Conditions: Metastatic Colorectal Carcinoma Recurrent Colorectal Carcinoma Refractory Colorectal Carcinoma Stage IV Colorectal Cancer AJCC v7 Stage IVA Colorectal Cancer AJCC v7 Stage IVB Colorectal Cancer AJCC v7
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 133
Healthy volunteers: no

Brief summary:
This randomized phase II trial studies how well capecitabine and bevacizumab with or without atezolizumab work in treating patients with colorectal cancer that is not responding to treatment and has spread to other places. Immunotherapy with monoclonal antibodies, such as atezolizumab and bevacizumab, may help the body?s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving atezolizumab with capecitabine and bevacizumab may be a better way in treating colorectal cancer.

Detailed description:
PRIMARY OBJECTIVE:

I. To estimate the efficacy of capecitabine/bevacizumab + atezolizumab, as compared with capecitabine/bevacizumab + placebo in refractory metastatic colorectal cancer (mCRC) as measured by progression-free survival (defined as the time of randomization to the first occurrence of progression based on Response Evaluation Criteria in Solid Tumors version 1.1, clinical progression, or death from any cause on study as determined by the investigator).

SECONDARY OBJECTIVES:

I. To estimate the efficacy of capecitabine/bevacizumab + atezolizumab, as compared with capecitabine/bevacizumab + placebo in refractory mCRC as measured by objective response rate (defined as partial response plus complete response) as determined by the investigator using Response Evaluation Criteria in Solid Tumors version 1.1 and immune-related response criteria (irRC).

II. To estimate the efficacy of capecitabine/bevacizumab + atezolizumab as compared with capecitabine/bevacizumab + placebo in refractory mCRC as measured by overall survival (defined as death from any cause from the time of randomization until study completion).

III. To evaluate the safety and tolerability of atezolizumab in combination with bevacizumab and capecitabine in refractory mCRC as measured by the serious adverse events and adverse events \>= grade 3 according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.

CORRELATIVE OBJECTIVE:

I. To explore any correlation between tissue and blood based biomarkers and clinical outcomes.

OUTLINE: Patients are randomized 2:1 to Arm I:Arm II.

ARM I (ATEZOLIZUMAB, BEVACIZUMAB, CAPECITABINE): Patients receive atezolizumab intravenously (IV) over 30-60 minutes on day 1, bevacizumab IV over 30-90 minutes on day 1, and capecitabine orally (PO) twice daily (BID) on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

ARM II (PLACEBO, BEVACIZUMAB, CAPECITABINE): Patients receive placebo IV over 30-60 minutes on day 1, bevacizumab IV over 30-90 minutes on day 1, and capecitabine PO BID on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, every 3 months until progressive disease, then every 6 months thereafter.

Arms:
arm 1: Patients receive atezolizumab IV over 30-60 minutes on day 1, bevacizumab IV over 30-90 minutes on day 1, and capecitabine PO BID on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive placebo IV over 30-60 minutes on day 1, bevacizumab IV over 30-90 minutes on day 1, and capecitabine PO BID on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Atezolizumab intervention 2: Bevacizumab intervention 3: Capecitabine intervention 4: Laboratory Biomarker Analysis intervention 5: Placebo
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given PO intervention 4: Correlative studies intervention 5: Given IV

Protocol document:
Prot_SAP_000.pdf: 
 
 
ACCRU #RU021416I 
 
 
Addendum 6 
 
 
 
 
 
 
 
Academic and Community Cancer Research United (ACCRU) 
 
BACCI:  A Phase II Randomized, Double-Blind, Placebo-Controlled Study of Capecitabine 
Bevacizumab plus Atezolizumab versus Capecitabine Bevacizumab plus Placebo in Patients 
with Refractory Metastatic Colorectal Cancer 
 
 For any communications regarding this protocol, please contact the person indicated  
on the Protocol Resource page. This is a stand-alone document found on the  
ACCRU web site (www.ACCRU.org).  
 
 Study Chair 
 
ACCRU: Niharika Bansal Mettu, M.D. 
Duke University Medical Center 
10 Bryan Searle drive 
Suite 433 DUMC Box 3505 
Durham, NC 27710 
507/266-0800 
507/538-0906 (FAX) 
niharika.mettu@duke.edu 
 
Study Co-Chair: 
 
 
Statisticians: 
 
 
 
 
 
 
 
 
 
Drug Availability  
Commercial Agents: Capecitabine 
Drug Company Supplied: Bevacizumab, Atezolizumab  – IND #130760 
 
√ Study contributor(s) not responsible for patient care. 
 
