recurrence after 6 months 
of completing chemotherapy, patients will only be eligible after failing one 
additional line of chemotherapy used to treat the metastatic or locally advanced, 
unresectable disease. Patients who have received ≥3 lines of systemic 
chemotherapy for metastatic or locally advanced, unresectable disease are not 
eligible.   
 
NOTE: See Section 5.2e for criteria related to treatment for brain metastases.  
 
d. 
Patients must have completed prior chemotherapy, immunotherapy, or radiation 
therapy at least 14 days prior to Step 2 Randomization and all toxicity must be 
resolved to CTCAE v4.0 Grade 1 (with the exception of CTCAE v4.0 Grade 2 
neuropathy) prior to Step 2 Randomization. 
 
Clinical/Laboratory Criteria 
 
e. 
Brain metastases are allowed if they have been adequately treated with 
radiotherapy or surgery and stable for at least 30 days prior to Step 2 
Randomization. Eligible patients must be neurologically asymptomatic and without 
corticosteroid treatment for at least 7 days prior to Step 2 Randomization.  
 
f. 
Patients must have a Zubrod Performance Status of 0 or 1. (See Section 10.4) 

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g. 
Patients must be ≥ 18 years of age. 
 
h. 
Patients must have a complete physical examination and medical history within 28 
days prior to Step 2 Randomization. 
 
i. 
Patients must have adequate hematologic function as evidenced by all of the 
following within 14 days prior to Step 2 Randomization: ANC ≥ 1,500/mcL; platelets 
≥ 75,000/mcL; and hemoglobin ≥ 9 g/dL. 
 
j. 
Patients must have adequate hepatic function as evidenced by all of the following 
within 14 days prior to Step 2 Randomization: AST and ALT both ≤ 5 x institutional 
upper limit of normal (IULN); bilirubin ≤ 1.5 mg/dL. 
 
k. 
Patients must have adequate kidney function as evidenced by calculated 
creatinine clearance > 30 ml/min within 14 days prior to Step 2 Randomization. 
 
Calculated creatinine clearance = (140 - age) x wt (kg) x 0.85 (if female) 
72 x creatinine (mg/dl) 
 
l. 
Patients who have had an echocardiogram performed within 6 months prior to Step 
2 Randomization, must have ventricular ejection fraction (LVEF) ≥ 50% or ≥ within 
normal limits for the institution.   
 
m. 
Patients must have magnesium, potassium, calcium, sodium, bicarbonate, and 
chloride performed within 14 days prior to Step 2 Randomization.  Results of these 
tests do not determine eligibility, but the tests are required to establish baseline 
values.  Additional timepoints are noted in Section 9.0. 
 
n. 
Patients must not have an uncontrolled intercurrent illness including, but not limited 
to diabetes, hypertension, severe infection, severe malnutrition, unstable angina, 
Class III-IV New York Heart Association (NYHA) congestive heart failure (see 
Section 18.1), ventricular arrhythmias, active ischemic heart disease, or 
myocardial infarction within 6 months prior to Step 2 Randomization. 
 
o. 
Patients must not have any known previous or concurrent condition suggesting 
susceptibility to hypersensitivity or allergic reactions, including, but not limited to: 
known hypersensitivity to any of the study treatments or to excipients of 
recombinant human or humanized antibodies.  Patients with mild or seasonal 
allergies may be included after discussion with the Study Chairs. 
 
p. 
Patients must not be planning treatment with other systemic anti-cancer agents 
(e.g., chemotherapy, hormonal therapy, immunotherapy) or other treatments not 
part of protocol-specified anti-cancer therapy including concurrent investigational 
agents of any type.  
 
q. 
No prior malignancy is allowed except for adequately treated basal cell or 
squamous cell skin cancer, in situ cervical cancer, ductal carcinoma in situ, other 
low grade lesions such as incidental appendix carcinoid, or any other cancer from 
which the patient has been disease and treatment free for two years. Prostate 
cancer patients on active surveillance are eligible. 
 
r. 
Patients must not be pregnant or nursing due to risk of fetal or nursing infant 
harm.  Females of child-bearing potential must have a negative serum pregnancy 
test within 7 days prior to registration. Women/men of reproductive potential must 
have agreed to use an effective contraceptive method while on study and for at 
least 7 months after the last dose of study treatment.  A woman is considered to 

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be of "reproductive potential" if she has had menses at any time in the preceding 
12 consecutive months.  In addition to routine contraceptive methods, "effective 
contraception" also includes heterosexual celibacy and surgery intended to 
prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a 
hysterectomy, bilateral oophorectomy or bilateral tubal ligation.  However, if at any 
point a previously celibate patient chooses to become heterosexually active during 
the time period for use of contraceptive measures outlined in the protocol, he/she 
is responsible for beginning contraceptive measures. 
 
 

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Specimen Submission Criteria 
 
s. 
Patients must be given the opportunity to consent to the optional submission of 
tissue and blood for future research as outlined in Section 15.2.  
 
Regulatory Criteria 
 
t. 
Patients must be informed of the investigational nature of this study and must sign 
and give written informed consent in accordance with institutional and federal 
guidelines. The appropriate consent form for this registration is the Step 2 Consent 
Form.  
 
u. 
As a part of the OPEN registration process (see Section 13.4 for OPEN access 
instructions) the treating institution's identity is provided in order to ensure that the 
current (within 365 days) date of institutional review board approval for this study 
has been entered in the system. 
 
5.3 
Step 3 Crossover Registration (Optional) 
 
Clinical/Laboratory Criteria 
 
a. 
Patients must have documented disease progression as defined in Section 10.2d 
while on CETIRI (Arm 2) on this protocol. The Follow-up Tumor Assessment Form 
documenting disease progression must be submitted to SWOG prior to Step 3 
Crossover Registration. Registration to Step 3 Crossover must be within 28 days 
of discontinuation of CETIRI protocol treatment. Patients going off treatment for 
any other reason are not eligible. 
 
b. 
Patients must have a Zubrod Performance Status of 0 or 1. (See Section 10.4) 
 
c. 
Patients must have adequate hematologic function as evidenced by all of the 
following within 14 days prior to Step 3 Crossover Registration: ANC ≥ 1,500/mcL; 
platelets ≥ 75,000/mcL; and hemoglobin ≥ 9 g/dL. 
 
d. 
Patients must have adequate hepatic function as evidenced by all of the following 
within 14 days prior to Step 3 Crossover Registration: AST and ALT both ≤ 5 x 
institutional upper limit of normal (IULN); bilirubin ≤ 1.5 mg/dL. 
 
 
e. 
Patients must have adequate kidney function as evidenced by calculated 
creatinine clearance > 30 ml/min within 14 days prior to Step 3 Crossover 
Registration. 
 
Calculated creatinine clearance = (140 - age) x wt (kg) x 0.85 (if female) 
 
72 x creatinine (mg/dl) 
 
f. 
Patients must have left ventricular ejection fraction (LVEF) ≥ 50% or ≥ lower limit 
of normal for the institution by echocardiogram within 14 days prior to Step 3 
Crossover Registration. 
 
g. 
Patients must have a magnesium, potassium, calcium, sodium, bicarbonate, and 
chloride performed within 14 days prior to Step 3 Crossover Registration.  
Additional timepoints are noted in Section 9.0. 
 
 

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Regulatory Criteria 
 
h. 
Patients must be informed of the investigational nature of this study and must sign 
and give written informed consent in accordance with institutional and federal 
guidelines. The appropriate consent form for this registration is the Step 2 Consent 
Form.  
 
i. 
As a part of the OPEN registration process (see Section 13.4 for OPEN access 
instructions) the treating institution's identity is provided in order to ensure that the 
current (within 365 days) date of institutional review board approval for this study 
has been entered in the system. 
 
 
6.0 
STRATIFICATION FACTORS 
 
Patients will be assigned to treatment arms using block randomization with stratification based on 
prior use of irinotecan (yes vs. no) and HER-2/CEP17 ratio (> 5 vs ≤ 5) (32) 
 
 
7.0 
TREATMENT PLAN 
 
For treatment or dose modification questions, please contact Dr. Kanwal Raghav at 917/733-0356 
(or kpraghav@mdanderson.org) or Dr. Marwan Fakih at 626/471-4673 (or mfakih@coh.org).  For 
dosing principles or questions, please consult the SWOG Policy #38 "Dosing Principles for Patients 
on Clinical Trials" at http://swog.org (then click on "Policies and Manuals" under the "Visitors" menu 
and choose Policy 38). 
 
7.1 
Pre-Medication 
 
a. 
Arm 1: Trastuzumab + Pertuzumab (TP) 
 
Patients randomized to this arm do not need any premedication unless deemed 
necessary by treating physician. 
 
Note: Patients who experience infusion-associated symptoms, while receiving 
pertuzumab on-study, may subsequently be pre-medicated as per standard 
institutional practice. 
 
b. 
Arm 2: Irinotecan + Cetuximab (CETIRI)  
 
 
Patients randomized to this arm should receive: 
 
• 
Diphenhydramine (or other H1-antagonist) 50 mg intravenously, given once 
30-60 minutes prior to the first dose of cetuximab. 
• 
Dexamethasone 10 mg intravenously, given 30-60 minutes prior to irinotecan. 
• 
Patients may receive institutional recommended management for nausea. 
• 
Institutional standard pre-medication (including atropine for irinotecan) is 
allowed. 
 
NOTE: These may be modified at the discretion of the treating physician. 
 
7.2 
General considerations 
 
a. 
Similar to other monoclonal antibodies, pertuzumab has been associated with 
infusion-related reactions, such as chills, diarrhea, fatigue, headache, nausea, and 

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pyrexia, and with hypersensitivity reactions including anaphylaxis. Pertuzumab is 
contraindicated in patients with known hypersensitivity to pertuzumab or any of its 
excipients.  Since there is the potential for delayed onset infusion related reactions 
(IRRs), patients should be warned of this possibility and instructed to contact the 
treating physician with any concerns. 
 
b. 
For the first infusion of trastuzumab (Cycle 1), patients should be observed for 60 
minutes from the end of the infusion for fever and chills, or other infusion-related 
reactions.  If Cycle 1 is tolerated, then Cycle 2 and subsequent Q 21 day doses of 
6 mg/kg of trastuzumab may be administered over 30 (± 10) minutes, and patients 
will be observed as shown in Table 1 below. 
 
Table 1:  Infusion Time and Post-Infusion Observation Period for Trastuzumab 
 
Infusion 
Trastuzumab 
Dose (mg/kg) 
Infusion Time  
(min) a 
Post-Infusion Observation 
Period (min) a 
1st infusion 
8 
90 
60 
2nd and subsequent 
infusions 
6 
30 
30 
 
a After Cycle 1, ONLY shorten infusion and post-infusion observation times if the 
prior dose was well-tolerated. If patient has tolerated first 2 infusions, post 
infusion observation can be omitted for 3rd and subsequent infusions as per 
institutional guidelines and at discretion of treating physician. 
 
c. 
All infusion-related symptoms must have resolved before pertuzumab (if 
trastuzumab was given first) is given or the patient is discharged.  Patients who 
experience infusion-related symptoms may be premedicated as per standard 
institutional practice for subsequent infusions.    
 
d. 
The Administration of pertuzumab should be performed in a setting with 
emergency equipment and staff who are trained to monitor medical situations and 
respond to medical emergencies.  The initial dose of pertuzumab will be 
administered over 60 minutes and patients will be monitored for a further 60 
minutes following the completion of the infusion for any adverse effects.  The 
infusion should be slowed or interrupted if the patient experiences infusion-related 
symptoms.  If infusion-related symptoms occur, patients will be monitored until 
complete resolution of signs and symptoms.  If the infusion is well tolerated, 
subsequent doses may be administered over 30 minutes, and patients will be 
observed for a further 30 minutes (as shown in Table 2) for infusion-related 
symptoms.  All infusion-related symptoms must have resolved before the patient 
is discharged.  Patients who experience infusion-associated symptoms may 
subsequently be pre-medicated as per standard institutional practice. 
 
Table 2:  Infusion Time and Post-Infusion Observation Period for Pertuzumab 
 
Infusion 
Pertuzumab 
Dose (mg) 
Infusion Time  
(min) a 
Post-Infusion Observation 
Period (min) a 
1st infusion 
840 
60 
60 
2nd infusion and 
subsequent infusions 420 
30 
30 
a  After Cycle 1, ONLY shorten infusion and post infusion observation times if the 
prior dose was well tolerated. If patient has tolerated first 2 infusions, post 

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infusion observation can be omitted for 3rd and subsequent infusions as per 
institutional guidelines and at discretion of treating physician. 
 
 

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e. 
Irinotecan/Cetuximab doses omitted during a cycle will not be made up. 
Trastuzumab/Pertuzumab doses missed during a cycle should be made up as 
soon as possible. If patient has missed a dose of trastuzumab by one week or less, 
then the usual maintenance dose of 6 mg/kg should be administered as soon as 
possible. Do not wait until the next planned cycle. Subsequent trastuzumab 
maintenance doses should be administered 21 days later according to the three-
weekly schedule. If the patient has missed a dose of trastuzumab by more than 
one week, a re-loading dose of 8 mg/kg should be administered over 
approximately 90 minutes as soon as possible. Subsequent Trastuzumab 
maintenance doses (three-weekly schedule 6 mg/kg) should be administered 21 
days later according to three-weekly schedules. 
 
