Randomized Trial of Standard Chemotherapy Alone or Combined With Atezolizumab as Adjuvant Therapy for Patients With Stage III Colon Cancer and Deficient DNA Mismatch Repair
Phase: PHASE3
Conditions: Colon Adenocarcinoma, DNA Repair Disorder, Lynch Syndrome, Stage III Colon Cancer AJCC v8
Sponsor: National Cancer Institute (NCI)

 
 
 
 
1 
Protocol Update #18 
 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
 
PROTOCOL UPDATE TO ALLIANCE A021502 
 
 
RANDOMIZED TRIAL OF STANDARD CHEMOTHERAPY ALONE OR COMBINED WITH ATEZOLIZUMAB 
AS ADJUVANT THERAPY FOR PATIENTS WITH STAGE III COLON CANCER AND DEFICIENT DNA 
MISMATCH REPAIR 
 
 
 
 
 
 
X Update: 
 
 
Status Change: 
 
 
 
 
 
 
Eligibility changes 
 
 
Activation 
 
 
 
 
 
X Therapy / Dose Modifications / Study Calendar changes 
 
 
Closure 
 
 
 
 
 
 
Informed Consent changes 
 
 
Suspension / temporary closure 
 
 
 
 
 
 
 
Scientific / Statistical Considerations changes 
 
 
Reactivation 
 
 
 
 
 
 
X Data Submission / Forms changes 
 
 
 
 
 
 
 
 
X Editorial / Administrative changes 
 
 
 
 
 
 
 
 
X Other: CTSU template language 
 
  No recommended IRB level of review is provided by the Alliance as the CIRB is the IRB of record for 
this trial. The site has 30 days after the posting of this amendment to implement it at their site. Please 
refer to the CIRB amendment application and guidelines for further instructions. 
 
UPDATES TO THE PROTOCOL: 
Cover Page (p.1) 
• 
Language has been added to the cover page regarding the status as an FDA registration trial.  
• 
The spelling of Dr. 
 name has been corrected.  
• 
has been removed as study Co-Chair 
• 
 has replaced 
as the nursing contact.  
Study Resources (p. 2) 
• 
The Alliance Biorepository information has been updated.  
CTSU Address and contact information (p. 3) 
• 
CTSU Template language has been updated. 
Section 5.0 (Study Calendar) 
• 
Survival follow-up information has been removed from footnote *** and replaced with ‘See 
Section 12.0.’ 
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2 
 
• 
In footnote #9, a second sentence has been added as follows: ‘After the end of FOLFOX 
treatment, the timing of CEA testing should correspond with timing of radiographic imaging 
studies, where possible, but more frequent testing is at provider discretion.’ 
• 
A new section, 5.1 Vital Status (Survival) has been added.  
Section 6.1 (Data Collection and Submission) 
• 
CTSU Template language has been updated. 
• 
In section 6.1.1, the following information has been added to the list of baseline reports: 
‘Germline mutation testing report when requested by Alliance Statistics and Data Management 
Center to resolve discordant data entries.’ 
Section 11.1 (Schedule of Evaluations) 
• 
A third sentence has been added to the second bullet point: ‘After the end of FOLFOX treatment, 
the timing of CEA should correspond with the timing of radiographic imaging, where possible, 
but more frequent testing is at provider discretion. 
Section 12.0 (End of Treatment) 
• 
Sections 12.4 (Survival Follow-Up) and 12.5 (Lost to Follow-up) have been added.  
Appendix V (AIO Sites and Investigators) has been added back into the protocol. It was removed by 
mistake in a previous update. The remaining appendices have been renumbered.  
‘Gender’ has been replaced with ‘Sex’ throughout the protocol document (schema, eligibility and 
Correlative Science Companion Studies sections) as directed by NCI.  
 
UPDATES TO THE MODEL CONSENT: 
 
No changes to the model consent form. 
 
A replacement protocol and consent document have been issued. 
 
ATTACH TO THE FRONT OF EVERY COPY OF THIS PROTOCOL 
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Update #18 
Participating Organizations: Alliance / Alliance for Clinical Trials in Oncology (lead), ECOG-ACRIN / ECOG-
ACRIN Cancer Research Group, NRG / NRG Oncology, SWOG / SWOG, AIO / Arbeitsgemeinschaft Internistische 
Onkologie (see Appendix V for participating sites and investigators), COG/Children’s Oncology Group
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Study Resources 
Expedited Adverse Event Reporting 
http://eapps-ctep.nci.nih.gov/ctepaers/  
 Medidata Rave iMedidata portal 
https://login.imedidata.com  
OPEN (Oncology Patient Enrollment Network) 
https://open.ctsu.org  
 Biospecimen Management System 
http://bioms.allianceforclinicaltrialsinoncology.org  
 
Protocol Contacts 
A021502 Nursing Contact 
 APRN, MSN, CNP, FAPO 
Mayo Clinic 
A021502 Pharmacy Contact 
, PharmD, BCOP 
Nebraska Medicine  
 
IROC Ohio 
University of Cincinnati 
Digital Futures Research Building  
3080 Exploration Avenue Suite 310 
Cincinnati, OH 45206 
Tel: 513-556-7919 
Alliance021502@irocohio.org 
 
Alliance Biorepository at Mayo Clinic 
Please refer to the Correlative Science Manual 
on the A021502 study page on the CTSU website. 
 
 
Protocol-related questions may be directed as follows: 
Questions 
Contact (via email) 
Questions regarding patient eligibility, treatment, 
and dose modification: 
Study Chair, Nursing Contact, Protocol 
Coordinator, and (if applicable) Data Manager 
Questions related to data submission, Rave, or 
patient follow-up: 
Data Manager  
Questions regarding the protocol document and 
model informed consent: 
Protocol Coordinator 
Questions related to IRB review: 
Alliance Regulatory Inbox 
regulatory@allianceNCTN.org  
Questions regarding CTEP-AERS reporting: 
Pharmacovigilance Inbox 
pharmacovigilance@allianceNCTN.org  
Questions regarding drug supply: 
Pharmaceutical Management Branch (PMB) 
Questions regarding specimens/specimen 
submissions: 
Alliance Biorepository at Mayo Clinic 
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Alliance A021502 
 
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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
For regulatory requirements: 
For patient enrollments:  
For data submission: 
Regulatory documentation must 
be submitted to the Cancer Trials 
Support Unit (CTSU) via the 
Regulatory Submission Portal. 
(Sign in at https://www.ctsu.org, 
and select the Regulatory > 
Regulatory Submission.)  
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU Regulatory 
Office immediately at by phone 
or email: 1-866-651-CTSU 
(2878), or 
CTSURegHelp@coccg.org to 
receive further instruction and 
support. 
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-CTSU 
(2878) or 
CTSURegHelp@coccg.org for 
regulatory assistance. 
Refer to the patient enrollment 
section of the protocol for 
instructions on using the 
Oncology Patient Enrollment 
Network (OPEN). OPEN is 
accessed at 
https://www.ctsu.org/OPEN_S
YSTEM/ or 
https://OPEN.ctsu.org 
 
Contact the CTSU Help Desk 
with any OPEN-related 
questions by phone or email : 
1-888-823-5923, or 
ctsucontact@westat.com 
 
 
Data collection for this study 
will be done exclusively through 
Medidata Rave. Refer to the data 
submission section of the 
protocol for further instructions. 
 
 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific page located on the CTSU members’ website (https://www.ctsu.org).  
Permission to view and download this protocol and its supporting documents is restricted and is based 
on person and site roster assignment housed in the Roster Maintenance application and in most cases 
viewable and manageable via the Roster Update Management System (RUMS) on the CTSU members’ 
website. 
For clinical questions (i.e. patient eligibility or treatment-related) see Protocol Contacts, Page 2. 
For non-clinical questions (i.e., unrelated to patient eligibility, treatment, or clinical data 
submission) Contact the CTSU Help Desk by phone or email:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative. 
 
 
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Patients will be followed for recurrence and survival every 6 months for the first two years after registration, 
then survival every 6 months and recurrence once annually for years 3-5 after registration, and then survival 
every 6 months for years 5-8 after registration.  
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TABLE OF CONTENTS 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY ..................................................................... 1 
SCHEMA ..................................................................................................................................................... 5 
TABLE OF CONTENTS ........................................................................................................................... 7 
1.0 
BACKGROUND .............................................................................................................................. 9 
1.1 
Colorectal Cancer ........................................................................................................................... 9 
1.2 
Adjuvant Chemotherapy ................................................................................................................. 9 
1.3 
DNA Mismatch Repair Deficient Colon Cancers ........................................................................ 10 
1.4 
MSI and Immune Checkpoint Inhibition ...................................................................................... 10 
1.5 
Atezolizumab ............................................................................................................................... 11 
1.6 
Rationale for the Proposed Clinical Trial ..................................................................................... 13 
2.0 
OBJECTIVES ................................................................................................................................ 13 
2.1 
Primary Objective ......................................................................................................................... 13 
2.2 
Secondary Objectives ................................................................................................................... 13 
2.3 
Quality of Life Objective ............................................................................................................. 13 
2.4 
Potential Correlative Science Objectives ..................................................................................... 14 
3.0 
PATIENT SELECTION ............................................................................................................... 15 
3.1 
On-Study Guidelines .................................................................................................................... 15 
3.2 
Eligibility Criteria......................................................................................................................... 15 
4.0 
PATIENT REGISTRATION ....................................................................................................... 19 
4.1 
Investigator and Research Associate Registration with CTEP ..................................................... 19 
4.2 
Cancer Trials Support Unit Registration Procedures ................................................................... 20 
4.3 
Patient Registration Requirements ............................................................................................... 22 
4.4 
Patient Registration/Randomization Procedures .......................................................................... 23 
4.5 
Registration to Correlative Studies ............................................................................................... 24 
4.6 
Stratification Factors and Treatment Assignments ....................................................................... 25 
5.0 
STUDY CALENDAR .................................................................................................................... 26 
5.1 Vital Status (Survival) ...................................................................................................................... 28 
6.0 
DATA AND SPECIMEN SUBMISSION .................................................................................... 28 
6.1 
Data Collection and Submission .................................................................................................. 28 
6.2 
Specimen Collection and Submission .......................................................................................... 31 
6.3 
Imaging Submission - Required for All Patients .......................................................................... 32 
6.4 
Quality of Life Assessments ......................................................................................................... 34 
7.0 
TREATMENT PLAN/INTERVENTION ................................................................................... 37 
7.1 
Arm 1:  mFOLFOX6 Plus Atezolizumab ..................................................................................... 38 
7.2 
Arm 2:  mFOLFOX6 .................................................................................................................... 38 
8.0 
DOSE AND TREATMENT MODIFICATIONS........................................................................ 39 
8.1 
Ancillary Therapy, Concomitant Medications, and Supportive Care........................................... 39 
8.2 
Dose Modification General Guidelines ........................................................................................ 41 
9.0 
ADVERSE EVENTS ..................................................................................................................... 62 
9.1 
Routine Adverse Event Reporting ................................................................................................ 62 
9.2 
CTCAE Routine Reporting Requirements ................................................................................... 67 
9.3 
Expedited Adverse Event Reporting (Rave-CTEP-AERS) .......................................................... 67 
9.4 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for Atezolizumab 
(MPDL3280A, NSC 783608) ................................................................................................................. 71 
9.5 
CDUS Monitoring ........................................................................................................................ 75 
10.0 
DRUG INFORMATION ............................................................................................................... 76 
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1.0 
BACKGROUND 
1.1 
Colorectal Cancer  
In the United States, colorectal cancer (CRC) is the fourth most common malignancy and the 
second most frequent cause of cancer-related death [1]. Surgery is the primary modality of 
treatment for non-metastatic CRC, and a resection with ‘curative intent’ occurs in 80-85% of 
patients with stages I-III disease. Among patients with potentially curable CRC, pathologic stage 
(including depth of invasion into the bowel wall, involvement of regional lymph nodes, and 
distant metastasis) is critical in determining prognosis and whether chemotherapy treatment in 
addition to surgery is necessary. Overall, 35-40% of CRC patients have stage III disease at 
diagnosis (~50,000 people in the United States annually) [2]. Among patients with stage III 
colon cancer, ~30-50% will develop cancer recurrence (dependent on substage of stage III 
disease and other factors) despite curative-intent surgery and postoperative adjuvant 
chemotherapy.   
Pediatric Colorectal Cancer 
Colorectal cancer (CRC) is rare in the pediatric population, with approximately 350 patients 
ages 19 and under in the U.S. per year. Compared to adults, pediatric patients with CRC are 
more likely to have tumors with unfavorable histology and stage 3 and 4 disease [3]. Prognosis 
for these patients remains poor, with 5-year overall survival of approximately 40% [4]. Despite 
this, no pediatric specific CRC studies have been performed to date. Instead, the majority of 
pediatric patients are treated using adult protocols despite lack of data on pediatric outcomes 
[3]. CRC in the pediatric age group is often hereditary of which the most common hereditary 
susceptibility is due to Lynch Syndrome [5]. In patients with Lynch Syndrome, CRC usually 
presents after the 4th decade of life; fewer cases have been reported in children and adolescents. 
Pediatric and adult colon cancers from patients with Lynch Syndrome show deficient DNA 
mismatch repair and are thus, potential candidates for participation in A021502. 
1.2 
Adjuvant Chemotherapy 
The current standard of care for the adjuvant therapy of stage III colon cancer is oxaliplatin 
coupled with 5-fluorouracil infusion (FOLFOX-6) for 12 cycles (every 2 weeks) or 6 months. 
In 
2003, 
the 
first 
analysis 
of 
the 
Multicenter 
International 
Study 
of 
Oxaliplatin/Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) 
study was presented and showed a statistically significant improvement in disease-free survival 
with the addition of oxaliplatin to 5-fluorouracil plus leucovorin in stage III patients.[6] An 
update of the MOSAIC trial demonstrated a 5-year disease-free survival of 66% with FOLFOX 
compared to 59% with 5-fluorouracil and leucovorin that was limited to stage III patients.[7] 
The addition of oxaliplatin to fluoropyrimidine therapy increases the risk of toxicities, including 
bone marrow suppression and neurosensory symptoms, of which the latter is particularly 
problematic for some patients. At the completion of therapy in the MOSAIC trial, 12% of 
patients had grade 3 peripheral neuropathy and 92% had some level of neuropathy [8]. In a 
recent update, 15% of patients still had some level of residual neuropathy 4 years after the 
completion of adjuvant therapy.[7]  Progress in the adjuvant therapy of colon cancer has stalled 
overall based upon the failure of targeted agents including anti-VEGF (bevacizumab) or anti-
EGFR (cetuximab or panitumumab) antibodies to improve outcomes in patients with stage III 
disease in contrast to evidence of benefit in the metastatic setting [9-11].  
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Clinical trials being conducted in the U.S. and Europe are testing the hypothesis that 3 months 
of adjuvant FOLFOX or XELOX is non-inferior to 6 months. The IDEA (International Duration 
Evaluation of Adjuvant Chemotherapy) steering committee was formed to prospectively pool 
data from multiple ongoing trials. The TOSCA trial in Italy is randomizing 3450 high-risk stage 
II and stage III patients to 3 versus 6 months of adjuvant FOLFOX with an option for additional 
randomization to bevacizumab in stage IIIC patients. The SCOT trial in the UK is randomizing 
approximately 6500 stage II and III colon and rectal cancer patients to 3 versus 6 months of 
adjuvant FOLFOX/XELOX. In addition, the GERCOR and C80702 trials are each enrolling 
2000-2500 patients with stage III colon cancer to an adjuvant trial of 3 versus 6 months of 
FOLFOX, and smaller trials are also being conducted in Japan and Greece. Results of the IDEA 
pooled analysis of over 12,000 patients has been published and did not meet the non-inferiority 
cutoff. A non pre-specified risk analysis stratified patients into low and high risk based on T and 
N stage. Among patients with low risk tumors (T1-3N1), 3 months of therapy was non inferior 
to 6 months.  However, 3 months of the FOLFOX regimen was inferior to 6 months in patients 
with high-risk tumors (T4 and/or N2) [12]. Importantly, the study did not analyze tumors for 
dMMR status, so no data is yet available for this tumor subset. Accordingly, the duration of 
FOLFOX will remain 6 months in the ATOMIC trial as risk stratification in IDEA is unknown 
for patients with dMMR tumors.  
1.3 
DNA Mismatch Repair Deficient Colon Cancers 
Two primary pathways of CRC have been described and include tumors with chromosomal 
instability (CIN) or those with microsatellite instability (MSI). MSI colon cancers are typically 
right-sided, poorly differentiated and contain abundant tumor infiltrating lymphocytes (TILs). 
MSI is a consequence of deficient DNA mismatch repair (dMMR) that is sporadic in origin in 
two-thirds of cases and is hereditary in one-third due to Lynch Syndrome (LS).  LS is caused by 
a germline mutation in one of four MMR genes (MLH1, MSH2, MSH6, PMS1) with those in 
MLH1 or MSH2 accounting for more than 90% or cases [13].  Epigenetic inactivation of MLH1 
occurs in sporadic MSI CRCs and such tumors are enriched in BRAFV600E mutations [14].  CRCs 
with MSI/dMMR have been generally reported to have a better prognosis compared to tumors 
with proficient (p) MMR that are microsatellite stable (MSS). Data indicate that the association 
of dMMR/MSI with favorable prognosis is stronger in stage II versus stage III patients [15]. In 
this regard, dMMR status was not significantly associated with better overall survival in stage 
III colon cancers treated with the standard FOLFOX regimen in pooled data from 3 recent 
adjuvant chemotherapy trials (NCCTG N0147, PETACC-8, NSABP C-08) (unpublished data). 
Of note, the frequency of N2 disease (4 or more metastatic regional lymph nodes) which is a 
poor prognostic factor was similar among dMMR compared to pMMR colon cancers in the 
NCCTG N0147 trial [16]. Accordingly, there is an unmet need to improve outcomes in patients 
with stage III dMMR/MSI colon cancers.  
1.4 
MSI and Immune Checkpoint Inhibition 
MSI/dMMR CRCs are hypermutated and express abundant neopeptides that elicit a robust T 
cell immune response characterized by abundant tumor infiltrating lymphocytes (TILs) [17]. 
These TILs include cytotoxic CD8+ T cells as well as activated Th1 cells, characterized by IFNγ 
production and the Th1 transcription factor, TBET [17]. However, recent data indicate that this 
robust immune reaction fails to eradicate the tumors due to immune checkpoint proteins that are 
overexpressed in MSI/dMMR tumors compared to p(MSS cancers [17]. These findings link 
tumor genotype with the immune microenvironment, and may explain why MSI/dMMR tumors 
are not eliminated despite the anti-tumor Th1/CTL microenvironment. They further suggest that 
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blockade of specific checkpoints may be selectively efficacious in the MSI/dMMR subset of 
CRC.  In this regard, checkpoint inhibitors can enable a patient’s own T cells to eradicate tumor 
cells which appears to underlie the observed efficacy of an anti-programmed death-1 (PD-1) 
antibody in cancers with MSI-H.  Specifically, a recent phase II study in patients with MSI-H 
metastatic CRCs and MSI-H non CRCs (from Lynch Syndrome patients) showed that antiPD-1 
antibody, pembrolizumab, as monotherapy produced a 57% response rate in MSI-H tumors 
compared to 0% in MSS tumors, and PFS has not yet been reached [18]. This modest size patient 
cohort included CRC patients with Lynch Syndrome (LS), some sporadic MSI-H tumors, and 
extracolonic malignancies associated with LS. While only 4% of metastatic CRCs are MSI-H, 
the clinical benefit was very substantial and a similar experience is emerging in clinical practice. 
The anti-tumor efficacy of a checkpoint inhibitor may well apply to stage III disease where 10-
15% of tumors are MSI-H [19].   
Targeting PD-L1 is a similarly promising approach to targeting PD-1. In addition to binding to 
PD-1, PD-L1 is believed to exert negative signals on T cells by interacting with B7, and this 
interaction is blocked by PD-L1, but not PD-1, antibodies. PD-L1 inhibitors have shown 
objective anti-tumor responses in patients with a variety of solid tumors including GI 
malignancies [20-22] and a small number of MSI-H colon cancers (Genentech, unpublished 
data). As stated, the mechanism underlying the clinical benefit of PD-1/PD-L1 inhibitors in 
MSI-H tumors is believed to be related to hypermutation [23] with production of mutant proteins 
and expression of abundant neoantigens that elicit an enhanced immune response [24].  In this 
regard, neoantigen load is associated with clinical benefit from pembrolizumab in NSCLC and 
may be predictive in other tumor types [25]. Based primarily on the data for pembrolizumab in 
metastatic MSI-H tumors, MSI-H is the only biomarker that has been shown to predict the 
efficacy of checkpoint inhibitor therapy in CRCs. MSI tumors selectively demonstrated highly 
upregulated expression of multiple immune checkpoints, including five-PD-1, PD-L1, CTLA-4, 
LAG-3, and IDO [26]. Furthermore, PD-1 and/or PD-L1 may provide prognostic information in 
patients with nonmetastatic CRCs [27] [28]. Some, but not other, PD-L1-positive cancers have 
demonstrated higher response rates to anti-PD-1/PD-L1 therapies, suggesting that PD-L1 
expression may  enrich for anti-tumor responses. However, data indicate that PD-L1-negative 
tumors can respond favorably to checkpoint inhibitors indicating that PD-L1 is not a universal 
predictive biomarker.  PD-L1 is expressed on immune cells as well as tumor cells in various 
cancers.   
1.5 
Atezolizumab 
Atezolizumab is a humanized IgG1 monoclonal antibody that targets PD-L1 on immune cells 
and/or tumor cells and prevents interaction with either PD-1 receptor or B7.1 (CD80), both of 
which function as inhibitory receptors expressed on T cells. Interference of the PD-L1: PD-1 
and PD-L1:B7.1 interactions may enhance the magnitude and quality of the tumor-specific T-
cell response through increased T-cell priming, expansion, and/or effector function [29]. 
Atezolizumab was engineered to have minimal binding to Fc receptors and, by eliminating Fc-
effector function and antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-
mediated clearance of activated effector T cells is eliminated.  Overall, the nonclinical 
pharmacokinetic (PK) behavior observed for atezolizumab is consistent with that expected for 
a humanized IgG1 monoclonal antibody. Atezolizumab has shown anti-tumor activity in 
preclinical models and cancer patients, and is being investigated as a single agent in advanced 
cancer and in adjuvant therapy settings, as well as in combination with chemotherapy, targeted 
therapy, and cancer immunotherapy. Based upon results from randomized clinical trials, the 
FDA has granted priority review to atezolizumab, for patients with locally advanced or 
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metastatic non-small cell lung cancer (NSCLC) who express PD-L1 and have progressed after 
a platinum-containing regimen. Furthermore, atezolizumab was also granted priority review by 
the FDA for the treatment of patients with metastatic bladder cancer.   
To date, the use of PD-1/PD-L1 inhibitors in combination with chemotherapy has produced 
promising results in selected tumor types. Several preclinical studies indicate that certain 
chemotherapeutic agents can have an immunostimulatory effect [30] and in this regard, 
oxaliplatin can alter tumor immune status to transiently increase inflammation [31] [32]. This 
so called ‘immune priming’ may extend the inflammatory state to achieve enhanced and more 
durable responses. Unpublished data from Roche/Genentech indicate that FOLFOX alone or 
combined with bevacizumab and atezolizumab can increase cytotoxic CD8+ T cells and PD-L1 
expression in colorectal metastases which demonstrates immune priming. Data exist for the 
combination of the PD-L1 inhibitor, atezolizumab (MPDL3280A) with FOLFOX in patients 
with metastatic CRC. Single agent atezolizumab produced a 7.1% objective response rate (ORR) 
in 14 MSS CRCs, and responses were also seen for atezolizumab + bevacizumab in MSI tumors 
although the data remain premature in this subset. A phase I study evaluated the combination of 
atezolizumab (20 mg/kg q 3 weeks) combined with standard dose FOLFOX plus bevacizumab 
versus atezolizumab plus bevacizumab in patients with metastatic CRC [33]. In the 
atezolizumab + bevacizumab + FOLFOX study arm (n=23), there were 12 partial responses with 
an ORR of 52.2% and a median PFS of 14.1 months vs. an expected mPFS for FOLFOX + 
bevacizumab of 10-11 months (J Clin Oncol 33, 2015 (suppl. 3; abstr. 704)). All 23 patients had 
MSS tumors and in the FOLFOX-containing study arm, 70% of patients were previously 
untreated. A favorable safety profile was observed for both study arms containing atezolizumab 
and bevacizumab with or without FOLFOX and there was no increase in Grade 3 adverse events 
(AEs). Atezolizumab is being examined in patients with CRC as part of the biomarker-driven 
MODUL trial (NCT02291289) [34]. 
The phase I/II iMATRIX-atezolizumab study (NCT02541604, study GO29664) evaluated the 
safety, tolerability, PK, immunogenicity, and preliminary efficacy of atezolizumab 
monotherapy in pediatric and young adult patients with solid tumors [35]. This multicenter, 
open-label trial enrolled 87 patients with solid tumors with known or expected PD-L1 pathway 
involvement for which prior treatment was proven to be ineffective or intolerable, and for whom 
there was no curative standard-of-care treatment. The study included 69 patients aged < 18 
years, each of whom received a weight-adjusted dose of atezolizumab (15 mg/kg every 3 weeks 
[q3w]; maximum 1200 mg). Patients aged 18 years and older received a flat dose (1200 mg 
q3w). A total of 431 atezolizumab serum concentrations were used for the population-PK 
(popPK) analysis, which was compared to a prior two-compartment intravenous infusion input 
adult popPK model. Atezolizumab clearance and volume of distribution estimates were 
0.217 L/day and 3.01 L, respectively. Atezolizumab geometric mean trough exposures were 
~ 20% lower in pediatric patients versus young adults; this was not clinically meaningful as both 
groups achieved the target concentration (6 μg/mL). Safety was similar between pediatric and 
young adult patients with no exposure-safety relationship observed. A comparable rate (13% vs. 
11%) of atezolizumab anti-drug antibodies was seen in pediatric and young adult patients. 
Overall, a similar exposure-safety profile of atezolizumab was demonstrated in pediatric and 
young adult patients, supporting weight-based dosing in pediatric patients. 
Safety and Tolerability 
The risks identified in the nonclinical studies conducted with atezolizumab are consistent with 
the primary pharmacology of PD-L1/PD-1 pathway inhibition.  Atezolizumab has been 
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administered to approximately 3200 patients, with efficacy and safety findings consistent with 
non-clinical data. No dose limiting toxicities have been observed at any dose level and no 
maximum tolerated dose (MTD) was established. While inhibition of PD-L1/PD-1 may lead to 
anti-tumor immune activity and is generally well tolerated, it may also increase the risk of 
immune-mediated adverse events (IMAEs). Atezolizumab has been well-tolerated as 
monotherapy with the majority of AEs being Grade 1-2 and manageable (patients continue 
atezolizumab). The combination of atezolizumab with chemotherapy has not been associated 
with additive toxicity and is consistent with the known profile for each study treatment.  There 
is long term safety data from randomized trial of atezolizumab versus docetaxel in NSCLC [36] 
where 11% of patients in atezolizumab groups versus 39% in docetaxel group had treatment 
related grade 3 to grade 4 adverse events. 
1.6 
Rationale for the Proposed Clinical Trial 
The ability of immunotherapy to unleash a patient’s own T cells to kill MSI-H tumor cells is 
expected to occur in the adjuvant setting, as demonstrated in metastatic disease [37], and may 
result in reduced recurrence and improved patient survival. The rationale for combination of 
FOLFOX and atezolizumab is based upon the fact that FOLFOX is standard of care as adjuvant 
therapy for stage III colon cancer and promising data for combining chemotherapy with 
atezolizumab, including suggestion of immune priming. Since FOLFOX is standard adjuvant 
chemotherapy for stage III disease [38], it serves as the control arm for studies aiming to further 
improve patient outcomes. Atezolizumab will be continued as monotherapy for an additional 6 
months following completion of FOLFOX for 6 months (12 cycles). The rationale for this 
approach is late and sustained responders with the use of pembrolizumab in metastatic MSI-H 
CRC, the importance of a definitive study, and alignment with ongoing/planned adjuvant studies 
using atezolizumab in other malignancies. Furthermore, sustained stimulation of the immune 
system may be key for long-term benefit with immunotherapy. There is a precedent with the 
anti-CTLA-4 antibody ipilimumab that is approved for the adjuvant therapy of melanoma with 
treatment duration up to 3 years. We intend for the study outlined in this protocol to be definitive, 
and regard this study to have the potential to be practice-changing. 
2.0 
OBJECTIVES  
2.1 
Primary Objective  
To determine whether atezolizumab combined with FOLFOX and its continuation as 
monotherapy can significantly improve DFS compared to FOLFOX alone in patients with stage 
III colon cancers and dMMR. 
2.2 
Secondary Objectives 
To determine whether atezolizumab combined with FOLFOX and its continuation as 
monotherapy can significantly improve overall survival compared to FOLFOX alone in patients 
with stage III colon cancers and dMMR. 
To assess the adverse events (AE) profile and safety of each treatment arm, using the CTCAE 
and PRO-CTCAE (among patients aged ≥ 18 years). 
2.3 
Quality of Life Objective 
The quality of life objective will be to determine the impact of the addition of atezolizumab to 
FOLFOX on patient-reported neuropathy, health-related QOL, and functional domains of 
health-related QOL. The quality of life analysis will also access the efficacy of atezolizumab 
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adjusting for baseline QOL and fatigue measurements. Patient-reported outcomes will not be 
assessed in patients aged 12 to <18 years. 
2.4 
Potential Correlative Science Objectives 
Testing of banked specimens will not occur until an amendment to this treatment protocol (or 
separate correlative science protocol) is reviewed and approved in accordance with National 
Clinical Trials Network (NCTN) policies. 
2.4.1 To determine if the “Immunoscore” can predict the efficacy of atezolizumab for disease-
free survival among patients with stage III colon cancer. 
2.4.2 To assess whether circulating immune cell populations can predict the efficacy of 
atezolizumab as adjuvant therapy for stage III colon cancer. 
2.4.3 To explore the associations of genomic alterations identified in cfDNA with DFS in 
patients treated with FOLFOX with or without atezolizumab. 
2.4.4  To assess whether soluble markers of systemic inflammation in blood can predict the 
efficacy of atezolizumab as adjuvant therapy for stage III colon cancer. 
2.4.5  To assess the relationship between baseline plasma 25(OH) D levels, change in 25(OH)D 
levels, and DFS and OS in patients with stage III colon cancer receiving FOLFOX +/- 
atezolizumab. 
2.4.6  To determine the ability of using fecal microbiota and their metabolic products to predict 
survival benefit from anti-PD-L1 antibody therapy in dMMR colon cancer patients. 
2.4.7  To determine if hypermutation or hyper-indel status is associated with response to 
atezolizumab.  
2.4.8  To determine if unique mRNA expression signatures are predictive of disease-free 
survival among patients receiving adjuvant chemotherapy for stage III colon cancer.   
2.4.9  To determine if the efficacy of atezolizumab differs among dMMR cancers due to 
germline MMR mutation (MLH1, MSH2, MSH6, PMS2) versus those with MLH1 
hypermethylation and CIMP in patients with stage III colon cancer.  
2.4.10 To identify overall mutational burden and number of putative tumor neoantigens in colon 
carcinoma specimens. 
The following objectives apply to patients aged 12 to <18 years to evaluate the impact of 
atezolizumab on growth and development patterns in this population: 
2.4.11 To determine changes in growth patterns compared to baseline (relative to age-specific 
standards for height and weight). 
2.4.12 To determine changes in development patterns compared to baseline (relative to onset of 
menarche [for females] and pubertal changes). 
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3.0 
PATIENT SELECTION 
For questions regarding eligibility criteria, see the Study Resources page. Please note that the Study 
Chair cannot grant waivers to eligibility requirements.  
3.1 
On-Study Guidelines 
This clinical trial can fulfill its objectives only if patients appropriate for this trial are enrolled. 
All relevant medical and other considerations should be taken into account when deciding 
whether this protocol is appropriate for a particular patient. Physicians should consider the risks 
and benefits of any therapy, and therefore only enroll patients for whom this treatment is 
appropriate.  
Physicians should consider whether any of the following may render the patient inappropriate 
for this protocol: 
• 
Psychiatric illness which would prevent the patient from giving informed consent. 
• 
Medical condition such as uncontrolled infection, uncontrolled diabetes mellitus or 
cardiac disease which, in the opinion of the treating physician, would make this protocol 
unreasonably hazardous for the patient. 
• 
Patients with a “currently active” second malignancy other than non-melanoma skin 
cancers or cervical carcinoma in situ. Patients are not considered to have a “currently 
active” malignancy if they have completed therapy and are free of disease for ≥ 3 years, 
had a gastric or bowel carcinoid < 1 cm, or DCIS /LCIS of the breast without invasive 
cancer, or endometrial dysplasia/carcinoma in situ.  
• 
Patients are not considered to have a “currently active” malignancy if they had a 
sebaceous neoplasm (sebaceous adenoma, sebaceous epithelioma, sebaceous 
adenocarcinoma, keratoacanthoma, and squamous cell carcinoma) that was 
noninvasive. 
In addition: 
• 
Women and men of reproductive potential should agree to use an appropriate method 
of birth control throughout their participation in this study due to the teratogenic 
potential of the therapy utilized in this trial. Appropriate methods of birth control 
include abstinence, oral contraceptives, implantable hormonal contraceptives, or double 
barrier method (diaphragm plus condom). For women, birth control should begin at 
least 28 days prior to the start of therapy and continue for 5 months after completion of 
therapy. For men, birth control should begin prior to registration and continue for 5 
months after completion of therapy.  
3.2 
Eligibility Criteria  
When calculating days of tests and measurements, the day a test or measurement is done is 
considered Day 0. Therefore, if a test were done on a Monday, the Monday one week later would 
be considered Day 7. 
3.2.1 
 
Documentation of Disease 
Histologically proven stage III colon adenocarcinoma (any T [Tx, T1, T2, T3, or T4], 
N1-2M0; includes N1C). Tumors must be deemed to originate in the colon including 
tumors that extend into/involve the small bowel (e.g. those at the ileocecal valve). 
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DNA Mismatch Repair (MMR) Status: Presence of deficient (d) DNA mismatch repair 
(dMMR). MMR status must be assessed by immunohistochemistry (IHC) for MMR 
protein expression (MLH1, MSH2, MSH6, PMS2) where loss of one or more proteins 
indicates dMMR.  
dMMR may be determined either locally or by site-selected reference lab. 
Note: loss of MLH1 and PMS2 commonly occur together.  
FFPE tumor tissue is required for subsequent retrospective central confirmation of 
dMMR status. 
Patients with testing that did not show dMMR (loss of MMR protein) are not eligible to 
participate. Patients whose tumors show MSI-H by PCR-based assay are not eligible to 
participate unless they also have MMR testing by IHC and are found to have dMMR 
(i.e. loss of one or more MMR proteins). 
Patients who are known to have Lynch Syndrome, have been found to carry a specific 
germline mutation in an MMR gene (MLH1, MSH2, MSH6, PMS2), and have been 
shown to be dMMR by IHC are eligible to participate.  
3.2.2 
 
Disease Status 
Tumors must have been completely resected. In patients with tumor adherent to adjacent 
structures, en bloc R0 resection must be documented in the operative report or otherwise 
confirmed by the surgeon. Near or positive radial margins are acceptable so long as en 
bloc resection was performed. Proximal or distal margin positivity is not permitted.  
Entire tumor must be in the colon (rectal involvement is an exclusion). Surgeon 
confirmation that entire tumor was located in the colon is required only in cases where 
it is important to establish if the tumor is a colon vs. rectal primary. Patients with more 
than one primary colon adenocarcinoma are eligible if the qualifying stage III tumor is 
confined to the colon, and not rectum, and the other cancers of lower stage are removed 
in the en bloc R0 resection.  
Based upon the operative report and other source documentation, the location of the 
primary tumor will be categorized as proximal or distal to the splenic flexure (included 
with distal), and further categorization will be as follows: cecum/ascending, transverse, 
descending, sigmoid colon, or rectosigmoid colon.  
No evidence of residual involved lymph node disease or metastatic disease at the time 
of registration based on clinician assessment of imaging. The treating physician will 
determine if incidental lesions on imaging require workup to exclude metastatic disease.  
If based on review of images, the treating physician determines the patient to be stage 
III, then the patient is eligible. 
3.2.3 
 
Prior Treatment  
No prior medical therapy (chemotherapy, immunotherapy, biologic or targeted therapy) 
or radiation therapy for the current colon cancer except for one cycle of mFOLFOX6. 
Cycle 1 of mFOLFOX6 must have been administered per Appendix III.  
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3.2.4 
 
Age ≥ 12 years  
3.2.5 
 
Performance Status: 
• 
Patients <16 years of age: Lansky ≥ 50% 
• 
Patients 16 to <18 years of age: Karnofsky ≥ 50% 
• 
Patients ≥18 years of age: ECOG Performance Status ≤ 2 
3.2.6 
 
Not Pregnant and Not Nursing 
This study involves: 1) an investigational agent whose genotoxic, mutagenic and 
teratogenic effects on the developing fetus and newborn are unknown; and 2) an agent 
that has known genotoxic, mutagenic, and teratogenic effects. 
Therefore, for women of childbearing potential only, a negative pregnancy test done ≤ 
7 days prior to registration is required.  
A female of childbearing potential is a sexually mature female who: 1) has not 
undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally 
postmenopausal for at least 12 consecutive months (i.e. has had menses at any time in 
the preceding 12 consecutive months). 
3.2.7 
 
Required Initial Laboratory Values:  
Absolute Neutrophil Count (ANC) 
≥ 1500 mm3 
Platelet Count 
≥ 100,000 mm3* 
Creatinine 
or 
≤ 1.5 x upper limit of normal (ULN) 
Calculated Creatinine Clearance 
≥45 mL/min** 
Total Bilirubin 
≤ 1.5 x upper limit of normal (ULN)*** 
AST / ALT  
≤ 2.5 x upper limit of normal (ULN) 
TSH 
WNL**** 
*       Platelets ≥ 75,000 required for patients who received Cycle 1 of mFOLFOX6 
prior to registration 
**    By Cockcroft-Gault equation. Alternatively, for patients < 18 years of age, 
maximum serum creatinine ≤ the below age-sex-specific norms: 
Age 
Creatinine (mg/dL) 
Male 
Female 
12 years 
1.2 
1.2 
13 to <16 years 
1.5 
1.4 
16 to <18 years 
1.7 
1.4 
***    Except in the case of Gilbert disease 
**** Supplementation is acceptable to achieve a TSH WNL. In patients with 
abnormal TSH, if Free T4 is normal and patient is clinically euthyroid, patient 
is eligible. 
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3.2.8 
 
Comorbid Conditions 
No active known autoimmune disease, including colitis, inflammatory bowel disease 
(i.e. ulcerative colitis or Crohn’s disease), rheumatoid arthritis, panhypopituitarism, 
adrenal insufficiency. 
No known active hepatitis B or C. 
• 
Active Hepatitis B can be defined as:  
o HBsAg detectable for > 6 months; 
o Serum HBV DNA 20,000 IU/ml (105 copies/ml); lower values 2,000-
20,000 IU/ml (104-105 copies/ml) are often seen in HBeAg-negative 
chronic hepatitis B; 
o Persistent or intermittent elevation in ALT/AST levels;  
o Liver biopsy showing chronic hepatitis with moderate or severe 
necroinflammation. 
• 
Active Hepatitis C can be defined as:  
o Hepatitis C AB positive, AND  
o Presence of HCV RNA 
Excluded if known active pulmonary disease with hypoxia defined as:  
• 
Oxygen saturation < 85% on room air, or 
• 
Oxygen saturation < 88% despite supplemental oxygen 
No grade ≥ 2 peripheral motor or sensory neuropathy. 
Patients positive for HIV are eligible only if they meet all of the following: 
• 
A stable regimen of highly active anti-retroviral therapy (HAART) 
• 
No requirement for concurrent antibiotics or antifungal agents for the 
prevention of opportunistic infections 
• 
A CD4 count above 250 cells/mcL, and an undetectable HIV viral load on 
standard PCR-based tests 
3.2.9 
 