Research Coordinating Center 
Academic and Community Cancer Research United 
200 First Street Southwest 
Rochester, MN 55905 
FAX# 507-538-0906 
 


 
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  Addendum 6 
 
Document History 
(effective date) 
ACCRU Preactivation  
September 30, 2016 
ACCRU Activation/ Addendum 1 
Addendum 2 
Addendum 3 
Addendum 4 
Addendum 5                     
July 7, 2017 
September 22, 2017 
April 06, 2018 
June 15, 2018 
February 15, 2019 
                                   Addendum 6 
 
 
 
July 25, 2019


 
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Addendum 6 
Index 
 
Schema 
  1.0 
Background 
  2.0 
Goals 
  3.0 
Patient Eligibility 
  4.0 
Test Schedule 
  5.0  
Stratification Factors  
  6.0 
Registration/Randomization Procedures 
  7.0 
Protocol Treatment 
  8.0 
Dosage Modification Based on Adverse Events  
  9.0 
Ancillary Treatment/Supportive Care 
10.0 
Adverse Event (AE) Reporting and Monitoring  
11.0 
Treatment Evaluation Using RECIST Guideline 
12.0 
Descriptive Factors 
13.0 
Treatment/Follow-up Decision at Evaluation of Patient  
14.0 
Body Fluid Biospecimens 
15.0 
Drug Information 
16.0 
Statistical Considerations and Methodology 
17.0 
Pathology Considerations/Tissue Biospecimens 
18.0 
Records and Data Collection Procedures 
19.0 
Budget 
20.0 
References 
  
 
 
 


 
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  Addendum 6 
Schema 
 
*Cycle= 21 days 
Randomization
2:1
Bevacizumab
Capecitabine
Atezolizumab
Bevacizumab
Capecitabine
Placebo
Progression, refusal, 
unacceptable toxicity, 
alternative therapy at any time
Off Treatment Follow-Up (30 
days after last study drug)
Observation1 
(Every 12 weeks until 
progression or receipt of 
subsequent anti-cancer 
treatment documented) 
Event Monitoring2
Patients who end treatment 
without progression
Patients who end treatment due 
to progression
Event Monitoring2


 
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  Addendum 6 
Generic name:    Capecitabine 
Brand name(s):  Xeloda® 
Availability:   Commercially available 
Generic name:    Bevacizumab  
Brand name(s):  Avastin® 
Availability:   Clinical Research Services, a 
division of Rx Crossroads by McKesson 
Generic name:  
 
Atezolizumab 
Brand name(s):   
Availability:   Clinical 
Research 
Services, a 
division of Rx 
Crossroads by 
McKesson 
Generic name:    Placebo 
Brand name(s):  Placebo 
Availability:   Commercially  available 
 
Definitions 
1. Observation:  Part of the Active Monitoring phase of a study. The time period following the active treatment phase 
when the participant continues to receive cycles of evaluation in compliance with the Test Schedule and may be required 
to return to the consenting site for protocol tests. 
2. Event Monitoring:  Not part of the Active Monitoring phase of a study. The time period when the participant is no 
longer following the protocol test schedule. During Event Monitoring, the data collection schedule is dictated by the 
protocol but the visit schedule is determined by clinical practice at each participating site. During the Event Monitoring 
Phase of the study, the participant is being monitored for key study events such as progression, new primaries, and death.  
Participants may not be required to return to the consenting site for study-related reasons or be required to have research-
related tests performed.  Samples from biospecimens collected in the course of clinical care may be requested but cannot 
be required of the participant. 


 
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  Addendum 6 
1.0 
Background 
 