7.3 
Treatment – Arm 1: Trastuzumab + Pertuzumab (TP) a 
 
Patients assigned to TP will receive the following treatment until meeting one of the criteria 
in Section 7.6. 
 
Agent 
Dose 
Route 
Day 
Schedule 
 
Pertuzumab 
840 mg 
IV over 60 min 
1 
Cycle 1 only 
 
 
 
 
(21 days) given 
 
 
 
 
prior to trastuzumab 
 
Trastuzumab 
8 mg/kg 
IV over 90 min 
1 
Cycle 1 only 
 
 
 
 
(21 days) 
 
Pertuzumab 
420 mg 
IV over 30 min 
1 
Cycles 2+  
 
 
 
 
(q 21 days) given 
 
 
 
 
prior to trastuzumab 
 
Trastuzumab 
6 mg/kg 
IV over 30 min b 1 
Cycles 2+ 
 
 
 
 
(q 21 days) 
 
a Patients must be monitored for infusion reactions for 30-60 minutes after infusion of 
trastuzumab and/or pertuzumab for at least 2 cycles. 
b Only if patient tolerates the initial 90 minute infusion. If patient does not tolerate the initial 
90 minute infusion, subsequent infusions may be given over 120 minutes. 
 
7.4 
Treatment – Arm 2: Irinotecan + Cetuximab (CETIRI) 
 
Patients assigned to CETIRI will receive the following treatment until meeting one of the 
criteria in Section 7.6.  
 
Agent 
Dose 
Route 
Day 
Schedule 
 
Cetuximab 
500 mg/m2 
IV over 120 min 
1 
Cycle 1 only 
 
 
 
 
(14 days) given 
 
 
 
 
prior to irinotecan 
 
Cetuximab 
500 mg/m2 
IV over 60 min* 
1 
Cycles 2+ 
 
 
 
 
(q 14 days) given 
 
 
 
 
prior to irinotecan 
 
Irinotecan 
180 mg/m2 
IV over 90 min 
1 
All cycles 
 
 
 
 
(q 14 days) 

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* Only if patient tolerates the initial 120 minute infusion. 
 
7.5 
Crossover Following Disease Progression on CETIRI 
 
a. 
Following radiographic documentation by RECIST 1.1 (in Section 10.2d) of 
disease progression, patients initially randomized and treated with CETIRI may 
register to Step 3 Crossover Registration to be treated with trastuzumab and 
pertuzumab per the schedule and doses below. Patients must be eligible for Step 
3 Crossover Registration per Section 5.3. Patients must be re-staged at time of 
progression on CETIRI prior to registration to Step 3 Crossover Registration. 
Follow-up for these patients after crossover will be the same as those patients 
initially randomized to TP. 
 
b. 
Treatment – Arm 3: Trastuzumab + Pertuzumab (TP) a 
 
Patients who are registered to Step 3 Crossover Registration will receive the 
following treatment until meeting one of the criteria in Section 7.6. 
 
Agent 
Dose 
Route 
Day 
Schedule  
 
Pertuzumab 
840 mg 
IV over 60 min 
1 
Cycle 1 only 
 
 
 
 
(21 days) given 
 
 
 
 
prior to trastuzumab 
 
Trastuzumab 
8 mg/kg 
IV over 90 min 
1 
Cycle 1 only 
 
 
 
 
(21 days) 
 
Pertuzumab 
420 mg 
IV over 30 min 
1 
Cycles 2+  
 
 
 
 
(q 21 days) given 
 
 
 
 
prior to trastuzumab 
 
Trastuzumab 
6 mg/kg 
IV over 30 min b 1 
Cycles 2+ 
 
 
 
 
(q 21 days) 
 
a Patients must be monitored for infusion reactions for 30-60 minutes after infusion 
of trastuzumab and/or pertuzumab for at least 2 cycles. 
b Only if patient tolerates the initial 90 minute infusion. If patient does not tolerate 
the initial 90 minute infusion, subsequent infusions may be given over 120 
minutes. 
 
7.6 
Criteria for Removal from Protocol Treatment 
 
a. 
TP: Progression of disease (as defined in Section 10.2). 
 
b. 
CETIRI: If patient progresses per RECIST 1.1 (see Section 10.2d), patient has the 
option to register to Step 3 Crossover. Patients who choose not to crossover will 
be removed from protocol treatment. 
 
c. 
Symptomatic deterioration.  
 
d. 
Unacceptable toxicity. 
 
e. 
Treatment delay for any reason > 3 weeks.  
 

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f. 
The patient may withdraw from the study at any time for any reason. 
 
7.7 
Discontinuation of Treatment 
 
All reasons for discontinuation of treatment must be documented in the Off Treatment 
Notice. 
7.8 
Follow-Up Period 
 
Patients who are randomized to a treatment arm will be followed while on treatment and 
until death or 3 years after Step 2 Randomization, whichever occurs first. 
 
 
8.0 
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS 
 
8.1 
Two different versions of the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) will be used on this study 
 
a. 
Serious Adverse Event (SAE) reporting 
 
The CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 5.0 
will be utilized for SAE reporting only. The CTCAE Version 5.0 can be 
downloaded from the CTEP home page (https://ctep.cancer.gov).  All appropriate 
treatment areas should have access to a copy of the CTCAE Version 5.0. 
 
b. 
Routine toxicity reporting 
 
This study will utilize the CTCAE Version 4.0 for routine toxicity reporting.  A copy 
of the CTCAE Version 4.0 can be downloaded from the CTEP home page 
(https://ctep.cancer.gov).  All appropriate treatment areas should have access to a 
copy of the CTCAE Version 4.0. 
 
8.2 
General Considerations 
 
c. 
Where several toxicities with different grades or severity occur at the same time, 
the dose modification applied should be the greatest reduction applicable. 
 
d. 
The maximum dose delay for any reason is 3 weeks. 
 
e. 
If treating investigator feels an event is attributable to another drug or cause, then, 
after conversation with the Study Chair, other modification may be considered. 
 
f. 
Patients on CETIRI (Arm 2) may continue protocol treatment if either cetuximab or 
irinotecan (but not both) must be stopped. 
 
8.3 
Dose Modifications  
 
a. 
Dose reductions for TP are not permitted. For toxicity management see Sections 
8.4 and 8.5. 
 
 
b. 
Dose Levels for Treatment Modifications for CETIRI. For dose reductions and 
toxicity management, see Sections 8.4 and 8.6. 
 
Agent 
Starting Dose 
Level -1  
Level -2*  
 
Irinotecan 
180 mg/m2      
150 mg/m2          
125 mg/m2           

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Cetuximab 
500 mg/m2  
375 mg/m2            
250 mg/m2    
 
* Patients who require dose reductions below the values listed above will be 
removed from protocol treatment. 
 
 

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8.4 
Dose Modifications and Toxicity Management for TP and CETIRI 
 
a. 
Nausea and/or vomiting despite optimal medical management 
 
Institute the recommended management at first occurrence, if reoccurs despite 
optimal medical management, follow dose modification guidelines below. If 
symptoms 
do 
not 
improve, 
then 
other 
alternatives 
like 
aprepitant, 
prochlorperazine, or metoclopramide may be considered. 
 
Toxicity 
Grade 
Dose Modification  
CETIRI 
TP 
2 
Hold all treatment until 
recovery to ≤ Grade 1.  
Resume at same dose 
level. 
No change. 
 
3 or 4 
 
Hold all treatment until 
recovery to ≤ Grade 1. 
Reduce irinotecan by one 
dose level. 
 
If Grade 3-4 toxicity attributed to 
trastuzumab occurs, further 
dosing should be held until the 
toxicity improves to 
≤ Grade 1.  Trastuzumab should 
be restarted at full dose.  If 
Grade 3-4 toxicity recurs, 
trastuzumab should be 
discontinued. 
 
If Grade 3-4 toxicity attributed to 
pertuzumab occurs, further 
dosing should be held until the 
toxicity improves to 
≤ Grade 1.  Pertuzumab should 
be restarted at full dose.  If 
Grade 3-4 toxicity recurs, 
pertuzumab should be 
discontinued.   
 
 
 
b. 
Fatigue 
 
Toxicity 
Grade 
Dose Modification  
CETIRI 
TP 
 
 
 
2 (first 
occurrence) 
Continue at same dose 
No change. 
 
2 (second 
occurrence) 
 
Hold all treatment until 
recovery to ≤ Grade 1.  
 
 
No change. 
 
 

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Toxicity 
Grade 
Dose Modification  
CETIRI 
TP 
Resume at same dose 
level. 
 
3 or 4 
 
Hold all treatment until 
recovery to ≤ Grade 1. 
Reduce irinotecan by one 
dose level. 
 
If Grade 3-4 toxicity attributed to 
trastuzumab 
occurs, 
further 
dosing should be held until the 
toxicity 
improves 
to 
≤ 
Grade 1.  Trastuzumab should 
be restarted at full dose.  If 
Grade 
3-4 
toxicity 
recurs, 
trastuzumab 
should 
be 
discontinued. 
 
If Grade 3-4 toxicity attributed to 
pertuzumab occurs, further 
dosing should be held until the 
toxicity improves to ≤ 
Grade 1.  Pertuzumab should 
be restarted at full dose.  If 
Grade 3-4 toxicity recurs, 
pertuzumab should be 
discontinued.   
 
 
c. 
Hypersensitivity Reaction a,b, Cytokine Release b 
 
 
Toxicity Grade  
Dose Modification  
 
1 
Decrease infusion rate by 50% until symptoms resolve, 
then resume at the initial planned rate. 
 
2 
Stop infusion. Administer H1 and/or H2 blockers, and/or 
steroids according to institutional policy. Restart the 
infusion at 50% lower rate when symptoms resolve and 
pretreat before all subsequent doses. All subsequent 
doses should be administered at the lower infusion rate. 
 
3 or 4 
Stop the infusion. Discontinue treatment. 
 
a Similar to other monoclonal antibodies, pertuzumab has been associated with 
infusion-related reactions, such as chills, diarrhea, fatigue, headache, nausea, 
and pyrexia, and with hypersensitivity reactions including anaphylaxis. 
Pertuzumab is contraindicated in patients with known hypersensitivity to 
pertuzumab or any of its excipients.  Since there is the potential for delayed onset 
infusion related reactions (IRRs), patients should be warned of this possibility 
and instructed to contact the treating physician with any concerns. 
b  For reporting these events: NCI CTCAE 4.0 defines these reactions differently: 
“Cytokine release syndromes/acute infusion reactions are different from 
allergic/hypersensitivity reactions, although some of the manifestations 
arecommon to both AEs. An acute infusion reaction may occur with an agent 
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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. 
 
d. 
Infusion Reactions 
 
1. 
Mild-Moderate Infusion-Associated Events with Trastuzumab: During 
the first infusion with trastuzumab, a symptom complex consisting of chills 
and/or fever is observed in approximately 40% of patients.  Other signs 
and/or symptoms may include nausea, vomiting, pain, rigors, headache, 
cough, dizziness, rash, and asthenia.  These symptoms are usually mild 
to moderate in severity, and occur infrequently with subsequent 
trastuzumab infusions.  These symptoms may be treated as per standard 
institutional practice.  
 
2. 
Serious Infusion-Associated Events with Trastuzumab: Serious 
adverse 
reactions 
to 
trastuzumab 
infusion, 
including 
dyspnea, 
hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen 
saturation, and respiratory distress, can be serious and/or potentially fatal.  
Most of these events have occurred either during or shortly after the start 
of the first trastuzumab infusion.  Severe or moderate infusion-related 
symptoms may be managed by slowing or stopping the trastuzumab 
infusion, and implementing supportive therapy with oxygen, beta agonists, 
antihistamines, or corticosteroids. 
 
• 
If Grade 3 or Grade 4 toxicity occurs during the post-trastuzumab 
infusion observation period, the patient must be evaluated for a 
minimum of 1 hour from the time the toxicity was first observed 
until the resolution of any severe symptoms. 
 
3. 
Subsequent Pre-medication: Patients who have an infusion-associated 
adverse event with trastuzumab should receive prophylactic treatment 
with antihistamines and/or corticosteroids before all subsequent 
trastuzumab infusions.  Please refer to the Herceptinâ USPI for specific 
prophylactic pre-medications that are recommended. 
 
4. 
Pertuzumab Infusion-Associated Events: Observe patients closely for 
60 minutes after the first infusion and for 30 minutes after subsequent 
infusions of pertuzumab.  If a significant infusion-associated reaction 
occurs, slow or interrupt the infusion and administer appropriate medical 
therapies as per standard institutional practice.  Monitor patients carefully 
until complete resolution of signs and symptoms.  Consider permanent 
discontinuation in patients with severe infusion reactions. 
 
e. 
Hypomagnesemia 
 
Toxicity Grade  
Dose Modification 
 
1 or 2 
Supplement with magnesium and closely monitor patient 
for appropriate magnesium levels. 
 

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3 or 4 
Despite maximal medical management with magnesium, 
reduce cetuximab by one dose level. At second 
occurrence, discontinue cetuximab therapy. 
 