Concomitant Medications 
No other planned concurrent investigational agents or other tumor directed therapy 
(chemotherapy, radiation) while on study. 
No systemic daily treatment with either corticosteroids (>10 mg daily prednisone 
equivalents) or other immunosuppressive medications within 7 days of registration. 
3.2.10 Allergies 
No known history of severe allergic anaphylactic reactions to chimeric, human or 
humanized antibodies, or fusion proteins. 
No known hypersensitivity to CHO cell products or any component of the atezolizumab 
formulation. 
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• 
Selection as the treating, credit, or drug shipment investigator or consenting person in 
OPEN; 
• 
Ability to be named as the site-protocol Principal Investigator (PI) on the IRB approval; 
and 
• 
Assignment of the Clinical Investigator (CI) task on the Delegation of Tasks Log (DTL). 
In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB 
approval), consenting/treating/drug shipment investigator in OPEN, or as the CI on the DTL 
must be rostered at the enrolling site with a participating organization.  
For questions, please contact the RCR Help Desk by email at RCRHelpDesk@nih.gov. 
4.2 
Cancer Trials Support Unit Registration Procedures 
Permission to view and download this protocol and its supporting documents is restricted and is 
based on person and site roster assignment housed in the Roster Maintenance application and in 
most cases viewable and manageable via the Roster Update Management System (RUMS) on 
the Cancer Trials Support Unit (CTSU) members’ website.This study is supported by the NCI 
CTSU. 
IRB Approval 
As of March 1, 2019, all U.S.-based sites must be members of the NCI Central Institutional 
Review Board (NCI CIRB) in order to participate in Cancer Therapy Evaluation Program 
(CTEP) and Division of Cancer Prevention (DCP) studies open to the National Clinical Trials 
Network (NCTN) and NCI Community Oncology Research Program (NCORP) Research Bases.  
In addition, U.S.-based sites must accept the NCI CIRB review to activate new studies at the 
site after March 1, 2019. Local IRB review will continue to be accepted for studies that are not 
reviewed by the CIRB, or if the study was previously open at the site under the local IRB. 
International sites should continue to submit Research Ethics Board (REB) approval to the 
CTSU Regulatory Office following country-specific regulations.  
Sites participating with the NCI CIRB must submit the Study Specific Worksheet (SSW) for 
Local Context to the CIRB using IRBManager to indicate their intent to open the study locally. 
The NCI CIRB’s approval of the SSW is automatically communicated to the CTSU Regulatory 
Office, 
but 
sites 
are 
required 
to 
contact 
the 
CTSU 
Regulatory 
Office 
at 
CTSURegPref@ctsu.coccg.orgto establish site preferences for applying NCI CIRB approvals 
across their Signatory Network. Site preferences can be set at the network or protocol level. 
Questions about establishing site preferences can be addressed to the CTSU Regulatory Office 
by email or calling 1-888-651-CTSU (2878). 
Sites using their local IRB or REB, must submit their approval to the CTSU Regulatory Office 
using the Regulatory Submission Portal located in the Regulatory section of the CTSU website. 
Acceptable documentation of local IRB/REB approval includes: 
• 
Local IRB documentation; 
• 
IRB-signed CTSU IRB Certification Form; and/or 
• 
Protocol of Human Subjects Assurance Identification/IRB Certification/Declaration of 
Exemption Form. 
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In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the IRB/REB 
approval) must meet the following criteria for the site to be able to have an Approved status 
following processing of the IRB/REB approval record: 
• 
Have an active CTEP status; 
• 
Have an active status at the site(s) on the IRB/REB approval (applies to US and 
Canadian sites only) on at least one participating organization’s roster; 
• 
If using NCI CIRB, be active on the NCI CIRB roster under the applicable CIRB 
Signatory Institution(s) record; 
• 
Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile; 
• 
Lists all sites on the IRB/REB approval as Practice Sites in the Form FDA 1572 in the 
RCR profile; and 
• 
Have the appropriate CTEP registration type for the protocol. 
Additional Site Registration Requirements 
Additional site requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO);  
• 
An active roster affiliation with the NCI CIRB roster under at least one CIRB 
Signatory Institution (US sites only); and 
• 
Compliance with all applicable protocol-specific requirements (PSRs). 
4.2.1 
 
Downloading Site Registration Documents  
Download the site registration forms from the protocol-specific page located on the 
CTSU members’ website. Permission to view and download this protocol and its 
supporting documents is restricted to institutions and their associated investigators and 
staff on a participating roster. To view/download site registration forms: 
• Log in to the CTSU members’ website (https://www.ctsu.org)  
• Click on Protocols in the upper left of the screen 
• 
Enter the protocol number in the search field at the top of the protocol tree, or 
• 
Click on the By Lead Organization folder to expand, the select Alliance and 
protocol number A021502. 
• Click on Documents, Protocol Related Documents, and use the Document Type filter 
and select Site Registration to download and complete the forms provided. (Note: 
For sites under the CIRB, IRB data will load automatically to the CTSU) 
4.2.2 
 
Submitting Regulatory Documents  
Submit required forms and documents to the CTSU Regulatory Office using the 
Regulatory Submission Portal on the CTSU members’ website.  
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To access the Regulatory Submission Portal log in to the CTSU members’ website, go 
to the Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission 
Portal should alert the CTSU Regulatory Office immediately by phone or email: 1-866-
651-CTSU (2878), or CTSURegHelp@coccg.org to receive further instruction and 
support. 
NOTE: Until institutions receive a formal notice from the Alliance regarding 
termination to patient follow-up, institutions must not close this trial with the IRB 
of record for the study. Alliance members may refer to section 6.14 of the 
Alliance’s Policy and Procedures for additional information about study 
termination, or institutions may contact the Alliance Regulatory team at 
regulatory@alliancenctn.org with any questions. 
4.2.3 
Checking Site Registration Status 
Site registration status may be verified on the CTSU members’ website.  
• 
Click on Regulatory at the top of the screen; 
• 
Click on Site Registration; and 
• 
Enter the site’s 5-character CTEP Institution Code and click on Go. 
- 
Additional filters are available to sort by Protocol, Registration Status, 
Protocol Status, and/or IRB Type. 
Note: The status shown only reflects institutional compliance with site registration 
requirements as outlined within the protocol. It does not reflect compliance with 
protocol requirements for individuals participating on the protocol or the enrolling 
investigator’s status with NCI or their affiliated networks. 
4.2.4 
 
Delegation of Tasks Log (DTL) 
Each site must complete a protocol-specific Delegation of Tasks Log (DTL) using the 
DTL application in the Delegation Log section on the CTSU members’ website. The 
Clinical Investigator (CI) is required to review and electronically sign the DTL prior to 
the site receiving an approved site registration status and enrolling patients to the study. 
To maintain an approved site registration status the CI must re-sign the DTL at least 
annually and when a new version of the DTL is released; and activate new task 
assignments requiring CI sign-off. Any individual at the enrolling site on a participating 
roster may initiate the site DTL. Once the DTL is submitted for CI approval, only the 
designated DTL Administrators or the CI may update the DTL. Instructions on 
completing the DTL are available in the Help Topics button in the DTL application and 
describe DTL task assignments, CI signature, and CTEP registration requirements, as 
well as include a Master Task List. 
4.3 
Patient Registration Requirements 
Informed Consent: For patients ≥ 18 years of age: the patient must be aware of the neoplastic 
nature of his/her disease and willingly consent after being informed of the procedure to be 
followed, the experimental nature of the therapy, alternatives, potential benefits, side-effects, 
risks, and discomforts. Current human protection committee approval of this protocol and a 
consent form is required prior to patient consent and registration. Patients with impaired decision 
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making capacity may be enrolled on this study, where institutional policy and IRB of record 
allow. For patients aged 12 to <18 years: patients and/or their parents or legal guardians must 
sign and give written informed consent and assent in accordance with institutional and federal 
guidelines. 
Protected Health Information: Some of the tissue specimens collected for this study will be 
sent directly to a central laboratory agreed upon by the Alliance and the drug company 
supporting this study. These samples (or the required requisition form) will be labeled with study 
ID, surgical pathology number/block ID, and collection date. Some of the blood specimens 
collected for this study will be sent directly to Duke University. These samples will be labeled 
with patient initials, study ID, and collection date.   
Patient-completed Booklets: Patient questionnaire booklets are to be ordered prior to the 
registration of any patients. Patient completed booklets can be ordered by downloading and 
completing the CTSU supply request form (located under the site registration documents section 
of the A021502 CTSU site) and submitting it through the CTSU regulatory portal. Samples of 
the booklets are found in Appendix I, which are to be used for reference and IRB submission 
only. They are not to be used for patient completion. There is one booklet for PRO-CTCAE 
which is required per the study calendar for all patients. There is a second QOL booklet for 
patients who consent for the Quality of Life study. There is no booklet for the Registration 
Fatigue/Uniscale assessment (first page of Appendix I, required for all patients per the study 
calendar). If needed, the first page of Appendix I can be adapted to use as a source document. 
4.4 
Patient Registration/Randomization Procedures 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system available 
on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and with the LPOs 
registration/randomization systems or the Theradex Interactive Web Response System (IWRS) 
for retrieval of patient registration/randomization assignment. OPEN will populate the patient 
enrollment data in NCI’s clinical data management system, Medidata Rave. 
Requirements for OPEN access:   
• 
Active CTEP registration with the credentials necessary to access secure NCI/CTSU 
IT systems; 
• 
To perform enrollments or request slot reservations: Must be on an LPO roster, ETCTN 
corresponding roster, or participating organization roster with the role of Registrar. 
Registrars must hold a minimum of an Associate Plus (AP) registration type; 
• 
If a Delegation of Tasks Log (DTL) is required for the study, the registrars must hold 
the OPEN Registrar task on the DTL for the site; and 
• 
Have an approved site registration for the protocol prior to patient enrollment. 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient transfer 
in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB approval on their 
Form FDA 1572 in RCR. If a DTL is required for the study, the IVR or NPIVR must be assigned 
the appropriate OPEN-related tasks on the DTL. 
Prior to accessing OPEN, site staff should verify the following: 
• 
Patient has met all eligibility criteria within the protocol stated timeframes; and  
• 
All patients have signed an appropriate consent form and Health Insurance Portability 
and Accountability Act (HIPAA) authorization form (if applicable). 
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Note:  The OPEN system will provide the site with a printable confirmation of registration and 
treatment information. You may print this confirmation for your records.  
Access OPEN at https://open.ctsu.orgor from the OPEN link on the CTSU members’ website. 
Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org. For any additional questions, contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
COG Patient Registration Enrollment Information 
For COG Credited Enrollments ONLY: Prior to enrollment on this study, patients enrolling must 
be assigned a COG patient ID number. This number is obtained via the Patient Registry module 
in OPEN once authorization for the release of protected health information (PHI) has been 
obtained. The COG patient ID number is used to identify the patient in all future interactions 
with COG. If you have problems with the registration, please refer to the online help. For 
additional help or information, please contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. 
Note: This COG patient ID number is different from the A021502 patient ID which will be 
assigned during registration (Step 1) to this trial. 
4.5 
Registration to Correlative Studies 
There are three substudies within Alliance A021502. These correlative science studies must be 
offered to all patients ≥ 18 years of age enrolled on Alliance A021502 (although patients may 
opt to not participate); patients 12 to < 18 years of age may not participate in the Quality of Life 
Study (A021502-HO1), but must be offered the other two substudies. These substudies do not 
require separate IRB approval. The substudies included within Alliance A021502 are: 
• 
Quality of Life Study A021502-HO1 (Section 14.1) 
• 
Biomarker Study A021502-ST1 (Section 14.2) 
• 
Pharmacogenetic Study A021502-PP1 (Section 14.2) 
If a patient answers “yes” to “I choose to take part in the Quality of Life study and will fill out 
these forms,” Question #1 in the model consent, they have consented to participate in the 
substudy described in Section 14.1. The patient should be registered to Alliance A021502-HO1 
at the same time they are registered to the treatment trial (A021502). Questionnaires should be 
submitted per Section 6.4.   
If a patient answers “yes” to “I agree to have my tissue collected, and I agree that my tissue 
samples and related information may be kept in a Biobank for use in future health research,” “I 
agree to have my blood collected, and I agree that my blood samples and related information 
may be kept in a Biobank for use in future health research,” or “I agree to have my stool 
collected, and I agree that my stool samples and related information may be kept in a Biobank 
for use in future health research,” questions #2-4 in the model consent, they have consented to 
participate in the A021502-ST1 substudy described in Section 14.2. If a patient answers “yes” 
to “I agree to have my blood collected, and I agree that my blood samples and related 
information may be kept in a Biobank for use in future health research,” Question #2 in the 
model consent, they have consented to participate in the A021502-PP1 substudy described in 
Section 14.2. The patient should be registered to Alliance A021502-ST1 and/or A021502-PP1 
at the same time they are registered to the treatment trial (A021502). Samples should be 
submitted per Section 6.2.   
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4.6 
Stratification Factors and Treatment Assignments 
Permuted Block 
After a patient is registered, they will be assigned to one of the two treatment arms (Arm 1 vs. 
Arm 2) in a 1:1 ratio utilizing a permuted block schedule [39]. The stratification factors for this 
study are as follows: 
• 
Number of Positive Lymph Nodes: N1 (1-3 positive nodes)/N1C vs. N2 (≥4 positive 
nodes) (per AJCC 7) 
• 
T Stage: Tx/T1-T3 vs. T4 
• 
Primary Tumor Location: proximal (cecum, ascending colon, hepatic flexure, and 
transverse colon) vs. distal (splenic flexure, descending colon, sigmoid colon, and 
rectosigmoid junction) 
When combined, these stratification factors create eight stratum levels, each of which having its 
own patient allocation schedule. The possible block size for this study is four.  
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5.0 
STUDY CALENDAR 
The pre-study testing intervals are guidelines only. Laboratory and clinical parameters during treatment are to 
be followed using individual institutional guidelines and the best clinical judgment of the responsible physician. 
It is expected that patients on this study will be cared for by physicians experienced in the treatment and 
supportive care of patients on this trial.  
Pre-Study Testing Intervals  
• 
To be completed ≤ 28 DAYS before registration: Laboratory studies, history and physical; dMMR testing 
may be completed at any point prior to registration for the present tumor. 
• 
To be completed ≤ 80 DAYS before registration: Any imaging used to confirm lack of evidence of 
definitive metastatic disease (pre-surgery scans are acceptable) 
 
Prior to 
Registration* 
Arm 1: 
Day 1 of 
each cycle* 
Arm 2: 
Day 1 of 
each cycle* 
End of 
treatment 
follow-up** 
Post-treatment 
follow-up *** 
Tests & Observations 
History and Physical, Weight, 
PS 
A 
A 
A 
X 
X 
Height 
X 
X(1) 
X(1) 
X(1) 
 
Pulse, Blood Pressure 
X 
X 
X 
X 
 
O2 Saturation 
X(2) 
X(2) 
 
X(2) 
 
CTCAE Adverse Event 
Assessment 
 
X(3) 
X(3) 
X(3) 
X(3) 
PRO-CTCAE Adverse Event 
Assessment 
X(4) 
X(4) 
X(4) 
X(4) 
 
Registration Fatigue/ Uniscale 
Assessment 
X(5) 
 
 
 
 
Colonoscopy 
B 
 
 
 
B 
Tanner Staging 
X(1) 
C(1) 
C(1) 
X(1) 
X (1) 
Laboratory Studies 
Complete Blood Count, incl. 
Diff. 
X 
X 
X 
X 
 
Chemistry 
X(6) 
X(6) 
X(6) 
X(6) 
 
TSH 
X(7) 
X(7) 
 
 
 
Hep B Surface Ag & Hep C ab 
(Physician Discretion) 
X 
 
 
 
 
Serum or Urine HCG 
X(8) 
 
 
 
 
CEA 
X(9) 
X(9) 
X(9) 
 
X(9) 
CD4 Count & Viral Load 
X(10) 
 
 
 
 
dMMR Testing 
X 
 
 
 
 
Staging 
CT of Chest/Abd/Pelvis or 
MRI of Chest/Abd/Pelvis  
D 
E 
E 
E 
E 
Correlative Studies: For patients who consent to participate 
QOL Assessments 
Arm 1: At registration, prior to Cycles 4, 7, and 13, at the end of treatment, 
and 3 years from registration. Arm 2: At registration, prior to Cycles 4 and 
7, at the end of treatment, 12 months from registration, and 3 years from 
registration. See Sections 6.4, 14.1, and Appendix I. 
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Tissue, Blood, and Stool 
Samples 
See Sections 6.2 and 14.2. 
* 
Labs and visits completed prior to registration may be used for Day 1 of Cycle 1 (or Day 1 of Cycle 2) tests if 
obtained ≤ 14 days prior to treatment. For subsequent cycles, labs and visits may be obtained ≤ 2 business days 
prior to day of treatment. 
** 
Physical examination, adverse event assessment, labs (CBC and chemistry), and staging scans (if due per footnote 
D) are required 1 month (+/- 7 days) after the last day of the last treatment cycle. 
*** Patients will be followed for recurrence every 6 months (+/- 1 month) for the first two years after registration, and 
then once annually (+/- 1 month) for years 3-5 after registration. Recurrence follow-up will continue per the 
schedule above for 5 years after registration or until evidence of relapse, whichever comes first. See  Section 12.0 
for survival follow-up. 
1 
For patients aged 12 to <18 years. Staging should be performed until the patient has reached Tanner Stage V. 
2 
Oxygen saturation should be assessed at rest and after 1 minute walk. 
3 
Solicited AEs are to be collected starting prior to treatment until off-treatment (see Section 9.1). Routine AEs are 
to be collected starting after registration until the end of survival follow-up. For patients who complete one cycle 
of FOLFOX prior to registration, the first routine AE assessment should take place after registration but prior to 
Day 1 Cycle 2 of FOLFOX; see Section 9.3 for expedited SAE reporting. 
4 
Patients aged ≥ 18 years complete PRO-CTCAE by paper booklet ordered through the CTSU website. See Section 
9.1 for administration instructions. See Appendix I for PRO-CTCAE assessments for IRB submission and review 
only. See Section 4.3 for ordering instructions. PRO-CTCAE booklets should be administered at the following 
time points: ≤ 14 days prior to registration; Day 1 of each Cycle, and at the end of treatment. 
5 
To be completed after registration but ≤ 21 days prior to treatment. See Appendix I. 
6 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate (or total CO2), BUN, calcium, chloride, serum 
creatinine, glucose, potassium, total protein, SGOT (AST), SGPT (ALT), and sodium. 
7 
Perform at baseline and then every 8 weeks (+/- 14 days). 
8 
For women of childbearing potential (Section 3.2.6). Must be done ≤ 7 days prior to registration. 
9 
Perform at baseline, 6 weeks (+/- 7 days) after end of FOLFOX, then every 6 months (+/- 1 month) for 3 years, 
then every 12 months (+/- 1 month) for an additional 2 years, or until relapse. After the end of FOLFOX treatment, 
the timing of CEA testing should correspond with timing of radiographic imaging studies, where possible, but 
more frequent testing is at provider discretion. 
10 
HIV-positive patients should complete a CD4 count and viral load ≤ 28 days prior to registration. 
A 
Drug dosages need not be changed unless the calculated dose changes by ≥ 10%, however, if the site recalculates 
the dose for a lower percentage dose changes (i.e. dose changes that are < 10%) to adhere to institutional policy, 
then this will not be considered a protocol deviation. 
B 
Patients who did not receive a colonoscopy to the cecum prior to surgery are required to have a full colonoscopy 
no later than 6 weeks after the completion of chemotherapy, but exact timing within the specified window is per 
treating physician discretion. If recurrence is observed or suspected on imaging and it has colonic or rectal 
involvement that is not in close proximity to the surgical anastomosis, then a colonoscopy with biopsy is required 
to exclude a new primary malignancy in the colorectum. Colonoscopy and pathology reports from all additional 
colonoscopies performed during the treatment and follow-up periods should be submitted if possible. See Section 
11.3.1 for details on follow-up and Lynch Syndrome. 
C 
Perform only on Day 1 of Cycle 1 and Day 1 of Cycle 7. 
D 
Baseline abdominal/pelvic scans can include either: 1) a CT ABD/PELV, or 2) a MRI ABD/PELV. Chest imaging 
can be either chest CT or chest MRI. CT scans should be of diagnostic quality and performed with oral and IV 
contrast unless there is a medical contraindication. MRIs should be performed with IV contrast unless there is a 
medical contraindication. Supporting documentation is to be submitted, per Section 6.1.1. 
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E 
The same imaging modality used at baseline must be used for all subsequent scans. Every 6 months (+/- 1 month) 
for the first 2 years after registration, and then annually (+/- 3 months) for years 3-5 after registration or until 
evidence of relapse, whichever comes first. Imaging and reports are to be submitted per Section 6.3. Upon relapse 
documented by imaging, reports should be submitted for retrospective review by Study Chair per Section 6.1.1. 
5.1 Vital Status (Survival) 
To ensure current and complete survival data are available, updated vital status (survival) may 
be requested by the Alliance. The primary focus of a vital status (survival) determination is to 
identify if a trial participant is deceased.  
In support of regulatory requests to minimize missingness for safety and overall survival 
analysis, public record searches to obtain vital status (survival) for participants who withdrew 
consent from study or who were lost to follow-up may be requested by the Alliance.  
Per FDA Guidance: Data Retention When Subjects Withdraw from FDA-Regulated Clinical 
Trials (October 2008): If a subject withdraws from the interventional portion of a study and does 
not consent to continued follow-up of associated clinical outcome information, the investigator 
must not access for purposes related to the study the subject’s medical record or other 
confidential records requiring the subject’s consent. However, an investigator may review study 
data related to the subject collected prior to the subject’s withdrawal from the study, and may 
consult public records, such as those establishing survival status.  
A public record search would utilize information about the participant, from the time the 
participant consented to the study, to obtain an updated vital status (survival). No participants 
should be contacted during a public record search by the site research team. 
6.0 
DATA AND SPECIMEN SUBMISSION  
6.1 
Data Collection and Submission 
Medidata Rave is the clinical data management system being used for data collection for this 
trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments.  
Requirements to access Rave via iMedidata: 
• 
Active CTEP registration with the credentials necessary to access secure NCI/CTSU 
IT systems; and 
• Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, Rave 
Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  
Rave role requirements: 
• Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate Plus 
(AP) registration type; 
• Rave Investigator role must be registered as an Non-Physician Investigator (NPIVR) or 
Investigator (IVR); and 
• Rave Read Only or Rave SLA role must have at a minimum an Associates (A) 
registration type. 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types and 
documentation required. 
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This study has a Delegation of Tasks Log (DTL). Therefore, those requiring write access to 
Rave must also be assigned the appropriate Rave tasks on the DTL. 
Upon initial site registration approval for the study in the Regulatory application, all persons 
with Rave roles assigned on the appropriate roster will be sent a study invitation email from 
iMedidata. To accept the invitation, site staff must either click on the link in the email or log in 
to iMedidata via the CTSU members’ website under Data Management > Rave Home and click 
to accept the invitation in the Tasks pane located in the upper right corner of the iMedidata 
screen. Site staff 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 eLearning link in the Tasks pane located in 
the upper right corner of the iMedidata screen. If an eLearning is required for a study and has 
not yet been taken, the link to the eLearning will appear under the study name in the Studies 
pane located in the center of the iMedidata screen; once the successful completion of the 
eLearning has been recorded, access to the study in Rave will be granted, and a Rave EDC link 
will replace the eLearning link under the study name 
Action will be required by site staff (to activate their account) who have not previously activated 
their iMedidata/Rave account at the time of initial site registration approval for the study in the 
Regulatory application. Account activation instructions are located on the CTSU website in the 
Data Management section under the Data Management Help Topics > Rave Resources > 
Medidata Account Activation and Study Invitation (to activate your iMedidata account).  
Additional information on iMedidata/Rave is available on the CTSU members’ website in the 
Data Management Rave Resources section or by contacting the CTSU Help Desk at 1-888-823-
5923 or by email at ctsucontact@westat.com.   
A Data Submission Schedule is available on the Alliance study webpage within the Case 
Report Forms section. A Data Submission Schedule is also available on the CTSU website 
within the study-specific folders. 
Patient-completed questionnaire booklets for this study are to be ordered prior to the 
registration of any patients (see Section 4.3). Samples of questionnaire booklets are available in 
Appendix I for reference and IRB submission only. They are not to be used for patient 
completion. Booklets must be given to patients to complete and patients should be instructed to 
return the booklets to site staff in person, and site staff will enter patient responses into Rave.  
Major and critical protocol deviations for this study are to be reported in Rave according to 
the A021502 Deviations Guidance Memorandum available on the Alliance and CTSU websites. 
6.1.1 
 
Supporting Documentation to be Submitted to the Alliance  
This study requires supporting documentation for diagnosis, DNA mismatch repair 
(dMMR) status, recurrence, and other reports as specified in data submission. 
Additional source documentation is required for the protocol-specific central data 
monitoring plan; see Section 13.6 of this protocol and the Data Submission Schedule 
accompanying the All Forms Packet for further guidance. 
• 
Baseline: H&P, colonoscopy report*, radiologic images (submit to IROC 
Ohio see section 6.3), imaging report, pathology report from colonoscopy and 
surgery, operative report, result of dMMR testing (including methodology 
used, e.g. antibody names), laboratory reports for protocol-specified labs, 
clinic notes. Germline mutation testing report when requested by Alliance 
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Statistics and Data Management Center to resolve discordant data 
entries. 
*If a patient did not receive a colonoscopy to the cecum prior to surgery due 
to an obstructing tumor or other factors, then the patient is required to have a 
full colonoscopy no later than 6 weeks after the completion of chemotherapy, 
but exact timing within the specified window is per treating physician 
discretion, to exclude a new primary malignancy in the colorectum. 
• 
Treatment: Laboratory reports for protocol-specified labs 
• 
Restaging: Radiologic images (submit to IROC Ohio see section 6.3), imaging 
reports 
• 
Follow-up: Colonoscopy report* (if applicable) 
• 
Recurrence: Radiologic images (submit to IROC Ohio see section 6.3), 
imaging report, pathology report (if applicable), colonoscopy report* (if 
applicable), operative report (if applicable), laboratory reports for protocol-
specified labs, clinic notes. 
*If recurrence is observed or suspected on imaging and it has colonic or 
rectal involvement that is not in close proximity to the surgical 
anastomosis, then a colonoscopy with biopsy is required to exclude a new 
primary malignancy in the colorectum. Female patients with isolated 
recurrence involving the uterus should undergo biopsy to exclude a primary 
endometrial carcinoma, which is the most common extracolonic malignancy 
in patients with Lynch Syndrome.  
All supporting documentation is to be submitted via Rave (with the exception of 
radiologic images, which should be submitted to IROC Ohio per Section 6.3). Imaging 
reports should be submitted via Rave and to IROC Ohio per Section 6.3 along with 
radiologic images. 
In the event of a second primary or secondary malignancy, pathology reports, 
colonoscopy reports (if applicable), imaging reports (if applicable), and surgical reports 
(if applicable) are to be submitted. 
Additionally, colonoscopy and pathology reports (if applicable) from any colonoscopies 
performed during the treatment and clinical follow-up periods should be submitted 
wherever possible.  
Documentation of administration of all agents, including standard of care drug(s), 
should include total dose and start/stop dates for prolonged IV infusions ≥ 24 
hours. (Paraphrased from the CTMB Guidelines). 
6.1.2 
Data Quality Portal 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data Management. The Rave 
Home section displays a table providing summary counts of Total Delinquencies and 
Total Queries. DQP Queries, DQP Delinquent Forms, DQP Form Status and the DQP 
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Reports modules are available to access details and reports of unanswered queries, 
delinquent forms, forms with current status and timeliness reports. Site staff should 
review the DQP modules on a regular basis to manage specified queries and delinquent 
forms. 
The DQP is accessible by site staff who are rostered to a site and have access to the 
CTSU website. Staff who have Rave study access can access the Rave study data via 
direct links available on the DQP modules. 
CTSU Delinquency Notification emails are sent to primary contacts at sites twice a 
month. These notifications serve as alerts that queries and/or delinquent forms require 
site review, providing a summary count of queries and delinquent forms for each Rave 
study that a site is participating in. Additional site staff can subscribe and unsubscribe 
to these notifications using the CTSU Report and Information Subscription Portal on 
the CTSU members’ website. 
To learn more about DQP use and access, click on the Help Topics button displayed on 
the Rave Home, DQP Queries, DQP Delinquent Forms, DQP Form Status, and DQP 
Reports modules. 
6.2 
Specimen Collection and Submission  
Correlative Science Manual (CSM): The Alliance A021502 Correlative Science Manual 
(CSM) contains instructions for specimen collection, processing, and shipping. The manual 
can be found on the study-specific webpage on the Alliance, BioMS, and CTSU websites. 
Questions regarding the CSM should be directed to the contact(s) specified in the manual. 
For all patients registered to Alliance A021502: Retrospective dMMR confirmation testing and 
retrospective pathology review and biomarker testing will be performed using the paraffin 
embedded tissue from the surgical resection specimens. The submission of these samples for 
dMMR confirmation testing is required for all patients registered to this study. 
For patients registered to substudy A021502-ST1 and A021502-PP1: All participating 
institutions must ask patients for their consent to participate in the correlative substudies planned 
for Alliance A021502-ST1 and A021502-PP1, although patient participation is optional. 
Biomarker and pharmacogenomic studies will be performed. Rationale and methods for the 
scientific components of these studies are described in Section 14.2. For patients who consent 
to participate in A021502-PP1, buffy coats from the A021502-ST1 collection will be used. For 
patients who consent to participate in A021502-ST1, tissue, blood, and/or stool specimens will 
be collected at the time points listed below.  
 
Prior to 
treatment 
(blood kit  1) 
4 weeks (+/- 1 wk) 
after initiation of 
treatment 
(blood kit  2) 
4.5 months (+/- 1 wk) 
after initiation of 
treatment  
(blood kit    1) 
6 months (+/- 1 
month) after end 
of therapy 
(blood kit     1) 
Time of 
recurrence   
(blood kit  3) 
 
Mandatory for all patients registered to A021502: 
10 Superfrost® Plus 
Micro Slides 
X 
 
 
 
 
H&E slide AND 
FFPE tumor block 
X 
 
 
 
 
FFPE normal block 
X 
 
 
 
 
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For patients registered to A021502-ST1 and/or A021502-PP1 submit the following: 
FFPE tumor block 
X 
 
 
 
X 
EDTA platelet poor 
plasma & buffy coats 
in lavender top 
3 x 10 mL 
 
3 x 10 mL 
3 x 10 mL 
3 x 10 mL 
Whole blood in ACD 
yellow top 
3 x 8.5 mL 
3 x 8.5 mL 
3 x 8.5 mL 
3 x 8.5 mL 
 
Stool (fecal kit) 
3 x 25 mL 
 
3 x 25 mL 
3 x 25 mL 
 
6.3 
Imaging Submission - Required for All Patients 
Collection of CT or MRI images is required for patients consented on A021502. Quality images 
will be collected digitally for archival purposes. The same imaging modality (i.e. multiphase CT 
or MRI) used at baseline for each patient should be used for all subsequent evaluations to ensure 
accurate comparison. Images and local interpretation reports will be collected digitally at the 
following time points: 
• 
Baseline 
• 
Restaging (performed every 6 months [+/- 1 month] for the first 2 years after 
registration, then annually [+/- 3 months] for years 3-5 after registration) 
• 
Recurrence/relapse 
The complete CT or MRI scan data in digital DICOM format should be submitted 
electronically to the Imaging and Radiation Oncology Core at Ohio (IROC Ohio) upon 
patient registration or upon image acquisition completeness (restaging and/or recurrence) within 
the following time frames: 
• 
For imaging performed after the issuance of Update #14: submit within 30 business 
days 
• 
For imaging performed before the issuance of Update #14: submit within 60 business 
days of protocol amendment release 
BMP files, JPG files, or hard copies (films) are not acceptable. 
Imaging data should be submitted electronically to IROC Ohio via TRIAD (Section 6.3.1). The 
standard TRIAD based data transfer approach will be provided separately through IROC efforts 
via the specific trial e-mail, Alliance021502@irocohio.org, per the request of participating sites 
before their first imaging data submission. 
If the TRIAD approach is not achievable at a site, alternatively the site needs to de-identify the 
patient data using institutional procedures to remove patient name and medical record number 
while preserving the Alliance patient ID number (e.g. 112136) and protocol number (e.g. 
A021502), and use the following electronic approaches for data submission: 
1) Web Transfer (http://upload.imagingcorelab.com) 
Any PCs with internet access and web browser (e.g. Internet Explorer, Mozilla Firefox) 
can be used to web transfer DICOM images and other required files to IROC Ohio. The 
standard Web Transfer information will be provided separately through the specific trial 
e-mail, Alliance021502@irocohio.org, per the request of participating sites before the 
first imaging data submission. 
2) FTP Transfer 
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Any FTP software can be used to initiate access to the secure FTP Server of IROC Ohio. 
The standard FTP access information will be provided separately through the specific 
trial e-mail, Alliance021502@irocohio.org, per the request of participating sites before 
the first imaging data submission. 
3) Mail/CD Shipment 
If neither of the electronic data transfer approaches can be achieved, then the de-
identified images in digital DICOM format may be burned to a CD and mailed to IROC 
Ohio (however, electronic submission is preferred). Submit only one of the patient’s 
images per CD, with the Alliance patient ID number, study type, date of scans, and name 
of submitting institution. 
Submit these data to: 
 
IROC Ohio 
 
Attn: A021502 
 
University of Cincinnati 
 
Digital Futures Research Building 
3080 Exploration Avenue, Suite 310 
 
Cincinnati, OH 45206 
 
Tel: 513-556-7919 
 
E-mail: Alliance021502@irocohio.org 
If the imaging data submission is done via web transfer, FTP transfer, or mail/CD shipment, 
send an e-mail to IROC Ohio at the specific trial email, Alliance021502@irocohio.org, to 
inform them that the study has been submitted from the institution. Please include the following 
basic information of submitted data sets: 
1) Alliance Patient ID Number 
2) Scan Time Point (i.e. Baseline) 
3) Date of Scans 
4) Institution Name 
IROC 
Ohio 
will 
notify 
the 
site 
of 
receipt 
via 
the 
trial 
specific 
email 
Alliance021502@irocohio.org within the following time frames: 
• 
 For imaging performed after the posting of Update #14: IROC Ohio will notify the site 
within 5 business days of the data receipt and within 3 business days following the data 
receipt of the quality check report 
• 
For imaging performed before the posting of Update #14: IROC Ohio will notify the 
site within 10 business days of the data receipt and within 3 business days following the 
data receipt of the quality check report 
6.3.1 
Digital Imaging Data Submission Using Transfer of Images and Data (TRIAD) 
Transfer of Images and Data (TRIAD) is the American College of Radiology’s (ACR) 
image exchange application. TRIAD provides sites participating in clinical trials a 
secure method to transmit images. TRIAD anonymizes and validates the images as they 
are transferred. 
6.3.1.1 TRIAD Access Requirements 
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TRIAD Access Requirements: 
• 
A valid Cancer Therapy Evaluation Program (CTEP) Identity and Access 
Management (IAM) (CTEP-IAM) account.  
• 
Registration and Credential Repository (RCR) registration type of: Associate 
(A), Associate Plus (AP), Non-Physician Investigator (NPIVR), or 
Investigator (IVR) registration type. Refer to the CTEP Registration 
Procedures section for instructions on how to request a CTEP-IAM account 
and complete registration in RCR.  
• 
TRIAD Site User role on an NCTN or ETCTN roster. 
All individuals on the Imaging and Radiation Oncology Core provider roster have 
access to TRIAD and may submit images for credentialing purposes, or for enrollments 
to which the provider is linked in OPEN. 
6.3.1.2 TRIAD Installations 
To submit images, the individual holding the TRIAD Site User role will need to install 
the TRIAD application on their workstation. TRIAD installation documentation is 
available at https://triadinstall.acr.org/triadclient/. 
This process can be done in parallel to obtaining your CTEP-IAM account and RCR 
registration. 
For questions, contact TRIAD Technical Support staff via email TRIAD-
Support@acr.org or 1-703-390-9858. 
6.3.1.3 Procedures for Data Submission via TRIAD 
The standard TRIAD-based data transfer approach will be provided separately through 
IROC efforts via the specific trial e-mail, Alliance021502@irocohio.org, per the request 
of participating sites before their first imaging data submission. 
6.4 
Quality of Life Assessments 
Patient-completed questionnaire booklets for this study are to be ordered prior to the registration 
of any patients (see Section 4.3). Samples of questionnaire booklets are available in Appendix I 
for reference and IRB submission only. They are not to be used for patient completion. Booklets 
must be given to patients to complete and patients should be instructed to return the booklets to 
site staff in person and site staff will enter patient responses into Rave. At visits in which 
booklets are to be completed, the booklet should be given to the patient before any discussion 
of the patient’s health status or test results. Booklet administration schedule is provided below. 
Please note that PRO-CTCAE is contained in a separate booklet and is required for all patients 
18 years or older per the study calendar. The schedule below only pertains to patients aged ≥ 18 
years who consent to participate in the Quality of Life study.  
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ARM 1:   
mFOLFOX6 + atezolizumab 
≤ 14 Days Prior 
to Registration  
 Prior to  
Cycles 4, 7, & 13  
(+/-3 days) 
End of 
Treatment 
Visit  
(+/-7 days) 
3 Years after 
Registration 
(+/-28 days) 
For patients registered to A021502-HO1, submit patient-completed questionnaires* at the following time points: 
 
X 
X 
X 
X 
 
ARM 2:  
 mFOLFOX6 
≤ 14 Days 
Prior to 
Registration  
 Prior to 
Cycles 4 & 7  
(+/-3 days) 
 End of 
Treatment 
Visit  
(+/-7 days) 
12 Months 
after 
Registration 
(+/-14 days) 
3 Years after 
Registration 
(+/-28 days) 
For patients registered to A021502-HO1, submit patient-completed questionnaires* at the following time points: 
 