1.1 
Introduction 
 
Colorectal cancer and anti-VEGF therapy 
Initial treatment of metastatic colorectal cancer (mCRC) involves a 5-fluorouracil (5-FU) 
based chemotherapy backbone with anti-VEGF therapy, and upon disease progression, 
multiple studies have suggested a benefit for continued anti-VEGF therapy across lines of 
therapy in metastatic colorectal cancer. The BRiTE registry demonstrated that the use of 
bevacizumab beyond progression was associated with a doubling of overall survival (OS, 
hazard ratio [HR] 0.49, median 19.9 vs 31.8 months) (Grothey, Sugrue et al. 2008). The 
ARIES registry demonstrated that bevacizumab beyond progression was independently 
associated with improved post progression survival (HR 0.51; 95% CI, 0.42–0.61) 
(Bendell, Bekaii-Saab et al. 2012). In the VELOUR study for second line metastatic 
colorectal cancer, the addition of aflibercept to FOLFIRI chemotherapy was associated 
with an improvement in overall survival (HR 0.81; median 12.1 vs 13.5 months), 
progression free survival (PFS, HR 0.76; median 4.7 vs 6.9 months), and objective 
response rate (ORR 19.8% vs 11.1%), and there was also a benefit in patients who had 
progressed on bevacizumab, both for PFS (HR 0.66) and OS (HR 0.86) (Van Cutsem, 
Tabernero et al. 2012). The ML18147 study of second line chemotherapy +/- 
bevacizumab in patients who had progressed on a first line bevacizumab containing 
regimen, was found a significant improvement in overall survival for continued 
bevacizumab therapy (Bennouna, Sastre et al. 2013). In addition, the TRC-0301 study, a 
phase II multicenter trial that evaluated the response to bevacizumab combined with 5-
FU and leucovorin, was associated with rare objective responses (ORR 4%; 95% CI, 
1.1% to 9.9%) and had a PFS of 3.5 months and a median OS of 9.0 months (Chen, 
Mooney et al. 2006). Lastly, regorafenib was recently FDA approved based upon an 
improvement in overall survival in the CORRECT study, but due to significant toxicities, 
its clinical use is limited despite its regulatory approvals (Grothey, Van Cutsem et al. 
2013). Taken together, these data support the potential value of ongoing VEGF inhibition 
in mCRC. Given the contribution of inflammation and immune escape to colon cancer 
progression, targeting of inflammatory and immune check point pathways are attractive 
approaches to enhance the benefits of VEGF therapy in order to improve outcomes of 
patients with mCRC. 
 
PD-1/PD-L1 targeted therapies 
Programmed death ligand 1 (PD-L1) is a ligand for programmed death 1 (PD-1), a T-cell 
co-inhibitory receptor, and these molecules contribute to the ability of tumor cells to 
evade the host’s immune system (Brahmer, Tykodi et al. 2012). Therapies targeting the 
PD-1/PD-L1 axis have made a dramatic impact on the treatment of several cancer types. 
The PD-1 inhibitors nivolumab and pembrolizumab are currently FDA approved for the 
treatment of melanoma and non-small cell lung cancer (Squibb ; 2015). Positive phase II 
and/or phase III data for the PD-1 inhibitors nivolumab and pembrolizumab and/or the 
PD-L1 inhibitor atezolizumab have been reported in multiple other tumor types, 
including renal cell (Motzer, Escudier et al. 2015; Motzer, Rini et al. 2015; Sznol, 
McDermott et al. 2015; Weinstock and McDermott 2015), bladder (Bajorin, Plimack et 
al. 2015; Bellmunt, Sonpavde et al. 2015; Kates, Sopko et al. 2015; Rosenberg, Petrylak 
et al. 2015), gastric (Muro, Bang et al. 2014; Fuchs, Denker et al. 2015), small cell lung 
(Antonia, Bendell et al. 2015; Ott, Elez Fernandez et al. 2015), ovarian (Hamanishi, 
Mandai et al. 2015), triple negative breast (Callahan, Bendell et al. 2014; Disis and 
Stanton 2015), hepatocellular (El-Khoueiry, Melero et al. 2015), glioblastoma (Sampson, 


 
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  Addendum 6 
Vlahovic et al. 2015), and microsatellite instability high (MSI high) colorectal cancers. 
Numerous studies with these agents in these and other indications are currently ongoing.  
 
PD-L1 therapy with bevacizumab 
In addition to promoting tumor angiogenesis, there is increasing evidence that VEGF 
plays a role in cancer immune evasion through several different mechanisms. For 
example, experiments with activated endothelial cells suggested that in the tumor 
microenvironment, VEGF may reduce lymphocyte adhesion to vessel walls, thus 
contributing to decreased immune cell recruitment to the tumor site. Some 
immunosuppressive activities of VEFG can be reversed by inhibition of VEGF signaling. 
Thus, mice exposed to pathophysiologic levels of VEGF exhibited impaired dendritic cell 
function, which could be restored by blockade of VEGFR-2. In a murine melanoma 
model, VEGF blockade synergized with adoptive immunotherapy, as evidenced by 
improved anti-tumor activity, prolonged survival, and increased trafficking of T cells into 
tumors. 
 
In patients, bevacizumab treatment has been shown to increase dendritic cell maturation, 
a finding also seen in preclinical models. Synergistic effects have also been observed in a 
clinical study combining an immunomodulatory antibody (anti-CTLA-4; ipilimumab) 
and bevacizumab. Hodi et al. described increased T-cell trafficking in post-treatment 
biopsies, as well as marked increases in central memory cells in peripheral blood in the 
majority of patients (Hodi, O'Day et al. 2010). 
 