 
 

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f. 
Other clinically significant non-hematologic toxicities 
 
Toxicity Grade  
Dose Modification 
 
3 or 4 
Hold all treatment and monitor toxicity at least weekly. If 
toxicity resolves to ≤ Grade 1 within 3 weeks, reduce 
irinotecan by one dose level and resume treatment.  If 
Grade 
3-4 
toxicity 
attributed 
to 
trastuzumab 
or 
petruzumab occurs, further dosing should be held until the 
toxicity improves to ≤ Grade 1. Trastuzumab and 
pertuzumab should be restarted at full dose. If Grade 3-4 
toxicity recurs, trastuzumab and pertuzumab should be 
discontinued. 
 
 
8.5 
Toxicity Management for TP Only 
 
a. 
Cardiac Disorders 
 
During the course of therapy with trastuzumab and pertuzumab patients should be 
monitored for signs and symptoms of heart failure (i.e., dyspnea, tachycardia, new 
unexplained cough, neck vein distention, cardiomegaly, hepatomegaly, 
paroxysmal nocturnal dyspnea, orthopnea, peripheral edema, and rapid 
unexplained weight gain).  The diagnosis must be confirmed using the same 
method used to measure LVEF at baseline (either ECHO or MUGA).  
 
Management of Symptomatic Cardiac Changes.  Patients who develop signs 
and symptoms of heart failure NCI CTCAE v4.0 Grade 2, 3, or 4 should have 
trastuzumab and pertuzumab held and should receive treatment for heart failure  
(NYHA Class III or IV) as prescribed by the HFSA (e.g., ACE inhibitors, 
angiotensin-II receptor blockers, beta blockers, diuretics, and cardiac glycosides, 
as needed).  Consideration should be given to obtaining a cardiac consultation.  
LVEF should be reassessed after 3 weeks (using the same method of 
measurement). 
 
If the symptoms of heart failure resolve with treatment, and cardiac function (as 
measured by ECHO or MUGA) improves, trastuzumab and pertuzumab may be 
restarted after discussion with the patient concerning the risks and benefits of 
continued therapy.  If the patient is benefiting clinically from HER-2-targeted 
treatment, the benefit of continued treatment may outweigh the risk of cardiac 
dysfunction.  If trastuzumab and pertuzumab are restarted, continued surveillance 
with noninvasive measures of LVEF (MUGA or ECHO) will continue per protocol.  
 
 

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b. 
Management of Asymptomatic Decreases in LVEF.  If routine LVEF 
measurements document asymptomatic LVEF decreases during treatment, 
patient management should follow guidelines outlined below. 
 
Toxicity  
 
Management 
 
LVEF ≥ 50% and 
Continue treatment and repeat LVEF in 3 weeks. 
drop > 10%  
 
OR 
 
LVEF < 50% and 
drop < 5%   
 
LVEF < 50% and 
Hold treatment and repeat LVEF in 3 weeks. If LVEF 
drop ≥ 5%  
drop is < 5% or LVEF is ≥ 50% continue treatment. If 
LVEF drop is ≥ 5% and LVEF is < 50% discontinue 
protocol treatment. 
 
 
c. 
Diarrhea 
 
Toxicity Grade  
Dose Modification 
 
1 or 2 
No. change. To prevent dehydration, early treatment of 
diarrhea with anti-diarrheal medication should be 
considered and patients treated with fluids and electrolyte 
replacement, as clinically indicated. 
 
3 or 4 
Hold further dosing until toxicity improves to </= Grade 1.  
Pertuzumab should be restarted at full dose.  If Grade 3-
4 toxicity recurs, pertuzumab should be discontinued.   
 
 
8.6 
Dose Modifications and Toxicity Management for CETIRI Only 
 
a. 
Diarrhea despite optimal medical management  
 
 
Recommended management: Loperamide 4 mg at first onset, followed by 2 mg 
with each loose movement until diarrhea-free for 12 hours (maximum dosage: 16 
mg/24 hours). 
 
Toxicity Grade  
Dose Modification 
 
2 
Hold irinotecan until recovery to ≤ Grade 1. Resume at 
same dose level. 
 
3 or 4 
Hold irinotecan until recovery to ≤ Grade 1. Reduce 
irinotecan by one dose level. 
 
 

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b. 
Neutropenia  
 
Toxicity Grade  
Dose Modification 
 
2 
Hold irinotecan until recovery to ≤ Grade 1. Resume at 
same dose level. 
 
3 or 4 
Hold all treatment until recovery to ≤ Grade 1. Reduce 
irinotecan by one dose level. Use of G-CSF (or PEGylated 
G-CSF) may be considered.* 
 
* G-CSF or pegylated G-CSF may be utilized per ASCO guidelines 
(http://jop.ascopubs.org/cgi/content/full/2/4/196).  
 
c. 
Thrombocytopenia  
 
Toxicity Grade  
Dose Modification 
 
2 
Hold irinotecan until recovery to ≤ Grade 1. Resume at 
same dose level. 
 
3 or 4 
Hold all treatment until recovery to ≤ Grade 1. Reduce 
irinotecan by one dose level. 
 
 
d. 
Blood Bilirubin Increased  
 
Toxicity Grade  
Dose Modification 
 
2 
Hold irinotecan until recovery to ≤ Grade 1. Resume at 
same dose level. 
 
3 or 4 
Hold irinotecan until recovery to ≤ Grade 1. Reduce 
irinotecan each by one dose level. 
 
 
e. 
Mucositis  
 
 
Toxicity Grade  
Dose Modification 
 
2 
Hold irinotecan until recovery to ≤ Grade 1. Resume at 
same dose level. 
 
3 or 4 
Hold all treatment until recovery to ≤ Grade 1. Reduce 
irinotecan by one dose level. 
 
 
 

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f. 
Pneumonitis  
 
Toxicity Grade  
Cetuximab Dose Modification 
 
2 
Hold cetuximab until recovery to ≤ Grade 1. Resume at 
same dose level. 
 
3 or 4 
Hold cetuximab until recovery to ≤ Grade 1 and until 
interstitial lung disease has been ruled out. Reduce 
cetuximab by one dose level. Discontinue protocol 
treatment if interstitial lung disease is confirmed by CT 
scan. 
 
 
g. 
Rash  
 
 
Toxicity Grade  
Dose Modification 
 
 
 
 
3 or 4 
At the first occurrence of rash, 
hold 
cetuximab 
until 
recovery to Grade ≤ 2. If there is improvement in the rash 
upon holding therapy. Then, resume at same dose. At 
second occurrence of rash, hold cetuximab until recovery 
to Grade ≤ 2. If there is improvement in the rash upon 
holding therapy, reduce cetuximab by one dose level and 
resume. At third occurrence, remove patient from 
cetuximab treatment. 
 
 
 
8.7 
White Blood Cell Growth Factors 
 
If used, white blood cell growth factors, including biosimilars, must be used per ASCO 
guidelines (http://jco.ascopubs.org/content/24/19/3187.full) and NCCN Guidelines®  
Myeloid Growth Factors  
(http://www.nccn.org/professionals/physician_gls/pdf/myeloid_growth.pdf). 
 
8.8 
Dose Modifications Contacts 
 
For treatment or dose modification questions, please contact Dr. Kanwal Raghav at 
917/733-0356 (or kpraghav@mdanderson.org) or Dr. Marwan Fakih at 626/471-4673 (or 
mfakih@coh.org). 
 
8.9 
Adverse Event Reporting 
 
Toxicities (including suspected reactions) that meet the expedited reporting criteria as 
outlined in Section 16.0 of the protocol must be reported to the Operations Office, Study 
Chair and NCI via CTEP-AERS, and to the IRB per local IRB requirements. 
 

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9.0 
STUDY CALENDAR 
9.1 
Arm 1: Trastuzumab and Pertuzumab (TP) 
Cycle 1 
Cycle 2 
Cycle 3+ 
Ω 
%  
REQUIRED STUDIES 
Step 1 
Step 2 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Every 
FU 
prior to 
prog 
FU after 
prog 
  
Initial Reg 
Rand 
1 
2 
3 
4 
5 
6 
7 
8 
9 
3 m 
PHYSICAL  ∑  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History and Physical Exam   
 
X   
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
Weight and Performance Status 
 
X 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
Toxicity Notation 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
Disease Assessment †  
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
LABORATORY  ∑  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC/Differential/Platelets   
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
“KRAS/NRAS/BRAF status” for Step 1  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
AST and ALT 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
Serum creatinine/Calculated creatinine 
clearance 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
Total bilirubin 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
Magnesium/Potassium/ 
Calcium/Sodium/Bicarb/ Chloride § 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
Pregnancy Test Ɣ 
 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
SPECIMEN SUBMISSION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tissue for HER2 Testing £ 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tissue for Banking Δ 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for Banking  Π 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
X-RAYS AND SCANS   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Images for Disease Assessment † 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
Image Submission   β 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
ECHO Scan δ 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
TREATMENT  ∑  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Trastuzumab 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 

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Click here for Footnotes. 
Pertuzumab  
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 

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9.2 
Arm 2: Cetuximab + Irinotecan (CETIRI) 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4+ 
Ω 
% 
REQUIRED STUDIES 
Step 1 
Step 2 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
FU 
prior to 
prog 
FU after 
prog 
  
Initial Reg 
Rand 
1 
2 
3 
4 
5 
6 
7 
8 
PHYSICAL  ∑  
 
 
 
 
 
 
 
 
 
 
 
 
History and Physical Exam   
 
X   
X 
 
X 
 
X 
 
X 
 
X 
X 
Weight and Performance Status 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
Toxicity Notation 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
Disease Assessment  † 
 
X 
 
 
 
 
 
 
X 
 
X 
 
LABORATORY  ∑  
 
 
 
 
 
 
 
 
 
 
 
 
CBC/Differential/Platelets   
 
X 
 
 
X 
 
X 
 
X 
 
 
 
“KRAS/NRAS/BRAF status” for Step 1 
X 
 
 
 
 
 
 
 
 
 
 
 
AST and ALT 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
Serum creatinine/Calculated creatinine 
clearance 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
Total bilirubin 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
Magnesium/Potassium/ 
Calcium/Sodium/Bicarb/ 
Chloride § 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
Pregnancy Test Ɣ 
 
X 
X 
 
 
 
 
 
 
 
 
 
SPECIMEN SUBMISSION 
 
 
 
 
 
 
 
 
 
 
 
 
Tissue for HER2 Testing £ 
X 
 
 
 
 
 
 
 
 
 
 
 
Tissue for Banking  Δ 
 
X 
 
 
 
 
 
 
 
 
 
 
Blood for Banking  Π 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X-RAYS AND SCANS   
 
 
 
 
 
 
 
 
 
 
 
 
Images for Disease Assessment † 
 
X 
 
 
 
 
 
 
X 
 
X 
 
Image Submission β 
 
X 
 
 
 
 
 
 
X 
 
X 
 
TREATMENT  ∑  
 
 
 
 
 
 
 
 
 
 
 
 
Cetuximab 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
Irinotecan  
 
 
X 
 
X 
 
X 
 
X 
 
 
 

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9.3 
Arm 3: Trastuzumab and Pertuzumab (TP) 
 
Click here for footnotes. 
Cycle 1 
Cycle 2 
Cycle 3+ 
Ω 
%  
REQUIRED STUDIES 
Step 3 
Crossover Reg 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Every 
FU 
prior to 
prog 
FU after 
prog 
  
1 
2 
3 
4 
5 
6 
7 
8 
9 
3 m 
PHYSICAL  ∑  
 
 
 
 
 
 
 
 
 
 
 
 
 
History and Physical Exam   
X   
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
Weight and Performance Status 
X 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
Toxicity Notation 
 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
Disease Assessment † 
X 
 
 
 
 
 
 
X 
 
 
 
X 
X 
LABORATORY  ∑  
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC/Differential/Platelets   
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
AST and ALT 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
Serum creatinine/Calculated creatinine 
clearance 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
Total bilirubin 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
Magnesium/Potassium/ 
Calcium/Sodium/Bicarb/ 
Chloride § 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
Pregnancy Test Ɣ 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
Blood for Banking  Π 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
X-RAYS AND SCANS   
 
 
 
 
 
 
 
 
 
 
 
 
 
Images for Disease Assessment † 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
ECHO Scan δ 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
TREATMENT  ∑  
 
 
 
 
 
 
 
 
 
 
 
 
 
Trastuzumab 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
Pertuzumab  
 
X 
 
 
X 
 
 
X 
 
 
 
 
 

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NOTE: Forms are found on the protocol abstract page on the SWOG website (www.swog.org).  Forms submission guidelines are found in Section 14.0. 
 
NOTE: Unless indicated otherwise in the protocol, scheduled procedures and assessments (treatment administration, toxicity assessment for continuous treatment, 
disease 
assessment, 
specimen 
collection 
and 
follow-up 
activities) 
must 
follow 
the 
established 
SWOG 
guidelines 
as 
outlined 
in 
https://swog.org/Visitors/Download/QA/Best%20Practices%20upddate.pdf.  
 