X 
X 
X 
X 
X 
*See Appendix I for FACT-C, FACT/GOG-NTX, and EQ-5D-5L questionnaires for IRB 
submission and review only. Patients must complete the questionnaires in booklet format. See 
Section 4.3 for ordering instructions. 
Submission of Completed Booklets: The data from the booklets are to be entered into Medidata 
Rave by site staff. Data entry should correlate with the cycles notes in the above schedules (e.g. 
entered within Cycles 4, 7, or 13).  
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7.0 
TREATMENT PLAN/INTERVENTION 
Protocol treatment is to begin within 14 days after registration.  
It is acceptable for individual therapy doses to be delivered ≤ a 24-hour (business day) window 
before and after the protocol-defined date for a scheduled dose. For example, if the treatment due 
date is a Friday, the window for treatment includes the preceding Thursday through the following 
Monday. In addition, patients are permitted to have a new cycle of immunotherapy/chemotherapy 
delayed up to 7 days for major life events (e.g. serious illness in a family member, major holiday, 
vacation that cannot be rescheduled) without this being considered a protocol violation. 
Documentation to justify this delay should be provided. 
Patients with stage III, dMMR colon cancer will be randomized in 1:1 fashion to receive either Arm 
1: mFOLFOX6 for 12 cycles total with atezolizumab starting at Cycle 1 or Cycle 2 of mFOLFOX6 
with continuation of atezolizumab for a total of 12 months (6 months, i.e. 13 cycles of atezolizumab 
monotherapy), or Arm 2: mFOLFOX6 for 12 cycles, which is a total of 6 months. One cycle will be 
defined as 14 days of treatment.  
Cycle 1 of mFOLFOX6 must be started within 10 weeks of surgical resection of the primary cancer. 
Please note that best practice is 3 to 6 weeks between surgery and Cycle 1 of chemotherapy. Cycle 1 
of mFOLFOX6 may be given prior to registration. Once results of the local dMMR testing are 
complete and patients are found to have dMMR, patients may register and will then be randomized 
to Arm 1 or Arm 2. The standard of care for the time window between the start of mFOLFOX6 Cycle 
1 and start of mFOLFOX6 Cycle 2 is 14 days, however, up to 28 days are allowed between Day 14 
of Cycle 1 and Day 1 of Cycle 2 to allow for delays due to toxicity or patient decision making.  
For patients who received one cycle of mFOLFOX6 prior to registration and who are on Arm 1, 
atezolizumab will start with Cycle 2 of mFOLFOX6. If Cycle 1 of mFOLFOX6 is administered prior 
to registration, it must be administered per Appendix III. For patients who did not have a cycle of 
mFOLFOX6 prior to registration and who are on Arm 1, atezolizumab will start with Cycle 1 of 
mFOLFOX6.  
Chemotherapy and immunotherapy must be administered at the registering institution, including the 
one cycle of mFOLFOX6 the patient may have received prior to registration. Treatment will continue 
until disease recurrence or unacceptable adverse event or inability to tolerate treatment occurs 
(despite all allowed dose reductions). Otherwise treatment will continue until completion of the full 
treatment program and entrance onto clinical follow-up. Also, see Section 12.0 for additional 
information regarding discontinuation of treatment. Administration of atezolizumab should be 
performed in a setting with emergency medical facilities and staff who are trained to monitor for and 
respond to medical emergencies. 
The initial dose of atezolizumab will be delivered over 60 (±15) minutes. If the first infusion is 
tolerated without infusion associated AEs, the second infusion may be delivered over 30 (±10) 
minutes. If the 30-minute infusion is well tolerated, all subsequent infusions may be delivered over 
30 (±10) minutes. For the first infusion, the patient’s vital signs (heart rate, respiratory rate, blood 
pressure, and temperature) should be determined within 60 minutes before, during (every 15 [±5] 
minutes), and 30 (±10) minutes after the infusion. For subsequent infusions, vital signs should be 
collected within 60 minutes before and within 30 minutes after the infusion. Vital signs should be 
collected during the infusion only if clinically indicated. Patients should be informed about the 
possibility of delayed post-infusion symptoms and instructed to contact their study physician if they 
develop such symptoms. 
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No premedication will be allowed for the first dose of atezolizumab. Premedication may be 
administered for Cycles ≥ 2 at the discretion of the treating physician.   
7.1 
Arm 1:  mFOLFOX6 Plus Atezolizumab 
The agents in the table below are listed in the order of intended administration. 
Agent 
Dose 
Route 
Duration 
Days 
Cycle 
Atezolizumab 
840mg* 
IV 
Over 60 min (+/- 15 min) for 1st 
dose, then Over 30min (+/- 10 
min) for all subsequent doses 
Day 1 
Every 14 days 
Oxaliplatin 
85mg/m2 
IV 
Over 2 hours (+/- 30 min) 
Day 1 
Every 14 days 
Leucovorin** 
400mg/m2 
IV 
Over 2 hours (+/- 30 min) 
Day 1 
Every 14 days 
Fluorouracil 
400mg/m2 
+ 
2400mg/m2 
IV 
Bolus 
+ 
Over 46 hours (+/- 4 hours) 
Day 1 
+ 
Days 1-3 
Every 14 days 
* Patients 12 to < 18 years of age will receive a dose of 10 mg/kg up to a maximum flat dose of 
840 mg. The patient’s age on the day of treatment should be used to determine whether to use 
weight-based dosing. 
** Alternatively, leucovorin may be administered (via separate infusion containers) 
concurrently with oxaliplatin. Infusion duration may be adjusted according to institutional 
practice. 
Note: If the minimum durations are followed and/or concurrent administration of leucovorin 
and oxaliplatin occurs, then fluorouracil administration could be completed on Days 1-2.   
Atezolizumab should be the first drug administered regardless of cycle number as no 
premedication is allowed prior to the first dose of atezolizumab; see Section 7.0 and Section 
8.1.4 for additional details. 
Patients should receive 6 months (12 cycles total) of mFOLFOX6, including the cycle that may 
have been received prior to registration.  
For patients who started mFOLFOX6 after registration, atezolizumab should start on Day 
1 Cycle 1 of mFOLFOX6 (12 cycles in combination with mFOLFOX6 followed by 13 cycles 
as monotherapy for a total of 25 cycles of atezolizumab). 
For patients who receive one cycle of mFOLFOX6 prior to registration, atezolizumab 
should start on Day 1 Cycle 2 of mFOLFOX6 (11 cycles in combination with mFOLFOX6 
followed by 13 cycles as monotherapy for a total of 24 cycles of atezolizumab). 
7.2 
Arm 2:  mFOLFOX6 
 The agents in the table below are listed in the order of intended administration. 
Agent 
Dose 
Route 
Duration 
Days 
Cycle 
Oxaliplatin 
85mg/m2 
IV 
Over 2 hours (+/- 30min) 
Day 1 
Every 14 days 
Leucovorin* 
400mg/m2 
IV 
Over 2 hours (+/- 30 min) 
Day 1 
Every 14 days 
Fluorouracil 
400mg/m2 
+ 
2400mg/m2 
IV 
Bolus 
+ 
Over 46 hours (+/- 4 hours) 
Day 1 
+  
Days 1-3 
Every 14 days 
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* Alternatively, leucovorin may be administered (via separate infusion containers) concurrently 
with oxaliplatin. Infusion duration may be adjusted according to institutional practice. 
Note: If the minimum durations are followed and/or concurrent administration of leucovorin 
and oxaliplatin occurs, then fluorouracil administration could be completed on Days 1-2.   
Patients should receive 6 months (12 cycles total) of mFOLFOX6, including the cycle that may 
have been received prior to registration. 
8.0 
DOSE AND TREATMENT MODIFICATIONS 
8.1 
Ancillary Therapy, Concomitant Medications, and Supportive Care 
8.1.1 
Patients should not receive any other agent which would be considered treatment 
for the primary neoplasm or impact the primary endpoint. 
8.1.2 
Patients should receive full supportive care while on this study. 
This includes blood product support, antibiotic treatment, and treatment of other newly 
diagnosed or concurrent medical conditions. All blood products and concomitant 
medications such as antidiarrheals, analgesics, and/or antiemetics received from the first 
day of study treatment administration until 30 days after the final dose will be recorded 
in the medical records. 
8.1.3 
Treatment with hormones for cancer treatment or other chemotherapeutic 
agents may NOT be administered. Exceptions include: 
• 
Steroids given for adrenal failure (steroid supplementation should be at 
physiologic dosing or as described in Section 8.1.12) 
• 
Hormones administered for non-disease-related conditions (e.g. insulin for 
diabetes) 
• 
Intermittent use of dexamethasone as an antiemetic (see Section 8.1.4 for 
maximum dose requirements). 
8.1.4 
Antiemetics may be used at the discretion of the attending physician, with the 
exception of steroids above. 
As this regimen has high emetogenic potential, it is recommended that all subjects on 
study should receive an aggressive prophylactic antiemetic regimen, consisting of a 
5HT-3 antagonist +/- NK1 antagonist. Steroids are permitted for antiemetic prophylaxis 
during mFOLFOX6 chemotherapy, but must be limited to a maximum of equivalent 
dexamethasone 10 mg daily for 2 days every 14 days, see Section 8.1.12 below for 
additional details. 
8.1.5 
Diarrhea management is per the discretion of the treating physician. 
For symptoms of diarrhea (and/or abdominal cramping) that occur at any time during a 
treatment cycle, it is suggested that patients should be instructed to take an anti-
diarrheal, such as loperamide. It is recommended that the anti-diarrheal should be 
started at the earliest sign of: (1) a poorly formed or loose stool; (2) an increase in bowel 
movements by 1 to 2 episodes per day compared to baseline, or (3) an increase in stool 
volume or liquidity. Additional anti-diarrheal measures may be implemented at the 
discretion of the treating physician. Patients should also be instructed to increase fluid 
intake to help maintain fluid and electrolyte balance during episodes of diarrhea, and IV 
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fluids should be considered for severe diarrhea, at the discretion of the treating 
physician. 
8.1.6 
Radiation therapy may not be administered while a subject is on the study. 
8.1.7 
Surgery 
Patients who require surgery during protocol treatment may proceed as such, unless the 
surgery involves resection of recurrent colon cancer. Study drug can be held for a 
maximum of 42 days. If the patient requires an interruption of > 42 days, then they will 
be removed from protocol therapy. 
8.1.8 
Alliance Policy Concerning the Use of Growth Factors 
• 
Please note that during treatment on mFOLFOX6, WBC growth factors are 
NOT required and may be used at the discretion of the physician. 
• 
Blood products and growth factors should be utilized at the discretion of the 
treating physician as clinically warranted and following institutional policies 
and recommendations. The use of growth factors should follow published 
guidelines of the American Society of Clinical Oncology 2015 Clinical 
Practice Guidelines Update to the Recommendations for the Use of WBC 
Growth Factors.  J Clin Oncol 33(28): 3199-212, 2015. 
• 
The use of erythropoiesis–stimulating agents (ESAs) are NOT allowed, as this 
is an adjuvant therapy trial and use of ESAs is against the FDA label. 
• 
If filgrastim/pegfilgrastim, tbo-filgrastim, or sargramostim are used, they must 
be obtained from commercial sources. 
8.1.9 
Hypersensitivity/Infusion Reactions 
Chemotherapy infusion reactions: Treat hypersensitivity and infusion reactions as per 
institutional standards. 
8.1.10 Neurologic Toxicity Due to Oxaliplatin 
Patients receiving oxaliplatin on this study should be counseled to avoid cold drinks, 
chewing of ice chips, and exposure to cold water or air because the neurotoxicity often 
seen with oxaliplatin appears to be exacerbated by exposure to cold. The period of time 
during which the patient is at risk for these cold-induced sensory neuropathies is not 
well documented. Patients should exercise caution regarding cold exposure during the 
treatment period. Peripheral sensory neuropathies can occur at any time after receiving 
oxaliplatin therapy. 
Supportive care is allowed at the discretion of the treating physician. For pharyngo-
laryngeal dysesthesia, it is recommended to increase the duration of oxaliplatin infusion 
to 6 hours for subsequent cycles. 
8.1.11 Extravasation 
Extravasation of oxaliplatin has been associated with necrosis. Extravasation should be 
treated according to institutional guidelines. 
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8.1.12 Fatigue 
Fatigue is the most common adverse event associated with immune checkpoint inhibitor 
therapy. This may be associated with a flu-like illness. Consider evaluation for 
associated or underlying organ involvement including pituitary disease, thyroid disease, 
and liver disease, or muscle inflammation. 
8.1.13 Fever 
Patients may experience isolated fever during infusion reactions or up to several days 
after infusion.  Continued fever over the course of 1-2 weeks may represent autoimmune 
events, or infection. Appropriate workup should be initiated, at the discretion of the 
treating physician. 
8.1.14 Supplementation 
Electrolyte abnormalities should be adequately corrected with appropriate 
supplementation upon discovery. 
8.1.15 Vaccination 
Flu vaccine, pneumococcal vaccine, and any other relevant vaccines are recommended 
PRIOR to initiation of protocol therapy, at the discretion of the treating physician. 
Patients should not receive live attenuated vaccines while on study treatment. 
8.2 
Dose Modification General Guidelines 
• 
If multiple adverse events are seen, administer dose based on greatest reduction required 
for a single adverse event observed. Reductions or holds for new cycles of treatment are 
based on treatment given in the preceding cycle and adverse events observed since the 
prior dose (with the exception of blood counts which should use Day 1 of cycle counts). 
• 
Dose modifications of 5-FU, oxaliplatin, and atezolizumab may occur independently of 
each other, based on the pattern of toxicity. Patients unable to tolerate one or more drugs 
due to toxicity will remain on treatment with the other drugs. If oxaliplatin is omitted, 
5-FU and leucovorin should both continue to be given. 
• 
During mFOLFOX6, if 5-FU is omitted, leucovorin should also be omitted.  
• 
Once the dose of any drug has been reduced, the dose cannot be re-escalated.  
• 
There are no further dose reductions beyond those listed in the tables below for each 
drug. If further dose reduction is required, that drug should be discontinued. 
• 
CTEP-AERS reporting may be required for some adverse events (see Section 9.4). 
• 
NOTE: PRO-CTCAE data should not be used for determining attribution, dose 
modifications, or reporting of serious adverse events. 
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8.2.1 
 
Dose Modifications for mFOLFOX6 
Dose 
Level 
5-FU bolus 
(mg/m2) 
5-FU infusion 
(mg/m2) 
Leucovorin 
(mg/m2) 
Oxaliplatin 
(mg/m2) 
0* 
 
400 
2400 
400 
85 
-1 
 
320 
1920 
400 
65 
-2 
 
270 
1600 
400 
50 
-3 
 
230 
1360 
400 
40 
*Dose level 0 refers to the starting dose.  If 5-FU is skipped, leucovorin is also skipped. 
If a dose reduction beyond level -3 is required for oxaliplatin, oxaliplatin will be 
discontinued. Continue 5-FU/leucovorin. 
If a dose reduction beyond level -3 is required for 5-FU, discontinue mFOLFOX6.  
If more than one dose reduction applies, use the most stringent (i.e. the greatest dose 
reduction). 
If mFOLFOX6 is delayed due to toxicity for ≥ 4 weeks, counting from the originally 
scheduled day of treatment that was held, discontinue mFOLFOX6.  
8.2.1.1 Hematologic Toxicity 
For grade 2 neutrophil count decreased on Day 1, delay 5FU and oxaliplatin until 
grade ≤ 1, then resume oxaliplatin and 5FU at same dose.  
For grade 3 neutrophil count decreased on Day 1, delay 5FU and oxaliplatin until 
grade ≤ 1, then resume with one dose level decreased of oxaliplatin and 5FU. 
For recurring grade 3 neutrophil count decreased, delay 5FU and oxaliplatin until 
grade ≤ 1, then discontinue 5FU bolus and resume 5FU infusion and oxaliplatin with 
one dose level decreased. 
For grade 4 neutrophil count decreased or febrile neutropenia (defined as grade 3 
or 4 neutropenia and T ≥ 38.5°C), delay 5FU and oxaliplatin until grade ≤ 1, then 
discontinue 5FU bolus and resume 5FU infusion and oxaliplatin with one dose level 
decreased. 
For recurring grade 4 neutrophil count decreased or recurring febrile neutropenia, 
delay 5FU and oxaliplatin until grade ≤ 1, then discontinue 5FU bolus and resume 5FU 
infusion and oxaliplatin with two dose levels decreased. 
For grade 2 platelet count decreased, delay 5FU and oxaliplatin until grade ≤ 1, then 
resume oxaliplatin with one dose level decreased and 5FU at same dose. 
For grade 3 or 4 platelet count decreased, delay 5FU and oxaliplatin until grade ≤ 1, 
then resume 5FU and oxaliplatin with one dose level decreased. 
8.2.1.2 Gastrointestinal Toxicity with Optimal Medical Management 
For grade 2 diarrhea, delay 5FU and oxaliplatin until recovery to grade ≤ 1, then 
resume 5FU and oxaliplatin at the same dose level.  
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For grade 3 diarrhea, delay 5FU and oxaliplatin until recovery to grade ≤ 1, then 
resume oxaliplatin at the same dose level and 5FU with one dose level decreased.  
For grade 4 diarrhea, delay 5FU and oxaliplatin until recovery to grade ≤ 1 or baseline, 
then resume 5FU and oxaliplatin at the next lower dose level. 
For grade 3 nausea or vomiting or grade 4 vomiting, delay 5FU and oxaliplatin until 
recovery to grade ≤ 1, then resume 5FU and oxaliplatin at the next lower dose level. 
8.2.1.3 Mucositis 
For grade 3 mucositis, delay 5FU and oxaliplatin until recovery to grade ≤ 1, then 
resume oxaliplatin at the same dose level and 5FU at the next lower dose level.  
For grade 4 mucositis, delay 5FU and oxaliplatin until recovery to grade ≤ 1, then 
resume 5FU and oxaliplatin at the next lower dose level. 
8.2.1.4 Neuropathy (Sensory or Motor) 
Toxicity Scale for the Sensory Neuropathies Associated with Oxaliplatin (using the 
Oxaliplatin Specific Neurotoxicity Scale) 
 
Symptoms 
Grade 1 Paresthesias/dysesthesias* of short duration that resolve and do not 
interfere with function. 
Grade 2 Paresthesias/dysesthesias* interfering with function, but not with 
activities of daily living (ADL) 
Grade 3 Paresthesias/dysesthesias* with pain or with functional impairment that 
also interfere with ADL. 
Grade 4 Persistent paresthesias/dysesthesias* that are disabling or life threatening.  
 
* May be cold-induced 
For grade 2 neurotoxicity persisting between treatments, continue mFOLFOX6 with 
one dose level reduction of oxaliplatin for all subsequent cycles.  
For grade 3 neurotoxicity resolving to grade ≤ 2 between treatments, continue 
mFOLFOX6 with one dose level reduction of oxaliplatin for all subsequent cycles.  
For grade 3 neurotoxicity persisting between treatments, discontinue oxaliplatin.  
For grade 4 neurotoxicity, discontinue oxaliplatin.  
For laryngopharyngeal dysesthesia, increase the duration of oxaliplatin infusion to 6 
hours for all subsequent cycles.  
8.2.1.5 Hepatobiliary Toxicity 
For grade 3 or 4 bilirubin increased, delay 5FU and oxaliplatin until recovery to grade 
≤ 1, then resume 5FU and oxaliplatin at the next lower dose level. 
For grade 3 or 4 ALT/AST increased, discontinue 5FU and oxaliplatin.  
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8.2.1.6 Renal Insufficiency 
For grade 3 or 4 creatinine increased and NOT attributed to study treatment, delay 
5FU and oxaliplatin until grade ≤ 1, then restart at the same doses. 
8.2.1.7 Pulmonary Toxicities 
For ≥ grade 3 cough, dyspnea, hypoxia, pneumonitis, or pulmonary infiltrates, 
delay oxaliplatin until interstitial lung disease is ruled out. Continue 5FU/leucovorin. 
Discontinue all protocol therapy if interstitial lung disease is confirmed. 
8.2.1.8 Thrombotic Microangiopathy 
For ≥ grade 3 hemolytic uremic syndrome (HUS), discontinue oxaliplatin.  
8.2.1.9 Cardiovascular Toxicities 
For grade 3 or 4 myocardial infarction, discontinue mFOLFOX6. 
For grade 2 ischemia cerebrovascular, discontinue mFOLFOX6. 
8.2.2 
Dose Modifications for Atezolizumab 
Administration of atezolizumab will be performed in a setting with emergency medical 
facilities and staff who are trained to monitor for and respond to medical emergencies. 
Premedication is not permitted for the first dose of atezolizumab. Premedication with 
antihistamines or antipyretics/analgesics (e.g., acetaminophen) may be administered for 
subsequent infusions at the discretion of the treating physician. The management of 
Infusion Related Reactions will be according to severity as follows: 
• 
In the event that a patient experiences a Grade 1 Infusion Related Reaction 
during Cycle 1, the infusion rate should be reduced to half the rate being given 
at the time of event onset. Once the event has resolved, the investigator should 
wait for 30 minutes while delivering the infusion at the reduced rate. If 
tolerated, the infusion rate may then be increased to the original rate. 
• 
In the event that a patient experiences a Grade 2 Infusion Related Reaction, or 
flushing, fever, or throat pain, the infusion should be immediately interrupted 
and the patient should receive aggressive symptomatic treatment. The infusion 
should be restarted only after the symptoms have adequately resolved to 
baseline grade. The infusion rate at restart should be half of the infusion rate 
that was in progress at the time of the onset of the Infusion Related Reaction. 
For subsequent infusions, administer oral premedication with antihistamine 
and anti-pyretic and monitor closely for Infusion Related Reactions. 
• 
For Grade 3 or 4 Infusion Related Reactions, the infusion should be stopped 
immediately, and aggressive resuscitation and supportive measures should be 
initiated (e.g., oral or IV antihistamine, anti-pyretic, glucocorticoids, 
epinephrine, bronchodilators, oxygen). Atezolizumab should be permanently 
discontinued. Resumption of atezolizumab may be considered in patients who 
are deriving benefit and have fully recovered from the immune-related event; 
retreatment requires consultation with, and consent of, the trial Principal 
Investigator (PI). 
General AE Management and Dose Modification Guidelines 
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There will be no dose reduction for atezolizumab in this study.  
Patients may temporarily suspend study treatment for up to 84 days (12 weeks) beyond 
the scheduled date of delayed infusion if study drug-related toxicity requiring dose 
suspension is experienced. If atezolizumab is held because of AEs for 84 days beyond 
the scheduled date of infusion, the patient will be discontinued from atezolizumab and 
will be followed for safety and efficacy as specified in this protocol. If the AE resolves 
within 84 days and the patient is receiving corticosteroid therapy for the event, 
atezolizumab may be held for longer than 84 days (up to 4 weeks) in order to allow 
tapering of the steroid dose to ≤10 mg oral prednisone or equivalent. 
Dose interruptions for reasons other than toxicity, such as surgical procedures, may be 
allowed. The acceptable length of interruption will be at the discretion of the study PI 
in consultation with CTEP. 
The primary approach to grade 1 to 2 irAEs is supportive and symptomatic care with 
continued treatment with atezolizumab; for higher-grade irAEs, atezolizumab should be 
withheld and oral and/or parenteral steroids administered. Recurrent grade 2 irAEs may 
also mandate withholding atezolizumab or the use of steroids. Assessment of the benefit 
risk balance should be made by the investigator, with consideration of the totality of 
information as it pertains to the nature of the toxicity and the degree of clinical benefit 
a given patient may be experiencing prior to further administration of atezolizumab. 
Atezolizumab should be permanently discontinued in patients with life threatening 
irAEs. 
Management of Specific AEs 
Management of certain AEs of concern, including immune-related pneumonitis, 
hepatitis, colitis, endocrinopathies, pancreatitis, neuropathies, meningoencephalitis, and 
potential ocular toxicities are presented in the Atezolizumab Investigator’s Brochure. 
See the Agent Administration Guidelines including the “Administration of First and 
Subsequent Atezolizumab Infusions” table for guidelines for the management of 
Infusion Related Reactions and Anaphylaxis. 
Atezolizumab has been associated with risks such as the following: IRRs and immune-
related hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, hypothyroidism, 
hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré syndrome, 
myasthenic 
syndrome 
or 
myasthenia 
gravis, 
facial 
paresis, 
myelitis, 
meningoencephalitis, myocarditis, pericardial disorders, nephritis, myositis, and severe 
cutaneous adverse reactions. Immune-mediated reactions may involve any organ 
system and may lead to hemophagocytic lymphohistiocytosis and macrophage 
activation syndrome. Neutropenia and lymphopenia associated with chemotherapy may 
increase the risk for developing an infection in patients receiving atezolizumab in 
combination with chemotherapy. 
Pulmonary events 
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been 
associated with the administration of atezolizumab. Patients will be assessed for 
pulmonary signs and symptoms throughout the study and will have computed 
tomography (CT) scans of the chest performed at every tumor assessment. 
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All pulmonary events should be thoroughly evaluated for other commonly reported 
etiologies such as pneumonia or other infection, lymphangitic carcinomatosis, 
pulmonary embolism, heart failure, chronic obstructive pulmonary disease, or 
pulmonary hypertension. Management guidelines for pulmonary events are provided in 
the table below. 
Event 
Management 
Pulmonary event, 
Grade 1  
● Continue atezolizumab and monitor closely. 
● Re-evaluate on serial imaging. 
● Consider patient referral to pulmonary specialist. 
Pulmonary event, 
Grade 2 
● Withhold atezolizumab for up to 12 weeks after event onset. a 
● Refer patient to pulmonary and infectious disease specialists and consider 
bronchoscopy or BAL. 
● Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day oral 
prednisone. 
● If event resolves to Grade 1 or better, resume atezolizumab. b 
● If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab. 
● For recurrent events, treat as a Grade 3 or 4 event. 
Pulmonary event, 
Grade 3 or 4 
● Permanently discontinue atezolizumab.  
● Bronchoscopy or BAL is recommended. 
● Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day oral 
prednisone. 
● If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
● If event resolves to Grade 1 or better, taper corticosteroids over ≥1 month. 
BAL   bronchoscopic alveolar lavage 
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to the equivalent of ≤10 mg/day oral prednisone. The acceptable 
length of the extended period of time must be determined by the investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over ≥1 month to the equivalent of ≤10 mg/day oral 
prednisone before atezolizumab can be resumed. 
Hepatic events 
Immune-mediated hepatitis has been associated with the administration of 
atezolizumab. Eligible patients must have adequate liver function, as manifested by 
measurements of total bilirubin and hepatic transaminases, and liver function will be 
monitored throughout study treatment. Management guidelines for hepatic events are 
provided in the table below. 
Patients with right upper-quadrant abdominal pain and/or unexplained nausea or 
vomiting should have liver function tests (LFTs) performed immediately and reviewed 
before administration of the next dose of study drug. 
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For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or 
neoplastic etiologies should be considered and addressed, as appropriate. 
Event 
Management 
Hepatic event, Grade 1 • Continue atezolizumab. 
• Monitor LFTs until values resolve to within normal limits or to baseline values.  
Hepatic event, Grade 2 
All events: 
• Monitor LFTs more frequently until return to baseline values.  
Events of >5 days’ duration: 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day oral prednisone. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab. 
Hepatic event, Grade 3 
or 4 
• Permanently discontinue atezolizumab. 
• Consider patient referral to gastrointestinal specialist for evaluation and liver biopsy 
to establish etiology of hepatic injury.  
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day oral prednisone. 
• If event does not improve within 48 hours after initiating corticosteroids, consider 
adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over ≥1 month. 
LFT  =  liver function test. 
a Atezolizumab may be withheld for a longer period of time (i.e., >12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to the equivalent of ≤10 mg/day oral prednisone.  The acceptable 
length of the extended period of time must be determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥1 month to the equivalent of ≤10 mg/day oral 
prednisone before atezolizumab can be resumed. 
Gastrointestinal events 
Immune-mediated colitis has been associated with the administration of atezolizumab. 
Management guidelines for diarrhea or colitis are provided in the table below.  
All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies. For events of significant duration or magnitude or associated with signs of 
systemic inflammation or acute-phase reactants (e.g., increased C-reactive protein, 
platelet count, or bandemia): Perform sigmoidoscopy (or colonoscopy, if appropriate) 
with colonic biopsy, with three to five specimens for standard paraffin block to check 
for inflammation and lymphocytic infiltrates to confirm colitis diagnosis. 
Event 
Management 
Diarrhea or colitis, 
Grade 1 
• Continue atezolizumab. 
• Initiate symptomatic treatment. 
• Endoscopy is recommended if symptoms persist for >7 days. 
• Monitor closely. 
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Event 
Management 
Diarrhea or colitis, 
Grade 2 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Initiate symptomatic treatment. 
• Patient referral to GI specialist is recommended. 
• For recurrent events or events that persist  >5 days, initiate treatment with 
corticosteroids equivalent to 1−2 mg/kg/day oral prednisone.  
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab. 
Diarrhea or colitis, 
Grade 3 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to GI specialist for evaluation and confirmatory biopsy. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day IV 
methylprednisolone and convert to 1−2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab. 
Diarrhea or colitis, 
Grade 4 
• Permanently discontinue atezolizumab. 
• Refer patient to GI specialist for evaluation and confirmation biopsy. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day IV 
methylprednisolone and convert to 1−2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
• If event does not improve within 48 hours after initiating corticosteroids, consider 
adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over ≥1 month. 
GI = gastrointestinal. 
a Atezolizumab may be withheld for a longer period of time (i.e., >12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to the equivalent of ≤10 mg/day oral prednisone.  The acceptable 
length of the extended period of time must be determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥1 month to the equivalent of ≤10 mg/day oral 
prednisone before atezolizumab can be resumed.  
Endocrine disorders 
Thyroid disorders, adrenal insufficiency, diabetes mellitus, and pituitary disorders have 
been associated with the administration of atezolizumab. Management guidelines for 
endocrine events are provided in the table below. 
Patients experiencing one or more unexplained AEs possibly indicative of endocrine 
dysfunction (including headache, fatigue, myalgias, impotence, mental status changes, 
and constipation) should be investigated for the presence of thyroid, pituitary, or adrenal 
endocrinopathies. The patient should be referred to an endocrinologist if an 
endocrinopathy is suspected. Thyroid stimulating hormone (TSH) and free T3 and T4 
levels should be measured to determine whether thyroid abnormalities are present.  
Pituitary hormone levels and function tests [e.g., TSH, growth hormone, luteinizing 
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hormone, follicle-stimulating hormone, testosterone, prolactin, adrenocorticotropic 
hormone (ACTH) levels, and ACTH stimulation test] and MRI of the brain (with 
detailed pituitary sections) may help to differentiate primary pituitary insufficiency 
from primary adrenal insufficiency. The table below describes dose management 
guidelines for hyperthyroidism, hypothyroidism, symptomatic adrenal insufficiency, 
and hyperglycemia. 
Event 
Management 
Asymptomatic 
hypothyroidism 
• Continue atezolizumab. 
• Initiate treatment with thyroid replacement hormone. 
• Monitor TSH weekly. 
Symptomatic hypothyroidism 
• Withhold atezolizumab. 
• Initiate treatment with thyroid replacement hormone. 
• Monitor TSH weekly. 
• Consider patient referral to endocrinologist. 
• Resume atezolizumab when symptoms are controlled and thyroid function is 
improving. 
Asymptomatic 
hyperthyroidism 
TSH ≥0.1 mU/L and <0.5 mU/L: 
• Continue atezolizumab. 
• Monitor TSH every 4 weeks. 
TSH <0.1 mU/L: 
• Follow guidelines for symptomatic hyperthyroidism. 
Symptomatic 
hyperthyroidism 
• Withhold atezolizumab. 
• Initiate treatment with anti-thyroid drug such as methimazole or carbimazole 
as needed. 
• Consider patient referral to endocrinologist. 
• Resume atezolizumab when symptoms are controlled and thyroid function is 
improving. 
• Permanently discontinue atezolizumab.  
Symptomatic adrenal 
insufficiency, Grade 2−4  
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to endocrinologist. 
• Perform appropriate imaging. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day IV 
methylprednisolone and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• If event resolves to Grade 1 or better and patient is stable on replacement 
therapy, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better or patient is not stable on 
replacement therapy while withholding atezolizumab, permanently 
discontinue atezolizumab.  
Hyperglycemia, Grade 1 or 2  
• Continue atezolizumab. 
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Event 
Management 
• Investigate for diabetes. If patient has Type 1 diabetes, treat as a Grade 3 
event. If patient does not have Type 1 diabetes, treat as per institutional 
guidelines. 
• Monitor for glucose control. 
Hyperglycemia, Grade 3 or 4 
• Withhold atezolizumab. 
• Initiate treatment with insulin. 
• Monitor for glucose control. 
• Consider referral to endocrinologist, particularly if patient is deemed to have 
atezolizumab-induced diabetes; if so, obtain C-peptide level paired with 
glucose, autoantibody levels (e.g. GAD65, islet cell autoantibodies), and 
hemoglobin A1C level. 
• If patient is found to have diabetic ketoacidosis or hyperglycemic 
hyperosmolar syndrome, treat as per institutional guidelines with appropriate 
management and laboratory values (e.g. anion gap, ketones, blood pH, etc.) 
reported.  
• Resume atezolizumab when symptoms resolve and glucose levels are stable. 
Hypophysitis (pan-
hypopituitarism), Grade 2 or 
3  
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to endocrinologist. 
• Perform brain MRI (pituitary protocol). 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day IV 
methylprednisolone and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• Initiate hormone replacement if clinically indicated. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab.  
• For recurrent hypophysitis, treat as a Grade 4 event. 
Hypophysitis (pan-
hypopituitarism), Grade 4  
• Permanently discontinue atezolizumab.  
• Refer patient to endocrinologist. 
• Perform brain MRI (pituitary protocol). 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day IV 
methylprednisolone and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• Initiate hormone replacement if clinically indicated. 
MRI = magnetic resonance imaging; TSH = thyroid-stimulating hormone. 
a Atezolizumab may be withheld for a longer period of time (i.e., >12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to the equivalent of ≤10 mg/day oral prednisone.  The acceptable 
length of the extended period of time must be determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥1 month to the equivalent of ≤10 mg/day oral 
prednisone before atezolizumab can be resumed.  
Ocular events 
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An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events). 
Management guidelines for ocular events are provided in the table below. 
Event 
Management 
Ocular event, Grade 
1  
• Continue atezolizumab. 
• Patient referral to ophthalmologist is strongly recommended. 
• Initiate treatment with topical corticosteroid eye drops and topical immunosuppressive 
therapy. 
• If symptoms persist, treat as a Grade 2 event. 
Ocular event, Grade 
2 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Patient referral to ophthalmologist is strongly recommended. 
• Initiate treatment with topical corticosteroid eye drops and topical immunosuppressive 
therapy. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab. 
Ocular event, Grade 
3 or 4 
• Permanently discontinue atezolizumab. 
• Refer patient to ophthalmologist. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day oral prednisone.  
• If event resolves to Grade 1 or better, taper corticosteroids over ≥1 month. 
a Atezolizumab may be withheld for a longer period of time (i.e., >12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to the equivalent of ≤10 mg/day oral prednisone.  The acceptable 
length of the extended period of time must be determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥1 month to the equivalent of ≤10 mg/day oral 
prednisone before atezolizumab can be resumed.  
Immune-mediated Cardiac Events 
Immune-mediated myocarditis and pericarditis have been associated with the 
administration of atezolizumab. Management guidelines for cardiac events are provided 
in the table below. 
Immune-mediated Myocarditis 
Immune-mediated myocarditis has been associated with the administration of 
atezolizumab. Immune-mediated myocarditis should be suspected in any patient 
presenting with signs or symptoms suggestive of myocarditis, including, but not limited 
to, laboratory (e.g., B-NP [B-Natriuretic Peptide]) or cardiac imaging abnormalities, 
dyspnea, chest pain, palpitations, fatigue, decreased exercise tolerance, or syncope. 
Myocarditis may also be a clinical manifestation of myositis or associated with 
pericarditis (see section on pericardial disorders below) and should be managed 
accordingly. 
Immune-mediated myocarditis needs to be distinguished from myocarditis resulting 
from infection (commonly viral, e.g., in a patient who reports a recent history of 
gastrointestinal illness), ischemic events, underlying arrhythmias, exacerbation of 
preexisting cardiac conditions, or progression of malignancy. All patients with possible 
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myocarditis should be urgently evaluated by performing cardiac enzyme assessment, an 
electrocardiogram (ECG), a chest X-ray, an echocardiogram, and a cardiac MRI as 
appropriate per institutional guidelines. A cardiologist should be consulted. An 
endomyocardial biopsy may be considered to enable a definitive diagnosis and 
appropriate treatment, if clinically indicated. 
Patients with signs and symptoms of myocarditis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in the table below. 
Event 
Management 
Immune-related 
myocarditis, Grade 2 
• Withhold atezolizumab for up to 12 weeks after event onset a. 
• Refer patient to cardiologist. 
• Initiate treatment as per institutional guidelines and consider antiarrhythmic 
drugs, temporary pacemaker, ECMO, or VAD as appropriate. 
• Consider treatment with corticosteroids equivalent to 1−2 mg/kg/day IV 
methylprednisolone and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• If symptoms resolve to below Grade 2 (i.e. patient is completely 
asymptomatic), resume atezolizumab. b 
• If symptoms do not resolve to below Grade 2 while withholding atezolizumab, 
permanently discontinue atezolizumab. 
Immune-related 
myocarditis, Grade 3-4 
• Permanently discontinue atezolizumab. 
• Refer patient to cardiologist. 
• Initiate treatment as per institutional guidelines and consider antiarrhythmic 
drugs, temporary pacemaker, ECMO, or VAD as appropriate. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day IV 
methylprednisolone and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
• If symptoms resolve to below Grade 2, taper corticosteroids over ≥1 month. 
ECMO = extracorporeal membrane oxygenation; VAD = ventricular assist device. 
a Atezolizumab may be withheld for a longer period of time (i.e., >12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to the equivalent of ≤10 mg/day oral prednisone.  The acceptable 
length of the extended period of time must be documented by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥1 month to the equivalent of ≤10 mg/day oral 
prednisone before atezolizumab can be resumed. 
 
Immune-mediated Pericardial Disorders 
Immune-mediated pericarditis should be suspected in any patient presenting with chest 
pain and may be associated with immune-mediated myocarditis (see section on 
myocarditis above). 
Immune-mediated pericardial effusion and cardiac tamponade should be suspected in 
any patient presenting with chest pain associated with dyspnea or hemodynamic 
instability. 
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Patients should be evaluated for other causes of pericardial disorders such as infection 
(commonly viral), cancer related (metastatic disease or chest radiotherapy), cardiac 
injury related (post myocardial infarction or iatrogenic), and autoimmune disorders, and 
should be managed accordingly. 
All patients with suspected pericardial disorders should be urgently evaluated by 
performing an ECG, chest X-ray, transthoracic echocardiogram, and cardiac MRI as 
appropriate per institutional guidelines. A cardiologist should be consulted. 
Pericardiocentesis should be considered for diagnostic or therapeutic purposes, if 
clinically indicated. 
Patients with signs and symptoms of pericarditis, pericardial effusion, or cardiac 
tamponade, in the absence of an identified alternate etiology, should be treated 
according to the guidelines in the table below. Withhold treatment with atezolizumab 
for Grade 1 pericarditis and conduct a detailed cardiac evaluation to determine the 
etiology and manage accordingly. 
Event 
Management 
Immune-mediated 
myocarditis, Grade 2−4 
 
Immune-mediated 
pericardial disorders, 
Grade 2−4 
• 
Permanently discontinue atezolizumab.  
• 
Refer patient to cardiologist. 
• 
Initiate treatment as per institutional guidelines and consider antiarrhythmic 
drugs, temporary pacemaker, ECMO, VAD, or pericardiocentesis as 
appropriate. 
• 
Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day IV 
methylprednisolone and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• 
If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
• 
If event resolves to Grade 1 or better, taper corticosteroids over ≥1 month. 
ECMO = extracorporeal membrane oxygenation; VAD = ventricular assist device. 
Infusion-Related Reactions and Cytokine-Release Syndrome 
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  
However, patients who experience an infusion-related reaction (IRR) or cytokine-
release syndrome (CRS) with atezolizumab may receive premedication with 
antihistamines, antipyretics, and/or analgesics (e.g., acetaminophen) for subsequent 
infusions. Metamizole (dipyrone) is prohibited in treating atezolizumab-associated 
IRRs because of its potential for causing agranulocytosis. 
IRRs are known to occur with the administration of monoclonal antibodies and have 
been reported with atezolizumab. These reactions, which are thought to be due to release 
of cytokines and/or other chemical mediators, occur within 24 hours of atezolizumab 
administration and are generally mild to moderate in severity. 
CRS is defined as a supraphysiologic response following administration of any immune 
therapy that results in activation or engagement of endogenous or infused T cells and/or 
other immune effector cells. Symptoms can be progressive, always include fever at the 
onset, and may include hypotension, capillary leak (hypoxia), and end-organ 
dysfunction (Lee et al., 2019). CRS has been well documented with chimeric antigen 
receptor T-cell therapies and bispecific T-cell engager antibody therapies but has also 
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been reported with immunotherapies that target PD-1 or PD-L1 (Rotz et al., 2017; 
Adashek and Feldman 2019) including atezolizumab. 
There may be significant overlap in signs and symptoms of IRRs and CRS, and in 
recognition of the challenges in clinically distinguishing between the two, consolidated 
guidelines for medical management of IRRs and CRS are provided in the table below. 
Management Guidelines for Infusion-Related Reactions and Cytokine-Release 
Syndrome 
Event 
Management 
Grade 1a  
Feverb with or 
without 
constitutional 
symptoms 
● Immediately interrupt infusion. 
● Upon symptom resolution, wait 30 minutes and then restart infusion at half the rate 
being given at the time of event onset. 
● If the infusion is tolerated at the reduced rate for 30 minutes, the infusion rate may be 
increased to the original rate. 
● If symptoms recur, discontinue infusion of this dose. 
● Administer symptomatic treatment,c including maintenance of IV fluids for hydration. 
● In case of rapid decline or prolonged CRS (> 2 days) or in patients with significant 
symptoms and/or comorbidities, consider managing as per Grade 2. 
● For subsequent infusions, consider administration of oral premedication with 
antihistamines, anti-pyretics, and/or analgesics, and monitor closely for IRRs and/or 
CRS. 
Grade 2a 
Feverb with 
hypotension not 
requiring 
vasopressors 
and/or 
Hypoxia requiring 
low-flow oxygend 
by nasal cannula or 
blow-by 
● Immediately interrupt atezolizumab infusion. 
● Upon symptom resolution, wait for 30 minutes and then restart infusion at half the rate 
being given at the time of event onset. 
● If symptoms recur, discontinue infusion of this dose. 
● Administer symptomatic treatment.c 
● For hypotension, administer IV fluid bolus as needed. 
● Monitor cardiopulmonary and other organ function closely (in the ICU, if appropriate). 
Administer IV fluids as clinically indicated and manage constitutional symptoms and 
organ toxicities as per institutional practice. 
● Rule out other inflammatory conditions that can mimic CRS (e.g., sepsis).  If no 
improvement within 24 hours, initiate workup and assess for signs and symptoms of 
HLH or MAS. 
● Consider IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or dexamethasone 
10 mg every 6 hours). 
● Consider anti-cytokine therapy.e 
● Consider hospitalization until complete resolution of symptoms. If no improvement 
within 24 hours, manage as per Grade 3, that is, hospitalize patient (monitoring in the 
ICU is recommended), permanently discontinue atezolizumab. 
● If symptoms resolve to Grade 1 or better for 3 consecutive days, the next dose of 
atezolizumab may be administered. For subsequent infusions, consider administration of 
oral premedication with antihistamines, anti-pyretics, and/or analgesics and monitor 
closely for IRRs and/or CRS. 
● If symptoms do not resolve to Grade 1 or better for 3 consecutive days, contact the 
Principal Investigator. 
Grade 3a 
Feverb with 
● Permanently discontinue atezolizumab. 
● Administer symptomatic treatment.c 
● For hypotension, administer IV fluid bolus and vasopressor as needed. 
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hypotension 
requiring a 
vasopressor (with 
or without 
vasopressin)  
and/or 
Hypoxia requiring 
high-flow oxygend 
by nasal cannula, 
face mask, non-
rebreather mask, or 
venturi mask 
● Monitor cardiopulmonary and other organ function closely; monitoring in the ICU is 
recommended.  Administer IV fluids as clinically indicated and manage constitutional 
symptoms and organ toxicities as per institutional practice. 
● Rule out other inflammatory conditions that can mimic CRS (e.g., sepsis).  If no 
improvement within 24 hours, initiate workup and assess for signs and symptoms of 
HLH or MAS. 
● Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or dexamethasone 
10 mg every 6 hours). 
● Consider anti-cytokine therapy.e 
● Hospitalize patient until complete resolution of symptoms.  If no improvement within 
24 hours, manage as per Grade 4, that is, admit patient to ICU and initiate 
hemodynamic monitoring, mechanical ventilation, and/or IV fluids and vasopressors as 
needed; for patients who are refractory to anti-cytokine therapy, experimental 
treatments may be considered at the discretion of the investigator. 
Grade 4a 
Feverb with 
hypotension 
requiring multiple 
vasopressors 
(excluding 
vasopressin) and/or 
Hypoxia requiring 
oxygen by positive 
pressure (e.g., 
CPAP, BiPAP, 
intubation and 
mechanical 
ventilation) 
● Permanently discontinue atezolizumab. 
● Administer symptomatic treatment.c 
● Admit patient to ICU and initiate hemodynamic monitoring, mechanical ventilation, 
and/or IV fluids and vasopressors as needed.  Monitor other organ function closely.  
Manage constitutional symptoms and organ toxicities as per institutional practice. 
● Rule out other inflammatory conditions that can mimic CRS (e.g., sepsis).  If no 
improvement within 24 hours, initiate workup and assess for signs and symptoms of 
HLH or MAS. 
● Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or dexamethasone 
10 mg every 6 hours). 
● Consider anti-cytokine therapy.e For patients who are refractory to anti-cytokine 
therapy, experimental treatmentsf may be considered at the discretion of the 
investigator. 
●  Hospitalize patient until complete resolution of symptoms. 
ASTCT= American Society for Transplantation and Cellular Therapy; BiPAP= bi-level positive airway 
pressure; CAR= chimeric antigen receptor; CPAP= continuous positive airway pressure; CRS= cytokine-
release syndrome; HLH= hemophagocytic lymphohistiocytosis; IRR = infusion-related reaction; MAS= 
macrophage activation syndrome. 
Note: The management guidelines have been adapted from NCCN guidelines for management of CAR T-cell-
related toxicities (Version 2.2019). 
a. Grading system for management guidelines is based on ASTCT consensus grading for CRS.  NCI CTCAE 
(version as specified in the protocol) should be used when reporting severity of IRRs, CRS, or organ toxicities 
associated with CRS on the Adverse Event eCRF. Organ toxicities associated with CRS should not influence 
overall CRS grading.  
b. Fever is defined as temperature ≥38°C not attributable to any other cause. In patients who develop CRS and 
then receive anti-pyretic, anti-cytokine, or corticosteroid therapy, fever is no longer required when 
subsequently determining event severity (grade).  In this case, the grade is driven by the presence of 
hypotension and/or hypoxia. 
c. Symptomatic treatment may include oral or IV antihistamines, anti-pyretics, analgesics, bronchodilators, 
and/or oxygen.  For bronchospasm, urticaria, or dyspnea, additional treatment may be administered as per 
institutional practice. 
d. Low flow is defined as oxygen delivered at ≤6 L/min, and high flow is defined as oxygen delivered at >6 
L/min. 
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e. There are case reports where anti-cytokine therapy has been used for treatment of CRS with immune 
checkpoint inhibitors (Rotz et al. 2017; Adashek and Feldman 2019), but data are limited, and the role of such 
treatment in the setting of antibody-associated CRS has not been established. 
f. Refer to Riegler et al. for information on experimental treatments for CRS. 
 