Footnotes: 
 
∑  Protocol treatment and parameters will continue at these intervals until progression of disease or until patient has met any of the guidelines in Section 7.6. 
Ɣ  
Females of child bearing potential must have a negative serum pregnancy test within 7 days of C1/D1, If pregnancy test completed at time of registration was 
completed within 7 days of C1/D1, it does not need to be repeated. Subsequently, a serum or urine pregnancy test must be completed every 3 months for Arms 
1 and 3 (TP).  If urine pregnancy test is subsequently utilized and is positive, confirm with serum pregnancy test. 
† 
Disease assessment and CT/MRI/PET-CT must be performed every 6 weeks through Week 12 and then every 8 weeks until progression.  
§ 
Results of these tests do not determine eligibility but are performed prior to registration in order to obtain baseline measurements. 
Ω 
After off treatment prior to disease progression, scans for disease assessment and physical assessments (with lab tests performed at the discretion of the 
treating investigator) should take place every 8 weeks until progression. 
β 
Submit scans as outlined in Section 14.0 and Section 15.3. 
% 
After off treatment following disease progression, physical assessments (with lab tests performed at the discretion of the treating investigator) should take place 
every 6 months for three years from the time of Step 2 Randomization as clinically indicated. 
¥  
Must be done within 28 days prior to registration. 
£  
Required specimen submission for patients. See Section 15.1 for additional information. 
Δ 
Optional specimen submission for patients. See Section 15.2 for additional information. 
δ  
All patients in treatment Arms 1  and 3 must have baseline ECHO prior to starting treatment and must have LVEF ≥ 50% or ≥ lower limit of normal for the 
institution by echocardiogram. Baseline ECHO for Arm 1 patients must be performed within 3 months prior to randomization or after randomization prior to 
starting treatment. Baseline ECHO for Arm 3 patients must be performed within 14 days prior to Step 3 Crossover Registration. ECHOs must then be performed 
once every 3 months (Arms 1 and 3) while on treatment with trastuzumab and pertuzumab. 
Π 
Collect 20 mL of blood in lavender top (EDTA) tubes after randomization and prior to C1D1 (+/- 3 days), on C2D1 (+/- 3 days), at each restaging (including 
restaging during treatment on crossover arm), and off treatment. Process plasma from samples per the guidelines in Section 15.2b. 
 

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10.0 
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS 
 
This study will use the RECIST 1.1 guidelines.  (33) 
 
10.1 
Measurability of Lesions 
 
a. 
Measurable disease 
 
Measurable disease is defined differently for lymph nodes compared with other 
disease and will be addressed in a separate section below. 
 
1. 
Lesions that can be accurately measured in at least one dimension 
(longest diameter to be recorded) as ≥ 2.0 cm  by chest x-ray, by ≥ 1.0 cm  
with CT or MRI scans, or ≥ 1.0 cm with calipers by clinical exam. All tumor 
measurements must be recorded in decimal fractions of centimeters (or 
millimeters). 
 
The defined measurability of lesions on CT scan is based on the 
assumption that CT slice thickness is 0.5 cm or less.  If CT scans have 
slice thickness greater than 0.5 cm, the minimum size for a measurable 
lesion should be twice the slice thickness.   
 
2. 
Malignant lymph nodes are to be considered pathologically enlarged and 
measurable if it measures ≥ 1.5 cm in SHORT AXIS (greatest diameter 
perpendicular to the long axis of the lymph node) when assessed by scan 
(CT scan slice recommended being no greater than 0.5 cm). 
 
b. 
Non-measurable disease:  All other lesions (or sites of disease), including small 
lesions (longest diameter < 1.0 cm or pathologic lymph nodes with ≥ 1.0 cm to < 
1.5 cm short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered non-measurable as are previously radiated 
lesions that have not progressed. 
 
c. 
Notes on measurability 
 
1. 
For CT and MRIs, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior 
scans.  Body scans should be performed with breath-hold scanning 
techniques, if possible.  
 
2. 
PET-CT:  At present, the low dose or attenuation correction CT portion of 
a PET-CT is not always of optimal diagnostic CT quality for use with 
RECIST measurements.  However, if the site can document that the CT 
performed as part of a PET-CT is of identical diagnostic quality to a 
diagnostic CT, then the CT portion of the PET-CT can be used for RECIST 
measurements and can be used interchangeably with conventional CT. 
 
3. 
Ultrasound: Ultrasound is not useful in assessment of lesion size and 
should not be used as a method of measurement. 
 

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4. 
Cystic lesions that meet the criteria for radiographically defined simple 
cysts should not be considered as malignant lesions (neither measurable 
nor non-measurable) since they are, by definition, simple cysts. 
 
 
5. 
If a target lesion becomes very small some radiologists indicate that it is 
too small to measure.  If the lesion is actually still present, a default 
measurement of 0.5 cm should be applied.  If the radiologist believes the 
lesion has gone, a default measurement of 0.0cm should be recorded. 
 
10.2 
Objective Status at Each Disease Evaluation   
 
Objective Status is to be recorded at each evaluation. All measurable lesions up to a 
maximum of 2 lesions per organ 5 lesions in total, representative of all involved organs, 
should be identified as target lesions at baseline. All other lesions (or sites of disease) 
including any measurable lesions over and above the 5 target lesions should be identified 
as non-target lesions.  Measurements must be provided for target measurable lesions, 
while presence or absence must be noted for non-target measurable and non-measurable 
disease.   
 
For studies that use disease progression as an endpoint, whole body scanning at specific 
intervals is necessary to determine that progression is NOT present outside of the “target” 
areas. Therefore, in these studies it is not acceptable to image only the “target” areas of 
the body in follow-up scans. For study-specific imaging requirements, see the Study 
Calendar in Section 9.0.   
 
a. 
Complete Response (CR):  Complete disappearance of all target and non-target 
lesions (with the exception of lymph nodes mentioned below).  No new lesions.  
No disease related symptoms.   Any lymph nodes (whether target or non-target) 
must have reduction in short axis to < 1.0 cm.  All disease must be assessed using 
the same technique as baseline. 
 
b. 
Partial Response (PR): Applies only to patients with at least one measurable 
lesion. Greater than or equal to 30% decrease under baseline of the sum of 
appropriate diameters of all target measurable lesions.  No unequivocal 
progression of non-measurable disease.  No new lesions.  All target measurable 
lesions must be assessed using the same techniques as baseline. 
 
c. 
Stable: Does not qualify for CR, PR, Progression or Symptomatic Deterioration.  
All target measurable lesions must be assessed using the same techniques as 
baseline. 
 
d. 
Progression: One or more of the following must occur:  20% increase in the sum 
of appropriate diameters of target measurable lesions over smallest sum observed 
(over baseline if no decrease during therapy) using the same techniques as 
baseline, as well as an absolute increase of at least 0.5 cm.  Unequivocal 
progression of non-measurable disease in the opinion of the treating physician (an 
explanation must be provided).  Appearance of any new lesion/site.  Death due to 
disease without prior documentation of progression and without symptomatic 
deterioration (see Section 10.2e). 
 
 
Notes regarding new lesions:  FDG-PET imaging can complement regular scans 
in identifying new lesions according to the following algorithm.  
 

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1. 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a 
sign of progression based on a new lesion. 
 
2. 
No FDG-PET at baseline and a positive FDG-PET at follow-up 
corresponding to a potential new site of disease must have a confirmation 
by anatomical assessment (e.g. CT, MRI, x-ray) as new site of disease to 
be considered progressive disease.  In such a case, the date of 
progressive disease will be the date of the initial abnormal FDG-PET. 
 
e. 
Symptomatic deterioration:  Global deterioration of health status requiring 
discontinuation of treatment without objective evidence of progression.  Efforts 
should be made to obtain objective evidence of progression after discontinuation. 
 
f. 
Assessment inadequate, objective status unknown.  Progression or 
symptomatic deterioration has not been documented, and one or more target 
measurable lesions have not been assessed or inconsistent assessment methods 
were used. 
 
g. 
Objective status notes: 
 
1. 
Non-measurable and non-target measurable disease do not affect 
Objective Status  in determination of CR (must be absent--a patient who 
otherwise has a CR, but who has non-measurable or non-target 
measurable disease present or not assessed, will be classified as having 
a PR). However, non-measurable and non-target lesions are included in 
determination of progression (if new sites of disease develop or if 
unequivocal progression occurs in the opinion of the treating physician).  
 
2. 
An objective status of PR or stable cannot follow one of CR.  Stable can 
follow PR only in the rare case that tumor increases too little to qualify as 
progression, but enough that a previously documented 30% decrease no 
longer holds. 
 
3. 
In cases for which initial flare reaction is possible (hypercalcemia, 
increased bone pain, erythema of skin lesions), objective status is not 
progression unless either symptoms persist beyond 4 weeks or there is 
additional evidence of progression.   
 
4. 
Lesions that appear to increase in size due to presence of necrotic tissue 
will not be considered to have progressed.  
 
5. 
For bone disease documented on bone scan only, increased uptake does 
not constitute unequivocal progression. However, increase in the soft 
tissue component of a lesion as measured by CT or MRI would constitute 
progression. 
 
6. 
Appearance of new pleural effusions does not constitute unequivocal 
progression unless cytologically proven of neoplastic origin, since some 
effusions are a toxicity related to therapy or other medical conditions. 
Increase in the size of an existing effusion does not constitute unequivocal 
progression, since the fluid status of the patient could alter the size of the 
effusion.  
 

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7. 
If CR determination depends on a lesion for which the status is unclear by 
the required tests, it is recommended the residual lesion be investigated 
with biopsy or fine needle aspirate.   
 
 

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10.3 
Best Response 
 
This is calculated from the sequence of objective statuses. 
 
a. 
CR:  Two or more objective statuses of CR a minimum of four weeks apart 
documented before progression or symptomatic deterioration. 
 
b. 
PR: Two or more objective statuses of PR or better a minimum of four weeks apart 
documented before progression or symptomatic deterioration, but not qualifying as 
CR. 
 
c. 
Unconfirmed CR:  One objective status of CR documented before progression or 
symptomatic deterioration but not qualifying as CR or PR. 
 
d. 
Unconfirmed PR:  One objective status of PR documented before progression or 
symptomatic deterioration but not qualifying as CR, PR or unconfirmed CR. 
 
e. 
Stable/no response:  At least one objective status of stable/no response 
documented at least 6 weeks after registration and before progression or 
symptomatic deterioration, but not qualifying as anything else above. 
 
f. 
Increasing disease:  Objective status of progression within 12 weeks of 
registration, not qualifying as anything else above.   
 
g. 
Symptomatic deterioration: Objective status of symptomatic deterioration within 12 
weeks of registration, not qualifying as anything else above.   
 
h. 
Inadequate assessment, response unknown:  Progression or symptomatic 
deterioration greater than 12 weeks after registration and no other response 
category applies. 
 
10.4 
Performance Status:   
 
Patients will be graded according to the Zubrod Performance Status Scale. 
 
POINT  
DESCRIPTION 
 
0 
Fully active, able to carry on all pre-disease performance without 
restriction. 
 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light housework, office 
work. 
 
2 
Ambulatory and capable of self-care but unable to carry out any work 
activities; up and about more than 50% of waking hours.   
 
3 
Capable of limited self-care, confined to bed or chair more than 50% of 
waking hours.   
 
4 
Completely disabled; cannot carry on any self-care; totally confined to 
bed or chair.   
 
 

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10.5 
Progression-Free Survival 
 
From date of randomization to date of first documentation of progression or symptomatic 
deterioration (as defined above), or death due to any cause.  Patients last known to be 
alive without report of progression are censored at date of last contact. 
 
10.6 
Time to Death 
 
From date of randomization to date of death due to any cause.  Patients last known to be 
alive are censored at date of last contact. 
 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
11.1 
Sample Size and Primary Analysis 
 
We estimate the median PFS of patients treated with cetuximab and irinotecan to be 3 
months in this select population with HER-2 amplification. (34,35) Assuming dual anti-
HER-2 therapy offers an increase in PFS to 5.1 months (HR 0.59, for results to be 
considered clinically significant), we will need 122 eligible patients, based on a two-sided 
type I error of 5% and 80% power. Assuming a 6% ineligibility rate, we will need to 
randomize 130 patients. We expect 33 months of accrual and 7 months of follow-up. 
 
All potentially eligible patients will be registered (Step 1 Registration) and screened for 
HER-2 amplification status per ASCO/CAP guidelines and HERACLES criteria. (36,37) 
Patients who meet those criteria are then eligible for randomization (Step 2 Randomization) 
to treatment with trastuzumab and pertuzumab, or cetuximab and irinotecan. We estimate 
that approximately 2381 patients will be screened in order to enroll the 130 HER-2-
amplified patients necessary for the study.  
 
From activation on October 9, 2017 until May 28, 2021, 47 patients were randomized to 
this study. Given this slow accrual rate, it was determined that a smaller sample size will 
be targeted. Assuming a HR of 0.5 (median PFS of 6 months in the TP arm), 7 months of 
follow-up, 90% power and a 1-sided alpha of 0.10, the new design requires 62 eligible 
patients. Given the likelihood of continued slow accrual, the trial will be closed to enrollment 
when 62 patients have been randomized or on December 31, 2021, whichever occurs first. 
 
The primary analysis of PFS will be conducted in all eligible patients according to the intent-
to-treat principle, using the stratified log rank test with stratification by prior use of irinotecan 
and by HER-2/CEP17 ratio. No interim futility analysis will be performed since an early 
closure is planned. 
 
11.2 
Other Analyses 
 
Secondary endpoints will include overall survival, response, and toxicity. Distributions of 
overall survival in each arm will be estimated using the method of Kaplan-Meier and 
compared using the stratified log-rank test. The overall response rate (ORR), including 
confirmed complete and partial responses per RECIST 1.1, will be compared using the 
Cochran-Mantel-Haenszel test. With 31 patients per arm, overall survival at a particular 
timepoint and ORR can be estimated to within 18% (95% confidence interval) in each 
treatment arm.  
 
Patients receiving at least one dose of drug on any arm will be included in the assessment 
of adverse events. Adverse event monitoring is conducted by the study coordinators, 
disease committee chair, and Adverse Event Coordinator and study statistician on an 

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ongoing basis, with notification to the DSMC and CTEP should any concerns arise. Any 
events reported through the CTEP-AERS system are reported immediately, and reports 
are sent to the above group for all other AEs on a monthly basis. Thirty-one eligible patients 
in each arm are sufficient to estimate the probability of a particular toxicity to within 18% 
(95% confidence interval). Any toxicity occurring with at least 7% probability is likely (90% 
chance) to be seen at least once. 
 
Patients progressing on CETIRI will be provided the opportunity to cross over to the 
experimental intervention. This will facilitate enrollment in the protocol in a competitive 
landscape for study enrollment. PFS, OS, and ORR among patients who register to Arm 3 
will be summarized using descriptive statistics. 
 
11.3 
Translational Medicine 
 
The associations between each biomarker and PFS will be explored via Kaplan-Meier 
curves and Cox regression. The associations between biomarker and response will be 
explored via Logistic regression. Power calculations are based on associations between 
biomarker and outcomes separately by treatment arm. We assume a median PFS of 3 
months and a response rate of 15% in the control arm. 
 
Objectives 
 
a. 
To evaluate if the following biomarkers are prognostic of clinical efficacy in patients 
receiving TP or CETIRI.  
 
1. 
We hypothesize that higher HER-2/CEP17 signal ratio values are 
associated with improved outcomes. Dichotomizing by a median split (low 
vs high), 31 patients provide 80% power to detect a hazard ratio of 2.6 for 
PFS by HER-2/CEP17 signal ratio (corresponding to a median PFS of 7.8 
months for the HER-2/CEP17-high subgroup) using a two-sided alpha of 
0.10. With 31 patients evaluable for response in each treatment arm, we 
will have 80% power to detect a difference in response of 42% 
(corresponding to a response rate of 57% in the HER-2/CEP17-high 
subgroup) using a two-sided alpha of 0.10. We will also evaluate HER-
2/CEP17 signal ratio as a continuous variable.  
 
2. 
We hypothesize HER-2 gene copy number (GCN) ≥ 20 is associated with 
improved outcomes. Assuming 60% of patients have GCN ≥ 20, 31 
patients in each arm provides 80% power to detect a hazard ratio of 2.65 
for PFS by GCN (corresponding to a median PFS of 7.95 months for the 
GCN-high subgroup) using a two-sided alpha of 0.10. With 31 patients 
evaluable for response in each treatment arm, we will have 80% power to 
detect a difference in response of 43% (corresponding to a response rate 
of 58% in the GCN-high subgroup) using a two-sided alpha of 0.10. 
 
11.4 
Data and Safety Monitoring 
 
A Data and Safety Monitoring Committee will oversee the conduct of the study.  The 
Committee consists of four members from outside of the SWOG, 3 SWOG members, 3 
non-voting representatives from the National Cancer Institute (NCI), and the Group 
Statistician (non-voting).  The members of this Committee will receive confidential reports 
every 6 months from the SWOG Statistics and Data Management Center, and will meet at 
the Group's bi-annual meetings as necessary.  The Committee will be responsible for 
decisions regarding possible termination and/or early reporting of the study. 
 

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12.0 
DISCIPLINE REVIEW 
 
Discipline Review is not applicable to this study 
 
 
13.0 
REGISTRATION GUIDELINES 
 
13.1 
Registration Timing 
 
a. 
Specimens must be submitted as described in Section 15.1 on the day of Step 1 
Registration. If tumor is HER-2 amplified, patient must be registered to Step 2 
Randomization prior to initiation of treatment (no more than ten working days prior 
to planned start of treatment). 
 
b. 
Patients must be registered to Step 3 Optional Crossover prior to initiation of 
treatment (no more than ten days prior to planned start of treatment and within 28 
days of discontinuation of CETIRI treatment). 
 
13.2 
Investigator/Site Registration 
 
Prior to the recruitment of a patient for this study, investigators must be registered members 
of a Cooperative Group.  Each investigator must have an NCI investigator number and 
must maintain an “active” investigator registration status through the annual submission of 
a complete investigator registration packet to CTEP. 
 
a. 
CTEP Investigator Registration Procedures 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute 
(NCI) policy require all investigators participating in any NCI-sponsored clinical trial 
to register and to renew their registration annually. 
 
Registration requires the submission of: 
 
• 
a completed Statement of Investigator Form (FDA Form 1572) with an 
original signature 
• 
a current Curriculum Vitae (CV) 
• 
a completed and signed Supplemental Investigator Data Form (IDF) 
• 
a completed Financial Disclosure Form (FDF) with an original signature 
 
Fillable PDF forms and additional information can be found on the CTEP website 
at <http://ctep.cancer.gov/investigatorResources/investigator_registration.htm>.   
 
For questions, please contact the CTEP Investigator Registration Help Desk by 
email at <pmbregpend@ctep.nci.nih.gov>. 
 
b. 
CTEP Associate Registration Procedures 
 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access 
Management (IAM) application is a web-based application intended for use by both 
Investigators (i.e., all physicians involved in the conduct of NCI-sponsored clinical 
trials) and Associates (i.e., all staff involved in the conduct of NCI-sponsored 
clinical trials). 
 

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Associates will use the CTEP-IAM application to register (both initial registration 
and annual re-registration) with CTEP and to obtain a user account. 
 
Investigators will use the CTEP-IAM application to obtain a user account only. (See 
CTEP Investigator Registration Procedures above for information on registering 
with CTEP as an Investigator, which must be completed before a CTEP-IAM 
account can be requested.) 
 
An active CTEP-IAM user account will be needed to access all CTEP and CTSU 
(Cancer Trials Support Unit) websites and applications, including the CTSU 
members’ website. 
 
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
http://ctep.cancer.gov/branches/pmb/associate_registration.htm.   For questions, 
please contact the CTEP Associate Registration Help Desk by email at 
ctepreghelp@ctep.nci.nih.gov.    
 
c. 
CTSU Registration Procedures 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
1. 
IRB Approval:   
 
Each investigator or group of investigators at a clinical site must obtain 
IRB approval for this protocol and submit IRB approval and supporting 
documentation to the CTSU Regulatory Office before they can be 
approved to enroll patients.  Assignment of site registration status in the 
CTSU Regulatory Support System (RSS) uses extensive data to make a 
determination of whether a site has fulfilled all regulatory criteria including 
but not limited to: an active Federal Wide Assurance (FWA) number, an 
active roster affiliation with the Lead Network or a participating 
organization, a valid IRB approval, and compliance with all protocol 
specific requirements. 
 
Sites participating on the NCI CIRB initiative that are approved by the 
CIRB for this study are not required to submit IRB approval documentation 
to the CTSU Regulatory Office. For sites using the CIRB, IRB approval 
information is received from the CIRB and applied to the RSS in an 
automated process. Signatory Institutions must submit a Study Specific 
Worksheet for Local Context (SSW) to the CIRB via IRBManager to 
indicate their intent to open the study locally.  The CIRB’s approval of the 
SSW is then communicated to the CTSU Regulatory Office.  In order for 
the SSW approval to be processed, the Signatory Institution must inform 
the CTSU which CIRB-approved institutions aligned with the Signatory 
Institution are participating in the study. 
 
2. 
Downloading Site Registration Documents:   
 
Site registration forms may be downloaded from the S1613 protocol 
page located on the CTSU members’ website.  
 
Go to https://www.ctsu.org and log in to the members’ area using 
your CTEP-IAM username and password 
 
Click on the Protocols tab in the upper left of your screen 
 
Either enter the protocol # in the search field at the top of the protocol 
tree, or 
 
Click on LPO Documents, select the Site Registration documents link, 

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and download and complete the forms provided.   
 
Click on the By Lead Organization folder to expand 
 
Click on the SWOG link to expand, then select S1613. Click on LPO 
Documents, select the Site Registration documents link, and 
download and complete the forms provided. 
 
3. 
Requirements for S1613 Site Registration: 
 
• 
CTSU Transmittal Sheet (optional)  
• 
•IRB approval (For sites not participating via the NCI CIRB; local 
IRB documentation, an IRB-signed CTSU IRB Certification Form, 
Protocol of Human Subjects Assurance Identification/IRB 
Certification/Declaration of Exemption Form, or combination is 
accepted ) 
 
4. 
Submitting Regulatory Documents:  
 
Submit required forms and documents to the CTSU Regulatory Office, 
where they will be entered and tracked in the CTSU RSS.  
 
ONLINE: www.ctsu.org (members’ section)  Regulatory Submission 
Portal 
EMAIL: CTSURegulatory@ctsu.coccg.org (for regulatory document 
submission only) 
FAX: 215/569-0206 
MAIL:  CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
 
5. 
Checking Your Site’s Registration Status: 
 
You can verify your site registration status on the members’ section of the 
CTSU website.   
 
 
Go to https://www.ctsu.org and log in to the members’ area using your 
CTEP-IAM username and password 
 
Click on the Regulatory tab at the top of your screen 
 
Click on the Site Registration tab 
 
Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status given only reflects compliance with IRB documentation 
and institutional compliance with protocol-specific requirements as 
outlined by the Lead Network. It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling 
investigator’s status with the NCI or their affiliated networks. 
 
13.3 
OPEN Registration Requirements 
 
The individual registering the patient must have completed the appropriate SWOG 
Registration Worksheet.  The completed form must be referred to during the registration 
but should not be submitted as part of the patient data. 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available on a 24/7 basis.  To access 
OPEN, the site user must have an active CTEP-IAM account (check at < https://eapps-

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ctep.nci.nih.gov/iam/index.jsp >) and a 'Registrar' role on either the LPO or participating 
organization roster. 
 
OPEN will also ask additional questions that are not present on the SWOG Registration 
Worksheet.  The individual registering the patient must be prepared to provide answers to 
the following questions: 
 
a. 
Institution CTEP ID 
 
b. 
Protocol Number 
 
c. 
Registration Step 
 
d. 
Treating Investigator 
 
e. 
Credit Investigator 
 
f. 
Patient Initials 
 
g. 
Patient’s Date of Birth 
 
h. 
Patient SSN (SSN is desired, but optional.  Do not enter invalid numbers.) 
 
i. 
Country of Residence 
 
j. 
ZIP Code 
 
k. 
Gender (select one): 
• 
Female Gender 
• 
Male Gender 
 
l. 
Ethnicity (select one): 
• 
Hispanic or Latino 
• 
Not Hispanic or Latino 
• 
Unknown 
 
m. 
Method of Payment (select one): 
• 
Private Insurance 
• 
Medicare 
• 
Medicare and Private Insurance 
• 
Medicaid 
• 
Medicaid and Medicare 
• 
Military or Veterans Sponsored NOS 
• 
Military Sponsored (Including Champus & Tricare) 
• 
Veterans Sponsored 
• 
Self Pay (No Insurance) 
• 
No Means of Payment (No Insurance) 
• 
Other 
• 
Unknown 
 
n. 
Race (select all that apply): 
• 
American Indian or Alaska Native 
• 
Asian 
• 
Black or African American 
• 
Native Hawaiian or other Pacific Islander 

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• 
White 
• 
Unknown 
 
13.4 
Registration Procedures 
 
a. 
All site staff will use OPEN to enroll patients to this study.  OPEN is integrated with 
the CTSU Enterprise System for regulatory and roster data and, upon enrollment, 
initializes the patient in the Rave database.  OPEN can be accessed at 
https://open.ctsu.org, from the OPEN tab on the CTSU members’ side of the 
website at https://www.ctsu.org, or from the OPEN Patient Registration link on the 
SWOG CRA Workbench. 
 
b. 
Prior to accessing OPEN site staff should verify the following: 
 
• 
All eligibility criteria have been met within the protocol stated timeframes and 
the affirmation of eligibility on the Registration Worksheet has been signed by 
the registering investigator or another investigator designate. Site staff should 
refer to Section 5.0 to verify eligibility. 
 
• 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
 
c. 
The OPEN system will provide the site with a printable confirmation of registration 
and treatment information.   Please print this confirmation for your records. 
 
d. 
Further instructional information is provided on the OPEN tab on the CTSU 
members’ side of the website at https://www.ctsu.org or at https://open.ctsu.org.  
For any additional questions contact the CTSU Help Desk at 888/823-5923 or 
ctsucontact@westat.com.   
 
13.5 
Exceptions to SWOG registration policies will not be permitted. 
 
a. 
Patients must meet all eligibility requirements. 
 
b. 
Institutions must be identified as approved for registration. 
 
c. 
Registrations may not be cancelled. 
 
d. 
Late registrations (after initiation of treatment) will not be accepted. 
 
 
14.0 
DATA SUBMISSION SCHEDULE 
 
14.1 
Data Submission Requirement 
 
Data must be submitted according to the protocol requirements for ALL patients registered, 
whether or not assigned treatment is administered, including patients deemed to be 
ineligible.  Patients for whom documentation is inadequate to determine eligibility will 
generally be deemed ineligible 
 
14.2 
Master Forms 
 
Master forms can be found on the protocol abstract page on the SWOG website 
(www.swog.org) and (with the exception of the sample consent form and the Registration 
Worksheet) must be submitted on-line via the Web; see Section 14.3a for details. 