Pancreatic events 
Symptoms of abdominal pain associated with elevations of amylase and lipase, 
suggestive of pancreatitis, have been associated with the administration of 
atezolizumab. The differential diagnosis of acute abdominal pain should include 
pancreatitis. Appropriate workup should include an evaluation for ductal obstruction, 
as well as serum amylase and lipase tests. Management guidelines for pancreatic events, 
including pancreatitis, are provided in the table below. 
Event 
Management 
Amylase and/or lipase elevation, 
Grade 2 
Amylase and/or lipase >1.5−2.0 × ULN: 
• Continue atezolizumab. 
• Monitor amylase and lipase weekly. 
• For prolonged elevation (e.g., >3 weeks), consider treatment with 
corticosteroids equivalent to 10 mg/day oral prednisone. 
Asymptomatic with amylase and/or lipase >2.0−5.0 × ULN: 
• Treat as a Grade 3 event. 
Amylase and/or lipase elevation, 
Grade 3 or 4 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to GI specialist. 
• Monitor amylase and lipase every other day. 
• If no improvement, consider treatment with corticosteroids equivalent to 
1−2 mg/kg/day oral prednisone. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. c 
• For recurrent events, permanently discontinue atezolizumab. 
Immune-related pancreatitis, 
Grade 2 or 3 
 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to GI specialist. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day IV 
methylprednisolone and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab.  
• For recurrent events, permanently discontinue atezolizumab. 
Immune-related pancreatitis, 
Grade 4 
• Permanently discontinue atezolizumab. 
• Refer patient to GI specialist. 
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Event 
Management 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day IV 
methylprednisolone and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over ≥1 
month. 
a Atezolizumab may be withheld for a longer period of time (i.e., >12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to the equivalent of ≤10 mg/day oral prednisone.  The acceptable 
length of the extended period of time must be determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥1 month to the equivalent of ≤10 mg/day oral 
prednisone before atezolizumab can be resumed.  
Dermatologic events 
Treatment-emergent rash has been associated with atezolizumab. The majority of cases 
of rash were mild in severity and self-limited, with or without pruritus. A dermatologist 
should evaluate persistent and/or severe rash or pruritus. Although uncommon, cases of 
severe cutaneous adverse reactions such as Stevens-Johnson syndrome and toxic 
epidermal necrolysis have been reported with atezolizumab. A biopsy should be 
considered unless contraindicated. Management guidelines for dermatologic events are 
provided in the table below. 
Event 
Management 
Dermatologic event, 
Grade 1  
● Continue atezolizumab. 
● Consider treatment with topical corticosteroids and/or other symptomatic therapy 
(e.g., antihistamines). 
Dermatologic event, 
Grade 2  
● Continue atezolizumab. 
● Consider patient referral to dermatologist for evaluation and if indicated, biopsy. 
● Initiate treatment with topical corticosteroids. 
● Consider treatment with higher-potency topical corticosteroids if event does not 
improve. 
Dermatologic event, 
Grade 3  
● Withhold atezolizumab for up to 12 weeks after event onset. a 
● Refer patient to dermatologist for evaluation and if indicated, biopsy. 
● Initiate treatment with corticosteroids equivalent to 10 mg/day oral prednisone, 
increasing dose to 1-2 mg/kg/day if event does not improve within 48-72 hours. 
● If event resolves to Grade 1 or better, resume atezolizumab. b 
● If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab.  
Dermatologic event, 
Grade 4 
● Permanently discontinue atezolizumab.  
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Event 
Management 
Stevens-Johnson 
syndrome or toxic 
epidermal necrolysis 
(any grade) 
Additional guidance for Stevens-Johnson syndrome or toxic epidermal necrolysis: 
• Withhold atezolizumab for suspected Stevens-Johnson syndrome or toxic epidermal 
necrolysis. 
• Confirm diagnosis by referring patient to a specialist (dermatologist, 
ophthalmologist, or urologist as relevant) for evaluation and, if indicated, biopsy. 
• Follow the applicable treatment and management guidelines above. 
● If Stevens-Johnson syndrome or toxic epidermal necrolysis is confirmed, 
permanently discontinue atezolizumab. 
a Atezolizumab may be withheld for a longer period of time (i.e., >12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to the equivalent of ≤10 mg/day oral prednisone. The acceptable 
length of the extended period of time must be determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥1 month to the equivalent of ≤10 mg/day oral 
prednisone before atezolizumab can be resumed. 
Neurologic disorders 
Myasthenia gravis and Guillain-Barré syndrome have been observed with single agent 
atezolizumab. Patients may present with signs and symptoms of sensory and/or motor 
neuropathy. Diagnostic work-up is essential for an accurate characterization to 
differentiate between alternative etiologies. Management guidelines for neurologic 
disorders, and specific guidelines for myelitis, are provided in the table below. 
Event 
Management 
Immune-mediated 
neuropathy, Grade 1 
• 
Continue atezolizumab. 
• 
Investigate etiology. 
• 
Any cranial nerve disorder (including facial paresis) should be managed as 
per Grade 2 management guidelines below. 
Immune-mediated 
neuropathy, including 
facial paresis, Grade 2 
• 
Withhold atezolizumab for up to 12 weeks after event onset. a 
• 
Investigate etiology and refer patient to neurologist. 
• 
Initiate treatment as per institutional guidelines. 
• 
For general immune-mediated neuropathy: 
o 
If event resolves to Grade 1 or better, resume atezolizumab. b 
o 
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. c 
• 
For facial paresis: 
o 
If event resolves fully, resume atezolizumab. b 
o 
If event does not resolve fully while withholding atezolizumab, 
permanently discontinue atezolizumab. c 
Immune-mediated 
neuropathy, including 
facial paresis, Grade 3 or 
4 
• 
Permanently discontinue atezolizumab. c  
• 
Refer patient to neurologist. 
• 
Initiate treatment as per institutional guidelines. 
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Event 
Management 
Myasthenia gravis and 
Guillain-Barré syndrome 
(any grade) 
• 
Permanently discontinue atezolizumab. c 
• 
Refer patient to neurologist. 
• 
Initiate treatment as per institutional guidelines. 
• 
Consider initiation of corticosteroids equivalent to 1−2 mg/kg/day oral or IV 
prednisone. 
a Atezolizumab may be withheld for a longer period of time (i.e., >12 weeks after event onset) to allow 
for corticosteroids (if initiated) to be reduced to the equivalent of ≤10 mg/day oral prednisone.  The 
acceptable length of the extended period of time must be based on an assessment of benefit−risk by the 
investigator and in alignment with the protocol requirements for the duration of treatment and documented by 
the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥1 month to the equivalent of ≤10 mg/day oral 
prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered 
from the immune-mediated event.  The decision to re−challenge patients with atezolizumab should be based 
on investigator's assessment of benefit−risk and documented by the investigator (or an appropriate delegate). 
  
Immune-Mediated Meningoencephalitis 
Immune-mediated meningoencephalitis is an identified risk associated with the 
administration of atezolizumab. immune-mediated meningoencephalitis should be 
suspected in any patient presenting with signs or symptoms suggestive of meningitis or 
encephalitis, including, but not limited to, headache, neck pain, confusion, seizure, 
motor or sensory dysfunction, and altered or depressed level of consciousness. 
Encephalopathy from metabolic or electrolyte imbalances needs to be distinguished 
from potential meningoencephalitis resulting from infection (bacterial, viral, or fungal) 
or progression of malignancy, or secondary to a paraneoplastic process. 
All patients being considered for meningoencephalitis should be urgently evaluated 
with a CT scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, 
or edema. If deemed safe by the treating physician, a lumbar puncture should be 
performed, and a neurologist should be consulted. 
Patients with signs and symptoms of meningoencephalitis, in the absence of an 
identified alternate etiology, should be treated according to the guidelines in the table 
below. 
Event 
Management 
Immune-related 
meningoencephalitis, all 
grades 
• Permanently discontinue atezolizumab. 
• Refer patient to neurologist. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day IV 
methylprednisolone and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over ≥1 month. 
Renal events 
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Immune-mediated nephritis has been associated with the administration of 
atezolizumab. Eligible patients must have adequate renal function. Renal function, 
including serum creatinine, should be monitored throughout study treatment.  Patients 
with abnormal renal function should be evaluated and treated for other more common 
etiologies (including prerenal and postrenal causes, and concomitant medications such 
as non-steroidal anti-inflammatory drugs). Refer the patient to a renal specialist if 
clinically indicated. A renal biopsy may be required to enable a definitive diagnosis and 
appropriate treatment. 
Patients with signs and symptoms of nephritis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in the table below. 
Event 
Management 
Renal event, Grade 1 
• Continue atezolizumab. 
• Monitor kidney function, including creatinine, closely until values resolve to within 
normal limits or to baseline values.  
Renal event, Grade 2 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to renal specialist. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day oral prednisone. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab. 
Renal event, Grade 3 
or 4 
• Permanently discontinue atezolizumab. 
• Refer patient to renal specialist and consider renal biopsy. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day oral prednisone. 
• If event does not improve within 48 hours after initiating corticosteroids, consider 
adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over ≥1 month. 
a Atezolizumab may be withheld for a longer period of time (i.e., >12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to the equivalent of ≤10 mg/day oral prednisone. The acceptable 
length of the extended period of time must be determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥1 month to the equivalent of ≤10 mg/day oral 
prednisone before atezolizumab can be resumed. 
Immune-Mediated Myositis 
Immune-mediated myositis has been associated with the administration of 
atezolizumab. Myositis or inflammatory myopathies are a group of disorders sharing 
the common feature of inflammatory muscle injury; dermatomyositis and polymyositis 
are among the most common disorders. Initial diagnosis is based on clinical (muscle 
weakness, muscle pain, skin rash in dermatomyositis), biochemical (serum creatine 
kinase increase), and imaging (electromyography/MRI) features, and is confirmed with 
a muscle biopsy. 
Patients with signs and symptoms of myositis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in table below. 
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Event 
Management 
Immune-mediated 
myelitis, Grade 1 
• 
Continue atezolizumab unless symptoms worsen or do not improve. 
• 
Investigate etiology and refer patient to a neurologist.  
Immune-mediated 
myelitis, Grade 2 
• 
Permanently discontinue atezolizumab.  
• 
Investigate etiology and refer patient to a neurologist. 
• 
Rule out infection. 
• 
Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day oral 
prednisone. 
Immune-mediated 
myelitis, Grade 3 or 4 
• 
Permanently discontinue atezolizumab. 
• 
Refer patient to a neurologist. 
• 
Initiate treatment as per institutional guidelines. 
 
Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome 
Immune-mediated reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome 
(MAS). 
Patients with suspected HLH should be diagnosed according to published criteria by 
McClain and Eckstein (2017). A patient should be classified as having HLH if five of 
the following eight criteria are met: 
• 
Fever ≥ 38.5°C 
• 
Splenomegaly 
• 
Peripheral blood cytopenia consisting of at least two of the following: 
– 
Hemoglobin < 90 g/L (9 g/dL) (<100 g/L [10 g/dL] for infants < 4 weeks old) 
– 
Platelet count < 100 × 109/L (100,000/mcL) 
– 
ANC < 1.0 × 109/L (1000/mcL) 
• 
Fasting triglycerides >2.992 mmol/L (265 mg/dL) and/or fibrinogen <1.5 g/L 
(150 mg/dL) 
• 
Hemophagocytosis in bone marrow, spleen, lymph node, or liver 
• 
Low or absent natural killer cell activity 
• 
Ferritin >500 mg/L (500 ng/mL) 
• 
Soluble interleukin 2 (IL-2) receptor (soluble CD25) elevated ≥ 2 standard 
deviations above age-adjusted laboratory-specific norms 
Patients with suspected MAS should be diagnosed according to published criteria for 
systemic juvenile idiopathic arthritis by Ravelli et al. (2016). A febrile patient should 
be classified as having MAS if the following criteria are met: 
• 
Ferritin >684 mg/L (684 ng/mL) 
• 
At least two of the following: 
– 
Platelet count ≤ 181 × 109/L (181,000/mcL) 
– 
AST ≥48 U/L 
– 
Triglycerides >1.761 mmol/L (156 mg/dL) 
– 
Fibrinogen ≤3.6 g/L (360 mg/dL) 
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Patients with suspected HLH or MAS should be treated according to the guidelines in 
below. 
Event 
Management 
Suspected HLH or 
MAS 
● Permanently discontinue atezolizumab and contact Medical Monitor. 
● Consider patient referral to hematologist. 
● Initiate supportive care, including intensive care monitoring if indicated per 
institutional guidelines. 
● Consider initiation of IV corticosteroids and/or an immunosuppressive agent. 
● If event does not improve within 48 hours after initiating corticosteroids, consider 
adding an immunosuppressive agent. 
● If event resolves to Grade 1 or better, taper corticosteroids over ≥1 month. 
HLH=hemophagocytic lymphohistiocytosis; MAS=macrophage activation syndrome. 
9.0 
ADVERSE EVENTS 
The prompt reporting of adverse events is the responsibility of each investigator engaged in clinical 
research, as required by Federal Regulations. Beginning April 1, 2018, adverse events must be 
described and graded using the terminology and grading categories defined in the NCI’s Common 
Terminology Criteria for Adverse Events (CTCAE), Version 5.0. The CTCAE is available at 
ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
Attribution 
to 
protocol 
treatment for each adverse event must be determined by the investigator and reported on the required 
forms. Please refer the NCI Guidelines: Adverse Event Reporting Requirements for further details 
on AE reporting procedures.  
To complement CTCAE reporting, patients aged ≥ 18 years will self-report their side effects using 
the PRO-CTCAE. The specific PRO-CTCAE items for this protocol can be found in Appendix I.  
They can also be found at: http://healthcaredelivery.cancer.gov/pro-ctcae/instrument.html. 
NOTE: PRO-CTCAE data should not be used for determining attribution, dose modifications, or 
reporting of serious adverse events. 
9.1 
Routine Adverse Event Reporting  
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 according to the Study Calendar in Section 5.0. For this trial, the Form “Adverse Events” 
is used for routine AE reporting in Rave. 
9.1.1 
Rave-CTEP-AERS integration 
The Rave Cancer Therapy Evaluation Program Adverse Event Reporting System 
(CTEP-AERS) integration enables evaluation of post-baseline Adverse Events (AE) 
entered in Rave to determine whether they require expedited reporting and facilitates 
entry in CTEP-AERS for those AEs requiring expedited reporting. 
All AEs that occur after start of treatment are collected in Medidata Rave using the 
Adverse Event form, which is available for entry at each treatment course or reporting 
period, and used to collect AEs that start during the period or persist from the previous 
reporting period. AEs that occur 30 days after the last administration of the 
investigational agent/intervention are collected using the Late Adverse Event form. 
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The CRA will enter AEs that occur prior to the start of treatment on a baseline form that 
is not included in the Rave-CTEP-AERS integration. AEs that occur prior to enrollment 
must begin and end on the baseline Adverse Events form and should not be included on 
the standard Adverse Events form that is available at treatment unless there has been an 
increase in grade. 
Prior to sending AEs through the rules evaluation process, site staff should verify the 
following on the Adverse Event form in Rave: 
• 
The reporting period (course/cycle) is correct; and 
• 
AEs are recorded and complete (no missing fields) and the form is query free. 
The CRA reports AEs in Rave at the time the Investigator learns of the event. If the 
CRA modifies an AE, it must be re-submitted for rules evaluation. 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for rules 
evaluation by completing the Expedited Reporting Evaluation form. Both NCI and 
protocol-specific reporting rules evaluate the AEs submitted for expedited reporting. A 
report is initiated in CTEP-AERS using information entered in Medidata Rave for AEs 
that meet reporting requirements. The CRA completes the report by accessing CTEP-
AERS via a direct link on the Medidata Rave Expedited Reporting Evaluation form. 
Contact 
the 
CTSU 
Help 
Desk 
at 
1-888-823-5923 
or 
by 
email 
at 
ctsucontact@westat.com if you have any issues submitting an expedited report in 
CTEP-AERS. 
In the rare occurrence that Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497. Once Internet connectivity is restored, 
the 24-hour notification that was phoned in must be entered immediately into CTEP-
AERS using the direct link from Medidata Rave. 
Additional information about the CTEP-AERS integration is available on the CTSU 
website: 
• 
Study specific documents: Protocols > Documents> Protocol Related 
Documents> Adverse Event Reporting; and   
• 
Additional resources: Resources > CTSU Operations Information> User Guides 
& Help Topics. 
• 
NCI requirements for SAE reporting are available on the CTEP website:  
• 
NCI Guidelines for Investigators: Adverse Event Reporting Requirements is 
available 
at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguid
elines.pdf 
PRO-CTCAE paper booklets ordered from the CTSU website are to be administered by a 
nurse/CRA and completed by the patient at scheduled times according to the Study Calendar in 
Section 5.0 and entered into Rave. 
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CTCAE v5.0 Term 
PRO-CTCAE v1.0 Term 
CTCAE v5.0 System Organ 
Class (SOC) 
Adrenal insufficiency 
 
Endocrine disorders 
Hypophysitis 
 
Endocrine disorders 
Blood and lymphatic system 
disorders – Other, specify 
 
Blood and lymphatic system 
disorders 
Autoimmune disorder3 
 
Immune system disorders 
Cytokine release syndrome4 
 
Immune system disorders 
Immune system disorders – 
Other, specify3, 4 
 
Immune system disorders 
Flu like symptoms4 
 
General disorders and 
administration site conditions 
Uveitis 
 
Eye disorders 
Retinopathy 
 
Eye disorders 
Generalized muscle weakness3 
 
Musculoskeletal and 
connective tissue disorders 
Rhabdomyolysis 
 
Musculoskeletal and 
connective tissue disorders 
Musculoskeletal and connective 
tissue disorder – Other, specify3 
 
Musculoskeletal and 
connective tissue disorders 
Atrial fibrillation 
 
Cardiac disorders 
Myocarditis 
 
Cardiac disorders 
Pericarditis 
 
Cardiac disorders 
Vasculitis 
 
Vascular disorders 
* If the AE is not clinically indicated, then its presence/absence would not need to be solicited for that time point. 
AEs of special interest have been incorporated above, please note the clarifications below: 
1. Cases of potential drug-induced liver injury that include an elevated ALT or AST 
in combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy's Law and based on the following observations: 
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a. Treatment-emergent ALT or AST > 3 x baseline value in combination with 
total bilirubin > 2 x ULN (of which > 35% is direct bilirubin) 
b. Treatment-emergent ALT or AST > 3 x baseline value in combination with 
clinical jaundice 
2. Suspected transmission of an infectious agent by the study treatment, as defined 
below: 
a. Any organism, virus, or infectious particle (e.g. prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, 
is considered an infectious agent. A transmission of an infectious agent                 
may be suspected from clinical symptoms or laboratory findings that 
indicate an infection in a patient exposed to a medicinal product. This term 
applies only when a contamination of study treatment is suspected. 
3. Neurological Disorders: Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, and meningoencephalitis 
4. Events suggestive of hypersensitivity, infusion-related reactions, cytokine release 
syndrome, 
influenza-like 
illness, 
macrophage 
activation 
syndrome, 
hemophagocytic lymphohistiocytosis 
9.2 
CTCAE Routine Reporting Requirements 
In addition to the solicited adverse events listed in Section 9.1, the following table outlines the 
combinations of time points, grades and attributions of AEs that require routine reporting to the 
Alliance Statistics and Data Center. Questions about routine reporting should be directed to the 
Data Manager. 
NOTE: PRO-CTCAE data should not be used for determining attribution, dose modifications, 
or reporting of serious adverse events. 
Combinations of CTCAE Grade & Attribution Required for Routine AE Data Submission on 
Case Report Forms (CRFs) 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
 
 
a 
a 
a 
Unlikely 
 
 
a 
a 
a 
Possible 
a 
a 
a, b 
a, b 
a, b 
Probable 
a 
a 
a, b 
a, b 
a, b 
Definite 
a 
a 
a, b 
a, b 
a, b 
a) Adverse Events CRF - Applies to AEs occurring between registration and within 30 days 
of the patient’s last treatment date, or as part of the Clinical Follow-Up Phase. 
b) Late Adverse Events CRF - Applies to AEs occurring greater than 30 days after the 
patient’s last treatment date up to the end of the survival follow-up period. 
9.3 
Expedited Adverse Event Reporting (Rave-CTEP-AERS) 
Investigators are required by Federal Regulations to report serious adverse events as defined in 
the table below. Alliance investigators are required to notify the Alliance Central Protocol 
Operations Program, the Study Chair, and their Institutional Review Board if a patient has a 
reportable serious adverse event. The descriptions and grading scales found in the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) Version 5.0 will be utilized for AE 
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o 
“24-Hour notification, 10 Calendar Days” - The SAE must initially be reported via CTEP-AERS within 
24 hours of learning of the SAE, followed by a complete expedited report within 10 calendar days of 
the initial 24-hour report. 
1SAEs 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 notifications are required for all SAEs followed by a complete report 
• 
Within 5 calendar days for Grade 4-5 SAEs 
• 
Within 10 calendar days for Grade 1-3 SAEs 
2For studies using nuclear medicine or molecular imaging IND agents (NM, SPECT, or PET), the SAE 
reporting period is limited to 10 radioactive half-lives, rounded UP to the nearest whole day, after the 
agent/intervention was last administered.  Footnote “1” above applies after this reporting period. 
 
Effective Date: August 30, 2024 
• 
 
Additional Instructions or Exclusions to CTEP-AERS Expedited Reporting Requirements for 
Phase 2 and 3 Trials Utilizing an Agent Under a CTEP IND or non-CTEP IND: 
• 
All adverse events reported via CTEP-AERS (i.e. serious adverse events) should also be 
forwarded to your local IRB. 
• 
Alliance A021502 uses a drug under a CTEP IND. The reporting requirements for investigational 
agents under a CTEP IND should be followed for all agents (any arm) in this trial. 
• 
Grade 3 or 4 hematosuppression resulting in hospitalization does not require CTEP-AERS, but 
should be submitted as part of study results. 
• 
All new malignancies must be reported via CTEP-AERS whether or not they are thought to be 
related to either previous or current treatment. All new malignancies should be reported, i.e. solid 
tumors 
(including 
non-melanoma 
skin 
malignancies), 
hematologic 
malignancies, 
myelodysplastic syndrome/acute myelogenous leukemia, and in situ tumors. In CTCAE version 
5.0, the event(s) may be reported as one of the following: (1) Leukemia secondary to oncology 
chemotherapy, (2) Myelodysplastic syndrome, or (3) Treatment-related secondary malignancy. 
Whenever possible, the CTEP-AERS reports for new malignancies should include tumor 
pathology, history or prior tumors, prior treatment/current treatment including duration, any 
associated risk factors or evidence regarding how long the new malignancy may have been 
present, when and how the new malignancy was detected, molecular characterization or 
cytogenetics of the original tumor (if available) and of any new tumor, and new malignancy 
treatment and outcome, if available. New primary malignancies should be reported using study 
Form Notice of New Primary.  
• 
Grade 1-3 nausea or vomiting resulting in hospitalization does not require AERS reporting, but 
should be reported via routine AE reporting.  
• 
Grade 3 or 4 nausea or vomiting not resulting in hospitalization does not require AERS reporting, 
but should be reported via routine AE reporting 
• 
Grade 1-3 oral mucositis resulting in hospitalization does not require AERS reporting, but should 
be reported via routine AE reporting 
• 
Grade 3 or 4 oral mucositis not resulting in hospitalization does not require AERS reporting, but 
should be reported via routine AE reporting 
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• 
Grade 1-3 peripheral sensory neuropathy resulting in hospitalization does not require AERS 
reporting, but should be reported via routine AE reporting.  
• 
Grade 3 peripheral sensory neuropathy not resulting in hospitalization does not require AERS 
reporting, but should be reported via routine AE reporting 
• 
Grade 1-3 hand foot syndrome resulting in hospitalization does not require AERS reporting, but 
should be reported via routine AE reporting 
• 
Grade 3 hand foot syndrome not resulting in hospitalization does not require AERS reporting, 
but should be reported via routine AE reporting 
• 
Grade 1-3 hypersensitivity reaction resulting in hospitalization does not require AERS reporting, 
but should be reported via routine AE reporting.  
• 
Grade 3 or 4 hypersensitivity reaction not resulting in hospitalization does not require AERS 
reporting, but should be reported via routine AE reporting 
• 
Grade 1-3 dehydration resulting in hospitalization does not require AERS reporting, but should 
be reported via routine AE reporting 
• 
Grade 3 dehydration not resulting in hospitalization does not require AERS reporting, but should 
be reported via routine AE reporting 
• 
Grade 1-3 fatigue resulting in hospitalization does not require AERS reporting, but should be 
reported via routine AE reporting.  
• 
Grade 3 or 4 fatigue not resulting in hospitalization does not require AERS reporting, but should 
be reported via routine AE reporting 
• 
Treatment expected adverse events include those listed in Section 10.0 and in the Comprehensive 
Adverse Events and Potential Risks list (CAEPR) below. 
• 
CTEP-AERS reports should be submitted electronically. 
• 
Pregnancy, as well as its outcome, must be reported as an AE in Rave and submitted for rules 
evaluation. 
• 
Pregnancy loss 
 Pregnancy loss is defined in CTCAE as “Death in utero.” 
 Any 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. 
• 
A neonatal death should be reported expeditiously as Grade 4, “Death neonatal” under the 
General disorders and administration SOC. 
• 
Death due to progressive disease should be reported as Grade 5 “Disease progression” under the 
system organ class (SOC) “General disorders and administration site conditions.” Evidence that 
the death was a manifestation of underlying disease (e.g. radiological changes suggesting tumor 
growth or progression: clinical deterioration associated with a disease process) should be 
submitted. 
• 
Any death occurring within 30 days of the last dose, regardless of attribution to the investigational 
agent/intervention requires expedited reporting within 24 hours. 
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• 
Any death occurring greater than 30 days after the last dose of the investigational 
agent/intervention requires expedited reporting within 24 hours only if it is possibly, probably, 
or definitely related to the investigational agent/intervention. 
9.4 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for Atezolizumab 
(MPDL3280A, NSC 783608) 
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 3097 patients. Below is the CAEPR for 
Atezolizumab (MPDL3280A). 
NOTE: PRO-CTCAE data should not be used for determining attribution, dose modifications, 
or reporting of serious adverse events. 
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. 
 
 
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2Atezolizumab, being a member of a class of agents involved in the inhibition of “immune checkpoints,” 
may result in severe and possibly fatal immune-mediated adverse events probably due to T-cell activation 
and proliferation. Immune-mediated adverse reactions have been reported in patients receiving 
atezolizumab. Adverse events potentially related to atezolizumab may be manifestations of immune-
mediated adverse events. In clinical trials, most immune-mediated adverse reactions were reversible and 
managed with interruptions of atezolizumab, administration of corticosteroids and supportive care. 
 
3Infusion reactions, including high-grade hypersensitivity reactions, anaphylaxis, and cytokine release 
syndrome, which have been observed following administration of atezolizumab, may manifest as fever, 
chills, shakes, itching, rash, hypertension or hypotension, or difficulty breathing during and immediately 
after administration of atezolizumab. 
 
4Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
Adverse events reported on atezolizumab (MPDL3280A) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that atezolizumab (MPDL3280A) 
caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(pancytopenia); Febrile neutropenia 
CARDIAC DISORDERS - Cardiac arrest; Ventricular tachycardia 
GASTROINTESTINAL DISORDERS - Constipation; Dry mouth; Ileus 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema limbs; Malaise; 
Multi-organ failure 
HEPATOBILIARY DISORDERS - Portal vein thrombosis 
INVESTIGATIONS - Lymphocyte count decreased; Neutrophil count decreased; Weight loss; White blood 
cell decreased 
METABOLISM AND NUTRITION DISORDERS - Hypophosphatemia; Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; Muscle cramp: Pain in 
extremity 
NERVOUS SYSTEM DISORDERS - Headache 
PSYCHIATRIC DISORDERS - Confusion; Insomnia; Suicide attempt 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Breast pain 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary hemorrhage; 
Pulmonary hypertension; Respiratory failure 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin2; Hyperhidrosis 
VASCULAR DISORDERS - Hypertension; Hypotension; Thromboembolic event 
 
Note: Atezolizumab (MPDL3280A) 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. 
9.5 
CDUS Monitoring 
The assigned monitoring method for this protocol is CDUS-Abbreviated. 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to CTEP 
on a quarterly basis by FTP burst of data.  Reports are due January 31, April 30, July 31, and 
October 31.  Instructions for submitting data using the CDUS can be found on the CTEP website: 
(http://ctep.cancer.gov/reporting/cdus.html). 
Note: If your study has been assigned to CDUS-Complete reporting, all adverse events (both 
routine and expedited) that have occurred on the study and meet the mandatory CDUS reporting 
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guidelines must be reported via the monitoring method identified above. If your study has been 
assigned to CDUS-Abbreviated reporting, no adverse event reporting (routine or expedited) is 
required to be reported via CDUS, but expedited adverse events are still required to be submitted 
via CTEP-AERS. 
10.0 DRUG INFORMATION  
10.1 
General Considerations 
Chemotherapy drug dosages need not be changed unless the calculated dose changes by ≥ 10%. 
10.2 
Fluorouracil (Adrucil®, 5FU) 
Procurement 
Commercial supplies. Pharmacies or clinics shall obtain supplies from normal commercial 
supply chain or wholesaler. 
Formulation 
Commercially available for injection 50 mg/mL (10 mL, 20 mL, 50 mL, and 100 mL). 
Preparation, Storage and Stability 
Store intact vials at room temperature and protect from light. A slight discoloration may occur 
with storage but usually does not denote decomposition. Dilute in 50 – 1000 mL of 0.9% NaCl 
or D5W. If exposed to cold, a precipitate may form; gentle heating to 60ºC will dissolve the 
precipitate without impairing the potency. Solutions in 50 – 1000 mL 0.9% NaCl or D5W or 
undiluted solutions in syringes are stable for 72 hours at room temperature. Fluorouracil should 
not be co-administered with either diazepam, doxorubicin, daunorubicin, idarubicin, cisplatin, 
or cytarabine. However, fluorouracil and leucovorin are compatible for 14 days at room 
temperature. Fluorouracil is compatible with vincristine, methotrexate, and cyclophosphamide. 
Administration 
Fluorouracil may be given IV bolus or IV infusion. Refer to the treatment section for specific 
administration instructions.  Avoid extravasation, may be an irritant. 
Drug Interactions 
Fluorouracil may increase effects of warfarin. Avoid ethanol (due to GI irritation). Avoid black 
cohosh. 
Pharmacokinetics 
Distribution: Vd ~ 22% of total body water; penetrates extracellular fluid, CSF, and third space 
fluids (e.g. pleural effusions and ascitic fluid) 
Metabolism: Hepatic (90%); via a dehydrogenase enzyme; Fluorouracil must be metabolized to 
be active. 
Half-life Elimination: Biphasic: Initial: 6-20 minutes; two metabolites, FdUMP and FUTP, have 
prolonged half-lives depending on the type of tissue. 
Excretion: Lung (large amounts as CO2); urine (5% as unchanged drug) in 6 hours. 
Adverse Events 
Consult the package insert for the most current and complete information. 
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Common Known Potential Toxicities, > 10%:   
Dermatologic: Dermatitis, pruritic maculopapular rash, alopecia. 
Gastrointestinal (route and schedule dependent): Heartburn, nausea, vomiting, anorexia, 
stomatitis, esophagitis, anorexia, diarrhea. GI toxicity (anorexia, nausea, and vomiting) is 
generally more severe with continuous-infusion schedules. 
Emetic Potential: <1000 mg: Moderately low (10% to 30%) ≥ 1000 mg: Moderate (30% to 60%) 
Hematologic: Leukopenia; Myelosuppressive (tends to be more pronounced in patients 
receiving bolus dosing of FU). Decreased white blood cell count with increased risk of infection; 
decreased platelet count with increased risk of bleeding. 
Local: Irritant chemotherapy.  
Less Common Known Potential Toxicities, 1% - 10%:  
Dermatologic: Dry skin 
Gastrointestinal: GI ulceration 
Rare Known Potential Toxicities, <1% (Limited to Important or Life-threatening):  
Cardiac enzyme abnormalities, chest pain, coagulopathy, dyspnea, ECG changes similar to 
ischemic changes, hepatotoxicity; hyperpigmentation of nail beds, face, hands, and veins used 
in infusion; hypotension, palmar-plantar syndrome (hand-foot syndrome), photosensitization. 
Cerebellar ataxia, headache, somnolence, ataxia are seen primarily in intracarotid arterial 
infusions for head and neck tumors. 
Nursing Guidelines 
Monitor complete blood count and platelet count.  Instruct patient to report signs and symptoms 
of infection, unusual bruising or bleeding to the physician. 
Administer antiemetics as indicated. 
Diarrhea may be dose–limiting; encourage fluids and treat symptomatically. 
Assess for stomatitis; oral care measures as indicated. May try vitamin E oil dabbed on sore, six 
times daily.  Cryotherapy recommended with IV push administration. 
Monitor for neurologic symptoms (headache, ataxia). 
Inform patient of potential alopecia. 
Those patients on continuous infusion may need instruction regarding central intravenous 
catheters and portable intravenous or IA infusion devices. 
5FU–induced conjunctivitis is a common problem.  Advise patient to report any eye soreness or 
redness to the healthcare team. 
Photosensitivity may occur.  Instruct patients to wear sun block when outdoors. 
10.3 
Leucovorin Calcium 
Procurement 
Commercial supplies. Pharmacies or clinics shall obtain supplies from normal commercial 
supply chain or wholesaler 
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Formulation 
**Note: Levoleucovorin is a different from leucovorin.   
Leucovorin is available as: 
• 
Solution for Injection 100 mg/10mL (10mL, 30 mL) 
• 
Lyophilized Powder for Injection 50 mg, 100 mg, 200 mg, 350 mg, 500 mg 
Preparation, Storage and Stability 
Powder for Injection: Store at room temperature of 25°C (77°F).  Protect from light. Solutions 
reconstituted with bacteriostatic water for injection U.S.P., must be used within 7 days. 
Solutions reconstituted with SWFI must be used immediately.  Parenteral admixture is stable 
for 24 hours stored at room temperature (25°C) and for 4 days when stored under refrigeration 
(4°C).  Powder for injection: Reconstitute with SWFI or BWFI; dilute with D5W or NS for 
infusion.  When doses > 10 mg/m2 are required, reconstitute using sterile water for injection, 
not a solution containing benzyl alcohol.   
Solution for Injection: Prior to dilution, store vials under refrigeration at 2°C to 8°C (36°F to 
46°F).  Protect from light.  Dilute in D5W or NS for infusion.  
Administration 
Should be administered IV infusion (2 hours) and is not intended for intrathecal use.  
Combination Therapy with Fluorouracil: Fluorouracil is usually given after, or at the midpoint, 
of the leucovorin infusion. Leucovorin is usually administered by IV infusion. Other 
administration schedules have been used; refer to individual protocols. 
Drug Interactions 
Capecitabine: Leucovorin Calcium-Levoleucovorin may enhance the adverse/toxic effect of 
Capecitabine. Risk C: Monitor therapy 
Fluorouracil (Systemic): Leucovorin Calcium-Levoleucovorin may enhance the adverse/toxic 
effect of Fluorouracil (Systemic). This effect is associated with the ability of leucovorin or 
levoleucovorin to enhance the anticancer effects of fluorouracil. Risk C: Monitor therapy 
Fluorouracil (Topical): Leucovorin Calcium-Levoleucovorin may enhance the adverse/toxic 
effect of Fluorouracil (Topical). Risk C: Monitor therapy 
Fosphenytoin: Leucovorin Calcium-Levoleucovorin may decrease the serum concentration of 
Fosphenytoin. Risk C: Monitor therapy 
Glucarpidase: May decrease serum concentrations of the active metabolite(s) of Leucovorin 
Calcium-Levoleucovorin. Specifically, 6S-5-methyltetrahydrofolateconcentrations may be 
reduced. Glucarpidase may decrease the serum concentration of Leucovorin Calcium-
Levoleucovorin. Management: Avoid leucovorin administration within 2 hours of glucarpidase 
dosing. Continue to administer the pre-glucarpidase leucovorin dose for at least the first 48 hours 
after glucarpidase administration, and dose based on methotrexate concentration thereafter. Risk 
D: Consider therapy modification 
PHENobarbital: Leucovorin Calcium-Levoleucovorin may decrease the serum concentration of 
PHENobarbital. Risk C: Monitor therapy 
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Phenytoin: Leucovorin Calcium-Levoleucovorin may decrease the serum concentration of 
Phenytoin. Risk C: Monitor therapy 
Primidone: Leucovorin Calcium-Levoleucovorin may decrease the serum concentration of 
Primidone. Additionally, leucovorin/levoleucovorin may decrease concentrations of active 
metabolites of primidone (e.g. phenobarbital). Risk C: Monitor therapy 
Raltitrexed: Leucovorin Calcium-Levoleucovorin may diminish the therapeutic effect of 
Raltitrexed. Risk X: Avoid combination 
Tegafur: Leucovorin Calcium-Levoleucovorin may enhance the adverse/toxic effect of Tegafur. 
This effect is associated with the ability of leucovorin or levoleucovorin to enhance the 
anticancer effects of fluorouracil. Risk C: Monitor therapy 
Trimethoprim: Leucovorin Calcium-Levoleucovorin may diminish the therapeutic effect of 
Trimethoprim. Management: Avoid concurrent use of leucovorin or levoleucovorin with 
trimethoprim (plus sulfamethoxazole) for Pneumocystis jiroveci pneumonia. If trimethoprim is 
used for another indication, monitor closely for reduced efficacy. Risk X: Avoid combination 
Pharmacokinetics 
Absorption: Oral, IM: Well absorbed 
Metabolism: Intestinal mucosa and hepatically to 5-methyl-tetrahydrofolate (5MTHF; active) 
Bioavailability: Saturable at oral doses >25 mg; 25 mg (97%), 50 mg (75%), 100 mg (37%) 
Half-life Elimination: ~4-8 hours 
Time to Peak: Oral: ~2 hours; IV: Total folates: 10 minutes; 5MTHF: ~1 hour 
Excretion: Urine (primarily); feces 
Adverse Events 
Consult the package insert for the most current and complete information. 
Dermatologic: Rash, pruritus, erythema, urticaria 
Hematologic: Thrombocytosis 
Respiratory: Wheezing 
Miscellaneous: Allergic reactions, anaphylactoid reactions 
Nursing Guidelines 
Headache may occur.  Advise patient that analgesics such as Tylenol may help.  Instruct patient 
to report any headache that is unrelieved. 
Observe for sensitization reaction (rash, hives, pruritus, facial flushing, and wheezing).  
May potentiate the toxic effects of fluoropyrimidine (5-FU) therapy, resulting in increased 
hematologic and gastrointestinal (diarrhea, stomatitis) adverse effects. Monitor closely. 
May cause mild nausea or upset stomach. Administer antiemetics if necessary and evaluate for 
their effectiveness. 
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10.4 
Oxaliplatin (Eloxatin®, OXAL) 
Procurement 
Commercial supplies. Pharmacies or clinics shall obtain supplies from normal commercial 
supply chain or wholesaler. 
Formulation 
Commercially Available for Injection as: Solution [preservative free]: 5 mg/mL (10 mL, 20 mL, 
and 40 mL) 
Preparation, Storage and Stability 
Refer to package insert for complete preparation and dispensing instructions. Store intact vials 
in original outer carton at room temperature and; do not freeze. According to the manufacturer, 
solutions diluted for infusion are stable up to 6 hours at room temperature or up to 24 hours 
under refrigeration. Oxaliplatin solution diluted with D5W to a final concentration of 0.7 mg/mL 
(polyolefin container) has been shown to retain >90% of its original concentration for up to 30 
days when stored at room temperature or refrigerated; artificial light did not affect the 
concentration (Andre, 2007). As this study did not examine sterility, refrigeration would be 
preferred to limit microbial growth. Do not prepare using a chloride-containing solution (e.g. 
NaCl). Dilution with D5W (250 or 500 mL) is required prior to administration. Infusion solutions 
do not require protection from light. 
Administration 
Refer to the treatment section for specific administration instructions. Administer as I.V. 
infusion over 2 hours. Flush infusion line with D5W prior to administration of any concomitant 
medication. Patients should receive an antiemetic premedication regimen. Cold temperature 
may exacerbate acute neuropathy. Avoid mucositis prophylaxis with ice chips during oxaliplatin 
infusion. 
Drug Interactions 
Increased Effect/Toxicity: Nephrotoxic agents may increase Oxaliplatin toxicity.  
When administered as sequential infusions, observational studies indicate a potential for 
increased toxicity when platinum derivatives (carboplatin, cisplatin, oxaliplatin) are 
administered before taxane derivatives (docetaxel, paclitaxel). 
Decreased Effect: Oxaliplatin may decrease plasma levels of digoxin 
Pharmacokinetics 
Distribution: Vd: 440 L 
Protein Binding: >90% primarily albumin and gamma globulin (irreversible binding to 
platinum) 
Metabolism: Nonenzymatic (rapid and extensive), forms active and inactive derivative phase: 
16.8 hours 
Excretion: Primarily urine (~54%); feces (~2%) 
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Adverse Events 
Consult the package insert for the most current and complete information. Percentages reported 
with monotherapy. 
Common Known Potential Toxicities, > 10%:   
Central nervous system: Fatigue, fever, pain, headache, insomnia 
Gastrointestinal: Nausea, diarrhea, vomiting, abdominal pain, constipation, anorexia, stomatitis  
Hematologic: Anemia, thrombocytopenia, leukopenia 
Hepatic: Liver enzymes increased 
Neuromuscular & skeletal: Back pain, peripheral neuropathy (may be dose limiting). The most 
commonly observed oxaliplatin-related toxicity is acute and cumulative neurotoxicity, observed 
in patients treated at doses above 100 mg/m2/cycle.  This neurotoxicity has included paresthesias 
and dysesthesias of the hands, feet, and perioral region as well as unusual laryngopharyngeal 
dysesthesias characterized by a loss of sensation of breathing without any objective evidence of 
respiratory distress (hypoxia, laryngospasm, or bronchospasm).  OXAL neurotoxicity appears 
to be exacerbated by exposure to cold.  Patients on this study will be counseled to avoid cold 
drinks and exposure to cold water or air.  Should a patient develop laryngopharyngeal 
dysesthesia, their oxygen saturation should be evaluated via a pulse oximeter; if normal, an 
anxiolytic agent should be given and the patient observed in the clinic until the episode has 
resolved.  Because this syndrome may be associated with the rapidity of OXAL infusion, 
subsequent doses of OXAL should be administered as a 6-hour infusion (instead of the normal 
2-hour infusion). 
Acute and cumulative neurotoxicities are dose limiting for OXAL.  The acute neurotoxicity is 
characterized by paresthesias and dysesthesias that may be triggered or exacerbated by exposure 
to cold.  These symptoms occur within hours of exposure and are usually reversible over the 
following hours or days.  Cumulative doses of OXAL above 680 mg/m2 may produce functional 
impairment characterized by difficulty performing activities requiring fine sensory-motor 
coordination; impairment is caused by sensory rather than motor changes.  
The likelihood of experiencing neurotoxicity is directly related to the total cumulative dose of 
OXAL administered.  The relative risk of developing neurotoxicity was 10%, 50%, and 75% in 
patients who received total cumulative OXAL doses of 780 mg/m2, 1,170 mg/m2, and 1,560 
mg/m2, respectively.  Both acute and cumulative neurotoxicities due to OXAL have lessened in 
82% of patients within 4 to 6 months, and have completely disappeared by 6 to 8 months in 41% 
of patients.  In addition, the likelihood that neurologic symptoms will regress has been shown 
to correlate inversely with cumulative dose.  
Respiratory: Dyspnea, cough 
Less Common Known Potential Toxicities, 1% - 10%:  
Cardiovascular: Edema, chest pain, peripheral edema, flushing, thromboembolism 
Central nervous system: Dizziness 
Dermatologic: Rash, alopecia, hand-foot syndrome 
Endocrine & metabolic: Dehydration, hypokalemia 
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Gastrointestinal: Dyspepsia, taste perversion, flatulence, mucositis, gastroesophageal reflux, 
dysphagia 
Genitourinary: Dysuria 
Hematologic: Neutropenia 
Local: Injection site reaction 
Neuromuscular & skeletal: Rigors, arthralgia 
Ocular: Abnormal lacrimation 
Renal: Serum creatinine increased 
Respiratory: URI, rhinitis, epistaxis, pharyngitis, pharyngolaryngeal dysesthesia 
Miscellaneous: Allergic reactions, hypersensitivity (includes urticaria, pruritus, facial flushing, 
shortness of breath, bronchospasm, diaphoresis, hypotension, syncope, hiccup 
Rare Known Potential Toxicities, <1% (Limited to Important or Life-threatening):  
Gastrointestinal: Life threatening enteric sepsis secondary to neutropenia and diarrhea. 
Hepatic: Veno-occlusive disease of the liver is a rare serious adverse event that has occurred in 
association with administration of oxaliplatin and fluorouracil.  
Otic: Clinical ototoxicity occurs in less than 1% of patients following oxaliplatin administration, 
and severe ototoxicity has not been reported. 
Nursing Guidelines 
GI toxicity similar to cisplatin occurs with doses above 30 mg/m2. It can be almost constant and 
frequently severe, but not always dose-limiting. Monitor for nausea and vomiting and treat 
accordingly. 
Dose-limiting side effect can be paresthesias of hands, fingers, toes, pharynx, and occasionally 
cramps which develops with a dose-related frequency (>90 mg/m2). Duration of symptoms tend 
to be brief (less than a week) with the first course, but longer with subsequent courses.  Phase I 
patients have reported exacerbation of paresthesias by touching cold surfaces or exposure to 
cold. Advise patient of these possibilities and instruct patient to report these symptoms to the 
health care team. Also advise patient to refrain from operating dangerous machinery that 
requires fine sensory-motor coordination, if symptoms appear. 
These sensory neuropathies developed after subsequent courses with increasing intensity (Grade 
3 toxicity after the fourth course) and with increasing duration. In 63% of the patients tested in 
phase I at high doses (135-200 mg/m2), neuropathies became long-term with slow reversal over 
several months. Disabling walking and handwriting difficulties, as well as mouth and throat 
dysesthesias and laryngospasms were seen.  Instruct patient to report any swallowing difficulties 
or gait changes. 
OXAL is incompatible with NS. Flush lines with D5W prior to and following OXAL infusion. 
Low back pain is a common side effect, perhaps a form of hypersensitivity reaction. Instruct 
patient in good body mechanics, advise light massage, heat, etc. 
Laryngopharyngeal dysesthesia (LPD) occurs in about 15% of patients and is acute, sporadic, 
and self-limited. It usually occurs within hours of infusion, is induced or exacerbated by 
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exposure to cold, and presents with dyspnea and dysphagia. The incidence and severity appear 
to be reduced by prolonging infusion time. Instruct patient to avoid ice and cold drinks the day 
of infusion.   
Comparison of the Symptoms and Treatment of Laryngopharyngeal Dysesthesias and Platinum 
Hypersensitivity Reactions 
Comparison of the Symptoms and Treatment of Laryngopharyngeal Dysesthesias and 
Platinum Hypersensitivity Reactions 
Clinical Symptoms 
Laryngopharyngeal 
Dysesthesias 
Platinum Hypersensitivity 
Dyspnea 
Present 
Present 
Bronchospasm 
Absent 
Present 
Laryngospasm 
Absent 
Present 
Anxiety 
Present 
Present 
O2 saturation 
Normal 
Decreased 
Difficulty swallowing 
Present (loss of sensation) 
Absent 
Pruritus 
Absent 
Present 
Urticaria/Rash 
Absent 
Present 
Cold-induced symptoms 
Yes 
No 
BP 
Normal or increased 
Normal or decreased 
Treatment 
Anxiolytics, observation in a 
controlled clinical setting 
until symptoms abate or at 
the physicians’ discretion 
Oxygen, steroids, 
epinephrine, 
bronchodilators; fluids and 
vasopressors, if appropriate 
Treatment anxiolytics, observation in a controlled clinical setting until symptoms abate or at the 
physicians’ discretion oxygen, steroids, epinephrine, bronchodilators; fluids and vasopressors, 
if appropriate 
Alopecia is rare with OXAL alone, but is seen with 5-FU-OXAL combination. Advise patient. 
Mild-moderate diarrhea has been seen – usually of short duration. Treat accordingly. See 
Section 8.1 for ancillary treatment. 
Respiratory problems (i.e. pulmonary fibrosis, cough, dyspnea, rales, pulmonary infiltrates, 
hypoxia, air hunger and tachypnea) have been observed in patients administered OXAL.  In rare 
cases, death has occurred due to pulmonary fibrosis. Please monitor and instruct the patient to 
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submission of FDA form 1572 (Statement of Investigator), NCI Biosketch, Agent Shipment 
Form, and Financial Disclosure Form (FDF). If there are several participating investigators at 
one institution, CTEP-supplied investigational agents for the study should be ordered under the 
name of one lead participating investigator at that institution. 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) application. 
Access to OAOP requires the establishment of a CTEP Identity and Access Management (IAM) 
account and the maintenance of an “active” account status, a “current” password, and active 
person registration status.  For questions about drug orders, transfers, returns, or accountability, 
call or email PMB any time. Refer to the PMB’s website for specific policies and guidelines 
related to agent management. 
Description 
Atezolizumab is a humanized IgG1 monoclonal antibody consisting of two heavy chains (448 
amino acids) and two light chains (214 amino acids). Atezolizumab targets human PD-L1 and 
inhibits its interaction with its receptor PD-1. Atezolizumab also blocks the binding of PD-L1 
to B7.1, an interaction that is reported to provide additional inhibitory signals to T cells (Butte 
et al. 2007). 
Formulation 
Atezolizumab is provided by Genentech/F.Hoffmann-La Roche LTD and distributed by the 
Pharmaceutical Management Branch, CTEP, NCI. The agent is supplied in a single-use, 20-mL 
glass vial as a colorless-to-slightly-yellow, sterile, preservative-free clear liquid solution 
intended for IV administration. Each 20 mL vial contains 1200 mg of atezolizumab and is 
formulated in glacial acetic acid (16.5 mg), L-histidine (62mg) polysorbate 20 (8 mg), and 
sucrose (821.6 mg), with a pH of 5.8. The vial is designed to deliver 20 mL (1200 mg) of 
atezolizumab solution but may contain more than the stated volume to enable delivery of the 
entire 20 mL volume. 
Storage 
2°C-8°C (36°F-46°F). Vial contents should not be frozen or shaken and should be protected 
from direct sunlight. 
If a storage temperature excursion is identified, promptly return atezolizumab to 2°C-8°C (36°F-
46°F) and quarantine the supplies.  Provide a detailed report of the excursion (including 
documentation 
of 
temperature 
monitoring 
and 
duration 
of 
the 
excursion) 
to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
Stability 
Stability studies are ongoing. 
CAUTION:  No preservative is used in atezolizumab; therefore, the vial is intended for single 
use only. Discard any unused portion of drug remaining in a vial. 
Preparation 
The prescribed dose of atezolizumab should be diluted in 0.9% NaCl to a concentration between 
3.2 mg/mL and 16.8 mg/mL and infused with or without a low-protein binding 0.2 or 0.22 
micrometer in-line filter. The IV bag may be constructed of polyvinyl chloride (PVC), 
polyolefin (PO), polyethylene (PE). The prepared solution may be stored at 2°C-8°C for up to 
24 hours or at ambient ≤ 25°C (77°F) for 6 hours from the time of preparation. If the dose 
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solution is stored at 2°C–8°C (36°F–46°F), it should be removed from refrigeration and allowed 
to reach room temperature prior to administration. These times include the storage and 
administration times for the infusion. Do not shake or freeze infusion bags containing the dose 
solution. 
Route of Administration 
IV infusion. 
Method of Administration 
Atezolizumab is administered as an intravenous infusion over 60 minutes. If the first infusion is 
tolerated, all subsequent infusions may be delivered over 30 minutes. Do not administer 
atezolizumab as an intravenous push or bolus. No premedication is indicated for administration 
of Cycle 1 of atezolizumab. Patients who experience an infusion related reaction with Cycle 1 
of atezolizumab may receive premedication with subsequent infusions. 
Potential Drug Interactions 
Cytochrome P450 enzymes as well as conjugation/glucuronidation reactions are not involved in 
the metabolism of atezolizumab. No drug interaction studies for atezolizumab have been 
conducted or are planned. There are no known interactions with other medicinal products or 
other form of interactions. 
Pharmacokinetics 
Vdss: 6.9 L 
Half-life Elimination: 27 days 
Adverse Events 
Consult the investigator’s brochure and package insert for the most current and complete 
information.   
Warnings and precautions include immune-related pneumonitis, hepatitis, colitis, 
endocrinopathies, myasthenic syndrome/Myasthenia Gravis, Guillain-Barre syndrome, 
meningoencephalitis, pancreatitis, ocular inflammatory toxicity, infection, infusion reaction, 
embryo-fetal toxicity. 
> 10%: All grades 
Gastrointestinal: Nausea, constipation, diarrhea, abdominal pain, vomiting 
General Disorders and Administration: Fatigue, pyrexia, peripheral edema 
Infection and Infestation: Urinary tract infection 
Metabolism and Nutrition Disorders: Decreased appetite 
Musculoskeletal and Connective Tissue Disorders: Back/Neck pain, arthralgia 
Renal and urinary disorders: Hematuria 
Respiratory, Thoracic, and Mediastinal Disorders: Dyspnea, cough 
Skin and Subcutaneous Tissue Disorders: Rash, pruritus,  
< 1% to 10%: Grades 3-4 
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Abdominal pain, acute kidney injury, anemia, dehydration, intestinal obstruction, liver enzyme 
increase, pneumonia, sepsis, urinary obstruction, and venous thromboembolism  
Nursing Guidelines 
Anti PD-L1 side effects vary greatly from those of traditional chemotherapy and can vary in 
severity from mild to life threatening. Instruct patients to report any side effects to the study 
team immediately. Side effects may be immediate or delayed up to months after discontinuation 
of therapy. Most side effects are reversible with prompt intervention of corticosteroids 
Diarrhea can be common and can be very severe, leading to colonic perforation. Instruct patients 
to report ANY increase in the number of stools and/or change in baseline, blood in the stool, 
abdominal pain to the study team immediately.  
Rash/pruritus/dermatitis is seen. Patients should report any rash to the study team. Treat per 
Section 8.0 and monitor for effectiveness.  
Monitor LFT’s closely as elevations in these levels could indicate early onset autoimmune 
hepatitis. Patients should also be instructed to report any jaundice, or right upper quadrant pain 
to the study team immediately. 
Pneumonitis can be seen and may be mild (only seen on imaging) to severe. Patients should be 
instructed to report any SOB, dyspnea, cough, chest pain, etc. to the study team immediately. 
Patients reporting these symptoms should have a pulse ox checked and consider immediate 
imaging per the treating MD. 
Endocrinopathies (including hypopituitarism, hypothyroidism, hypophysistis, and adrenal 
insufficiency) are a concern given the mechanism of action of this agent.  Patients may present 
only with the vague sense of fatigue and “not feeling well.” Additional symptoms may be that 
of nausea, sweating and decreased activity tolerance. Instruct patients to report these signs or 
symptoms immediately and obtain appropriate labs as ordered by MD.  
Pancreatitis is possible with anti PD-L1 therapy based on mechanism of action. Instruct patients 
to report abdominal pain, nausea and vomiting to the study team. 
Patients who are started on steroid therapy for any side effects of anti PD-L1 toxicity should be 
instructed to take the steroids as ordered, and not to discontinue abruptly as symptoms may 
return and be severe. Patients may be on steroid therapy for weeks. Instruct patients to report 
any increase or change in side effects with any dosage decrease as patients may need a slower 
taper. 
Female patients of childbearing potential should utilize contraception and take active measures 
to avoid pregnancy while undergoing atezolizumab treatment and for at least 150 days after the 
last dose of atezolizumab. 
Agent Inventory Records 
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the receipt, dispensing, and final disposition of all agents received from the PMB using 
the appropriate NCI Investigational Agent (Drug) Accountability Record (DARF) available on 
the CTEP forms page.  Store and maintain separate NCI Investigational Agent Accountability 
Records for each agent, strength, formulation and ordering investigator on this protocol. 
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Investigator Brochure Availability 
The current versions of the IBs for the agents will be accessible to site investigators and research 
staff through the PMB OAOP application. Access to OAOP requires the establishment of a 
CTEP IAM account and the maintenance of an “active” account status, and a “current” password 
and active person registration status. Questions about IB access may be directed to the PMB IB 
Coordinator via email. 
Useful Links and Contacts 
• CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov  
• PMB Online Agent Order Processing (OAOP) application: https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx  
• CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/ 
• CTEP Associate Registration and IAM Account Help: ctepreghelp@ctep.nci.nih.gov 
• IB Coordinator: IBCoordinator@mail.nih.gov  
• PMB email: PMBAfterHours@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575 Monday through Friday between 
8:30 am and 4:30 pm (ET) 
11.0 MEASUREMENT OF RECURRENCE 
Relapse of disease will be evaluated in this study using CEA testing and radiographic imaging. An 
elevated CEA level alone (without radiographic or pathologic evidence of disease) does not 
qualify as relapsed disease. For patients who have signs or symptoms for which imaging is clinically 
indicated, the decision of timing of radiographic studies remains at the discretion of the treating 
clinician. However, for asymptomatic surveillance after the completion of FOLFOX, the timing of 
CEA testing and radiographic imaging has been standardized (see Section 5.0). 
11.1 
Schedule of Evaluations 
For the purposes of this study, patients should be reevaluated for recurrence at the following 
intervals: 
• 
Radiographic Imaging: every 6 months (+/- 1 month) for the first 2 years after 
registration, then yearly for an additional 3 years (i.e. years 3-5 after registration). 
Patients should follow the schedule outlined in the Study Calendar (Section 5.0).  
• 
CEA Testing: 6 weeks after completion of FOLFOX, then every 6 months (+/- 1 month) 
for 3 years, then yearly (+/- 1 month) for an additional 2 years. Patients should follow 
the schedule outlined in the Study Calendar (Section 5.0). After the end of FOLFOX 
treatment, the timing of CEA should correspond with the timing of radiographic 
imaging, where possible, but more frequent testing is at provider discretion. 
Supporting documentation of relapse should be submitted per Section 6.1.1.  
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11.2 
Guidelines for Evaluation of Recurrence 
11.2.1 Measurement Methods   
All measurements should be recorded in metric notation (i.e. decimal fractions of 
centimeters) using a ruler or calipers. 
The same method of assessment and the same technique should be used throughout the 
treatment and follow-up phases.  
Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used at the same evaluation.  
11.2.2 Acceptable Modalities for Measurable Disease 
• 
Conventional CT and MRI: This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 mm 
or less. If CT scans have slice thickness greater than 5 mm, the minimum size 
for a measurable lesion should be twice the slice thickness. 
As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type 
and site of disease. The lesions should be measured on the same pulse 
sequence. Ideally, the same type of scanner should be used, and the image 
acquisition protocol should be followed as closely as possible to that used with 
prior scans. Body scans should be performed with breath-hold scanning 
techniques, if possible. 
• 
Chest X-ray: Lesions on chest x-ray are acceptable as measurable lesions 
when they are clearly defined and surrounded by aerated lung. However, CT 
scans are preferable. 
11.3 
Definition of Relapsed Disease 
11.3.1 Radiographic Recurrence  
On radiologic assessment the following must be present: at least one new malignant 
lesion, which also includes any lymph node that was normal at baseline.  
Whenever possible, radiographic relapsed disease should be confirmed by biopsy. 
The use of cytology to confirm the neoplastic origin of any effusion that appears is 
mandatory to determine progressive disease. 
Follow-up colonoscopies should be performed to monitor for relapse, with frequency at 
the discretion of the treating investigator. However, per current guidelines, follow-up 
colonoscopies should be performed either annually or every other year in patients with 
known or suspected Lynch Syndrome, as patients with Lynch Syndrome have increased 
rates of synchronous primary colon cancers. See Section 5.0 and Section 6.1 for 
additional details. 
Elevated CEA level alone (without radiographic or pathologic evidence of disease) does 
not qualify as relapsed disease. An elevated CEA should trigger a diagnostic workup.  
The primary endpoint of this study is disease-free survival (DFS), defined as the time 
from randomization to first documentation of disease recurrence (primary tumor 
relapse) or death. Patients who do not have a DFS event will be censored for DFS at 
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their last disease assessment date. Confirmed second primary colon cancer and 
second primaries of other types do not qualify as relapsed disease and will not be 
included as an event for the DFS endpoint, which is consistent with the conduct of 
recent adjuvant phase III trials.  
Recurrence can be defined as presence of primary tumor relapse. 
Second primary can be defined as presence of a new secondary type of unrelated cancer.  
A second primary colon cancer does not represent disease recurrence/relapse from the 
initially resected primary colon cancer. Recurrences typically occur in close proximity 
to the surgical anastomosis or at distant sites in the body. Second colon primaries do not 
involve the surgical anastomosis and can be diagnosed at colonoscopy and confirmed 
with biopsy. An extracolonic second primary cancer is a tumor that will typically 
present at a single site that is not believed to represent a recurrence or metastasis from 
the primary tumor. Both second primaries and extracolonic tumors are increased in 
patients with Lynch Syndrome, where the most common extracolonic cancer is 
endometrial cancer, although other potential sites include, but are not limited to, the 
small intestine and renal collecting system. If an extracolonic cancer is suspected, 
biopsy is recommended whenever possible. Based upon the medical literature, the 
risk of second primaries during the limited period of follow-up during this adjuvant trial 
is relatively low in the Lynch Syndrome population. 
In the event that the local treating investigator determines that a disease recurrence is 
suspected, or a second primary or extracolonic malignancy is suspected, the protocol 
requires the following documentation to be submitted to Alliance for review by the 
Study Chair: 
• 
Primary Tumor Relapse (DFS event): imaging report, pathology report (if 
applicable), colonoscopy report* (if applicable), operative report (if 
applicable) 
• 
Suspected Second Primary or Extracolonic Malignancy (not DFS event): 
pathology report, colonoscopy report* (if applicable), imaging report (if 
applicable), and surgical report (if applicable) 
*If recurrence is observed or suspected on imaging and it has colonic or 
rectal involvement that is not in close proximity to the surgical 
anastomosis, then a colonoscopy with biopsy is required to exclude a new 
primary malignancy in the colorectum. Female patients with isolated 
recurrence that involves the uterus should undergo biopsy to exclude a primary 
endometrial carcinoma which is the most common extracolonic malignancy in 
patients with Lynch Syndrome. 
Determination of a DFS event will be done by the local treating investigator. There will 
be no independent central review. Documentation of patient relapse/new primary will 
be reviewed by the Alliance Study Chair. Both the assessments of the local investigator 
and of the Alliance Study Chair will be recorded in the CRF. The primary analysis will 
be based on the assessment from the local treating investigator.  
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12.0 END OF TREATMENT 
12.1 
Duration of Treatment 
Patients who continue to be in remission will continue on therapy for a total of 12 cycles 
mFOLFOX6 + atezolizumab followed by 6 months of atezolizumab alone if assigned to Arm 1 
or 12 cycles mFOLFOX6 in total if assigned to Arm 2. After treatment is completed, patients 
will be followed per the Study Calendar in Section 5.0. 
Disease Recurrence: Remove from protocol therapy any patient with disease recurrence. 
Document details, including tumor measurements, on data forms. (Patients will be followed for 
recurrence and survival every 6 months (+/- 1 month) for the first two years after registration, 
then survival every 6 months and recurrence once annually for years 3-5 after registration, and 
then survival every 6 months for years 5-8 after registration. Recurrence follow-up will continue 
per the schedule above for 5 years after registration or until evidence of relapse, whichever 
comes first. Survival follow-up will continue per the schedule above for 8 years after registration 
or until death, whichever comes first.) 
Discontinuation of Study Agent: If the patient discontinues protocol therapy due to reasons other 
than recurrence, prior to the completion of planned therapy as per Section 7.0, patients should 
be followed for disease status and survival per the study calendar (Section 5.0). 
Discontinuation of Specimen Submission: If the patient discontinues protocol therapy for any 
reason, specimens should continue to be collected and submitted after discontinuation of 
adjuvant therapy per Section 6.2. 
12.2 
Managing Ineligible Patients and Registered Patients Who Never Receive Protocol 
Intervention  
Definition of ineligible patient: 
A study participant who is registered to the trial but does not meet all of the eligibility criteria 
is deemed to be ineligible.  
Follow-up for ineligible patients who continue with protocol treatment: 
Patients who are deemed ineligible after registering may continue protocol treatment, provided 
the treating physician, study chair, and executive officer agree there are no safety concerns if 
the patient continues protocol treatment. All scans, tests, and data submission are to continue as 
if the patient were eligible. Notification of the local IRB may be necessary per local IRB 
policies. 
Follow-up for ineligible patients who discontinue protocol treatment: 
For patients who are deemed ineligible after registering to the trial, who start treatment, but then 
discontinue study treatment, the same data submission requirements are to be followed as for 
those patients who are eligible and who discontinue study treatment. 
Follow-up for patients who are registered, but who never start study treatment: 
For all study participants who are registered to the trial but who never receive study intervention 
(regardless of eligibility), the follow-up requirements are specified below.  
Baseline, off-treatment, and post-treatment follow up (i.e. relapse, recurrence, and survival) 
data submission required. See the Data Submission Schedule accompanying the All Forms 
Packet. 
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12.3 
Extraordinary Medical Circumstances 
If at any time the constraints of this protocol are detrimental to the patient's health and/or the 
patient no longer wishes to continue protocol therapy, protocol therapy shall be discontinued. In 
this event: 
• 
Document the reason(s) for discontinuation of therapy on data forms. 
• 
Follow the patient for protocol endpoints as required by the Study Calendar. 
12.4 
Survival Follow-up 
Patients will be followed for survival every 6 months (+/- 1 month) for 8 years after registration 
or until death, whichever comes first. 
12.5 
Lost to Follow-Up 
A patient can be deemed lost to follow-up after two years and at least 3 unsuccessful documented 
attempts to contact the patient. The two-year period starts on the last successful contact of the 
patient. All attempted patient contacts must be documented in the patient’s research record. The 
attempted contacts must be recorded in Rave as “no contact” and complete the Lost to Follow-
up form after two years of no contact. 
13.0 STATISTICAL CONSIDERATIONS 
This study is a two-arm randomized phase III trial comparing the outcomes of patients with stage III 
colon cancer whose tumors have dMMR status treated with 1) mFOLFOX6 alone and 2) mFOLFOX6 
with atezolizumab and its continuation as monotherapy. Patients will be randomized in 1:1 fashion 
to either mFOLFOX6 alone or mFOLFOX6 with atezolizumab. Efficacy analyses will be based on 
the intention to treat principle and all randomized patients (including adult and patients aged <18 
years) will be included for the analysis i.e. patients will be assigned to the treatment group they were 
randomized to regardless of the actual treatment received. Analysis related to adverse events will be 
based on the safety population. All patients who were randomized and received any amount of 
protocol therapy will be considered evaluable for safety and patients will be assigned to the treatment 
group they actually received.  
13.1 
Study Endpoint 
13.1.1 Primary Endpoint 
The primary endpoint of this study is the disease-free survival (DFS), defined as the 
time from randomization to first documentation of disease recurrent or death. Patients 
who do not have a DFS event will be censored for DFS at their last disease assessment 
date. Confirmed second primary colon cancer and second primaries of other types will 
not be included as an event for the DFS endpoint. 
13.1.2 Secondary Endpoints 
Overall Survival (OS) 
The secondary endpoint of this study is the overall survival, defined as the time from 
randomization to death, from any cause. Patients who do not have an OS event will be 
censored for OS at the date they were last known to be alive. 
Adverse Events (AEs) 
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CTCAE AEs and grade for each type of AE will be recorded for each patient separately 
for the first 12 cycles (mFOLFOX6 +/- atezolizumab) and the 6 months of continuation 
of atezolizumab. Similarly, scores (0-4) and maximum score for each PRO-CTCAE 
item will be recorded for each patient (≥18 years of age) separately for these two 
periods. 
13.2 
Sample Size and Accrual 
We anticipate randomizing a maximum of 700 adult patients (350 per arm) per statistical design. 
Patients aged 12 to <18 years old will be accrued and randomized, but they will not be counted 
toward the sample size of 700.  If the study reaches full accrual of 700 adult patients, enrollment 
will be closed to both adult and patients aged 12 to <18 years at the same time.   
When both NSABP C-08 and NCCTG N0147 adjuvant trials were simultaneously accruing 
patients, the NSABP C-08 trial accrued 110-130 patients/month and NCCTG N0147 
concurrently accrued 20-30 patients/month. Of these 150 patients/month accrual capacity, we 
estimate that 12% of colon cancers will show dMMR which calculates to 18 patients/month or 
216 patients/year. 
One and a half years after trial opening, if the accrual rate exceeds the projection (e.g. >25 
patients /month), we will consider amending the protocol to raise the accrual target and to allow 
the detection of a hazard ratio (HR) of > 0.6. 
13.2.1 Pathology Considerations 
We recognize that local/reference lab testing and central lab confirmatory testing may 
be performed using different antibodies and platforms for immunohistochemistry. 
Accordingly, and because of concerns over potential discrepant local/reference versus 
central testing results, central confirmation review will be performed retrospectively for 
all samples that had local or site-selected reference lab dMMR testing performed. We 
will examine the concordance rate after the first 100 samples have been tested and 
continue monitoring the rate every 100 samples thereafter. The discrepancy rate will be 
closely monitored for all reviewed samples by the A021502 Statisticians. If it is 
determined that the discrepancy rate of reviewed samples is high enough to impact the 
study power (e.g. decrease the study power to less than 85%), then an amendment to 
increase the sample size to account for this increased discrepancy rate may be 
considered. 
13.3 
Power Justification 
The best historical data available on the outcome of patients with stage III colon cancer comes 
from Intergroup Study N0147, where the 3-year DFS in MSI-H stage III patients treated with 
mFOLFOX6 was 75% [40]. We assume an accrual period of 3.24 years, minimum follow-up on 
all patients of 2.05 years, exponential survival, and that a one-sided log-rank test for superiority 
will be conducted at level 0.025. Additionally, we assume a dropout rate of 1.25% per year.  
Based on these assumptions, a sample size of 350 adult patients per arm (700 adult patients in 
total) will result in 165 events which are required to provide 90% power to detect a hazard ratio 
(HR) of 0.6 between the two treatment arms. The 3-year DFS estimate for the atezolizumab arm 
corresponding to this HR is 84.147%.  
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13.4 
Statistical Analysis Plan 
13.4.1 Primary Endpoint 
Treatment Efficacy Decision Rules 
Interim Analysis: Two interim analyses will be performed to assess treatment futility 
and superiority. The first interim analysis, for both efficacy and futility, will be 
performed at the time at which 50% of the projected number of events have occurred. 
The second interim analysis is for efficacy only and will be performed at the time at 
which 75% of the projected number of events have occurred. The number of DFS events 
will be the total number of DFS events observed from both adult and patients aged <18 
years. O’Brien-Fleming type stopping boundary will be used to control for overall alpha 
level. Gamma family spending function with parameter -5 will be used for futility 
boundary. The futility boundary will be considered non-binding. The specific hazard 
ratio and critical p-values for declaring superiority or futility at each analysis are 
specified in table below. Specifically, for example, at 1st interim analysis, if the hazard 
ratio of mFOLFOX6+atezo vs. mFOLFOX6 alone is greater or equal to 1.021 
(equivalently, p-value ≥ 0.538), the mFOLFOX6+atezo regimen will be considered 
inefficacious; if the hazard ratio is less or equal to 0.523 (equivalently, p-value ≤0.002), 
the mFOLFOX6+atezo regimen will be deemed effective. When DFS crosses either 
futility of efficacy boundary, the accrual will be suspended (if still ongoing), the 
enrolled patients followed per protocol, and the data will be reported.   
Final Analysis: The primary efficacy analysis will be performed at the time where 165 
DFS events have occurred.  The number of DFS events will be the total number of DFS 
events observed from both adult and patients aged <18 years. The specific hazard ratio 
and critical p-values for declaring superiority or futility at each analysis are specified in 
table below.  Specifically, at the final analysis, if the hazard ratio is less or equal to 
0.731 (equivalently, p-value ≤0.022), the mFOLFOX6+atezo regimen will be deemed 
effective; otherwise, mFOLFOX6+atezo regimen will be considered to have not met the 
criteria for efficacy.  
Analysis time 
point (% 
events) 
Number of 
events 
Critical p-
value for 
efficacy 
HR for 
efficacy 
Critical p-
value for 
futility 
HR for futility 
50% 
83 
0.002 
0.523 
0.538 
1.021 
75% 
124 
0.009 
0.655 
NA 
NA 
100% 
165 
0.022 
0.731 
0.022 
0.731 
Operating Characteristics: The table below shows the operating characteristics 
assuming the DFS follows exponential survival functions. The table below includes the 
operating characteristics according to the monitoring plan outlined above.  The 
proportion of times that 1) the study would stop early at 1st interim analysis due to 
futility of mFOLFOX6+atezo, 2) the study would stop early at 1st or 2nd interim analyses 
due to efficacy of mFOLFOX6+atezo, and 3) the study would conclude 
mFOLFOX6+atezo is superior to mFOLFOX6 alone at the final analysis, are tabulated 
by true 3-year rates and equivalent true hazard ratio for DFS by treatment groups. 
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True 3-year DFS rate† 
True 
Hazard 
Ratio 
%‡ of times the 
study will be 
stopped early for 
futility 
%‡ of times the 
study will be 
stopped early for 
efficacy 
%‡ of times that 
mFOLFOX6 + 
atezo is superior 
at the final 
analysis 
mFOLFOX6 
alone 
mFOLFOX6 
+ atezo 
1st 
interim 
analysis 
2nd 
interim 
analysis 
1st 
interim 
analysis 
2nd 
interim 
analysis 
0.75 
0.841 
0.60 
0.81 
NA 
24.96 
42.59 
89.26 
0.75 
0.829 
0.65 
2.07 
NA 
15.50 
35.93 
77.51 
0.75 
0.818 
0.70 
4.69 
NA 
13.49 
27.14 
59.37 
0.75 
0.794 
0.8 
13.17 
NA 
2.52 
11.35 
29.74 
0.75 
0.772 
0.9 
28.16 
NA 
0.6 
3.51 
5.84 
0.75 
0.75 
1 
46.12 
NA 
0.13 
0.8 
2.66 
DFS: disease-free survival  
† Although we use the 3-year rates to illustrate each scenario, the hypothesis testing is based on the entire 
survival curve.  
‡ Proportions are based on 10,000 replicates in the simulation study. 
Analysis Plan: DFS will be compared between treatment arms using the stratified log 
rank test at one-sided level 0.025. The stratification factors listed in Section 4.6, as 
collected at the time of randomization in OPEN, will be used for the analysis. If there 
are zero DFS events observed in any of the strata, unstratified log-rank test will be used. 
If zero DFS events are observed in a certain stratum at an interim analysis and 
unstratified log-rank is used, all subsequent analyses for DFS will use unstratified log-
rank test. The HR for DFS will be estimated using a Cox proportional hazards model 
and the 95% CI for the HR will be provided. If a stratified log-rank test is used, stratified 
HR will be considered, and if an unstratified log-rank test is used, unstratified HR will 
be considered. Kaplan-Meier methodology will be used to estimate the median DFS for 
each treatment arm, and Kaplan-Meier curves will be produced. Brookmeyer-Crowley 
methodology will be used to construct the 95% CI for the median DFS for each 
treatment arm (Brookmeyer and Crowley 1982). 
Sensitivity Analysis Plan:  
1) One additional censoring rule will be added for missed disease assessments. For 
patients with a DFS event who missed one or more scheduled assessments 
immediately prior to the DFS event, the DFS event will be censored at the last tumor 
assessment prior to the missed disease assessment. 
2) For patients with a DFS event who missed one or more scheduled disease 
assessments immediately prior to the DFS event, the DFS event will be dated on the 
earliest missed assessment (after the last known tumor assessment). This sensitivity 
analysis is aimed to assess the impact of missing disease assessment.  
13.4.2  Secondary Endpoints 
Overall Survival: The distribution of overall survival will be estimated using the method 
of Kaplan-Meier. Overall survival will be compared between treatment arms using the 
stratified log-rank test, only if DFS is statistically significant. The stratification factors 
listed in Section 4.6, as collected at the time of randomization in OPEN, will be used 
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for the analysis. If there are zero OS events observed in any of the strata, unstratified 
log-rank test will be used. If zero OS events are observed in a certain stratum at an 
interim analysis and unstratified log-rank is used, all subsequent analyses for OS will 
use unstratified log-rank test. The HR for OS will be estimated using a Cox proportional 
hazards model and the 95% CI for the HR will be provided. If a stratified log-rank test 
is used, stratified HR will be considered, and if an unstratified log-rank test is used, 
unstratified HR will be considered. 
We assume an accrual period of 3.24 years, with accrual target of 700 patients, 
exponential survival, and that a one-sided log-rank test for superiority will be conducted 
at level 0.025. Five-year OS in MSI-H stage III patients treated with mFOLFOX6 was 
78.3% (unpublished manuscript by Sinicrope et al.). Based on these assumptions, 163 
events are required to provide 90% power to detect a hazard ratio (HR) of 0.6 between 
the two treatment arms. The 5-year OS estimate corresponding to this HR is 86.35%.  
There will be one interim analysis for overall survival (OS) which will be carried out if 
DFS crosses an interim efficacy stopping boundary, or at the time of the final DFS 
analysis, if no interim DFS boundary is crossed. The interim analysis will be for efficacy 
only. One final OS analysis will be conducted after approximately 163 deaths are 
observed. The number of OS events will be the total number of OS events observed 
from both adult and patients aged <18 years. The O’Brien-Fleming type stopping 
boundary will be used to control for overall alpha level. The HR and critical p-values 
for declaring efficacy for OS are specified in the table below. 
Analysis Time Point 
(% death events) 
Expected Number of OS 
Events 
Critical P-Value for 
Efficacy (1-sided) 
HR for Efficacy 
1st DFS IA (28%)a 
46 
0.00002 
0.302 
2nd DFS IA (42%)a 
68 
0.001 
0.451 
DFS PA (57%)b 
93 
0.003 
0.563 
100% (Final) 
163 
0.024 
0.734 
a. 
If DFS crosses efficacy stopping boundary at that analysis 
b. 
If DFS was not crossed at either DFS interim analysis 
IA = interim analysis; PA = primary analysis 
The actual critical values used will be determined by the observed OS events at the time 
of the DFS analysis as well as that (those) at the previous DFS analysis (analyses) where 
applicable. 
13.4.3 Adverse Events (AE) 
AEs and the grade for each type of adverse event will be recorded for each patient 
separately for the first 12 cycles (mFOLFOX6 +/- atezolizumab) and the 6 months of 
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continuation of atezolizumab. Similarly, scores (0-4) and maximum score for each 
PRO-CTCAE item will be recorded for each patient separately for these two periods. 
For CTCAE data, the frequency tables will be reviewed to determine the patterns. The 
overall adverse event rates will be compared between treatment groups using Chi-
square test (or Fisher’s exact test if the data in contingency table is sparse). 
PRO-CTCAE data will, at minimum, be analyzed similarly to CTCAE data. Reasons 
for missed PRO-CTCAE assessments will be collected and we will describe the extent 
of missing data as well as its patterns and causes. The initial analysis of each PRO-
CTCAE item will use all available scores in an analysis which mirrors the approach 
used for the CTCAE data. Supplemental analysis will use model-based multiple 
imputation incorporating baseline patient characteristics and physician-rated 
performance status (which is collected at each cycle). CTCAE data may be incorporated 
as axillary data into multiple imputation models for AEs which are captured by both 
PRO-CTCAE and CTCAE. Results from supplemental analysis will be descriptively 
compared to the results of the initial analysis to assess the robustness of results to 
missing data. Since a preferred or optimal statistical methodology for PRO-CTCAE 
data is yet to be determined, additional analyses of PRO-CTCAE data beyond those 
specified above may be undertaken based on the current state of the science at time of 
data maturity for this study. 
13.5 
Adverse Event Stopping Rule 
The monitoring rules specified below are based on the knowledge available at study 
development. We note that the Adverse Event Stopping Rule may be adjusted in the event of 
either (1) the study re-opening to accrual, or (2) at any time during the conduct of the trial and 
in consideration of newly acquired information regarding the adverse event profile of the 
treatment(s) under investigation. The study team may choose to suspend accrual because of 
unexpected adverse event profiles that have not crossed the specified rule below. 
Death within 60 days is a tool that has proved useful in reviewing adverse event data as it 
removes any possible subjectivity. It has the caveat of including all deaths, from any cause, even 
those not related to therapy [41]. The following table provides a listing of the death rate seen in 
other large randomized trials in stage III or II/III colon cancer [8, 42-45]. Note: a consistent 
metric has not been used for all of these trials. Some studies have utilized a ‘pure’ 60-day all-
cause mortality rate, whereas others have excluded deaths not felt to be due to treatment. 
Trial 
Experimental Arm 
Control Arm 
Regimen 
Death Rate 
Regimen 
Death Rate 
X-ACT 
Capecitabine 
0.80% 
5FU/LV 
1.03% 
MOSAIC 
FOLFOX 
0.54% 
LV5FU2 
0.54% 
NSABP C-07 
FLOX 
1.25% 
5FU/LV 
1.16% 
NSABP C-08 
(death within 60 days) 
FOLFOX+bevacizumab 
0.96% 
FOLFOX 
0.90% 
N0147 
FOLFOX+cetuximab 
0.70% 
FOLFOX 
0.10% 
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(death within 60 days) 
Based on these experiences, we consider a rate of death within 60 days of 1.25% on the 
mFOLFOX6+atezo arm as the upper threshold of acceptability for this trial. We will monitor 
this rate continuously. If at any time the 80% two-sided confidence interval for the rate of death 
within the first 60 days after initiation of mFOLFOX6+atezo excludes 1.25% to the right (i.e. 
only includes values greater than 1.25%), the Alliance Data Safety Monitoring Board (DSMB) 
and CTEP will be immediately notified to discuss the possible need to enact a protocol 
amendment or to discontinue the trial. 
This study will be monitored by the Alliance DSMB, an NCI-approved functioning body. 
Reports containing efficacy, adverse event, and administrative information will be provided to 
the DSMB every six months as per NCI guidelines.  
13.6 
Protocol-specific Monitoring Plan 
This trial will utilize both central and on-site monitoring in order to ensure complete and 
consistent data collection.  
Central Data Monitoring and Source Data Verification 
Centralized data monitoring activities will be performed for the first three treatment cycles for 
the first two patient cases enrolled at each site (as identified by a unique CTEP Institution Code) 
and then for every fourth patient case enrolled thereafter at the site. The cases selected for central 
data monitoring will be reviewed for completeness and consistency via source data verification 
(SDV) with source documents compared to the data reported via the electronic Case Report 
Forms in Rave. Central data monitoring with SDV will be performed for all patients for key 
eligibility and response/disease outcomes. 
A source document is a document in which data collected for a clinical trial is first recorded. 
This data is usually later entered in the Case Report Forms. The ICH-GCP guidelines define 
source documents as original documents, data, and records.   
The following data and documents will be reviewed via centralized data monitoring and source 
documents should be uploaded within the two weeks after registration: 
1) Informed Consent: Deidentified last page of the signed and dated informed consent 
document including any pages with responses indicated by patient for optional studies 
(patient’s full signature should be redacted, but date should be retained). 
2) Key Eligibility Criteria: 
a. Documentation of Disease: MMR laboratory report. 
b. Disease Status: Pathology report, operative report, imaging reports, and 
additional relevant source documents. 
c. Prior Treatment: Clinic notes and other relevant source documents. 
d. Comorbid Conditions: Pathology report, laboratory reports, clinic notes, and 
other relevant source documents. 
See the Data Submission Schedule, available on the Alliance and CTSU websites, 
for additional details regarding source data verification of key eligibility criteria. 
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3) Treatment Verification/IP Administration: Applicable drug administration and 
dosing records to document the first three cycles of treatment. 
4) Laboratory Test Results: laboratory reports, clinic notes (if applicable) 
5) Disease Evaluations: Applicable radiology, imaging assessment, and colonoscopy 
reports to document disease evaluations and primary endpoint. 
Sites should ensure that patient identifiers have been removed from all pages that will be 
uploaded and add study-specific identifying information (i.e. Alliance Patient ID) and then scan 
and upload all documents to Rave. Please ensure that all pages are legible and correct. 
In the event central monitoring or review of performance indicators (KPIs) identify deficiencies, 
then additional central monitoring, an unscheduled on-site monitoring visit, or an audit visit may 
be triggered. Deficiencies or KPIs that may elicit one of these responses include, but are not 
limited to: 
• 
Accrual rate 
• 
Eligibility 
• 
Early termination 
• 
Data submission timeliness 
• 
Outstanding forms 
• 
Outstanding queries 
• 
Query responsiveness 
• 
Protocol deviations 
On-site Monitoring 
Member networks that accrue less than five patients per year will not be monitored on site, 
unless other deficiencies have been identified, and thus indicate the need for a monitoring visit. 
Member networks that accrue five or more patients will be monitored approximately every 12 
months. Member networks that accrue 10 or more patients per year will be monitored 
approximately every 6 months. 
The first on-site monitoring visit will occur after the fifth patient has been enrolled and within 
6 months after the fifth patient enrollment. Thereafter, on-site monitoring visits will occur at 
approximately 12-month intervals during the treatment phase of the study.  
At the end of each on-site monitoring visit, the monitor will debrief the site study team and 
highlight areas that need improvement (if applicable). Any actions or findings will be 
documented in a visit follow-up letter, and on-site monitoring visit follow-up letters will be 
distributed to the Site Principal Investigator and Lead Clinical Research Professional within 4 
weeks (30 days) of the last day of the on-site monitoring visit, but no later than 6 weeks (42 
days). 
All affiliate/component sites will be monitored at the main member site during scheduled on-
site visits, unless a separate on-site visit is deemed necessary. All records from 
affiliate/component sites must be accessible to monitors. 
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Routine monitoring visits will be scheduled at approximately 6-12-month intervals, depending 
on accrual and other KPIs to ensure proper oversight of trial execution. On-site monitoring visits 
will only be conducted during the treatment phase. Central data monitoring will continue and 
sites will be audited per the Alliance auditing schedule during the follow-up phase.  
Frequency of monitoring visits may be adjusted and will be determined based upon factors such 
as enrollment rate, data quality, protocol compliance, site performance, and the available amount 
of data to be monitored. 
Inadequate attention to the protection of rights and safety of human patients, unreported or 
underreported safety information, or other non-compliance may result in an increase in the 
percentage of patient data monitored or monitoring visit frequency. 
At selected sites, a minimum of 25% of patients will be selected for on-site SDV of the 
following:  
• 
Primary endpoint 
• 
Secondary endpoints 
At selected sites, a minimum of 25% of patients will be selected for on-site SDV of the 
following:  
• Eligibility 
At selected sites, 100% of patients will be selected for on-site SDV of the following: 
• 
Informed consent 
• 
Expedited adverse events/serious adverse events 
• 
Treatment administration 
• 
Patient termination 
On-site audits will be conducted according to the NCI Clinical Trials Monitoring Branch 
guidelines. 
On-site monitoring will be conducted according to Alliance procedures. 
13.7 
Descriptive Factors  
• 
Number of Lymph Nodes Resected and Examined: ≥ 12 vs. < 12 
• 
Tumor Characteristics, Perforation: Yes vs. No 
• 
Tumor Characteristics, Obstruction: Yes vs. No 
• 
Tumor Characteristics, Adherence: Yes vs. No 
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In addition, reported studies have not assessed the impact of atezolizumab using patient-
reported outcomes.  The purpose of this correlative study is to assess the impact of 
atezolizumab (both short-term during treatment as well as long-term at the 3-year post-
registration time point) on patient-reported neuropathy, overall quality of life, and 
functioning. We will also assess health utilities and quality adjusted life years (QALYs) 
to fulfill Genentech requirements, and to combine PROs with overall survival data to 
complement the efficacy findings of the main protocol. Additionally, we intend to 
further investigate a methodological question about the relationship between bother 
from side effects and newly developed PRO-CTCAE items which are collected within 
the standard adverse event reporting of the main protocol. 
14.1.2 Objectives 
Primary: Compare peripheral neuropathy during the first six months of the study as 
assessed by the FACT/GOG-NTX (NTX subscale score – sensory items) between 
patients randomized to mFOLFOX6 + atezolizumab vs. mFOLFOX6. We hypothesize 
that patient-reported neuropathy will be non-inferior in the mFOLFOX6 + atezolizumab 
arm compared to the mFOLFOX6 arm. 
Secondary: Compare health-related quality of life (HRQL) during the first six months 
of the study as assessed by the FACT-C Trial Outcome Index (TOI) between patients 
randomized to mFOLFOX6 + atezolizumab vs. mFOLFOX6. We hypothesize that 
HRQL will be non-inferior in the mFOLFOX6 + atezolizumab arm compared to the 
mFOLFOX6 arm. 
Exploratory: Compare health utilities during the first six months of the study as assess 
by the EQ-5D-5L between patients randomized to mFOLFOX6 + atezolizumab vs. 
mFOLFOX6. We hypothesize that the health utilities will be non-inferior in the 
mFOLFOX6 + atezolizumab arm compared to the mFOLFOX6 arm.  
Exploratory: Compare patient-reported neuropathy and HRQL at the 3-year long-term 
follow-up between patients randomized to mFOLFOX6 + atezolizumab vs. 
mFOLFOX6. We hypothesize that patient-reported neuropathy and HRQL of the 
mFOLFOX6 + atezolizumab arm will be non-inferior to that of the mFOLFOX6 alone 
arm.  
Exploratory: Explore the relationship between patient-reported symptom bother using 
the single item from the FACT-C “I am bothered by side effects of treatment” and 
patient-reported symptomatic toxicity profile as measured by PRO-CTCAE (which is 
collected within the standard adverse event reporting of the main protocol). 
14.1.3 Methods 
The FACT-C quality of life questionnaire will be used to assess the quality of life of 
patients randomized to each treatment arm [12]. This questionnaire is comprised of 38 
validated questions that can be used in assessing quality of life in the study population. 
The FACT-C will be completed by consented patients at registration and approximately 
3 months, 6 months, 12 months, and 3 years after registration. Patient-reported 
neuropathy will also be assessed using the 11 additional questions of the FACT/GOG-
NTX [47]. EQ-5D-5L is a short, 6-question, instrument which assesses a patient’s 
overall quality of life or health state [48]. The addition of the EQ-5D-5L will allow for 
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computation and comparison between arms of health utilities and QALYs and is needed 
in the current protocol to satisfy European Union reimbursement agency requirements. 
For information regarding ordering and administering booklets, see Section 4.3 and 
Section 6.4. Booklets will be administered at the following time points in Arm 1: at 
registration, prior to treatment on Cycles 4, 7, and 13, at end of treatment, and 3 years 
after registration.  In Arm 2, time points were designed to match those of Arm 1, though 
require post-treatment time points since treatment is only 6 months in duration on this 
arm. Thus time points in Arm 2 include: at registration, prior to treatment on cycles 4 
and 7, at end of treatment, 12 months, and 3 years after registration. The booklet 
contains 55 questions and it is anticipated that the booklet will take approximately 10-
15 minutes for the patient to complete at each administration time point. We anticipate 
having booklets available in English and Spanish. Patients who consent to participate 
in this quality of life study (A021502-HO1) may decline to complete a booklet at any 
time. The primary reason for each missed booklet will be collected on a case report 
form. 
14.1.4 Statistical Considerations 
All questionnaires will be scored according to published scoring algorithms. The 
primary analysis over the first six months of treatment will involve a single mixed model 
for the primary endpoint of FACT/GOG-NTX NTX sensory neuropathy subscale score 
(sum of NTX1-4). A mixed model will compare time points up to the 1 year time point 
between randomized arms.  In addition to a randomized arm covariate, the model will 
include a randomized arm-by-time interaction term and will use the planned cycle of 
assessment as the categorical time value.  Unstructured covariance will initially be used, 
though alternative covariance structures will be investigated with the final covariance 
structure selected based on minimization of the Akaike information criterion. A contrast 
will be used to compare mean change from baseline at 6 months between arms. If the 
two-sided 95% confidence interval excludes a difference of 1.9 endpoints (on the 0-16 
point NTX sensory neuropathy scale) favoring the mFOLFOX6 arm, then non-
inferiority will be concluded. The difference of 1.9 points represents 0.5 standard 
deviations, or a clinically meaningful effect based on the work of Normal et al [49], 
using the pooled standard deviation (computed as 3.8 points) of the sensory neuropathy 
scale as reported at the end of treatment in Cella et al [50].  For the secondary endpoint 
of HRQOL (measured by the FACT-C TOI), a similar analysis will be undertaken with 
a non-inferiority cutoff of 6 points (which is the minimally important difference for the 
FACT-C TOI [51] favoring mFOLFOX6. Group differences and confidence intervals 
will also be constructed using standard effect sizes (i.e. differences in terms of standard 
deviation units) to aid in interpretation. Supplemental analysis will include similar non-
inferiority analyses for other scales of the FACT/GOG-NTX and FACT-C, including 
the constituent scales of the TOI, using published minimally important differences 
and/or standard effect sizes (i.e. 0.5 standard deviations) as cutoffs for non-inferiority 
at 6 months, and will include comparison of the mean changes from baseline at each of 
the remaining post-baseline time points. The change from 6 months to 1 year will also 
be compared between arms. In preliminary analyses, baseline patient characteristics will 
be compared between arms using t-tests for continuous variables and chi-squared tests 
for categorical variables in the cohort of patients who are evaluable for the primary 
analysis of this substudy. In the event that meaningful imbalances or other confounding 
factors are identified, supplemental analyses to the primary and secondary analyses will 
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incorporate baseline patient characteristics or other confounding factors as covariates in 
mixed models. 
Primary patient-reported outcome analysis will be conducted at the time that all 
consented patients have completed the 1-year assessment visit (or are no longer being 
followed for QOL).  The analysis of the 3-year time point will occur at the time that all 
consented patients have completed the 3-year assessment visit (or are no longer being 
followed for QOL).  Timing of release of the data for presentation will be at the 
discretion of the DSMB. Patients will be analyzed according to the randomized 
treatment arm assignment.  All randomized patients who consent for participation in the 
PRO component with a baseline endpoint value and at least one endpoint value post-
registration will be included in the analysis for a given endpoint.  In the primary 
analysis, all observations available will be used.  See below for information regarding 
analyses to account for missing data. 
Exploratory analysis will include similar mixed model comparisons of change from 
baseline in EQ-5D-5L health utility scores at 6 months with a non-inferiority margin of 
0.06 points [52]. Patient QALYs will be computed using the area-under-the-curve 
approach (with and without discounting) and will include all data through the follow-
up of the last consented patient (i.e. the earliest censored patient).  A population-based 
approach will also be used such that the area-under-the-curve of a quality-adjusted 
survival curve (mean health utility multiplied by the proportion of patients surviving 
based on Kaplan-Meier estimates) is the mean quality-adjusted survival for the 
population.  Mean quality-adjusted survival will then be compared between arms using 
a bootstrap approach. Exploratory analysis will also include comparison of the mean 
changes from baseline at the 3-year time point using a contrast from a mixed model 
(similar to the primary analysis, however including data through the 3-year time point). 
Finally, exploratory methodological analysis will include regression analyses at fixed 
time points to assess the relationship between patient-reported bother and PRO-CTCAE 
symptom profiles.  The goal is to investigate what drives symptom bother – individual 
symptoms (e.g. worst symptom score) or cumulative symptom experience (e.g. average 
symptom score). Potential PRO-CTCAE cut-points may also be explored.  Graphical 
procedures throughout analysis will include plots of average values over time by arm 
for each primary, secondary, and exploratory endpoint. 
For all statistical analyses, two-sided 95% confidence intervals will be used (p-values 
<0.05 will be considered statistically significant for hypothesis testing).  For interpreting 
the clinical significance of effects, 0.2, 0.5, and 0.8 standard deviation (SD) effects will 
be considered as small, moderate, and large based on Cohen [53] throughout.  
Minimally important differences for the FACT-C will also be used [51]. 
Missing data will be handled in a number of ways.  Missing items within a summary or 
scale score will be handled according to each questionnaire’s published scoring 
algorithms.  Missing data at the summary or scale score level will be handled as follows.  
Baseline patient/disease characteristics will be compared between patients who do and 
do not provide data for the primary analysis.  We will also graphically explore patterns 
of missing data.  All analyses will be completed using all available data, followed by 
analyses completed using a range of imputation methods.  Lastly, we will employ 
pattern mixture models for longitudinal analyses. Output from all analyses will be 
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tabulated and descriptively compared to assess the degree to which missing data impacts 
study results. 
Power: Assuming that 490 patients are evaluable for the primary analysis (i.e. allowing 
up to 30% of patients to decline consent or be non-evaluable for the primary analysis), 
this QOL study has 91% power to exclude a 1.9 point difference (a moderate and 
clinically meaningful 0.5 standard deviation difference) in patient-reported neuropathy 
between arms using a two-sided alpha=0.05 test, assuming that the pooled standard 
deviation is 3.8 points and the true difference between the arms is 0.76 points (a small 
0.2 standard deviation difference) favoring mFOLFOX6. If the true difference between 
arms is 0 points, this sample size would have 90% power to exclude a 1.14 point 
difference (a small to moderate 0.3 standard deviation difference) in patient-reported 
neuropathy between arms using a two-sided alpha=0.05 test, again assuming that the 
pooled standard deviation is 3.8 points.  The secondary analysis has 98% power, if the 
true difference in HRQOL between arms is 2.12 points (a small 0.2 standard deviation 
difference) favoring mFOLFOX6 assuming that the non-inferiority margin of 6 points 
represents a 0.56 standard deviation difference (i.e. assuming the FACT-C TOI scale 
has a standard deviation of 10.6) [54]. 
14.2 
Biomarker and Pharmacogenetic Studies in Alliance A021502: Mandatory Collection, 
A021502-PP1, and A021502-ST1  
All blood specimens, other than those collected in ACD tubes (for immune cell biomarker 
studies), will be shipped to the Alliance Biorepository at Mayo Clinic, and the Biorepository 
will release samples upon request. TMA blocks will be constructed for future molecular and 
immunohistochemical studies, as the use of TMAs allows us to perform a high throughput 
screen of all available colon cancers in our study population. Construction will be conducted at 
the Alliance Biorepository at Mayo Clinic following their standard method. Two 2 mm tissue 
cores each from a tumor are placed in each TMA.  
Note: Testing of banked samples will not occur until an amendment to this treatment protocol 
(or separate correlative science protocol) is reviewed and approved in accordance with National 
Clinical Trials Network (NCTN) policies. 
14.2.1 Mandatory Sample Collection Biomarker Studies 
Mismatch Repair (MMR) Concordance Analysis 
Since the methodology used for determining MMR status is not standardized among 
local testing or reference laboratory sites, tumor tissue will be used for retrospective 
central confirmation of dMMR status where the testing methodology can be 
standardized. We aim to ensure that all patients whose tumors were found to show 
deficient MMR at baseline do indeed show dMMR upon central testing, thus ensuring 
a uniform study population. 
The retrospective central dMMR confirmation testing will be performed by a central 
laboratory agreed upon by the Alliance and the drug company supporting this study 
using the VENTANA MMR IHC panel. The name and shipping address for the central 
laboratory are included on the A021502 Requisition Form which can be found on the 
Alliance and CTSU websites. The first concordance analysis will be performed by the 
Alliance Statistics and Data Center after the first 100 samples have been tested.  
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While the local (or site-selected reference lab) testing must be MMR IHC per the 
eligibility section, the use of a specific testing protocol or strategy has not been required. 
The central laboratory will utilize the VENTANA MMR IHC panel which has been 
shown to produce a high rate of concordance with MSI testing by PCR using the 
Promega MSI Analysis system [ref in press]. The VENTANA MMR IHC panel tests 
all four MMR proteins associated with colorectal cancer: MLH1, MSH2, MSH6, and 
PMS2. A loss of expression of any one of these antibodies indicates dMMR, and 
therefore microsatellite instability (MSI-H). The VENTANA MMR IHC panel is 
currently FDA-approved for testing for Lynch Syndrome and for evaluating MMR 
proteins in solid tumors. 
The required formalin-fixed, paraffin-embedded (FFPE) tumor tissues submitted 
directly to the central laboratory on Superfrost® Plus Micro Slides (or unstained, 
charged 5 micron slides) within 30 days of mounting to ensure sufficient antibody 
stability will be tested using the Ventana detection kits and a Ventana Roche 
BenchMark ULTRA automated slide-stainer.  
The VENTANNA MMR IHC assay uses DAB immunoperoxidase (brown reaction 
product) as the reporter signal using a 3-step immunoperoxidase approach. Secondary 
reagents used for the 3-step assay are the OptiView DAB IHC Detection Kit and the 
OptiView Amplification Kit (PMS2 only).  
In 2018, Ventana released an updated configuration to their MMR IHC panel class II 
device, replacing the reagent dispenser for the PMS2 primary antibody clone EPR3947 
for clone A16-4. There was also an update to the platform from the Benchmark to the 
Ultra platform Prior to central laboratory adoption of the updated VENTANA MMR 
IHC panel, 279 ATOMIC study samples were evaluated with the discontinued PMS2 
reagent. To evaluate MMR status in these cases with the FDA approved assay 
configuration, FFPE Tissue samples with sufficient tissue available for testing will have 
sections cut l to be resubmitted for central laboratory testing as described above. 
Negative colon carcinoma controls will be run simultaneously alongside the locally-
determined dMMR positive samples to reduce variability. Results of the retrospective 
central dMMR confirmation testing will not be reported back to the site; instead, the 
results will be recorded directly in Rave by lab personnel. 
Mismatch Repair (MMR) interpretation is binary, intact or loss, thus there is no 
established threshold for this analysis. Assay testing results were collected on 
retrospective data sets (> 100) using separate training and validation sets, and results 
were validated using OPA, NPA, PPA, APA, and ANA. Standardization of testing 
conditions in order to minimize variance was achieved by using calibrators/controls and 
an automated slide-stainer, the Ventana BenchMark ULTRA. Either colorectal or 
normal tonsil tissue was used as controls and samples were stained as separate slides 
with slides. These controls were then included in each slide and stained as internal 
controls (for all slides, normal control cells [fibroblasts, lymphocytes, epithelial cells] 
act as internal positive controls) [55, 56].  
Reproducibility of the Ventana assay has been previously assessed using colorectal 
tissue and determining whether the respective MMR protein was intact or loss. 
Replicates were done in duplicate, and all studies produced an intra-lab reproducibility 
(%CV) of great than 90% OPA, which met the primary endpoint. The pooled-analysis 
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results of the inter-lab reproducibility study are as follows: OPA of 99.4%, PPA of 
99.8%, and NPA of 98.9%. For the inter-lab reproducibility study, each MMR antibody 
was tested on 3 intact and 3 loss colorectal cases for a total of 24 cases using 3 different 
labs. The assays were performed on whole colorectal tissue sections on 5 non-
consecutive runs over the course of 21 days. Assay results were analyzed by two 
different readers at each side, and the agreement between readers was 99.5%, and 
differences were resolved using either a panel or arbitration [57-60].  
An accuracy study was performed comparing the VENTANNA MMR IHC to molecular 
testing (NGS, MSI, MLHI promoter hypermethylation testing), and the results of the 
primary pooled-analysis results are as follows: OPA of 98.5%, PPA of 99.3%, and NPA 
of 89.7%. In the same study group, dMMR (loss) was compared to pMMR (intact) with 
the following results: OPA or 97.4%, PPA of 98.8%, and NPA of 94.6%. There were 
no staining artifacts noted during the accuracy study, however, staining and tissue 
artifacts would have been captured in the comments and then reflected in the 
interpretation guide. 
14.2.2 Optional (A021502-PP1 and A021502-ST1) Sample Collection Biomarker Studies 
Blood, tissue, and stool specimens will be collected and stored for future translational 
research for patients who consent to participate. Future studies may include: mutation 
analysis, immune cell biomarker studies, ctDNA, inflammation markers/cytokines, 
pharmacogenetic studies, future molecular and immunohistochemical studies, and 
microbiome profiling from stool samples. Testing of banked specimens will not occur 
until an amendment to this treatment protocol (or separate correlative science protocol) 
is reviewed and approved in accordance with National Clinical Trials Network (NCTN) 
policies. 
 