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14.3 
Data Submission Procedures 
 
a. 
Data collection for this study will be done exclusively through the Medidata Rave® 
clinical data management system. Access to the trial in Rave is granted through 
the iMedidata application to all persons with the appropriate roles assigned in 
Regulatory Support System (RSS). To access Rave via iMedidata, you must have 
an 
active 
CTEP-IAM 
account 
(check 
at 
https://eapps-
ctep.nci.nih.gov/iam/index.jsp) and the appropriate Rave role (Rave CRA, Read-
Only, Site Investigator) on either the LPO or participating organization roster at the 
enrolling site. 
 
Upon initial site registration approval for the study in RSS, all persons with Rave 
roles assigned on the appropriate roster will be sent a study invitation e-mail from 
iMedidata. To accept the invitation, site users must log into the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM user name and 
password, and click on the “accept” link in the upper right-corner of the iMedidata 
page. Please note, site users will not be able to access the study in Rave until all 
required Medidata and study specific trainings are completed. Trainings will be in 
the form of electronic learnings (eLearnings), and can be accessed by clicking on 
the link in the upper right pane of the iMedidata screen. 
 
Users that have not previously activated their iMedidata/Rave account at the time 
of initial registration approval for the study in RSS will also receive a separate 
invitation from iMedidata to activate their account. Account activation instructions 
are located on the CTSU website, Rave tab under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance). Additional 
information on iMedidata/Rave is available on the CTSU members’ website under 
the Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU help Desk at 
888/823-5923 or by e-mail at ctsucontact@westat.com.  
 
b. 
You may also access Rave® via the SWOG CRA Workbench.  Go to the SWOG 
web site (http://swog.org) and logon to the Members Area using your SWOG 
Roster ID Number and password. After you have logged on, click on Workbenches, 
then CRA Workbench to access the home page for the CRA Workbench and follow 
the link to Rave® provided in the left-hand navigation panel. 
 
To access the CRA Workbench the following must be done (in order): 
 
1. 
You are entered into the SWOG Roster and issued a SWOG Roster ID 
Number, 
2. 
You are associated as an investigator or CRA/RN at the institution where 
the patient is being treated or followed, 
3. 
Your Web User Administrator has added you as a web user and has given 
you the appropriate system permissions to view data for that institution. 
 
For assistance with points 1 and 2 call the Operations Office at 210/614-8808.  For 
point 3, contact your local Web User Administrator (refer to the "Who is my Web 
User Administrator?" function on the swog.org Members logon page). 
 
For 
difficulties 
with 
the 
CRA 
Workbench, 
please 
email 
technicalquestion@crab.org.  
 
c. 
Institutions participating through the Cancer Trials Support Unit (CTSU), please 
refer to the CTSU Participation Table. 

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14.4 
Data Submission Overview and Timepoints  
 
Step 1 Submission (required for all patients) 
 
a. 
WITHIN 48 HOURS OF STEP 1 INITIAL REGISTRATION:   
 
Submit the following per Section 15.1: 
 
Tissue specimens for central HER-2 testing (directly to Protean BioDiagnostics, 
Inc.). 
 
Pathology report with specimens to Protean BioDiagnostics, Inc. 
 
14.5 
Data Submission FOR PATIENTS WHO WILL NOT ENROLL TO STEP 2 
RANDOMIZATION: 
 
a. 
WITHIN 7 DAYS OF DECISION NOT TO RANDOMIZE PATIENT: 
 
Submit the S1613 Notice of Intention Not to Randomize form 
 
14.6 
Step 2 Submission (required for patients randomized to a treatment arm) 
 
a. 
WITHIN 7 DAYS AFTER STEP 2 RANDOMIZATION:  
 
Submit the following: 
 
S1613 Onstudy Forms 
 
Baseline Tumor Assessment Form (RECIST 1.1) 
 
Pathology Report (NOTE: Upload reports via the Source Documentation: Baseline 
form in Rave®. This submission is in addition to the pathology report submission to 
Protean BioDiagnostics, Inc. that is required by Section 15.1). 
 
Molecular testing reports for KRAS, NRAS, and BRAF (NOTE: Upload reports via 
the Source Documentation: Baseline form in Rave®.) 
 
Submit radiology reports from all scans performed to assess disease at baseline. 
(NOTE: Upload reports via the Source Documentation: Baseline form found in the 
Randomization Disease Assessment Folder in Rave®) 
 
Submit images from scans performed to assess disease to AG Mednet for Image 
Banking (see Section 15.3). 
 
b. 
WITHIN 28 DAYS AFTER STEP 2 RANDOMIZATION: 
 
If the patient consents, submit tissue specimens (including pathology report) as 
described in Section 15.2. 
 
c. 
WITHIN 14 DAYS AFTER EACH CYCLE OF TREATMENT (INCLUDING BOTH 
ON INITIAL TREATMENT ARM AND CROSSOVER TREATMENT ARM): 
 
Submit the following: 
 

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S1613 Treatment Form 
 
S1613 Adverse Event Form 
 
d. 
WITHIN 14 DAYS AFTER EACH DISEASE ASSESSMENT (INCLUDING BOTH 
ON 
TREATMENT 
AND 
OFF 
TREATMENT 
PRIOR 
TO 
DISEASE 
PROGRESSION)*: 
 
Submit the following: 
 
Follow Up Tumor Assessment Form (RECIST 1.1) 
 
Radiology reports from all scans used to assess disease (NOTE: Upload reports 
via the Source Documentation: Follow-up form in Rave®) 
 
Submit images from scans performed to assess disease to AG Mednet for banking 
as specified in Section 15.3.  
 
*For patients on CETIRI who continue to TP, submit disease assessments (in the 
Crossover Disease Assessment Folder) until second progression. However, 
submission of images to AG Mednet are not required for Arm 3.  
 
e. 
WITHIN 14 DAYS OF DISCONTINUATION OF TREATMENT (INCLUDING BOTH 
ON INITIAL TREATMENT AND CROSSOVER TREATMENT): 
 
Submit the following: 
 
Off Treatment Notice 
 
S1613 Treatment Form 
 
S1613 Adverse Event Form 
 
f. 
WITHIN 14 DAYS OF PROGRESSION/RELAPSE: 
 
Submit the following: 
  
Follow-up Tumor Assessment Form (RECIST 1.1) 
 
Radiology Reports (NOTE: Upload reports via the Source Documentation: Follow-
up form in Rave®.) 
 
Off Treatment Notice (if the patient was still on protocol treatment)  
 
Final S1613 Treatment Form (if the patient was still on protocol treatment) 
 
Final S1613 Adverse Event Form (if the patient was still on protocol treatment) 
 
Follow-Up Form (if the patient was off protocol treatment) documenting date, site 
and method for determining progression/relapse. 
 
NOTE: For patients on CETIRI (Arm 2) who continue to TP (Arm 3), submit disease 
assessments until second progression. 
 

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Submit images from scans performed to assess disease to AG Mednet for banking 
as specified in Section 15.3. Image submission may be batched. 
 
g. 
WITHIN 7 DAYS AFTER STEP 3 CROSSOVER REGISTRATION: 
 
Submit the following: 
 
Baseline Tumor Assessment Form (RECIST 1.1) 
 
S1613 Crossover Eligibility Form 
 
Radiology reports (NOTE: Upload reports via the Source Documentation: Baseline 
form found in the Crossover Disease Assessment Folder in Rave®) 
 
 

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h. 
AFTER OFF ALL PROTOCOL TREATMENT, EVERY 6 MONTHS FOR 3 YEARS 
FROM STEP 2 RANDOMIZATION:  
 
Submit the following: 
 
Follow Up Form 
 
Late Effects Form (if prior to treatment for progression or relapse or a second 
primary, and prior to non-protocol treatment, the patient experiences any severe 
[Grade ≥ 3] long term toxicity that has not been previously reported) 
 
i. 
WITHIN 4 WEEKS OF KNOWLEDGE OF DEATH: 
 
Submit the Notice of Death and final S1613 Treatment Form and S1613 Adverse 
Event Form (if the patient was still on protocol treatment) or Follow-Up Form (if the 
patient was off protocol treatment) documenting death information. 
 
 
15.0 
SPECIAL INSTRUCTIONS 
 
15.1 
Specimens for HER-2 testing (required for patients) 
 
All patients must submit specimens for central HER-2 testing on the day of Step 1 
Registration.  
 
a. 
Collection instructions are outlined in Section 15.1c and submission instructions 
are outlined in Section 15.1e. 
 
b. 
Specimens to be submitted (see Sections 9.1 and 9.2): 
 
1. 
1 H&E tumor tissue slide (an additional unstained slide may be submitted 
if unable to obtain H&E locally) 
 
2. 
6 unstained paraffin-embedded tissue charged slides (4-5 microns thick) 
 
NOTE: If patient is registered on a Friday, sites should hold tissue shipment until 
Monday. If tissue is received at lab and HER-2 status cannot be obtained, the site 
will be notified and additional tissue may be submitted for testing. 
 
c. 
Paraffin-embedded tissue must be fixed per the instructions on the SWOG 
Specimen Submission webpage  
(https://www.swog.org/clinical-trials/biospecimen-resources/biospecimen-
processing-and-submission-procedures#Formalin-Fixed%20Paraffin) 
and 
submitted to the lab in Section 15.1e. 
 
d. 
Specimen collection kits are not being provided for this submission; sites will use 
institutional supplies. 
 
e. 
SHIPPING SAMPLES 
 
1. 
SWOG Specimen Tracking System (STS) 
 
All specimen submissions for this study must be entered and tracked using 
the SWOG online Specimen Tracking system. SWOG members may log 
on the online system via the CRA Workbench. To access the CRA 

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Workbench, go to the SWOG Web site (http://swog.org) and logon to the 
Members Area. After you have logged on using your SWOG roster ID 
number and password, click on the CRA Workbench link to access the 
home page for CRA Workbench website. Non- SWOG users may log into 
SpecTrack using their CTSU UserID and password on the SpecTrack login 
page located at https://spectrack.crab.org select the option “SWOG – 
SWOG – CTSU”).  SpecTrack start-up instructions (both written and 
demo) are available after signing in to SpecTrack.  
 
A copy of the Shipment Packing List produced by the online Specimen 
Tracking system should be printed and placed in the pocket of the 
specimen bag if it has one, or in a separate resealable bag. The Specimen 
Submission Form is NOT required when the online system is used. 
 
ALL SPECIMENS MUST BE LOGGED VIA THIS SYSTEM; THERE ARE 
NO EXCEPTIONS. 
 
To report technical problems with Specimen Tracking, such as database 
errors 
or 
connectivity 
issues, 
please 
send 
an 
email 
to 
technicalquestion@crab.org. For procedural help with logging and 
shipping specimens, there is an introduction to the system on the 
Specimen Tracking main page (https://spectrack.crab.org/Instructions)  or 
contact the SWOG Statistics and Data Management Center at 206/652-
2267 to be routed to the Data Coordinator for further assistance. 
 
In the online specimen tracking system, the appropriate SWOG laboratory 
for submission of tissue samples for HER-2 testing is identified as follows: 
 
Lab #237:  
Dry Lab 
Attention: Catherine Wilson 
Protean BioDiagnostics, Inc. 
6555 Sanger Road  
Suite 225 
Orlando, FL 32827 
Phone: 754/946-4309 
E-mail: catherine.wilson@proteanbiodx.com 
 
Hannah Park 
E-mail: hannah.park@proteanbiodx.com  
 
2. 
Institutions will be notified by e-mail with the patient’s HER-2 testing results 
within 14 calendar days after specimen submission. A formal lab report 
will be FAXed on request. If the patient’s HER-2 results are NOT received 
by e-mail within 14 calendar days of submitting the specimen, please 
contact the SWOG Statistics and Data Management Center at 206/652-
2267. 
 
15.2 
Submission of Specimens for Banking (optional for patients registered to Step 2 
Randomization) 
 
Specimens for translational medicine and banking (submitted to the SWOG Biospecimen 
Bank– Solid Tissue, Myeloma and Lymphoma Division, Lab #201): 
 

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a. 
With patient’s consent, the following baseline specimens must be submitted after 
Step 2 Randomization and after crossover (Step 3) prior to beginning treatment on 
C1D1 (+/- 3 days) (see Sections 9.1 and 9.2): 
 
1. 
FFPE block or 10 unstained slides (10-micron on charged slides preferred; 
if not available, 5-micron and/or uncharged slides acceptable). Biopsy may 
be from either the primary or metastatic tumor site. 
 