 
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15.0 REFERENCES 
1. 
Jemal, A., et al., Cancer statistics, 2008. CA Cancer J Clin, 2008. 58(2): p. 71-96. 
2. 
O'Connell, M.J., Current status of adjuvant therapy for colorectal cancer. Oncology (Huntingt), 
2004. 18(6): p. 751-5; discussion 755-8. 
3. 
Poles, G.C., et al., Colorectal carcinoma in pediatric patients: A comparison with adult tumors, 
treatment and outcomes from the National Cancer Database. J Pediatr Surg, 2016. 51(7): p. 
1061-6. 
4. 
Sultan, I., et al., Distinct features of colorectal cancer in children and adolescents: a population-
based study of 159 cases. Cancer, 2010. 116(3): p. 758-65. 
5. 
Heath, J.A., et al., Childhood cancers in families with and without Lynch syndrome. Fam Cancer, 
2015. 14(4): p. 545-51. 
6. 
de Gramont, A., et al. Oxaliplatin/5-FU/LV in adjuvant colon cancer: Results of the international 
randomized mosaic trial. in Proc Am Soc Clin Oncol. 2003. 
7. 
de Gramont, A., et al., Oxaliplatin/5FU/LV in adjuvant colon cancer: Updated efficacy results of 
the MOSAIC trial, including survival, with a median follow-up of six years. J Clin Oncol, 2007. 
25(18S): p. Abstract 4007. 
8. 
Andre, T., et al., Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon 
cancer. N Engl J Med, 2004. 350(23): p. 2343-51. 
9. 
Alberts, S.R., et al., Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab 
on survival among patients with resected stage III colon cancer: a randomized trial. JAMA, 
2012. 307(13): p. 1383-93. 
10. 
Taieb, J., et al., Oxaliplatin, fluorouracil, and leucovorin with or without cetuximab in patients 
with resected stage III colon cancer (PETACC-8): an open-label, randomised phase 3 trial. 
Lancet Oncol, 2014. 15(8): p. 862-73. 
11. 
Allegra, C.J., et al., Phase III trial assessing bevacizumab in stages II and III carcinoma of the 
colon: results of NSABP protocol C-08. J Clin Oncol, 2011. 29(1): p. 11-6. 
12. 
Grothey, A., et al., Duration of Adjuvant Chemotherapy for Stage III Colon Cancer. New 
England Journal of Medicine, 2018. 378(13): p. 1177-1188. 
13. 
Stoffel, E.M. and C.R. Boland, Genetics and Genetic Testing in Hereditary Colorectal Cancer. 
Gastroenterology, 2015. 149(5): p. 1191-1203 e2. 
14. 
Domingo, E., et al., BRAF screening as a low-cost effective strategy for simplifying HNPCC 
genetic testing. J Med Genet, 2004. 41(9): p. 664-8. 
15. 
Warren, B., Adjuvant chemotherapy for breast disease: the nurse's role. Cancer Nurs, 1979. 2(1): 
p. 32-7. 
16. 
Sinicrope, F.A., et al., Molecular markers identify subtypes of stage III colon cancer associated 
with patient outcomes. Gastroenterology, 2015. 148(1): p. 88-99. 
17. 
Llosa NJ, e.a., The Vigorous Immune Microenvironment of Microsatellite Instable Colon Cancer 
Is Balanced by Multiple Counter-Inhibitory Checkpoints. Cancer Discovery, 2015. 5(43). 
18. 
Le, D.T., et al., PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. New England 
Journal of Medicine, 2015. 372(26): p. 2509-2520. 
Use of this document is governed by the terms of use on the first page of this document.

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19. 
Sinicrope, F.A. and D.J. Sargent, Molecular Pathways: Microsatellite Instability in Colorectal 
Cancer: Prognostic, Predictive, and Therapeutic Implications. Clinical Cancer Research, 2012. 
18(6): p. 1506-1512. 
20. 
Segal, N.e.a., Preliminary data from a multi-arm expansion study of MEDI4736, an anti-PD-L1 
antibody. J Clin Oncol, 2014. 32(15 suppl): p. May 20 supplement, 3002. 
21. 
Herbst, R.e.a., A study of MPDL3280A, an engineered PD-L1 antibody in patients with locally 
advanced or metastatic tumors. J Clin Oncol, 2013. 31(15_suppl): p. May 20 Supplement. 
22. 
Heery, C.e.a., Phase I open-label, multiple ascending dose trial of MSB0010718C, an anti-PD-L1 
monoclonal antibody, in advanced solid malignancies. J Clin Oncol, 2014. 32(15_suppl (May 20 
supplement)): p. 3064. 
23. 
Comprehensive molecular characterization of human colon and rectal cancer. Nature, 2012. 
487(7407): p. 330-7. 
24. 
Schwitalle, Y., et al., Immune response against frameshift-induced neopeptides in HNPCC 
patients and healthy HNPCC mutation carriers. Gastroenterology, 2008. 134(4): p. 988-97. 
25. 
Rizvi, N.A., et al., Cancer immunology. Mutational landscape determines sensitivity to PD-1 
blockade in non-small cell lung cancer. Science, 2015. 348(6230): p. 124-8. 
26. 
Llosa, N.J., et al., The vigorous immune microenvironment of microsatellite instable colon cancer 
is balanced by multiple counter-inhibitory checkpoints. Cancer Discov, 2015. 5(1): p. 43-51. 
27. 
Lee, L.H., et al., Patterns and prognostic relevance of PD-1 and PD-L1 expression in colorectal 
carcinoma. Modern pathology : an official journal of the United States and Canadian Academy of 
Pathology, Inc, 2016. 
28. 
Dunne, P.D., et al., Immune-Derived PD-L1 Gene Expression Defines a Subgroup of Stage II/III 
Colorectal Cancer Patients with Favorable Prognosis Who May Be Harmed by Adjuvant 
Chemotherapy. Cancer immunology research, 2016. 4(7): p. 582-91. 
29. 
Sharma, P. and J.P. Allison, The future of immune checkpoint therapy. Science, 2015. 348(6230): 
p. 56-61. 
30. 
Zitvogel, L., O. Kepp, and G. Kroemer, Immune parameters affecting the efficacy of 
chemotherapeutic regimens. Nat Rev Clin Oncol, 2011. 8(3): p. 151-160. 
31. 
Hato, S.V., et al., Molecular pathways: the immunogenic effects of platinum-based 
chemotherapeutics. Clin Cancer Res, 2014. 20(11): p. 2831-7. 
32. 
Shalapour, S., et al., Immunosuppressive plasma cells impede T-cell-dependent immunogenic 
chemotherapy. Nature, 2015. 521(7550): p. 94-8. 
33. 
Bendell, J.e.a., Safety and efficacy of MPDL3280A (anti-PDL1) in combination with bevacizumab 
(bev) and/or FOLFOX in patients (pts) with metastatic colorectal cancer (mCRC). J Clin Oncol, 
2015. 33(3_supple (January 20 Supplement)): p. 704. 
34. 
Schmoll, H., et al., 612TiPMODUL–A MULTICENTRE RANDOMISED CLINICAL TRIAL OF 
BIOMARKER-DRIVEN THERAPY FOR THE 1ST-LINE MAINTENANCE TREATMENT OF 
METASTATIC COLORECTAL CANCER (MCRC): A SIGNAL-SEEKING APPROACH. Annals of 
Oncology, 2014. 25(suppl 4): p. iv209. 
Use of this document is governed by the terms of use on the first page of this document.

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35. 
Shemesh, C.S., et al., Population pharmacokinetics, exposure-safety, and immunogenicity of 
atezolizumab in pediatric and young adult patients with cancer. J Immunother Cancer, 2019. 
7(1): p. 314. 
36. 
Fehrenbacher, L., et al., Atezolizumab versus docetaxel for patients with previously treated non-
small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled 
trial. Lancet, 2016. 387(10030): p. 1837-46. 
37. 
Le, D.T., et al., PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med, 
2015. 372(26): p. 2509-20. 
38. 
André , T., et al., Oxaliplatin, Fluorouracil, and Leucovorin as Adjuvant Treatment for Colon 
Cancer. New England Journal of Medicine, 2004. 350(23): p. 2343-2351. 
39. 
Zelen, M., The randomization and stratification of patients to clinical trials. J Chronic Dis, 1974. 
27(7-8): p. 365-75. 
40. 
Sinicrope, F.A., et al., Prognostic impact of deficient DNA mismatch repair in patients with stage 
III colon cancer from a randomized trial of FOLFOX-based adjuvant chemotherapy. J Clin 
Oncol, 2013. 31(29): p. 3664-72. 
41. 
Goldberg, R.M., et al., A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, 
and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J 
Clin Oncol, 2004. 22(1): p. 23-30. 
42. 
Twelves, C., et al., Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med, 
2005. 352(26): p. 2696-704. 
43. 
Wolmark, N., et al., A phase III trial comparing FULV to FULV plus oxaliplatin in stage II or III 
carcinoma of the colon: Results of NSABP Protocol C-07. Journal of Clinical Oncology, 2005. 
23(16): p. 246s-246s. 
44. 
Allegra, C.J., et al., Initial Safety Report of NSABP C-08: A Randomized Phase III Study of 
Modified FOLFOX6 With or Without Bevacizumab for the Adjuvant Treatment of Patients With 
Stage II or III Colon Cancer. Journal of Clinical Oncology, 2009. 27(20): p. 3385-3390. 
45. 
Alberts, S.R., et al., Effect of Oxaliplatin, Fluorouracil, and Leucovorin With or Without 
Cetuximab on Survival Among Patients With Resected Stage III Colon Cancer A Randomized 
Trial. Jama-Journal of the American Medical Association, 2012. 307(13): p. 1383-1393. 
46. 
Morucci, G., et al., Gc-protein-derived macrophage activating factor counteracts the neuronal 
damage induced by oxaliplatin. Anticancer Drugs, 2015. 26(2): p. 197-209. 
47. 
Calhoun, E.A., et al., Psychometric evaluation of the Functional Assessment of Cancer 
Therapy/Gynecologic Oncology Group-Neurotoxicity (Fact/GOG-Ntx) questionnaire for patients 
receiving systemic chemotherapy. Int J Gynecol Cancer, 2003. 13(6): p. 741-8. 
48. 
Pickard, A.S., et al., Psychometric comparison of the standard EQ-5D to a 5 level version in 
cancer patients. Med Care, 2007. 45(3): p. 259-63. 
49. 
Norman, G.R., J.A. Sloan, and K.W. Wyrwich, The truly remarkable universality of half a 
standard deviation: confirmation through another look. Expert Rev Pharmacoecon Outcomes 
Res, 2004. 4(5): p. 581-5. 
Use of this document is governed by the terms of use on the first page of this document.

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50. 
Cella, D., et al., Patient-reported peripheral neuropathy of doxorubicin and cisplatin with and 
without paclitaxel in the treatment of advanced endometrial cancer: Results from GOG 184. 
Gynecol Oncol, 2010. 119(3): p. 538-42. 
51. 
Yost, K.J., et al., Minimally important differences were estimated for the Functional Assessment 
of Cancer Therapy-Colorectal (FACT-C) instrument using a combination of distribution- and 
anchor-based approaches. J Clin Epidemiol, 2005. 58(12): p. 1241-51. 
52. 
Pickard, A.S., M.P. Neary, and D. Cella, Estimation of minimally important differences in EQ-5D 
utility and VAS scores in cancer. Health Qual Life Outcomes, 2007. 5: p. 70. 
53. 
Cohen, J., Statistical power analysis for the behavioral sciences. 1988, Hillsdale, N.J.: L. 
Erlbaum Associates. 
54. 
Uwer, L., et al., Responsiveness of EORTC QLQ-C30, QLQ-CR38 and FACT-C quality of life 
questionnaires in patients with colorectal cancer. Health Qual Life Outcomes, 2011. 9: p. 70. 
55. 
Fitzgibbons, P.L., et al., Recommendations for validating estrogen and progesterone receptor 
immunohistochemistry assays. Arch Pathol Lab Med, 2010. 134(6): p. 930-5. 
56. 
Chau, C.H., et al., Validation of analytic methods for biomarkers used in drug development. Clin 
Cancer Res, 2008. 14(19): p. 5967-76. 
57. 
Cicchetti, D.V. and A.R. Feinstein, High agreement but low kappa: II. Resolving the paradoxes. J 
Clin Epidemiol, 1990. 43(6): p. 551-8. 
58. 
Pepe, M.S., et al., Phases of biomarker development for early detection of cancer. J Natl Cancer 
Inst, 2001. 93(14): p. 1054-61. 
59. 
Hammond, M.E., et al., American Society of Clinical Oncology/College of American Pathologists 
guideline recommendations for immunohistochemical testing of estrogen and progesterone 
receptors in breast cancer (unabridged version). Arch Pathol Lab Med, 2010. 134(7): p. e48-72. 
60. 
Gross, D.S. and J.M. Rothfeld, Quantitative immunocytochemistry of hypothalamic and pituitary 
hormones: validation of an automated, computerized image analysis system. J Histochem 
Cytochem, 1985. 33(1): p. 11-20. 
 
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APPENDIX I 
QUALITY OF LIFE MEASURES 
 
 
Registration Fatigue/Uniscale Assessments 
 
At patient registration, this form is to be administered by a nurse/CRA, completed by the patient, 
and entered into Medidata Rave at the time of registration. 
 
If needed, this appendix can be adapted to use as a source document.  A booklet containing this 
assessment does not exist – please do not order this booklet. 
 
 
 
How would you describe: 
 
your level of fatigue, on the average in the past week including today? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
Fatigue 
 
 
 
 
 
 
 
 
 
Fatigue 
as bad  
as it can be 
 
your overall quality of life in the past week including today? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
As bad as 
it can be 
 
 
 
 
 
 
 
 
 
As good as 
it can be 
 
 
 
 
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Patient Booklet 
 
______________________________________________________________________________ 
 
You have been given a booklet to complete for this study. The booklet contains some 
questions about your ‘quality of life’ and the side effects you are experiencing as a patient 
receiving treatment for cancer. Your answers will help us to better understand how the 
treatment you are receiving is affecting the way you feel. 
 
 
1. This booklet contains three sets of questions:  
 
a. FACT-C (38 questions) 
b. FACT/GOG-NTX (11 questions) 
c. EQ-5D-5L (6 questions) 
 
2. Please follow the directions at the top of this questionnaire. 
 
3. You may choose not to answer any questions that make you feel uncomfortable. 
 
4. Please complete the booklet during your scheduled clinical visit and return it to your 
nurse, physician, or research coordinator. 
 
 
Thank you for taking the time to help us. 
 
 
 
 
 
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EQ-5D-5L 
 
Under each heading, please check the ONE box that best describes your health TODAY. 
MOBILITY 
 
I have no problems walking 
 
I have slight problems walking 
 
I have moderate problems walking 
 
I have severe problems walking 
 
I am unable to walk 
 
SELF-CARE 
 
I have no problems washing or dressing myself 
 
I have slight problems washing or dressing myself 
 
I have moderate problems washing or dressing myself 
 
I have severe problems washing or dressing myself 
 
I am unable to wash or dress myself 
 
USUAL ACTIVITIES (e.g. work, study, housework, family or leisure activities) 
 
I have no problems doing my usual activities 
 
I have slight problems doing my usual activities 
 
I have moderate problems doing my usual activities 
 
I have severe problems doing my usual activities 
 
I am unable to do my usual activities 
 
PAIN / DISCOMFORT 
 
I have no pain or discomfort 
 
I have slight pain or discomfort 
 
I have moderate pain or discomfort 
 
I have severe pain or discomfort 
 
I have extreme pain or discomfort 
 
ANXIETY / DEPRESSION 
 
I am not anxious or depressed 
 
I am slightly anxious or depressed 
 
I am moderately anxious or depressed 
 
I am severely anxious or depressed 
 
I am extremely anxious or depressed 
 
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The worst health 
you can imagine 
 
 
 
• 
We would like to know how good or bad your health is TODAY. 
• 
This scale is numbered from 0 to 100. 
• 
100 means the best health you can imagine. 
 0 means the worst health you can imagine. 
• 
Mark an X on the scale to indicate how your health is TODAY. 
• 
Now, please write the number you marked on the scale in the box below. 
 
  
 
 
YOUR HEALTH TODAY = 
10 
0 
20 
30 
40 
50 
60 
80 
70 
90 
100 
5 
15 
25 
35 
45 
55 
75 
65 
85 
95 
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National Cancer Institute PRO-CTCAE 
 
______________________________________________________________________________ 
 
You have been given a booklet to complete for this study. The booklet contains some 
questions about your ‘quality of life’ and the side effects you are experiencing as a patient 
receiving treatment for cancer. Your answers will help us to better understand how the 
treatment you are receiving is affecting the way you feel. 
 
 
1. This booklet contains one set of questions:  
 
a. National Cancer Institute PRO-CTCAE (20 questions) 
 
2. Please follow the directions at the top of this questionnaire. 
 
3. You may choose not to answer any questions that make you feel uncomfortable. 
 
4. Please complete the booklet during your scheduled clinical visit and return it to your 
nurse, physician, or research coordinator. 
 
 
Thank you for taking the time to help us. 
 
 
 
 
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○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very 
severe 
The PRO-CTCAE™ items and information herein were developed by the NATIONAL CANCER INSTITUTE at the 
NATIONAL INSTITUTES OF HEALTH, in Bethesda, Maryland, U.S.A. Use of the PRO-CTCAE™ is subject to 
NCI's Terms of Use. 
 
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APPENDIX II 
COLLABORATIVE AGREEMENTS PROVISIONS 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI under a 
Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical Company(ies) (hereinafter 
referred to as “Collaborator(s)”) and the NCI Division of Cancer Treatment and Diagnosis.  Therefore, 
the following obligations/guidelines, in addition to the provisions in the “Intellectual Property Option to 
Collaborator” (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within 
the terms of award, apply to the use of the Agent(s) in this study: 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can Agent(s) be 
transferred or licensed to any party not participating in the clinical study.  Collaborator(s) data for 
Agent(s) are confidential and proprietary to Collaborator(s) and shall be maintained as such by 
the investigators. The protocol documents for studies utilizing Agents contain confidential 
information and should not be shared or distributed without the permission of the NCI.  If a copy 
of this protocol is requested by a patient or patient’s family member participating on the study, 
the individual should sign a confidentiality agreement. A suitable model agreement can be 
downloaded from: http://ctep.cancer.gov. 
2. For a clinical protocol where there is an investigational Agent used in combination with (an)other 
Agent(s), each the subject of different Collaborative Agreements, the access to and use of data by 
each Collaborator shall be as follows (data pertaining to such combination use shall hereinafter be 
referred to as “Multi-Party Data”): 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement will be 
made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless additional 
disclosure is required by law or court order as described in the IP Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). Additionally, all 
Clinical Data and Results and Raw Data will be collected, used and disclosed consistent with all 
applicable federal statutes and regulations for the protection of human subjects, including, if 
applicable, the Standards for Privacy of Individually Identifiable Health Information set forth in 
45 C.F.R. Part 164. 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the NCI, 
who will then notify the appropriate investigators (Group Chair for Cooperative Group studies, or 
PI for other studies) of Collaborator's wish to contact them. 
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5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a DMC 
for this clinical trial. 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-Cooperative 
Group studies for immediate delivery to Collaborator(s) for advisory review and comment prior 
to submission for publication.  Collaborator(s) will have 30 days from the date of receipt for 
review.  Collaborator shall have the right to request that publication be delayed for up to an 
additional 30 days in order to ensure that Collaborator’s confidential and proprietary data, in 
addition to Collaborator(s)’s intellectual property rights, are protected.  Copies of abstracts must 
be provided to CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible 
and preferably at least three (3) days prior to submission, but in any case, prior to presentation at 
the meeting or publication in the proceedings. Press releases and other media presentations must 
also be forwarded to CTEP prior to release. Copies of any manuscript, abstract and/or press 
release/ media presentation should be sent to: 
Email: ncicteppubs@mail.nih.gov  
The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
 
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APPENDIX III STANDARD OF CARE FOLFOX PRIOR TO REGISTRATION CYCLE 1 
Patients may receive one cycle of mFOLFOX6 prior to registration to the trial, in the event that they 
are still in screening or have not yet made a decision to enroll. Treatment must be administered at the 
institution that intends to register the patient should they meet all eligibility criteria and consent to 
participate (i.e. the registering institution). The doses received of Cycle 1 of mFOLFOX6 must be 
the following: 
• 
5-FU 400 mg/m2 bolus followed by 2400 mg/m2 over 2 days 
• 
Leucovorin 400 mg/m2 * 
• 
Oxaliplatin 85 mg/m2 
* Minor variations (<10%) in leucovorin dose for prior to registration Cycle 1 of mFOLFOX6 
are permitted if needed to adhere to local institutional policy. 
Infusion rates and length of infusion are per institutional standard. Prior to receiving Cycle 2 of 
mFOLFOX6 on study, the patient must meet all lab parameters as described in eligibility criteria, 
which must be verified in the OPEN eligibility checklist, in order to be registered and randomized.  
Please note that Section 8.0 should be followed for Cycle 2 onward, based on the experienced toxicity 
with Cycle 1 and beyond.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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APPENDIX IV AIO GROUP-SPECIFIC APPENDIX 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
 
AIO-Studien-gGmbH 
 
AIO Group-specific Appendix 
for 
ALLIANCE A021502 
 
RANDOMIZED TRIAL OF STANDARD CHEMOTHERAPY ALONE OR COMBINED WITH ATEZOLIZUMAB  
AS ADJUVANT THERAPY FOR PATIENTS WITH STAGE III COLON CANCER  
AND DEFICIENT DNA MISMATCH REPAIR 
 
(ATOMIC: Adjuvant Trial of Deficient Mismatch Repair in Colon Cancer) 
Study codes: 
AIO-KRK-0317 
Alliance A021502  
MO39901 
EudraCT no.: 
2019-003562-40 
ClinicalTrials.gov Identifier:  
NCT02912559 
GSA version: 
Final V3.0, 06-OCT-2023 
Refers to protocol version: 
Update #14, 23-MAY-2023 
Investigational Product(s): 
Commercial Products(s): 
Atezolizumab 
5-Fluorouracil 
Oxaliplatin 
Calcium Folinate 
Sponsor: 
National Cancer Institute (NCI) 
Legal Representative of the Sponsor in 
Europe: 
AIO-Studien-gGmbH 
Principal Investigator, Study Chair: 
Dr. Frank A. Sinicrope, Rochester, MN, USA 
National Coordinating Investigator, 
Germany & E.U. 
: 
Prof. Dr. 
, Bochum, Germany 
Confidentiality 
The contents of the protocol are confidential and may neither be communicated verbally nor in 
writing without the agreement of AIO-Studien-gGmbH. 
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PREFACE 
The ATOMIC trial is a collaboration between: 
• 
The Alliance for Clinical Trials in Oncology (Alliance), a National Cancer Institute (NCI)-funded 
National Clinical Trials Network (NCTN) Group of academic and community-oriented sites that 
conducts cancer research. 
• 
The Arbeitsgemeinschaft Internistische Onkologie (AIO), a scientific non-profit organization under 
the umbrella of the German Cancer Society based in Berlin (DKG e.V.), Germany represented by 
its clinical trial branch AIO-Studien-gGmbH. 
• 
Genentech Inc., a biotechnology company based in San Francisco, CA. Genentech is a member of 
the Roche Group. 
• 
The National Cancer Institute - Cancer Therapy Evaluation Program (NCI/CTEP). The National 
Cancer Institute, hereinafter referred to as “NCI”, is part of the National Institutes of Health, an 
agency of the United States Government. The NCI funds the National Clinical Trials Network 
(NCTN) 
Alliance is the lead NCTN Group and is responsible for overall protocol development and study 
management of the trial. Alliance manages the participation of other participating organizations, including 
the international collaborating group and pharmaceutical partner.  
AIO is the international collaborating group and the legal representative of the sponsor in Europe for the 
study and has been delegated certain tasks and responsibilities.  
Roche/Genentech is the Marketing Authorization Holder for atezolizumab. NCI/CTEP is the US IND 
sponsor and overall study sponsor. 
Sites in Germany must refer to the current approved study protocol for 
conducting the study. This AIO Group-specific Appendix (AIO-GSA) 
includes regulatory provisions, additional information and clarifications 
regarding study conduct in Germany. Some sections of the AIO-GSA 
take precedence over specific protocol sections and are marked as such. 
 
 
 
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Contact Addresses 
Legal Representative of the Sponsor in Europe 
AIO-Studien-gGmbH 
Kuno-Fischer-Strasse 8 
14057 Berlin, Germany 
Phone +49 30 814534431 
Fax +49 30 322932926  
info@aio-studien-ggmbh.de 
National Coordinating Investigator, Germany & E.U. 
 
Prof. Dr. 
  
Abteilung für Hämatologie, Onkologie und 
Palliativmedizin 
Katholisches Klinikum Bochum 
Universitätsklinikum der Ruhr-Universität Bochum 
Gudrunstr. 56,  
44791 Bochum, Germany 
E.U. Biomarker Collection and Laboratory 
Institut für Pathologie 
Prof. Dr. 
der Ruhruniversität Bochum an den BG-Kliniken 
Bergmannsheil 
Bürkle-de-la-Camp-Platz 1 
44789 Bochum, German 
European Central dMMR Confirmation Testing 
Laboratory 
CellCarta (previously HistoGeneX) Belguim 
Sint-Bavostraat 78 
2610 Antwerpen (Wilrijk) 
Belgium 
Drug Supply 
Roche (atezolizumab) 
F. Hoffmann-La Roche Ltd 
Grenzacherstrasse 124 
CH-4070 Basel 
Switzerland 
kaiseraugst.gips-distribution@roche.com 
 
 
 
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APPROVAL OF THE AIO-GSA 
„RANDOMIZED TRIAL OF STANDARD CHEMOTHERAPY ALONE OR COMBINED WITH 
ATEZOLIZUMAB AS ADJUVANT THERAPY FOR PATIENTS WITH STAGE III COLON 
CANCER AND DEFICIENT DNA MISMATCH REPAIR“ - ATOMIC 
 
 
FINAL V3.0, 06-OCT-2023 
 
 
Dr. 
 (Legal representative of the Sponsor in Europe) 
 
 
 
 
 
   
Signature   
  
Date (DD Month YYYY)   
 
 
 
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Investigator’s agreement 
I have read the attached protocol entitled 
„RANDOMIZED TRIAL OF STANDARD CHEMOTHERAPY ALONE OR COMBINED WITH 
ATEZOLIZUMAB AS ADJUVANT THERAPY FOR PATIENTS WITH STAGE III COLON 
CANCER AND DEFICIENT DNA MISMATCH REPAIR“ - ATOMIC 
 
Version Update #14, 23-MAY-2023 
and the associated AIO Group-specific Appendix Version FINAL V3.0, 06OCT2023 
and agree to abide by all provisions set forth therein. 
I agree to comply with the International Conference on Harmonization Tripartite Guideline on Good 
Clinical Practice all applicable national regulations as well as the requirements of the appropriate 
Institutional Review Board/Independent Ethics Committee and any other institutional requirements. 
I agree to ensure that the confidential information contained in this document will not be used for any 
purpose other than the evaluation or conduct of the clinical investigation without the prior written consent 
of the study sponsor. 
I consent to report every serious clinical adverse event as well as any other adverse event as specified in 
the safety section of the protocol and this AIO-GSA and according §12 GCP-V within 24 hours after 
awareness, whether it is related to study medication or not. 
 
 
 
Investigator Name (printed) 
  
 
Signature   
  
Date (DD Month YYYY)   
Investigator’s Institution 
  
   
 
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Table of contents 
Contact Addresses .................................................................................................................. 133 
Approval of the AIO-GSA ....................................................................................................... 134 
Investigator’s agreement ........................................................................................................ 135 
Table of contents .................................................................................................................... 136 
1 
Patient selection, study locations and time frame ......................................................... 138 
1.1 
Inclusion criteria ........................................................ Error! Bookmark not defined. 
1.2 
Exclusion criteria ....................................................... Error! Bookmark not defined. 
1.3 
Withdrawel of subjects from study treatment ............ Error! Bookmark not defined. 
1.4 
Study sites ................................................................ Error! Bookmark not defined. 
1.5 
Study time frame for Germany and Austria .............. Error! Bookmark not defined. 
2 
Study medication ............................................................... Error! Bookmark not defined. 
2.1 
Investigational Medicinal Product (IMP) ............................................................... 142 
2.2 
Drug supply ............................................................... Error! Bookmark not defined. 
2.3 
Fluorouracil ............................................................... Error! Bookmark not defined. 
2.3.1 
Fluorouracil – preparation .................................... Error! Bookmark not defined. 
2.3.3 
Fluorouracil – special warnings and precautions . Error! Bookmark not defined. 
2.3.4 
Fluorouracil – safety profile .................................. Error! Bookmark not defined. 
2.4 
Calcium folinate ........................................................ Error! Bookmark not defined. 
2.4.1 
Calcium folinate  – preparation ............................. Error! Bookmark not defined. 
2.4.2 
Calcium folinate  – contraindications .................... Error! Bookmark not defined. 
2.4.3 
Calcium folinate – special warnings and precautionsError! Bookmark not defined. 
2.4.4 
Calcium folinate – safety profile ........................... Error! Bookmark not defined. 
2.5 
Oxaliplatin ................................................................. Error! Bookmark not defined. 
2.5.1 
Oxaliplatin – preparation ...................................... Error! Bookmark not defined. 
2.5.2 
Oxaliplatin – contraindications .............................. Error! Bookmark not defined. 
2.5.3 
Oxaliplatin – special warnings and precautions ... Error! Bookmark not defined. 
2.5.4 
Oxaliplatin – safety profile .................................... Error! Bookmark not defined. 
2.6 
Storage and dispensing ............................................ Error! Bookmark not defined. 
2.7 
Destruction ................................................................ Error! Bookmark not defined. 
2.8 
Documentation .......................................................... Error! Bookmark not defined. 
3 
Study procedures –alternative provisions for Germany and Austria ............................. 148 
3.1 
Schedule of study procedures .................................. Error! Bookmark not defined. 
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3.1.1 
Pre-Study testing (screening) ............................... Error! Bookmark not defined. 
3.1.2 
Treatment phase .................................................. Error! Bookmark not defined. 
3.1.3 
End of Treatment (EoT) ........................................ Error! Bookmark not defined. 
3.1.4 
Follow-up assessments ........................................ Error! Bookmark not defined. 
3.2 
Specimen collection and submission for dMMR status and other biomarkersError! Bookmark 
not defined. 
3.3 
Patient-reported outcomes ....................................... Error! Bookmark not defined. 
4 
Assessment of safety ........................................................ Error! Bookmark not defined. 
4.1 
Safety recording and reporting requirements ....................................................... 156 
4.2 
Sponsor obligations .................................................. Error! Bookmark not defined. 
4.2.1 
Reporting requirements and timelines for SAEs, AESIs, and other reportable events  
 
 .............................................................................. Error! Bookmark not defined. 
4.3 
Handling of safety parameters .................................. Error! Bookmark not defined. 
4.3.1 
Adverse events ..................................................... Error! Bookmark not defined. 
4.3.2 
Pregnancies and contraception ............................ Error! Bookmark not defined. 
5 
Ethical aspects .................................................................. Error! Bookmark not defined. 
5.1 
Risk-benefit assessment ....................................................................................... 161 
5.2 
Declaration of Helsinki/Good Clinical Practice ......... Error! Bookmark not defined. 
5.3 
Independent ethics committees and regulatory authorities .................................. 163 
5.3.1 
Approval of the study by the regulatory authority and EC ................................ 163 
5.3.2 
Notification about the study .............................................................................. 163 
5.3.3 
Reporting and documentation obligations ........................................................ 164 
6 
Study documentation, CRFs and record-keeping ......................................................... 164 
6.1 
Investigator's Files / Retention of documents ........... Error! Bookmark not defined. 
6.2 
Source documents and background data ................. Error! Bookmark not defined. 
6.3 
Audits and inspections .............................................. Error! Bookmark not defined. 
6.4 
Case Report Forms (CRF) ........................................ Error! Bookmark not defined. 
7 
Monitoring the study .......................................................... Error! Bookmark not defined. 
8 
Confidentiality of trial documents and patient records ...... Error! Bookmark not defined. 
 
 
 
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1. Patient selection, study locations and time frame 
Additional to the protocol 
1.1 
Inclusion criteria 
Precedence over protocol section 3.2 
1. 
Histologically proven stage III colon adenocarcinoma (any T [Tx, T1, T2, T3, or T4], N1-2M0; 
includes N1C). Tumors must be deemed to originate in the colon including tumors that extend 
into/involve the small bowel (e.g. those at the ileocecal valve) 
2. 
Presence of deficient (d) DNA mismatch repair (dMMR). MMR status must be assessed by 
immunohistochemistry (IHC) for MMR protein expression (MLH1, MSH2, MSH6, PMS2) where 
loss of one or more proteins indicates dMMR. Note: loss of MLH1 and PMS2 commonly occur 
together. Patients who are known to have Lynch syndrome and have been found to carry a specific 
germline mutation in an MMR gene (MLH1, MSH2, MSH6, PMS2) are eligible to participate. Note 
that patients who did not show dMMR (loss of MMR protein) are not eligible to participate. Patients 
whose tumors show MSI-H by polymerase chain reaction (PCR)-based assay are not eligible to 
participate unless they also have MMR testing by IHC and are found to have dMMR (i.e. loss of one 
or more MMR proteins).  
3. 
Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue for subsequent retrospective 
central confirmation of dMMR status.  
4. 
Tumor(s) completely resected. In patients with tumor adherent to adjacent structures, en bloc R0 
resection must be documented in the operative report or otherwise confirmed by the surgeon; near or 
positive radial margins are acceptable so long as en bloc resection was performed; proximal or distal 
margin positivity is not permitted 
5. 
Entire tumor in the colon (rectal involvement is an exclusion).[Note: Surgeon confirmation that 
entire tumor was located in the colon is required only in cases where it is important to establish if the 
tumor is a colon versus (vs.) rectal primary.]  Patients with more than one primary colon 
adenocarcinoma are eligible if the qualifying stage III tumor is confined to the colon, and not rectum, 
and the other cancers of lower stage are removed in the en bloc R0 resection. 
Based upon the operative report and other source documentation, the location of the primary tumor 
will be categorized as proximal or distal to the splenic flexure (included with distal), and further 
categorization will be as follows: cecum/ascending, transverse, descending, sigmoid colon, or 
rectosigmoid colon. [see also sec. 3.2.2. of the main protocol for guidance] 
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6. 
Age ≥ 18 years 
7. 
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 
8. 
Not pregnant and not nursing. For women of childbearing potential (WOCBP) only, a negative 
pregnancy test done ≤ 7 days prior to registration is required. A WOCBP is a sexually mature female 
who: 1) is not naturally postmenopausal (defined as at least 12 consecutive months with no menses 
without an alternative medical cause); OR 2) has not had a hysterectomy and/or bilateral 
oophorectomy (Note: Women with tubal ligation are still considered of child-bearing potential 
according to CTFG Guidance). Women and men of reproductive potential should agree to use an 
appropriate method of birth control throughout their participation in this study due to the teratogenic 
potential of the therapy utilized in this trial. 
9. 
Absolute neutrophil count (ANC) ≥ 1500/mm3 
10. Platelet count ≥ 100,000/mm3; platelets ≥ 75,000/mm3 required for patients who received cycle 1 of 
mFOLFOX6 prior to registration 
11. Creatinine ≤ 1.5 x upper limit of normal (ULN) or Calculated creatinine clearance ≥ 45 mL/min by 
Cockcroft-Gault equation 
12. Total bilirubin ≤ 1.5 x upper limit of normal (ULN), except in the case of Gilbert disease  
13. Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 x upper limit of normal 
(ULN) 
14. Thyroid-stimulating hormone (TSH) within normal limits (WNL). Supplementation is acceptable to 
achieve a TSH WNL. In patients with abnormal TSH, if free T4 is normal and patient is clinically 
euthyroid, patient is eligible 
1.2 
Exclusion criteria 
Precedence over protocol section 3.2 
1. 
Evidence of residual involved lymph node disease or metastatic disease at the time of registration 
based on clinician assessment of imaging. The treating physician will determine if incidental lesions 
on imaging require workup to exclude metastatic disease. If based on review of images, the treating 
physician determines the patient to be stage III, then the patient is eligible. 
2. 
Prior medical therapy (chemotherapy, immunotherapy, biologic or targeted therapy) or radiation 
therapy for the current colon cancer, except for one cycle of mFOLFOX6. Cycle 1 of mFOLFOX6 
must have been administered per Appendix III of the main protocol. 
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3. 
Active known autoimmune disease, including colitis, inflammatory bowel disease (i.e. ulcerative 
colitis or Crohn's disease), rheumatoid arthritis, panhypopituitarism, adrenal insufficiency 
4. 
Known active hepatitis B or C 
• 
Active hepatitis B can be defined as: 
 
Hepatitis B virus surface antigen (HBsAg) detectable for > 6 months; 
 
Serum hepatitis B virus (HBV) DNA 20,000 IU/mL(105 copies/mL); lower values 
2,000-20,000 IU/mL(104-105 copies/mL) are often seen in hepatitis B virus e antigen 
(HBeAg)-negative chronic hepatitis B; 
 
Persistent or intermittent elevation in ALT/AST levels; 
 
Liver biopsy showing chronic hepatitis with moderate or severe necroinflammation. 
• 
Active hepatitis C can be defined as: 
 
Hepatitis C antibody (AB) positive, AND 
 
Presence of hepatitis C virus (HCV) RNA 
5. Known active pulmonary disease with hypoxia defined as: 
• 
Oxygen saturation < 85% on room air, or 
• 
Oxygen saturation < 88% despite supplemental oxygen 
6. Grade ≥ 2 peripheral motor or sensory neuropathy 
7. HIV-positivity, unless all of the following are met: 
• 
A stable regimen of highly active anti-retroviral therapy (HAART) 
• 
No requirement for concurrent antibiotics or antifungal agents for the prevention of 
opportunistic infections 
• 
A CD4 count above 250 cells/µL, and an undetectable HIV viral load on standard PCR-
based tests 
8. Other planned concurrent investigational agents or other tumor directed therapy (chemotherapy, 
radiation) while on study 
9. Systemic daily treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other 
immunosuppressive medications within 7 days of registration 
10. Known history of severe allergic anaphylactic reactions to chimeric, human or humanized 
antibodies, or fusion proteins 
11. Known hypersensitivity to Chinese hamster ovary (CHO) cell products or any component of the 
atezolizumab formulation 
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12. Contraindications against any of the chemotherapeutic agents of the mFOLFOX6 regimen including 
but not limited to known allergy to 5-fluorouracil, oxaliplatin, or folinic acid 
13. Inability to provide consent because the patient does not understand the nature, significance, and/or 
implications of the clinical trial and therefore cannot form a rational intention in the light of the facts 
(e.g. patients with psychiatric illness).  
14. Medical condition such as uncontrolled infection, uncontrolled diabetes mellitus or cardiac disease 
which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for 
the patient. 
15. A “currently active” second malignancy other than non-melanoma skin cancers or cervical 
carcinoma in situ. Guidance: 
• 
Patients are not considered to have a “currently active” malignancy if they have 
completed therapy and are free of disease for ≥ 3 years, had a gastric or bowel carcinoid < 
1 cm, or DCIS/LCIS of the breast without invasive cancer, or endometrial 
dysplasia/carcinoma in situ. 
• 
Patients are not considered to have a “currently active” malignancy if they had a 
sebaceous neoplasm (sebaceous adenoma, sebaceous epithelioma, sebaceous 
adenocarcinoma, keratoacanthoma, and squamous cell carcinoma) that was noninvasive. 
 
1.3 
Withdrawal of subjects from study treatment 
Additional to protocol section 12  
Permanent discontinuation of study treatment 
An individual subject will not receive any study treatment if any of the following occur in the subject in 
question: 
1. Withdrawal of consent or lost to follow-up 
2. Adverse event (AE) that, in the opinion of the investigator or the sponsor, contraindicates further 
dosing 
3. Subject is determined to be ineligible with regard to inclusion and exclusion criteria for study 
participation at study entry and continuing protocol therapy might constitute a safety risk. Note: In 
this case, subject meets definition of ineligibility as given in protocol section 12.2. Refer to 
protocol section 12.2 for instructions on management of these subjects. 
4. Pregnancy or intent to become pregnant 
5. Any AE that meets criteria for discontinuation for the purpose of toxicity management (see 
protocol section 8.2.) 
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6. Subject noncompliance that, in the opinion of the investigator or sponsor, warrants withdrawal; 
e.g., refusal to adhere to scheduled visits 
7. Initiation of alternative anticancer therapy including another investigational agent 
8. Confirmation of disease recurrence. Refer to protocol section 12.1 for instructions. 
Subjects who are permanently discontinued from receiving protocol therapy will be followed for safety 
per AIO-GSA sections 3.1.3 and 3.1.4 unless consent is withdrawn or the subject is lost to follow-up.  
Withdrawal of consent 
If consent is fully withdrawn, the subject will not receive any further study treatment or further study 
observation. However, patients are requested and encouraged to at least perform an End-of-Treatment 
visit and to enter safety and survival follow-up. Data gathered until the day of full withdrawal will be 
used for future analyses. If patients only partially withdraw consent (e.g. refuse further treatment) but 
remain under study observation, all data recorded may be used without restriction. 
In the event of withdrawal of consent for the participation of any of the optional substudies (i.e. 
translational research aspects) of this trial, all unprocessed samples and accompanying paperwork will be 
destroyed at study subjects’ request. However, processed specimens and the research data generated from 
them will not be rescinded and may be used in study analyses. 
1.4 
Study sites 
13 sites from Germany will participate in this trial. 
1.5 
Study time frame for Germany 
Table 1: Study time line  
FPI: 
Q1/2021 
LPI: 
after approx. 14 months (Mar 2022) 
LPLT: 
after approx. 26 months (Feb 2023) 
End of Follow up period after LPI: 
after approx. 8 years (Mar 2030) 
Study report: 
after approx. 10 years 
2 
Study medication 
2.1 
Investigational Medicinal Product (IMP)   
Atezolizumab is the investigational medicinal product (IMP) of interest.  
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Fluorouracil, oxaliplatin and calcium folinate are standard-of-care medication in this setting. 
2.2 
Drug supply 
The experimental IMP atezolizumab will be supplied by Roche. The first site shipment will by generated 
automatically upon site initiation and activation. Subsequent shipments will be ordered by the site by 
email using the Consignment Request Form (‘S-Form’) provided by AIO-Studien-gGmbH in 
collaboration with Roche. 
Chemotherapy drugs will be sourced locally by sites. 
2.3 
Fluorouracil 
Precedence over protocol section 10.2 
Fluorouracil will be used as commercially available and handled/prepared according to Summary of 
Product Characteristics (SmPC) and local guidelines.  
Dosing will be according to protocol sections 7.1 and 7.2. 
An example reference of the current SmPC is deposited in the ISF.  
2.3.1 
Fluorouracil – preparation 
According to local standard and SmPC. 
2.3.2 
Fluorouracil – contraindications 
Fluorouracil is contraindicated in seriously debilitated patients or those with bone marrow depression 
after radiotherapy or treatment with other antineoplastic agents. 
Fluorouracil is strictly contraindicated in pregnant or breast feeding women. 
Fluorouracil should not be used in the management of non-malignant disease. 
Fluorouracil is contraindicated in patients who have had a serious hypersensitivity reaction to previous 
doses of fluorouracil or any of its constituents. 
Fluorouracil must not be taken or used concomitantly with brivudin, sorivudine and analogues. Brivudin, 
sorivudine and analogues are potent inhibitors of the enzyme dihydropyrimidine dehydrogenase (DPD) 
which degrades fluorouracil (see also sections 4.4 and 4.5 of the SmPC). 
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Fluorouracil is contraindicated in patients with known complete absence of dihydropyrimidine 
dehydrogenase (DPD) activity (see section 4.4 of the SmPC). 
2.3.3 
Fluorouracil – special warnings and precautions 
See section 4.4 of the SmPC. 
Women of childbearing potential and men have to use effective contraception during and up to 6 months 
after treatment. 
Dose modifications outlined in Section 8.2 of the protocol must be followed. 
2.3.4 
Fluorouracil – safety profile 
Refer to the current version of the SmPC.  
2.4 
Calcium folinate 
Supplements protocol section 10.3 
Any authorized calcium folinate product may be used. This includes leucovorin and levoleucovorin. The 
medicinal product will be used as commercially available and handled/prepared according SmPC and 
local guidelines.  
Dosing and administration will be according to protocol sections 7.1 and 7.2. 
2.4.1 
Calcium folinate  – preparation 
According to local standard and SmPC. 
2.4.2 
Calcium folinate  – contraindications 
Hypersensitivity to the active substance or to any of the excipients listed in the SmPC. 
The combination of calcium folinate with fluorouracil is not indicated in existing contraindications 
against fluorouracil, in particular pregnancy and lactation. 
2.4.3 
Calcium folinate – special warnings and precautions 
Calcium folinate may enhance the toxicity risk of 5-fluorouracil, particularly in elderly or debilitated 
patients. The most common manifestations are leucopenia, mucositis, stomatitis, and/or diarrhea, which 
may be dose limiting. Patients with diarrhea should be monitored with particular care until the diarrhoea 
has resolved, as rapid clinical deterioration leading to death can occur. 
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Toxicities observed under 5-fluorouracil/calcium folinate combination therapy require more stringent 
dose reductions of fluorouracil than toxicities observed under 5-fluorouracil monotherapy. 
Dose modifications outlined in Section 8.2 of the protocol must be followed. 
Because diarrhea may be a sign of gastrointestinal toxicity, patients presenting with diarrhea should be 
carefully monitored until the symptoms have disappeared completely, since a rapid clinical deterioration 
leading to death can occur. Especially the elderly and patients with a low physical performance due to 
their illness are prone to these toxicities. Therefore, particular care should be taken when treating these 
patients. 
Calcium folinate must not be mixed with 5-fluorouracil in the same IV injection or infusion. 
Calcium levels should be monitored in patients receiving combined 5-fluorouracil/calcium folinate 
treatment and calcium supplementation should be provided if calcium levels are low. 
Interaction with other medicinal products and other forms of interaction 
When calcium folinate is given in conjunction with a folic acid antagonist (e.g. cotrimoxazole, 
pyrimethamine) the efficacy of the folic acid antagonist may either be reduced or completely neutralized. 
Calcium folinate may diminish the effect of anti-epileptic substances: phenobarbital, primidone, 
phenytoin and succinimides, and may increase the frequency of seizures. 
(A decrease of plasma levels of enzymatic inductor anticonvulsant drugs may be observed due to an 
increase of hepatic metabolism, as folates are one of the cofactors.)  
2.4.4 
Calcium folinate – safety profile 
Calcium folinate enhances the toxicity of 5-fluorouracil. Generally, the safety profile depends on the 
applied regimen of 5-fluorouracil due to enhancement of the 5-fluorouracil induced toxicities. 
Please refer to the current version of the respective SmPC. 
2.5 
Oxaliplatin 
Replaces protocol section 10.4 
Oxaliplatin will be used as commercially available and handled/prepared according to SmPC and local 
guidelines.  
Dosing and administration will be according to protocol sections 7.1 and 7.2. 
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An example reference of the current SmPC is deposited in the ISF.  
2.5.1 
Oxaliplatin – preparation 
According to local standard and SmPC. 
2.5.2 
Oxaliplatin – contraindications  
According to the SmPC, oxaliplatin is contraindicated in patients who: 
• 
have a known history of hypersensitivity to oxaliplatin or to the excipient. 
• 
are breastfeeding. 
• 
have myelosuppression prior to starting first course, as evidenced by baseline neutrophils <2x109/L 
and/or platelet count of <100x109L  
• 
have a peripheral sensitive neuropathy with functional impairment prior to first course  
• 
have a severely impaired renal function (creatinine clearance less than 30 mL/min) 
2.5.3 
Oxaliplatin – special warnings and precautions  
Please refer to the current version of the SmPC for full guidance on special warnings and precaution 
Dose modifications outlined in Section 8.2 of the protocol must be followed. 
2.5.4 
Oxaliplatin – safety profile 
The most frequent adverse events of oxaliplatin in combination with 5-fluorouracil/folinic acid (5-FU/FA) 
were gastrointestinal (diarrhea, nausea, vomiting, mucositis), haematological (neutropenia, 
thrombocytopenia) and neurological (acute and dose cumulative peripheral sensory neuropathy). Overall, 
these adverse events were more frequent and severe with oxaliplatin and 5-FU/FA combination than with 
5-FU/FA alone. 
For further details, please refer to the current version of the SmPC.  
2.6 
Storage and dispensing 
The investigator should ensure that the IMP atezolizumab is stored in accordance with the environmental 
conditions (temperature, light, and humidity) as specified in protocol Section 10.5. If concerns regarding 
the quality or appearance of any IMP arise, the IMP should not be dispensed and Roche and AIO-Studien-
gGmbH should be contacted immediately. 
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Upon arrival of IMP at the site, site personnel (local pharmacy) will check it for damage and verify its 
identity, quantity, integrity of seals and temperature conditions, and report any deviations or product 
complaints to Roche and AIO-Studien-gGmbH upon discovery. 
2.7 
Destruction 
Any unused IMP may be disposed of at the study site under the following conditions: 
• 
On-site disposal practices must not expose humans to risks from the drug. 
• 
On-site disposal practices and procedures are in agreement with applicable laws and regulations, 
including any special requirements for controlled or hazardous substances. 
• 
Written procedures for on-site disposal are available and followed. The procedures must be filed 
with the ISF or pharmacy file and a copy provided to the sponsor upon request. 
If conditions for destruction cannot be met, please contact the AIO-Studien-gGmbH! 
2.8 
Documentation 
The local investigator (PI) of the site is responsible to maintain records of IMP delivery and inventory at 
the site, of its storage, the use for each patient, and the destruction of unused IMP. Destruction records 
must allow for traceability of each container, including disposal date, quantity disposed of, and 
identification of the person disposing the containers. The method of disposal, i.e., incinerator, licensed 
sanitary landfill, or licensed waste disposal vendor, must be documented. Accountability and disposal 
records must be complete, up-to-date, and available for the sponsor to review throughout the clinical trial 
period as per the study agreement. 
The investigator will also maintain records that adequately document that patients were administered the 
doses specified in the protocol. The date, time and amount will be documented in the drug accountability 
log by the investigator and his/her delegates. 
 