2. 
Collect 20 mL of blood in lavender top (EDTA) tubes on C1D1 (+/- 3 days), 
, on C2D1 (+/- 3 days) and at each restaging (including restaging during 
treatment on crossover arm), and off treatment. Process blood for plasma, 
aliquot, and store in a -70°C to -80°C freezer until shipment per the 
guidelines in Section 15.2b. Plasma may be frozen and batch shipped at 
least every 3 months (maximum 5 patients per shipment). 
 
b. 
Specimen collection and submission instructions can be accessed on the SWOG 
Specimen Submission webpage  
(https://www.swog.org/clinical-trials/biospecimen-resources/biospecimen-
processing-and-submission-procedures#Formalin-Fixed%20Paraffin) 
 
c. 
Specimen collection kits are not being provided for this protocol; sites will use 
institutional supplies. 
 
d. 
Shipping Samples 
 
1. 
SWOG Specimen Tracking System (STS) 
 
All specimen submissions for this study must be entered and tracked using 
the SWOG online Specimen Tracking system. SWOG members may log 
on the online system via the CRA Workbench. To access the CRA 
Workbench, go to the SWOG Web site (http://swog.org) and logon to the 
Members Area. After you have logged on using your SWOG roster ID 
number and password, click on the CRA Workbench link to access the 
home page for CRA Workbench website. Non- SWOG users may log into 
SpecTrack using their CTSU UserID and password on the SpecTrack login 
page located at https://spectrack.crab.org select the option “SWOG – 
SWOG – CTSU”).  SpecTrack start-up instructions (both written and 
demo) are available after signing in to SpecTrack.  
 
A copy of the Shipment Packing List produced by the online Specimen 
Tracking system should be printed and placed in the pocket of the 
specimen bag if it has one, or in a separate resealable bag. The Specimen 
Submission Form is NOT required when the online system is used. 
 
ALL SPECIMENS MUST BE LOGGED VIA THIS SYSTEM; THERE ARE 
NO EXCEPTIONS. 
 
To report technical problems with Specimen Tracking, such as database 
errors 
or 
connectivity 
issues, 
please 
send 
an 
email 
to 
technicalquestion@crab.org.  For procedural help with logging and 
shipping specimens, there is an introduction to the system on the 
Specimen Tracking main page (https://spectrack.crab.org/Instructions)  or 
contact the SWOG Statistics and Data Management Center at 206/652-
2267 to be routed to the Data Coordinator for further assistance. 
 

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In the online specimen tracking system, the appropriate SWOG laboratory 
for submission of tissue samples for HER-2 testing is identified as follows: 
 
 

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Lab #201:  
 
 
SWOG Biospecimen Bank 
Solid Tissue, Myeloma & Lymphoma Division 
Nationwide Children’s Hospital 
700 Children’s Drive, WA1340 
Columbus, OH 43205 
 
Phone: 614-722-2865 
Email: bpcbank@nationwidechildrens.org    
 
Plasma will be shipped frozen, on dry ice. Complete packaging and 
shipping instructions for both the plasma and the blocks or slides can be 
accessed 
on 
the 
SWOG 
Specimen 
Submission 
webpage 
(https://www.swog.org/clinical-trials/biospecimen-
resources/biospecimen-processing-and-submission-
procedures#Formalin-Fixed%20Paraffin). 
 
15.3 
Submission of Images for Banking (required for patients on TP [Arm 1] and CETIRI [Arm 
2]) 
 
All patients will undergo imaging at baseline and every 6 weeks through Week 12 and then 
every 8 weeks until progression. Images must be locally read and interpreted by the local 
site radiology service.  Imaging exams must then be submitted through AG Mednet for 
image banking. Image submission may be batched. Any imaging that is used for 
progression detection must be submitted. In addition, if imaging done for other reasons 
detects progression, it must also be submitted. Banked images may be used in future 
retrospective analysis. 
 
a. 
Instructions for Electronic Submission of Digital Images via AG Mednet to 
SWOG 
 
Digital images must be submitted electronically via the AG Mednet service 
provided by SWOG. (Please note that while AG Mednet service is provided by 
SWOG, SWOG will not be responsible for the cost of the exams). 
 
b. 
Electronic Submission Set-Up 
 
Upon IRB approval, you can begin the process to use the AG Mednet Desktop 
Agent. To request access, email agmednetadmin@swog.org and provide the 
following information: 
 
• Contact Name 
• Email Address 
• Phone Number 
• Site Name 
• NCI Site Code 
• Address 
• Trial Name 
• Trial ID 
• Date 
 
 

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c. 
Registration via the AG Mednet Portal 
 
1. 
If your site is qualified to participate in the trial, the SWOG Trial 
Administrator will invite you to the trial via the AG Mednet Portal. When 
you are added, you will receive a welcome email notification prompting 
you to register in the portal: https://portal.agmednet.net.  
 
2. 
Complete the 3 pages of registration information. This includes creating 
your own username and password and a challenge question and answer. 
 
3. 
When you are finished with registration, the portal will display a 
“Registration Complete” page. At this point you now have access to the 
trial. After you download the Desktop Agent, you will be able to login with 
your new username and password. You will also receive a registration 
confirmation email notification. 
 
d. 
Download the Desktop Agent and Login 
 
All participating sites need to download the AG Mednet Desktop Agent. The AG 
Mednet Desktop Agent can be accessed from a networked PC with Java 6 plugin 
installed. This plug-in ensures AG Mednet will run within the web browser. It is 
likely that you already have Java 6 installed. If you do not have Java 6 installed, 
downloading the Desktop Agent automatically downloads Java 6. 
 
1. 
Launch your web browser and type in the following URL. This will 
download 
the 
AG 
Mednet 
Desktop 
Agent 
to 
your 
system: 
https://portal.agmednet.net/Desktop-Agent.  
 
2. 
Type in your user name and password. 
 
3. 
Click “Launch” 
 
NOTE: This will place an icon on your desktop so, for future submissions, you can 
click on the “AG Mednet” icon, and it will automatically launch and request your 
user name and password when clicked. 
 
e. 
Submission (DICOM Exam) 
 
1. 
Click on the tab “DICOM Import” (top of screen). 
 
2. 
For CD/DVD, load a disc into your machine. 
 
 
3. 
A normal directory tree will be visible (close any DICOM viewers that may 
pop-up). Select the location of your DICOM files (i.e., the CD/DVD drive) 
or your PACS server. (NOTE: if sending from a PACS or Modality, use the 
DICOM Query or DICOM Receive Tab. Further details are available in the 
user guide on the Welcome Tab). 
 
4. 
Find the time-point you wish to submit and select the “DICOMDIR” file and 
click “Import Exam.” Click “Close” when complete*. 
 
 
5. 
Click the “Exam List” tab (top of screen). 
 

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6. 
Select the exam you want to submit from “Available Exams” by clicking on 
a row within the table. In the image preview, you will see a picture of the 
data selected. Please check this is what you intend to submit. If not, select 
a different exam or go back to step A or E and select a different exam from 
the exam list. 
 
7. 
In “Available Tasks for Selected Exam” (bottom left of screen), click 
“Assign Exam to Trial.” In pop-up box, select S1613 from drop-down list 
and click “Assign Trial.” 
 
8. 
In “Available Tasks for Selected Exam” (bottom left of screen), click 
“Deidentification” and click “Do Task.”. 
 
9. 
In the pop-up box, click into the first blank cell under “De-identified Value.” 
Follow the on screen guidance and enter required data. Then click the next 
blank cell below the first and repeat until all blank cells are populated. As 
you complete these cells, the red cross will turn into blue checks. If a red 
cross remains after data has been entered, please check that the data is 
correct and change if applicable. 
 
10. 
Click out of the cells and click “De-identify” (bottom of pop-up). AG Mednet 
will then remove any personal patient information from the DICOM 
metadata fields and replace this information with the study-specific data 
you entered in the table. Click close when complete. 
 
11. 
In “Available Tasks for Selected Exam” (bottom left of screen), click 
“Transmittal Form” and click “Do Task.” The Data Transmittal Form will 
open. Complete all mandatory fields according to the study protocol. If you 
attempt to save the form without completing all mandatory fields, an alert 
will appear, prompting you to complete the remaining fields. If you want to 
print the form, click the “Print” button prior to saving. When the form is 
complete, click the “Save” button. 
 
12. 
In “Available Tasks for Selected Exam” (bottom left of screen), click 
“Upload Exam” and click “Do Task.”. 
 
13. 
Data will now be transmitted. Upload time is variable (depending on 
network connection and the size and number of images), but AG Mednet 
can be left running in the background and the computer used for other 
work. Once the data has been transmitted, a message will pop-up and AG 
Mednet can be closed. 
 
14. 
You can import new exams and process them during the upload. 
 
15. 
After 15 minutes of inactivity, the Desktop Agent will lock out. However, 
this does not interfere with the upload. You only need to log back in if you 
want to import another exam. *In most cases, a DICOMDIR file will be 
generated by scanners. However, if this is not the case, please select “All 
Files” from the dropdown box at the bottom of the “DICOM Import” screen. 
Data can then be selected manually from the directory tree and “Import 
Exam” clicked. The process is then the same as where a DICOMDIR file 
exists. 
 
Note: The person responsible for activating the desktop agent 
should be involved in submitting the exams as the Desktop Agent 
requires specific log-in verification. All questions regarding AG 

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Mednet use should be directed to 888-9AGMEDNET, and hit 2 for 
the support option. 
 
 
 

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16.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
The following must be observed to comply with Food and Drug Administration regulations for the 
conduct and monitoring of clinical investigations; they also represent sound research practice: 
 
Informed Consent 
 
The principles of informed consent are described by Federal Regulatory Guidelines (Federal 
Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office for Protection from Research 
Risks Reports:  Protection of Human Subjects (Code of Federal Regulations 45 CFR 46).  They 
must be followed to comply with FDA regulations for the conduct and monitoring of clinical 
investigations. 
 
Institutional Review 
 
This study must be approved by an appropriate institutional review committee as defined by Federal 
Regulatory Guidelines (Ref. Federal Register Vol. 46, No. 17, January 27, 1981, part 56) and the 
Office for Protection from Research Risks Reports:  Protection of Human Subjects (Code of Federal 
Regulations 45 CFR 46). 
 
Drug Accountability 
 
An investigator is required to maintain adequate records of the disposition of investigational drugs 
according to procedures and requirements governing the use of investigational new drugs as 
described in the Code of Federal Regulations 21 CFR 312.  
 
Monitoring 
 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  Cumulative 
CDUS data will be submitted quarterly to CTEP by electronic means.  Reports are due January 31, 
April 30, July 31 and October 31. 
 
Confidentiality 
 
Please note that the information contained in this protocol is considered confidential and should 
not be used or shared beyond the purposes of completing protocol requirements until or unless 
additional permission is obtained. 
 
16.1 
Adverse Event Reporting Requirements 
 
a. 
Definition and Purpose 
 
Definition:  Adverse event means any untoward medical occurrence associated 
with the use of a drug in humans, whether or not considered drug related. (FDA, 
21 CFR 312.32). See Table 16.1 for definition of a Serious Adverse Event (SAE) 
and reporting requirements. 
 
Adverse event data collection and reporting, which are required as part of every 
clinical trial, are done to ensure the safety of patients enrolled in the studies as well 
as those who will enroll in future studies using similar agents. Adverse events are 
reported in a routine manner at scheduled times during a trial. (Directions for 
routine reporting are provided in Section 14.0.) Additionally, certain adverse events 
must be reported in an expedited manner to allow for more timely monitoring of 

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patient safety and care. The following guidelines prescribe expedited adverse 
event reporting for this protocol.  
 
b. 
Reporting method 
 
This study requires that expedited adverse events be reported to SWOG 
Operations Office using the Cancer Therapy Evaluation Program Adverse 
Event Reporting System (CTEP-AERS).  CTEP's guidelines for CTEP-AERS 
can be found at http://ctep.cancer.gov. 
 
c. 
When to report an event in an expedited manner 
 
Some adverse events require 24-hour notification (refer to Table 16.1) via 
CTEP-AERS.  
 
In the rare event when internet connectivity is disrupted a 24-hour notification 
is made to SWOG by telephone at 210-614-8808 or by email adr@swog.org.  
An electronic report MUST be submitted immediately upon re-establishment of 
internet connection. 
 
When the adverse event requires expedited reporting, submit the report via 
CTEP-AERS within the number of calendar days of learning of the event 
specified in Table 16.1 or 16.2, as applicable.  
 
d. 
Other recipients of adverse event reports 
 
The SWOG Operations Office will forward reports and documentation to the 
appropriate regulatory agencies and drug companies as required. 
 
Adverse events determined to be reportable to the Institutional Review Board 
responsible for oversight of the patient must be reported according to local 
policy and procedures. 
 
e. 
Expedited reporting for investigational agents 
 
Expedited reporting is required if the patient has received at least one dose of 
the investigational agent(s) as part of the trial. Reporting requirements are 
provided in Table 16.1. The investigational agent(s) used in Arms 1 and 3 of 
this study are pertuzumab and trastuzumab. If there is any question about the 
reportability of an adverse event or if on-line CTEP-AERS cannot be used or if 
internet connectivity is disrupted please telephone or email the SAE Program 
Manager at the Operations Office, 210/614-8808 or adr@swog.org, before 
preparing the report. 
 
 
 

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Table 16.1: 
 
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements 
for Adverse events that Occur on Studies under an Non-CTEP IND within 
30 
Days 
of 
the 
Last 
Administration 
of 
the 
Investigational 
Agent/Intervention1 – Trastuzumab and Pertuzumab (Arm 1 and Arm 3) 
  
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or 
not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via 
CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization       
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization       
≥ 24 hrs 
Not required 
NOTE:   Protocol specific exceptions to expedited reporting of serious adverse events are found in the 
Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR or Section 
16.1f. 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 
24-hour report. 
 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
 
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
 
May 5, 2011 
 

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f. 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting 
Requirements for Phase 1 and Early Phase 2 Studies Utilizing an Agent 
under a non-CTEP-IND: 
 
1. 
Group-specific instructions. 
 
Supporting Documentation Submission – Within 5 calendar days submit 
documentation supporting the CTEP-AERS report to the SWOG 
Operations Office by fax 210-614-0006. Specific instructions will be sent 
by email to the reporting site by the SAE Program Manager. 
 