 
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3 
Study procedures – alternative provisions for Germany  
Supplements the protocol 
3.1 
Schedule of study procedures 
The following section lists procedures which are mandatory for all patients. Additional procedures apply 
for patients participating in the optional substudies. See protocol sections 6.2 and 6.4 for assessment 
schedules. 
3.1.1 
Pre-Study testing (screening)  
NOTE: Any routine procedure which is performed during the 28-day screening window may be used as a 
pre-study test (screening assessment) in this trial.  
Any imaging used to confirm lack of evidence of definitive metastatic disease (pre-surgery scans are 
acceptable) must be completed ≤ 80 DAYS before registration. 
Documentation of any screening procedure in the CRF can only be performed after informed consent of 
the patient. All patients will be screened and screening procedures performed within 28 days prior to 
registration include the following: 
 
Mandatory procedures all arms: 
Procedure 
Instruction 
pCRF (additional 
documentation 
required) 
Informed Consent 
 
 
dMMR testing 
dMMR testing for the present tumor may be 
completed at any point prior to registration. 
Note that the patient can only be enrolled 
once positive dMMR test result is available. 
One cycle of mFOLFOX6 can be 
administered prior to enrollment.  
Y 
Demographics 
age, sex 
Y 
Medical and colon cancer 
history 
If hepatitis status is uncertain or undefined or 
unobtainable from medical records, HBV and 
HCV serologies should be obtained. 
Y 
Eligibility criteria 
see AIO-GSA sections 1.1 and 1.2 
 
Vital signs 
Blood pressure 
Heart rate 
Y 
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Oxygen saturation 
Oxygen saturation should be assessed at rest 
after 1 minute walk. 
Y 
Height 
 
 
Weight, BSA 
 
 
Full physical examination 
incl. general appearance, skin, lymph nodes, 
respiratory, cardiovascular, abdominal, head 
and neck (including ears, eyes, nose and 
throat), musculo-skeletal (including spine and 
extremities), genital/rectal, neurological and 
thyroid function 
Y 
Cardiac function tests 
QT interval monitoring acc. to local standards 
Y 
ECOG Performance Status  
 
Hematology 
Hematocrit 
Hemoglobin 
Red blood cell count 
Platelet count 
Lymphocytes 
Basophils 
Eosinophils 
Monocytes 
Neutrophils 
Total white cell count 
Y 
Chemistry 
Total protein 
Albumin 
Alkaline phosphatase 
Alanine aminotransferase 
Aspartate aminotransferase 
Bicarbonate 
Calcium  
Chloride 
Serum Creatinine 
Glucose 
Potassium 
Sodium 
Magnesium 
Total bilirubin 
Blood urea nitrogen 
Y 
Urinalysis 
acc. to local standards 
Y 
Thyroid function test 
TSH  
 
Reflexive free T4, free T3 if TSH high 
Y 
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Pregnancy test 
Serum HCG or high sensitivity urine HCG for 
WOCBP must be performed within 7 days 
prior to registration. 
Y 
Dihydropyrimidine 
Dehydrogenase (DPD) 
If DPD status is unknown, perform tests 
according to local standards. 
Y 
CD4 count & viral load 
Only for HIV-positive patients 
Y 
CEA 
 
 
Toxicities/ adverse events 
Document continuously using NCI-CTCAE 
v5.0 
 
Patient-reported outcomes 
NCI PRO-CTCAETM 
 
 
Radiologic tumor 
assessment 
Baseline abdominal/pelvic scans can include 
either: 1) a CT ABD/PELV, or 2) a MRI 
ABD/PELV. Chest imaging can be either 
chest CT or chest MRI. CT scans should be of 
diagnostic quality and performed with oral 
and IV contrast unless there is a medical 
contraindication. MRIs should be performed 
with IV contrast unless there is a medical 
contraindication. 
Y 
3.1.2 
Treatment phase 
The following procedures are to be performed on Day 1 (D1) +/- 2 business days of every 14-day cycle 
(Q2W) unless indicated otherwise: 
Mandatory procedures all arms: 
 
Procedure 
Instruction 
pCRF 
Vital signs 
Blood pressure 
Heart rate 
 
See also protocol Section 7.0 regarding initial 
atezolizumab dose for Arm 1 patients. 
Y 
Weight, BSA 
 
 
Physical examination 
targeted physical examination is to be 
performed according to clinical necessity 
including signs and symptoms of AEs 
 
Pregnancy test 
Serum HCG or high sensitivity urine HCG for 
WOCBP must be performed every other cycle 
[i.e. Q4W] 
Y 
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Cardiac function tests 
QT interval monitoring acc. to local standards 
whenever clinically indicated 
Y 
ECOG Performance Status 
 
 
Hematology 
Hematocrit 
Hemoglobin 
Red blood cell count 
Platelet count 
Lymphocytes 
Basophils 
Eosinophils 
Monocytes 
Neutrophils 
Total white cell count 
Y 
Chemistry 
Total protein 
Albumin 
Alkaline phosphatase 
Alanine aminotransferase 
Aspartate aminotransferase 
Bicarbonate 
Calcium  
Chloride 
Serum Creatinine 
Glucose 
Potassium 
Sodium 
Magnesium 
Total bilirubin 
Blood urea nitrogen 
Y 
Toxicities/ adverse events 
Document continuously using NCI-CTCAE 
v5.0 
 
Patient-reported outcomes 
NCI PRO-CTCAETM 
 
 
The following procedures are to be performed on Day 1 (D1) +/- 2 business days of every 14-day cycle 
(Q2W) unless indicated otherwise: 
Arm 1 only: 
Procedure 
Instruction 
pCRF 
Oxygen saturation 
Oxygen saturation should be assessed at rest 
after 1 minute walk. 
 
Study treatment 
Atezolizumab + mFOLFOX6 for 12 cycles, 
followed by atezolizumab alone for further 6 
months 
 
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(see protocol section 7.1 for further details) 
CEA 
6 weeks after end of FOLFOX 
 
 
Arm 1 only - Q4W 
Procedure 
Instruction 
pCRF 
Urinalysis 
acc. To local standard 
Y 
 
Arm 1 only – Q8W 
Procedure 
Instruction 
pCRF 
Thyroid function test 
TSH 
Reflexive free T4, free T3 if TSH high 
Y 
 
The following procedures are to be performed on Day 1 (D1) +/- 2 business days of every 14-day cycle 
(Q2W) unless indicated otherwise: 
Arm 2 only: 
Procedure 
Instruction 
pCRF 
Study treatment 
mFOLFOX6 for 12 cycles 
(see protocol section 7.2 for further details) 
 
 
Mandatory procedures all arms - Every 6 months (+/- 1 month) for the first 2 years after 
registration: 
Procedure 
Instruction 
pCRF 
Radiologic tumor assessment 
The same imaging modality used at 
baseline must be used for all subsequent 
scans. 
 
3.1.3 
End of Treatment (EoT) 
EoT visit should be conducted 1 month (+/- 7 days) after the last day of the last treatment cycle. The 
following procedures will be performed during the EoT visit: 
Mandatory procedures all arms: 
Procedure 
Instruction 
pCRF 
Vital signs 
Blood pressure 
 
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Heart rate 
Oxygen saturation 
Oxygen saturation should be assessed at 
rest after 1 minute walk. 
 
Weight, BSA 
 
 
Full physical examination 
incl. general appearance, skin, lymph 
nodes, respiratory, cardiovascular, 
abdominal, head and neck (including ears, 
eyes, nose and throat), musculo-skeletal 
(including spine and extremities), 
genital/rectal, neurological and thyroid 
function 
 
Cardiac function tests 
QT interval monitoring acc. to local 
standards 
Y 
Pregnancy test 
Serum HCG or high sensitivity urine HCG 
for WOCBP  
Y 
ECOG Performance Status 
 
 
Hematology 
Hematocrit 
Hemoglobin 
Red blood cell count 
Platelet count 
Lymphocytes 
Basophils 
Eosinophils 
Monocytes 
Neutrophils 
Total white cell count 
Y 
Chemistry 
Total protein 
Albumin 
Alkaline phosphatase 
Alanine aminotransferase 
Aspartate aminotransferase 
Bicarbonate 
Calcium  
Chloride 
Serum Creatinine 
Glucose 
Potassium 
Sodium 
Magnesium 
Total bilirubin 
Blood urea nitrogen 
Y 
Colonoscopy 
Patients who did not receive a colonoscopy 
to the cecum prior to surgery are required to 
 
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have a full colonoscopy no later than 6 
weeks after the completion of 
chemotherapy, but exact timing within the 
specified window is per treating physician 
discretion. 
Toxicities/ adverse events 
Document using NCI-CTCAE v5.0 
 
Patient-reported outcomes 
NCI PRO-CTCAETM 
 
 
Mandatory procedures all arms - Every 6 months (+/- 1 month) for the first 2 years after 
registration: 
Procedure 
Instruction 
pCRF 
Radiologic tumor assessment 
The same imaging modality used at 
baseline must be used for all subsequent 
scans. 
Y 
3.1.4 
Follow-up assessments 
Mandatory procedures all arms: 
Procedure 
Instruction 
pCRF 
Weight 
 
 
Physical examination 
targeted physical examination is to be 
performed according to clinical necessity 
including signs and symptoms of AEs 
 
ECOG Performance Status 
 
 
CEA 
every 6 months (+/- 1 month) for 3 years, 
then every 12 months (+/- 1 month) for an 
additional 2 years, or until relapse. 
Y 
Toxicities/ adverse events 
Document continuously using NCI-CTCAE 
v5.0 
 
Radiologic tumor 
assessment 
Every 6 months (+/- 1 month) for first 2 
years after registration, then annually for 
the next 3 years 
Y 
Survival 
Every 6 months (+/- 1 month) for up to 8 
years after registration 
Y 
 
3.2 
Specimen collection and submission for dMMR status and other biomarkers 
In addition to protocol section 6.2 and the Correlative Science Procedure Manual (CSM) 
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Tumor tissue: dMMR status can be determined either locally or by the central study lab in Bochum. 
Additional retrospective dMMR confirmation testing will be performed at CellCarta, Belgium, and the 
shipping address for this central laboratory is included on the A021502 Requisition Form-AIO which can 
be found on the Alliance and CTSU websites. An electronically completed A021502 Requisition Form-
AIO is required to be included with the mandatory tissue submission to the central laboratory for 
retrospective dMMR confirmation testing. All tissue specimens for German patients must be 
accompanied by an electronically completed A021502 Pathology Form-AIO. 
[Note: Surgical pathology tissue blocks should not be directly labeled in any manner. The institutional 
surgical pathology number (e.g. “S16-1234”) and the individual block identifier (e.g. “A3”) should be 
readable on the block. If tissue section slides are being submitted instead of the block, each tissue section 
slide should be labeled with the surgical pathology number and the block identifier. Please do NOT use 
sticky labels on slides.] 
All other mandatory specimens will be submitted to the AIO pathology hub specified in the AIO-
Appendix of the Correlative Science Procedure Manual where they will be collected, processed (if 
applicable) and later be shipped in batches to the Alliance Biorepository at Mayo Clinic. 
Blood and stool samples for correlative science (planned): 
Once translational research is implemented for the study in Germany optional specimens will be 
submitted either to the central AIO pathology hub or AIO central hub as specified in the AIO-Appendix 
of the Correlative Science Procedure Manual where they will be collected, processed (if applicable) and 
later be shipped in batches to the Alliance Biorepository at Mayo Clinic or Duke University. 
Specimens for German patients should not be labeled with patient initials or full date of birth (full 
labeling instructions in the AIO-Appendix of the Correlative Science Procedure Manual).  
3.3 
Patient-reported outcomes 
In addition to protocol appendix I 
Patients in Germany will receive German language versions of the questionnaires for quality of life 
measurement and NCI PRO-CTCAE given in Appendix I of the study protocol, whereas the Registration 
Fatigue/Uniscale Assessment ist not applicable for German patients. These questionnaires will be 
provided by AIO to AIO sites in a printed format. The questionnaires will be handed over to patients, and 
patients must date each page of the questionnaire at every time point. 
 
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4 
Assessment of safety 
4.1 
Safety recording and reporting requirements 
Supplement to protocol section 9 
AEs are to be recorded in the eCRF in Rave as detailed in protocol section 9.1. AE reports are to be 
printed from Rave and filed at the site. If applicable, additional AE information will be recorded in paper 
CRFs. For those adverse events that require immediate reporting (see AIO-GSA section ), the Rave-
CTEP-AERS integration for expedited event reporting will be used as described in study protocol section 
9.3. Reporting timelines given in the protocol will be replaced by those given in AIO-GSA section 
4.2.1.  
AIO-Studien-gGmbH will be notified by CTEP (NCI) of events that require reporting to competent 
authorities, investigators and ethics committees in Europe, and act accordingly. 
4.2 
Sponsor obligations 
In addition to protocol section 9 
The legal representative of the sponsor in Europe for Germany (AIO-Studien-gGmbH) will ensure 
compliance with all regulatory reporting requirements, including the notification of the appropriate Ethics 
Committees, Competent Authority, and participating investigators of all serious adverse events occurring 
at the sites in accordance with national law, ICH Good Clinical Practice, and European / EMA 
requirements. 
• 
An NCI Monitor (medical monitor) will medically review all SAE reports and perform the 
expectedness assessment. 
• 
Every SAE assessed by either the investigator or the sponsor as suspected to be related to IMP 
and assessed as being either unexpected or unexpected with regard to outcome or severity of the 
event (i.e., every suspected unexpected serious adverse reaction, SUSAR) will be relayed by the 
sponsor to the AIO-Studien-gGmbH. The latter will then transmit SUSAR reports to the 
Competent Authority, responsible ethics committee of the trial according to national regulations 
(Medicinal Products Act [AMG] and § 13 GCP-V in Germany). 
• 
Fatal or life-threatening SUSARs must be reported to authorities and ethics committee as soon as 
possible, but no later than 7 days after the sponsor received the initial information of their 
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occurrence. Additional important information on these cases may be reported as follow-up within 
additional 8 days. All others SUSARs have to be reported no later than 15 days after receiving the 
initial information.  
• 
Also, all AEs which might change the risk-benefit evaluation of the study drugs or otherwise 
fulfil the criteria outlined in GCP-V §13 (4) have to be handled/reported as SUSARs. 
• 
The NCI/Genentech assures to notify AIO-Studien-gGmbH of any SUSAR without delay in order 
to comply with these reporting timelines. 
4.2.1 
Reporting requirements and timelines for SAEs, AESIs, and other reportable events  
Replaces protocol section 9.3.1 
For each patient, the following events must be reported immediately, i.e. within 24 hours according to 
§ 12 Abs. 4 GCP-V, of the investigator learning of the event: 
• any adverse event or abnormal laboratory test value that is serious. This includes all events of 
special interest as incorporated into the listings of solicited adverse events as included in section 
9.1 of the main protocol. 
4.3 
Handling of safety parameters 
In addition to protocol section 9 
4.3.1 
Adverse events 
The protocol (section 9.1) provides lists of AEs to be solicited. In addition, AEs may be spontaneously 
reported or elicited during open-ended questioning, examination, or evaluation of a subject.  
NOTE: PRO-CTCAE data should not be used for determining attribution, dose modifications, 
or reporting of serious adverse events. 
It will be left to the investigator’s clinical judgment to determine whether an adverse event is related to 
study drug and of sufficient severity to require the subject’s removal from treatment or from the study. A 
subject may also voluntarily withdraw from treatment due to what he or she perceives as an intolerable 
AE. If either of these situations arises, the subject should be strongly encouraged to undergo an end-of-
treatment assessment and be under medical supervision until symptoms cease or the condition becomes 
stable. 
 
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4.3.2 
Pregnancies and contraception 
Supplement to protocol section 3.2.6. 
Reproductive status: 
For this trial, male subjects will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical condition). 
Female subjects will be considered of non-reproductive potential if they are either:  
(1) 
naturally postmenopausal (defined as at least 12 consecutive months with no menses) without an 
alternative medical cause;  
OR  
(2) 
have had a hysterectomy and/or bilateral oophorectomy. 
Counseling of study subjects and partners: 
Subjects should be informed that taking the study medication may involve unknown risks to the fetus if 
pregnancy were to occur during the study. In order to participate in the study, subjects of childbearing 
potential should adhere to the contraception requirements given below. If there is any question that a 
subject of childbearing potential will not reliably comply with the requirements for contraception, that 
subject should not be entered into the study. 
• 
Maternal exposure: Female subjects of reproductive potential birth control should begin at least 
28 days prior to the start of therapy should use appropriate method(s) of contraception during the 
study, for 5 months after the last dose of atezolizumab and for 6 months after the last dose of 
mFOLFOX6. A female patient must be instructed to immediately inform the investigator if she 
becomes pregnant during the study. Monitoring of the patient should continue until conclusion of 
the pregnancy. 
• 
Paternal exposure: Men who are receiving study drug and are sexually active with females of 
reproductive potential must use any contraceptive method with a failure rate of less than 1% per 
year. For men, birth control should begin prior to registration and continue for 5 months after the 
last dose of atezolizumab or 6 months after the last dose of mFOLFOX6, whichever applies.  
Male subjects must refrain from donating sperm during the study and for 7 months after the last 
dose of investigational products. A male study subject must be instructed to immediately inform 
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the investigator if a pregnancy occurs in his partner during the study and up to 7 months after last 
dose of study drug.  
Contraception 
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION 
• 
Hormonal methods of contraception, including oral contraceptive pills* (combination of estrogen 
and progesterone), vaginal ring, injectables, implants and intrauterine devices (IUDs) *NOTE: 
Due to the increased GI toxicity (nausea, vomiting, diarrhea) oral contraceptives must be 
combined with an additional method of contraception (e.g. a barrier method). 
• 
Nonhormonal IUDs, such as ParaGard® 
• 
Bilateral tubal ligation  
• 
Vasectomy 
• 
Complete abstinence if it is the patient’s preferred and usual lifestyle regardless of trial 
participation* 
*Complete abstinence is defined as complete avoidance of heterosexual intercourse and is an acceptable 
form of contraception for all IMPs. Subjects who choose complete abstinence are not required to use a 
second method of contraception. Acceptable alternate methods of highly effective contraception should 
be discussed in the event that the subject chooses to forego complete abstinence. 
UNACCEPTABLE METHODS OF CONTRACEPTION 
• 
Oral contraceptive pill alone 
• 
Diaphragm with spermicide 
• 
Cervical cap with spermicide 
• 
Vaginal sponge 
• 
Condom  
• 
Withdrawal (coitus interruptus) 
• 
Progestin only pills by WOCBP subject or male subject’s WOCBP partner  
• 
Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
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Pregnancies 
Please also refer to section 9.3 of the protocol for special reporting requirements  
Pregnancy of a subject or of a subject’s partner is not regarded as an AE unless there is a suspicion that 
the investigational product under study may have interfered with the effectiveness of a contraceptive 
medication. Congenital abnormalities/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs.  
For female subjects, the investigator will follow the pregnancy for outcome of both mother and child 
(including any premature terminations) and document in the patient’s records. This applies to all 
pregnancies occurring between the date of the informed consent and 5 months after the last dose of 
atezolizumab and for 6 months after the last dose of mFOLFOX6. The investigator should counsel the 
pregnant subject, discuss the risks of continuing the pregnancy, and possible effects on the fetus. 
For a pregnancy of a male subject’s partner occurring between the date of the informed consent and 6 
months after the last dose of mFOLFOX6, the outcome (spontaneous miscarriage, elective termination, 
ectopic pregnancy, normal birth, or congenital abnormality) of should, if possible, be followed up and 
documented in the patient records. The investigator should counsel the subject’s partner, discuss the risks 
of continuing the pregnancy, and possible effects on the fetus. Where the information/suspicion/fact of 
pregnancy is received, prior to obtaining information about the pregnancy, the investigator must obtain 
the consent of the subject’s partner and document as such in the patient records. 
 
 
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5 
Ethical aspects 
5.1 
Risk-benefit assessment 
Benefits: 
The primary objective of this trial is to determine whether atezolizumab combined with FOLFOX and its 
continuation as monotherapy can significantly improve the time to disease recurrence (DFS) compared to 
FOLFOX alone in patients with stage III colon cancers and dMMR in an adjuvant setting. The 
corresponding statistical hypothesis test (a log-rank test for superiority) achieves a 90% power at a 0.025 
one-sided significance level to detect a hazard ratio (HR) of 0.6 between the two treatments. This HR 
amounts to a clinically meaningful risk reduction of disease recurrence of 40 % [see protocol section 
13.3] in the experimental arm. In terms of median DFS this translates to an increase of the 3-year DFS 
estimate form 70% to 84.147%. 
The basic rationale for this trial is the promising efficacy of check-point inhibition (CPI) in metastatic 
colorectal cancer (CRC) with mismatch repair deficient tumors [Le DT et al., N Engl J Med 2015. 
372(26)]. Since the initiation of the ATOMIC trial, substantially more data has come forth which supports 
the efficacy of CPI in advanced CRC and other tumor entities with deficient DNA repair mechanisms 
[Diaz L. A. JCO 2018 36(4); Overman MJ et. al. Lancet Oncol. 2017 Sep;18(9); Moehler M et. al, Ann. 
Onc. 2020, 31]. Even in early stages of CRC, complete pathological remissions could be demonstrated 
[Chalabi et al. Nat Med. 2020 Apr;26(4)]. 
Risks: 
Potential risk of clinical 
significance 
Mitigation strategy 
Study intervention: atezolizumab + mFOLFOX6 
Lack of efficacy of the 
experimental treatment 
 
Two interim analyses will be performed to assess treatment 
futility and superiority. The first interim analysis, for both 
efficacy and futility, will be performed at the time at which 50% 
of the projected number of events have occurred. For further 
details see protocol section 13.4.1. 
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Adverse drug reactions to 
atezolizumab, increased 
toxicity of the combination 
treatment and 
unknown/undiscovered AEs 
• Safety assessment will be performed on a regular basis 
including assessment of relevant lab parameters to detect 
irAEs (e.g. thyroid function tests, liver function tests) [see 
protocol section 5.0 study calendar, and AIO-GSA section 3] 
• Comprehensive toxicity management guidelines are included 
in the protocol and the IB of atezolizumab. [see protocol 
section 8.2] 
• This study will be monitored by the Alliance DSMB, an NCI-
approved functioning body. Reports containing efficacy, 
adverse event, and administrative information will be 
provided to the DSMB every six months as per NCI 
guidelines. [see protocol section 13.5] 
• Adverse event stopping rules are in place [see section 13.5 of 
the protocol] 
Study-specific procedures 
Regular CT scans / exposure to 
ionizing radiation 
• Type and frequency of radiographic imaging (every 6 months 
(+/- 1 month) for the first 2 years after registration, then 
yearly for an additional 3 years) is tailored toward the 
objective assessment of the primary endpoint disease-free 
survival. Radiographic imaging cannot be omitted or reduced 
further without compromising the validity of the trial results.  
• As per GERMAN legislation a notification 
(§ 32 Abs. 1 StrlSchG) to the Federal Office for Radiation 
Protection has been submitted. 
 
Summary and conclusions: 
The IMP atezolizumab is an approved drug for various cancer indications including a combination 
treatment with conventional chemotherapy in triple-negative breast cancer (SmPC Tecentriq®). Other 
comparable CPI (e.g. pembrolizumab)  have demonstrated that combination with chemotherapy is 
feasible and efficacious (SmPC Keytruda®). The rationale for the clinical efficacy of CPI in mismatch-
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repair deficient CRC is supported by robust data. In summary, the risk-benefit assessment strongly favors 
the conduct of this trial. 
5.2 
Declaration of Helsinki/Good Clinical Practice 
Supplement to the protocol  
This study will be conducted in accordance with the ICH E6 guideline for Good Clinical Practice and 
with the Declaration of Helsinki, as adopted by the 18th World Medical Assembly, Helsinki, Finland, 
June 1964 and most recently amended by the 64th WMA General Assembly, Fortaleza, Brazil, October 
2013. The study will comply with the requirements of the ICH E2A guideline for Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting.  
In Germany, the study will comply with the German Medicinal Products Act (Arzneimittelgesetz, AMG) 
and the GCP-Verordnung (Ordinance on the implementation of Good Clinical Practice in the conduct of 
clinical trials on medicinal products for use in humans, GCP-V). National law will be superseded by the 
European Trials Regulation (536/2014) as it comes into effect and as applicable to ongoing trials. 
5.3 Independent ethics committees and regulatory authorities 
Supplement to the protocol  
5.3.1 Approval of the study by the regulatory authority and EC 
It is the responsibility of the legal representative of the sponsor in Europe, AIO-Studien-gGmbH, to 
obtain and maintain independent approval from the applicable competent authorities and a positive 
opinion from the ethics committees to conduct the study in accordance with applicable local legal 
requirements, statutes, and the European Clinical Trials Directive. 
Indemnity insurance will be contracted for the trial subjects in accordance with the applicable local law.  
For Germany, the sponsor names the "Leiter der klinischen Prüfung" (LKP) who has to be a physician 
with at least 2 years of experience in the conduct of clinical trials of drugs according to § 4 (25) and § 40 
(1) No. 5 AMG. 
5.3.2 Notification about the study 
The legal representative of the sponsor in Europe, AIO-Studien-gGmbH, is responsible to notify 
competent regional authority about the study and all investigators of the participating investigational sites, 
if applicable by local law. 
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5.3.3 Reporting and documentation obligations 
Regarding study conduct in Europe, the sponsor, the legal representative of the sponsor in Europe, and the 
investigators are responsible to comply with the reporting and documentation obligations in accordance 
with local legal requirements, statutes and the European Clinical Trials Directive. 
6 
Study documentation, CRFs and record-keeping 
6.1 
Investigator's Files / Retention of documents 
Supplement to the protocol  
The Investigator must maintain adequate and accurate records to enable the conduct of the study to be 
fully documented and the study data to be subsequently verified. These documents should be classified 
into the two separate categories Investigator's Study File and subject/patient data. 
The Investigator's Study File will contain all essential documents, including the protocol/amendments, the 
Investigator’s Brochure for atezolizumab and sample SmPCs for fluorouracil, oxaliplatin and folinic acid, 
patient information and informed consent form, ethics committee and regulatory authority approval, 
notification of the federal regulatory authority and competent regional authorities, if applicable, drug 
records, staff curriculum vitae and authorization forms, and other appropriate documents/correspondence, 
etc. 
Patient data include patient hospital/clinic records (e.g., NCI PRO-CTCAE assessments, quality of life 
questionnaires, medical reports, OP reports appointment book, medical records, pathology and laboratory 
reports, CT, MRI, etc.), signed informed consent forms and patient eligibility screening forms. 
The investigator must keep these two categories of documents on file for at least 10 years (or longer if 
legally required) OR until 1) the study has been terminated by Alliance and 2) until two years after the 
New Drug Application (NDA) or Biologic License Application (BLA) has been approved or withdrawn; 
whichever is longer. Source documentation, including informed consent forms, should be retained 
indefinitely at the registering institution. The documents must be archived in a secure place and treated as 
confidential material. 
6.2 
Source documents and background data 
Replaces protocol section 6.1.1 
Source documents are original medical records kept in the subjects’ medical files. They are supplemented 
by study-specific source documents, such as informed consent forms and quality of life questionnaires. In 
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the countries subject to this AIO-GSA, no remote source data verification will take place, and no source 
data will be systematically digitized and uploaded to eCRFs.  Radiologic images will be submitted to 
IROC, USA, at the timepoints specified in protocol section 6.3, via a third-party in Germany. 
The investigator will supply the sponsor upon request with any required background data from the study 
documentation or clinic records. This is particularly important when errors in data transcription are 
suspected. In case of special problems and/or governmental queries or requests for audit inspections, it is 
also necessary to have access to the complete study records, provided that patient confidentiality is 
protected. According to the standards of the data protection law, all data obtained in the course of a 
clinical study must be treated with discretion in order to guarantee the rights of the patient's privacy. 
6.3 
Audits and inspections 
Each trial site in Germany will be audited according to CTMB guidelines. Audits will occur within 18-
months of the first patient enrollment at each site.  
To ensure quality of data, study integrity, and compliance with the protocol and the various applicable 
regulations and guidelines, the legal representative of the sponsor in Europe (AIO-Studien-gGmbH) may 
conduct site visits to institutions participating to protocols. The investigator, by accepting to participate to 
this protocol, agrees to co-operate fully with any quality assurance visit undertaken by third parties, 
including representatives of the sponsor, national regulatory authorities or the company supplying the 
product under investigation, as well as to allow direct access to documentation pertaining to the clinical 
trial (including eCRF, source documents, hospital subject charts and other study files) to these authorized 
individuals. The investigator must inform the legal representative of the sponsor in Europe – AIO-
Studien-gGmbH- immediately in case a regulatory authority inspection is scheduled. If inspections will be 
performed in particular for this study by the competent authority, the competent authority/investigator has 
to send the inspection report to the Alliance within 5 working days.  
6.4 
Case Report Forms (CRF) 
Supplement to the protocol 
For each patient enrolled, a paper-based CRF and an eCRF (Medidata Rave®) must be completed by the 
principal investigator and/or authorized delegate of the study staff; the eCRF must be completed in 
English. This also applies to records for those patients who fail to complete the study. If a patient 
withdraws from the study, the reason must be noted in the pCRF and eCRF. 
 
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7 
Monitoring the study 
Replaces protocol section 13.6 
On-site monitoring will be conducted according to Alliance and AIO procedures. 
This trial will utilize both central and on-site monitoring in order to ensure complete and consistent data 
collection. In Germany centralized data monitoring activities, in particular the provision of supporting 
documents for such purposes will be restricted to trial documents that only contain the trial specific 
minimum of ‘data concerning health’ (according to article 4 GDPR) or does not contain any personal data 
of a trial subject [e.g. drug accountability log]. 
AIO-Studien-gGmbH will provide trained MONITORS for on-site monitoring to assist the investigator(s) 
in conducting the clinical study. Source data verification (SDV) will be carried out exclusively by on-site 
monitoring. In addition, the MONITOR has the responsibility to supplement site trainings provided by 
Alliance (online or remote) as well as familiarize the investigator(s) and the entire center staff involved in 
the study with all study procedures including the administration of IMP, to review the ongoing study with 
the investigator(s) to verify adherence to the protocol, and to deal with any problems that arise.  
The monitor will visit each clinical study site at the following time points: 
• 
before the first patient can be enrolled: site initiation visit (mandatory)  
• 
after enrolment of the first patient, and thereafter at appropriate time points to conduct SDV, 
eligibility reviews, case evaluations, query resolution, additional site trainings etc. 
• 
at study completion (close out visit).  
Further details on monitoring of the study in the E.U., e.g., the extent of source data verification, and 
GDPR and GCP compliant eligibility review & case evaluations will be laid out in the APPENDIX of the 
A021502-Monitoring Plan. 
At all times the MONITORS must maintain the confidentiality of the study documents.  
The investigator (or his/her deputy) agrees to cooperate with the MONITOR to ensure that any problems 
detected in the course of these monitoring visits are resolved. 
 
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8 
Confidentiality of trial documents and patient records 
Additional to the protocol 
The investigator and the sponsor (or designee) must assure that, as stipulated by the European and 
German data protection laws, all data obtained in the course of a clinical study are treated with discretion 
in order to guarantee the rights of the patients’ privacy. Patient-related data must be submitted to the 
sponsor in a pseudonymous manner. The investigator must keep a patient identification log showing 
codes and names. The investigator will maintain documents not for submission to sponsor, e.g., patients’ 
written consent forms, in strict confidence. 
 
 
 
 
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APPENDIX VI STOOL COLLECTION INSTRUCTIONS 
Patient Stool Collection Instructions 
NOTES: 
• 
Specimen should be collected Monday-Friday for this protocol. 
• 
Patients, after the stool is collected it needs to be divided into the smaller containers, place 
the stool containers into a Ziplock bag and seal. Place the bag into your refrigerator freezer 
until you can take it frozen to your next appointment for the study. 
• 
Sites Keep specimens frozen at -70/80°C until shipped. 
Set-up 
1. Fill out the areas of the BioMS Form. Using a waterproof pen ensure that the following 
information is provided: 
• 
Patient Initials (last, first, middle); put in a dash (-) if the middle initial is missing 
• 
Patient ID # 
• 
Date of Birth 
• 
Stool Collection Date 
• 
Stool Collection Time 
NOTE: You will be contacted to obtain missing information. 
2. Write the Study Number, Patient ID #, Patient Initials, Collection Date and Collection Time on a 
tube labels provided in the kit. 
3. After the labels are affixed to the collection tubes, wrap clear scotch tape around the tube labels to 
ensure the labels will remain intact during shipping. 
Specimen Collection: 
Inside your collection kit you should have: A white plastic bowl collection device, a flat wooden blade, 
3 tubes with “spoons” attached to cap, wypall pad, film, non-latex gloves and tongue blade. 
To collect your stool specimen: 
1. Place the holder under the seat of the toilet bowl towards the center back. 
2. Lower the toilet seat onto the holder. 
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3. 
 
4. Have a bowel movement into the bowl taking care to not urinate into the bowl 
5. Place Wypall pad on flat surface with the tubes, film and gloves. 
6. Put on gloves 
7. Place holder containing stool on Wypall pad to stabilize it. 
8. Using the “spoons” attached to the caps, carefully place some of the bowel movement into the 3 
tubes. If a “spoon” should break then use the flat wooden blade to transfer the stool. 
9. Place the caps onto the tubes and wrap the film around the cap of the tubes to seal the tube closed. 
Packaging Instructions: 
1. Complete the BioMS packing list and confirm that the specimen is correctly labeled 
2. Place the specimen into the Ziplock bag containing absorbent material. 
3. Place the Ziplock bag into the plastic transport bag. 
4. Place the completed original BioMS packing list into the outer pocket of the bag. Seal the bag 
5. Keep the bag with the specimen Frozen while you make transportation arrangements. 
Specimen Shipment: 
Specimen will be shipped via FedEx®. Care must be taken to ensure that the specimen is properly 
shipped. Specimen must be sent to BAP Monday – Friday, for arrival at our labs Tuesday – Saturday. 
Do NOT collect the specimen the day before, the day of, or the observed day of a United States federal 
holiday. Transportation services are frequently not available and the specimen may be compromised by 
delayed arrival at our labs. Call your local FedEx® office to determine service availability for pickups late 
in the day. 
1. Specimen must be completely packaged in shipping containers prior to FedEx® pickup: 
FROZEN SPECIMENS 
Place the “frozen specimen” transport bag, along with 3 to 4 lb. (2kg) of commercially-prepared 
dry ice, into the “frozen” Styrofoam® container. Pellets or chunks no more than 8 cm on a side are 
preferred. 
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NOTE: It is your responsibility to obtain dry ice when shipping frozen specimens via FedEx®. 
Mayo does not provide dry ice. Businesses that may have dry ice for purchase include ice cream 
shops, research labs, hospital and commercial blood banks, or chemical supply companies. 
2. Check that all of the required labels are clearly visible on the shipping boxes. Boxes will be 
delayed en route and specimen quality may be jeopardized if any of the required labels are 
missing, covered, or not filled out properly. 
3. US Sites Only - The brown colored shipping boxes will have a pre-addressed return label affixed 
to them. This label replaces the need for an airbill. Ship the specimen to BAP Monday-Thursday 
only. NOTE: the shipping label should be the approximate size of 3x5 and will contain the FedEx 
tracking number. If the only label on the box starts with a tracking number of “BB” this shipping 
box will require an additional FedEx form. Contact the Biospecimens Resource Manager for 
further assistance. 
Canadian Sites Only - Complete a pre-printed FedEx® airbill. Request “Priority Overnight” 
service. Indicate "Deliver Saturday" on the airbill if you ship on Friday. Ship the specimen to 
BAP Monday-Thursday only. 
4. Write your return address on the shipping container. 
5. Call FedEx® at 1-800-238-5355 early for same-day service. Provide the following information: 
• 
Exact location of pick-up site 
• 
Number of boxes in shipment 
6. Assist the FedEx® courier in finding the shipping box(es), if requested. 
 
 
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Instrucciones al paciente para recoger una muestra de heces 
NOTAS: 
• 
Para este protocolo, hay que recoger las muestras entre lunes y viernes. 
• 
Señores pacientes: una vez recogida la muestra, hay que dividirla en recipientes más 
pequeños y meterlos dentro de la bolsa plástica, congelada, que sirve para el transporte, 
contiene material absorbente y puede sellarse. Ponga la bolsa dentro del congelador hasta 
que pueda llevarla congelada a la siguiente cita del estudio. 
• 
Los lugares del estudio mantienen las muestras congeladas a menos 70 u 80°C, hasta 
enviarlas.  
Preparación 
1. Llene la información en el formulario BioMS con un bolígrafo a prueba de agua. Verifique que 
conste la siguiente información: 
• 
Iniciales del paciente (apellido, primer nombre, segundo nombre); ponga una raya (-) si 
falta la inicial del segundo nombre 
• 
Número de identificación del paciente 
• 
Fecha de nacimiento  
• 
Fecha en que se recoge la muestra 
• 
Hora en que se recoge la muestra 
NOTA: nos comunicaremos con usted para obtener cualquier información que falte. 
2. En las etiquetas de los tubos que se envían con el kit, escriba el número del estudio, el número de 
identificación del paciente, las iniciales del paciente y la fecha en que se recogió la muestra. 
3. Una vez pegadas las etiquetas a los frascos de las heces, envuelva con cinta adhesiva transparente 
las etiquetas de los tubos para garantizar que estas permanezcan intactas durante el envío. 
Obtención de la muestra: 
Dentro del kit para recoger la muestra, encontrará lo siguiente: un tazón blanco de plástico para 
recoger la muestra, 3 frascos con tapa café y «cucharas» pegadas a la tapa, una toalla Wypall, Parafilm, 
guantes sin látex y un palito de madera para usar en caso de que se rompa la cuchara.  
Para recoger la muestra de heces: 
1. Coloque el recipiente en el centro, por debajo del asiento del inodoro y hacia la parte posterior. 
2. Baje el asiento del inodoro para sujetar el recipiente. 
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3. 
 
4. Defeque dentro del tazón, pero tenga cuidado de no orinar dentro del tazón. (Si desea orinar, 
hágalo antes de colocar el recipiente para recoger la muestra). 
5. Extienda la toalla Wypall sobre una superficie plana, junto con los tubos, el Parafilm y los 
guantes. 
6. Póngase los guantes. 
7. Coloque el recipiente para recoger las heces sobre la toalla Wypall a fin de estabilizarlo. 
8. Con las «cucharas» que están pegadas a las tapas, meta con cuidado las heces dentro de los 3 
tubos.  Si la «cuchara» se rompe, haga el traspaso de las heces con el palito de madera. 
9. Tape los tubos y envuelva las tapas con la película plástica para que los tubos queden bien 
sellados. Verifique que las tapas estén bien cerradas en cada recipiente. 
(El Parafilm es una película plástica flexible que sirve para envíos). Desprenda el Parafilm del 
papel y úselo para envolver la parte superior de todos los recipientes. El Parafilm se quedará fijo, 
lo que garantizará que las muestras no contaminen otras cosas ni que se contaminen con 
sustancias externas. 
Instrucciones para el empaque: 
1. Llene la lista de empaque de BioMS y confirme que las muestras estén bien etiquetadas. 
2. Meta las muestras dentro de la bolsa plástica, congelada, que contiene material absorbente y sirve 
para el transporte. 
3. Meta la lista original de empaque de BioMS dentro del bolsillo exterior de la bolsa. Selle la bolsa. 
4. Mantenga congelada la bolsa que contiene la muestra, mientras hace los arreglos para el 
transporte. 
Envío de la muestra: 
La muestra se enviará por FedEx®. Hay que prestar mucha atención para garantizar que la muestra se 
envíe correctamente. Se puede enviar la muestra a BAP de lunes a viernes para que llegue a nuestros 
laboratorios entre el martes y el sábado. 
1. NO recoja la muestra el mismo día ni el día anterior a un feriado en los Estados Unidos, porque 
no suele haber servicio de transporte en esos días y la muestra puede comprometerse debido al 
retraso en llegar a nuestros laboratorios. Llame a la oficina local de FedEx® para averiguar si 
ofrecen servicio para recoger paquetes a última hora de la tarde. 
MUESTRAS CONGELADAS 
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Meta dentro del recipiente de poliestireno® la bolsa para transporte de «muestras congeladas» 
junto con 3 o 4 libras (2 kg) de hielo seco preparado comercialmente. Lo mejor es usar bolas o 
trozos que no excedan de 8 cm en un lado. 
NOTA: usted tiene la responsabilidad de conseguir el hielo seco cuando envíe muestras 
congeladas por FedEx®. Mayo no le provee el hielo seco. Los lugares donde pueden vender hielo 
seco son las heladerías, los laboratorios de investigación, los hospitales, los bancos de sangre que 
funcionan a nivel comercial y las compañías de suministros químicos. 
2.
Verifique que todas las etiquetas necesarias estén claramente visibles en las cajas para el envío. Si
alguna de las etiquetas faltara, estuviera cubierta o no se hubiese llenado bien, el transporte de las
cajas se retrasaría y la calidad de la muestra podría estar en peligro.
3.
Solo para los sitios en Estados Unidos: las cajas para envío que son de color café tienen pegada
una etiqueta para enviarnos la muestra. Esa etiqueta evita la necesidad de una guía aérea. Envíe la
muestra a BAP solamente de lunes a jueves. NOTA: la etiqueta para el envío debe tener un
tamaño aproximado de 3 x 5 y mostrar el número de FedEx para rastreo. Si la única etiqueta de la
caja muestra que el número de rastreo empieza por «BB», entonces esa caja para envíos requiere
otro formulario para FedEx. Comuníquese con el gerente de recursos para muestras biológicas
(Biospecimens Resource Manager) a fin de obtener más ayuda.
4.
Solo para los sitios en Canadá: llene la guía aérea de FedEx® previamente impresa. Solicite el
servicio «Priority Overnight» (entrega al siguiente día hábil). Si hace el envío en viernes, marque
«Deliver Saturday» (entregar en sábado) en la guía aérea. Envíe la muestra a BAP solamente de
lunes a jueves.
5.
Escriba su dirección en el recipiente para el envío.
6.
Llame a FedEx®, al 1-800-238-5355, temprano para que tenga el servicio ese mismo día. Brinde
la siguiente información:
•
Ubicación exacta del lugar donde se debe recoger el envío.
•
Cantidad de cajas que envía.
7.
Ayude a FedEx® a encontrar la(s) caja(s) del envío, en caso necesario.
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