2. 
The adverse events listed below also require expedited reporting via 
CTEP-AERS for this trial: 
• 
Asymptomatic decline in LVEF requiring treatment or leading to 
discontinuation of pertuzumab and/or tratuzumab 
• 
Congestive Heart Failure 
 
3. 
The adverse events listed below do not require expedited reporting via       
• 
The following events are to be monitored and carefully recorded, 
however these do not require expedited reporting for non-serious 
cases:  
o 
Infusion-related 
reactions/ARRs 
including 
anaphylactic 
deformities, hypersensitivity/anaphylaxis,  
o 
Infections,  
o 
Medication error,  
o 
Severe skin reactions,  
o 
Hepatobiliary toxicity, 
o 
Exacerbation of chemotherapy-associated neutropenia/febrile 
neutropenia, 
o 
Diarrhea Grade ≥ 3, 
o 
Mucositis, 
o 
Rash 
 
g. 
Expedited reporting for commercial agents 
 
Commercial reporting requirements are provided in Table 16.2. The 
commercial agent(s) used in Arm 2 of this study are cetuximab and irinotecan. 
If there is any question about the reportability of an adverse event or if Internet 
connectivity is disrupted please telephone or email the SAE Program Manager 
at the Operations Office, 210/614-8808 or adr@swog.org, before preparing the 
report. 
 
 

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Table 16.2 
 
 
ATTRIBUTIO
N 
 
Grade 4 
 
Grade 5a 
Unexpected 
Expected 
Unexpected 
Expected 
Unrelated or 
Unlikely 
 
 
CTEP-
AERS 
CTEP-
AERS 
Possible, 
Probable, 
Definite 
CTEP-
AERS 
 
CTEP-
AERS 
CTEP-
AERS 
CTEP-AERS:  Indicates an expedited report is to be submitted via CTEP-AERS within 
10 calendar days of learning of the eventb. 
a This includes all deaths within 30 days of the last dose of treatment with a commercial 
agent(s), regardless of attribution.  Any death that occurs more than 30 days after 
the last dose of treatment with a commercial agent(s) and is attributed (possibly, 
probably, or definitely) to the agent(s) and is not due to cancer recurrence must be 
reported according to the instructions above. 
 
b Submission of the on-line CTEP-AERS report plus any necessary amendments 
generally completes the reporting requirements. You may, however, be asked to 
submit supporting clinical data to the Operations Office in order to complete the 
evaluation of the event. If requested, the specified data should be sent within 5 
calendar days by fax to 210-614-0006.  
 
 
h. 
Reporting Secondary Malignancy, including AML/ALL/MDS 
 
1. 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, 
radiation or chemotherapy). A secondary malignancy is not considered 
a metastasis of the initial neoplasm. 
 
 
SWOG requires all secondary malignancies that occur following 
treatment with an agent under a Non-NCI IND to be reported via CTEP-
AERS.  Three options are available to describe the event. 
 
• 
Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myelocytic Leukemia [AML]) 
• 
Myelodysplastic syndrome (MDS) 
• 
Treatment-related secondary malignancy 
 
 
Any malignancy possibly related to cancer treatment (including 
AML/MDS) should also be reported via the routine reporting 
mechanisms outlined in each protocol. 
 
Second Malignancy: A second malignancy is one unrelated to the 
treatment of a prior malignancy (and is NOT a metastasis from the 
initial malignancy).  Second malignancies require ONLY routine 
reporting.  
 
For more information see: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/d
ocs/aeguidelines.pdf  

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2. 
Supporting documentation should be submitted to CTEP in accordance 
with instructions provided by the CTEP-AERS system.  Supporting 
documentation must also be submitted to SWOG Operations Office by 
fax to 210-614-0006.   
 
NOTE: If a patient has been enrolled in more than one NCI-sponsored study, 
the report must be submitted for the most recent trial. 
 
i. 
Reporting Pregnancy, Pregnancy Loss, and Death Neonatal 
 
1. 
Pregnancy Study participants who become pregnant while on study 
OR within 7 months of the last dose of study agent(s); that pregnancy 
should be reported in an expedited manner via CTEP-AERS as Grade 
3 “Pregnancy, puerperium and perinatal conditions – Other 
(pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC.   
 
Additionally, the pregnancy outcome for patients on study should be 
reported via CTEP-AERS at the time the outcome becomes known, 
accompanied by the same Pregnancy Report Form used for the initial 
report. 
 
2. 
Pregnancy Loss  Pregnancy loss is defined in CTCAE as “Death in 
utero.” Pregnancy loss should be reported expeditiously as Grade 4 
“Pregnancy loss” under the Pregnancy, puerperium and perinatal 
conditions SOC.   
 
A Pregnancy loss should NOT be reported as a Grade 5 event under the 
Pregnancy, puerperium and perinatal conditions SOC, as currently CTEP-
AERS recognizes this event as a patient death. 
 
 
3. 
Death Neonatal  “Death neonatal is defined in CTCAE as “Newborn 
death occurring during the first 28 days after birth.  A neonatal death 
should be reported expeditiously as Grade 4 “Death neonatal” under 
the General disorders and administration SOC. 
 
Neonatal death should NOT be reported as a Grade 5 event under the 
General disorders and administration SOC as currently CTEP-AERS 
recognizes this event as a patient death. 
 
 
NOTE:  When submitting CTEP-AERS reports for “Pregnancy, “Pregnancy loss”, 
or “Neonatal loss”, the Pregnancy Information Form should also be completed and 
faxed with any additional medical information to 210-614-0006.  The potential risk 
of exposure of the fetus to the investigational agent(s) or chemotherapy agent(s) 
should be documented in the “Description of Event” section of the CTEP-AERS 
report. 
 
The Pregnancy Information Form is available at: 
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm  
 
 
 

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17.0 
BIBLIOGRAPHY 
 
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Richman SD, Southward K, Chambers P, Cross D, Barrett J, Hemmings G, Taylor M, Wood H, 
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Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred DC, Bartlett JM, 
Bilous M, Fitzgibbons P, et al. Recommendations for human epidermal growth factor receptor 2 
testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists 
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15  
Bang YJ, Van Cutsem E, Feyereislova A et. al.; ToGA Trial Investigators. Trastuzumab in 
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Petti C, et al. A molecularly annotated platform of patient-derived xenografts ("xenopatients") 
identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer. Cancer 
Discov 1(6):508-523, 2011. 
17  
Bertotti A, Migliardi G, Galimi F, Sassi F, Torti D, Isella C, Cora D, Di Nicolantonio F, Buscarino M, 
Petti C, et al. A molecularly annotated platform of patient-derived xenografts ("xenopatients") 
identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer. Cancer 
Discov 1(6):508-523, 2011. 
 
18  
Martin V, Landi L, Molinari F, Fountzilas G, Geva R, Riva A, Saletti P, De Dosso S, Spitale A, Tejpar 
S, et al. HER2 gene copy number status may influence clinical efficacy to anti-EGFR monoclonal 
antibodies in metastatic colorectal cancer patients. Br J Cancer. 108(3):668-675, 2013. 
 
19  
Martin V, Landi L, Molinari F, Fountzilas G, Geva R, Riva A, Saletti P, De Dosso S, Spitale A, Tejpar 
S, et al. HER2 gene copy number status may influence clinical efficacy to anti-EGFR monoclonal 
antibodies in metastatic colorectal cancer patients. Br J Cancer. 108(3):668-675, 2013. 
 
20  
Yonesaka, K., Zejnullahu, K., Okamoto, I., Satoh, T., Cappuzzo, F., Souglakos, J., Ercan, D., 
Rogers, A., Roncalli, M., Takeda, M., et al. Activation of ERBB2 signaling causes resistance to the 
EGFR-directed therapeutic antibody cetuximab. Sci Transl Med. 3(99):99ra86, 2011. 
 
21  
Bertotti A, Migliardi G, Galimi F, Sassi F, Torti D, Isella C, Cora D, Di Nicolantonio F, Buscarino M, 
Petti C, et al. A molecularly annotated platform of patient-derived xenografts ("xenopatients") 
identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer. Cancer 
Discov 1(6):508-523, 2011. 
 
22  
Ramanathan R.K., Hwang, J.J., Zamboni, W.C., Sinicrope, F.A., Safran, H., Wong, M.K., Earle, M., 
Brufsky, A., Evans, T., Troetschel, M., et al. Low overexpression of HER-2/neu in advanced 
colorectal cancer limits the usefulness of trastuzumab (Herceptin) and irinotecan as therapy. A 
phase II trial. Cancer Invest. 22(6):858-865, 2004. 
 
23  
Ramanathan R.K., Hwang, J.J., Zamboni, W.C., Sinicrope, F.A., Safran, H., Wong, M.K., Earle, M., 
Brufsky, A., Evans, T., Troetschel, M., et al. Low overexpression of HER-2/neu in advanced 
colorectal cancer limits the usefulness of trastuzumab (Herceptin) and irinotecan as therapy. A 
phase II trial. Cancer Invest. 22(6):858-865, 2004. 
 
24  
Trusolino L, Martino C, Bencardino K, Lonardi S, Bergamo F, Zagonel V, Leone F, Depetris I, 
Martinelli E, et. al. Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, 
KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-
of-concept, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016. 
 
 

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25  
Trusolino L, Martino C, Bencardino K, Lonardi S, Bergamo F, Zagonel V, Leone F, Depetris I, 
Martinelli E, et. al. Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, 
KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-
of-concept, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016. 
 
26  
Hurwitz H, Hainsworth JD, Swanton C, et. al. Targeted therapy for gastrointestinaI (GI) tumors 
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in patients with advanced solid tumors. J Clin Oncol 34 (suppl 4S; abstr 653), 2016. 
 
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33(16):1809-24, 2015. 
 
28  
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chemotherapy combined with fluoropyrimidines versus irinotecan alone for overall survival and 
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fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol. 
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metastatic colorectal cancer. N Engl J Med. 351(4):337-45, 2004. 
 
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Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic factors in the 
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33  
Eisenhauer EA, et al, New response evaluation criteria in solid tumours: revised RECIST guideline 
(version 1.1). Eur J Cancer 45(2): p. 228-47, 2009. 
34  
Martin V, Landi L, Molinari F, Fountzilas G, Geva R, Riva A, Saletti P, De Dosso S, Spitale A, Tejpar 
S, et al. HER2 gene copy number status may influence clinical efficacy to anti-EGFR monoclonal 
antibodies in metastatic colorectal cancer patients. Br J Cancer. 108(3):668-675, 2013. 
 
35  
Yonesaka, K., Zejnullahu, K., Okamoto, I., Satoh, T., Cappuzzo, F., Souglakos, J., Ercan, D., 
Rogers, A., Roncalli, M., Takeda, M., et al. Activation of ERBB2 signaling causes resistance to the 
EGFR-directed therapeutic antibody cetuximab. Sci Transl Med. 3(99):99ra86, 2011. 
 
36  
Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred DC, Bartlett JM, 
Bilous M, Fitzgibbons P, et al. Recommendations for human epidermal growth factor receptor 2 
testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists 
clinical practice guideline update. Arch Pathol Lab Med. 138(2):241-56, 2014. 
 
37  
Valtorta E, Martino C, Sartore-Bianchi A, Penaullt-Llorca F, Viale G, Risio M, Rugge M, Grigioni W, 
Bencardino K, Lonardi S, et al. Assessment of a HER2 scoring system for colorectal cancer: results 
from a validation study. Mod Pathol 28(11):1481-91, 2015. 
 

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18.0 
APPENDIX 
 
18.1 
New York Heart Association Criteria 
 
18.2 
Receipt, Processing, and Distribution Instructions for the SWOG Biospecimen Bank 
 
 
 

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18.1 
New York Heart Association Criteria 
 
 
 
 
Need for 
Physical Ability 
 
Class 
Cardiac Symptoms 
Limitations 
Additional Rest* 
To Work** 
 
 
 
I 
None 
None 
None 
Full Time 
 
II 
Only moderate 
Slight 
Usually only slight 
Usually full time 
 
 
 
or occasional 
 
III 
Defined, with less 
Marked 
Usually moderate 
Usually part time 
 
than ordinary 
 
activity 
 
IV 
May be present 
Extreme 
Marked 
Unable to work 
 
even at rest, & any 
 
activity increases 
 
discomfort 
 
* To control or relieve symptoms, as determined by the patient, rather than as advised by the 
physician. 
** At accustomed occupation or usual tasks 
 

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18.2 
Receipt, Processing, and Distribution Instructions for the SWOG Biospecimen Bank 
 
Formalin-Fixed Paraffin-Embedded (FFPE) Tumor Tissue  
The SWOG Biospecimen Bank will receive 1 FFPE tumor tissue block or 10 unstained 
slides. Upon receipt, the FFPE specimens will be barcoded and banked at room 
temperature for long-term storage.  
 
Frozen Plasma from EDTA 
The SWOG Biospecimen Bank will receive frozen plasma aliquots from up to 6 time points. 
Upon receipt, these frozen vials will be barcoded and banked in a -80°C freezer for long-
term storage.