Therefore, combined treatment with PD-L1 and bevacizumab may augment the anti-
tumor immune response, resulting in improved and more durable clinical benefit. 
 
PD-L1 therapy with bevacizumab in colorectal cancer 
The safety and activity of atezolizumab in combination with bevacizumab and in 
combination with FOLFOX chemotherapy and bevacizumab have also recently been 
reported. Of the 13 patients who received atezolizumab plus bevacizumab, one patient 
had a partial response that was durable for 10 months; in addition, two patients had minor 
responses and stable disease lasting more than 12 and 18 months, respectively. Eight of 
these 13 patients had stable disease for at least 4 months, one of whom also had an 
unconfirmed partial response. In the first line FOLFOX and bevacizumab plus 
atezolizumab group the data are immature with a preliminary response rate of 44% and 
median PFS that is expected to exceed 12 months. Treatment in all groups was well 
tolerated, and there no unexpected safety signals. Biomarker studies noted increase in the 
frequency of activated CD8+ T cells in the periphery in patients treated with 
atezolizumab plus bevacizumab with or without FOLFOX; biomarker studies also 
suggested a potential signature to distinguish immunogenic versus non-immunogenic 
colorectal cancers (CD8, IFNγ, granzyme A, granzyme B, perforin and EOMES). Taken 
together, these data suggest that bevacizumab may increase the immunogenicity of 
colorectal cancers, the combination of atezolizumab plus bevacizumab may be associated 
with clinically meaningful response rates and disease control, and there are candidate 
biomarkers that may help identify those patients most likely to benefit from this 
combination regimen. The proposed randomized phase II study is meant to follow up 
these promising but preliminary findings. 
 
1.2 
Study Agents 
 
1.21 
Capecitabine 


 
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  Addendum 6 
 
Capecitabine (5'-deoxy-5-fluoro-N-[(pentyloxy) carbonyl]-cytidine, Xeloda®) 
is a fluoropyrimidine carbamate with antineoplastic activity (van Kuijk, 
Nijdam et al. 2011). Capecitabine is an orally administered precursor of 5’-
DFUR which is preferentially converted to the active compound 5-FU in 
malignant tissues via thymidine phosphorylase (dThdPase). After oral 
administration, capecitabine is rapidly and extensively absorbed, metabolized 
in the liver to 5’-DFCR, and then converted to 5’–DFUR by cytidine 
deaminase, which is principally located in hepatic and tumor tissue. The final 
step (metabolism of 5’-DFUR to 5-FU by dThdPase) exploits the higher 
concentrations of dThdPase in tumor tissues compared with adjacent healthy 
tissues. This enzymatic cascade potentially reduces systemic exposure to 5-FU 
and allows for a more dose intensive regimen. 
 
As of February 2007, capecitabine has received regulatory approval for the 
following therapeutic indications (van Kuijk, Nijdam et al. 2011): 
 
Capecitabine monotherapy is approved for: 
 
a. First-line treatment of patients with mCRC when treatment with 
fluoropyrimidine therapy alone is preferred. Approval has been granted 
in over 70 countries including the US, EU, Canada, Switzerland, and 
Australia. 
 
b. Adjuvant treatment of patients following surgery of stage III colon 
cancer. Approval has been granted in over 70 countries including the US, 
EU, Canada, Switzerland, and Australia. 
 
c. Treatment of patients with metastatic breast cancer that is either (i) 
resistant to both paclitaxel and anthracycline-containing regimens (or 
patients resistant to paclitaxel and for whom further anthracycline 
therapy is not indicated (e.g., patients who have received cumulative 
doses of 400 mg/m2 of doxorubicin or doxorubicin equivalents) or (ii) in 
combination with docetaxel after failure of prior anthracycline-
containing therapy. 
 
In more than 50 countries including the US, Switzerland, and Canada, approval 
has been granted for: 
 
d. Treatment of patients with locally advanced or metastatic breast cancer 
after failure of taxanes and an anthracycline-containing chemotherapy 
regimen or for who further anthracycline therapy is not indicated. 
Approval has been granted in the EU. 
 
e. First-line treatment of patients with inoperable advanced gastric cancer. 
Approval has been granted in South Korea. 
 
Combination therapy is approved for capecitabine (van Kuijk, Nijdam et al. 
2011) in: 
 
f. 
Combination with docetaxel for treatment of patients with metastatic 


 
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  Addendum 6 
breast cancer after failure of prior anthracycline containing 
chemotherapy. Approval has been granted in the US and the EU. 
 
g. Combination with a platinum-based regimen in the treatment of patients 
with inoperable advanced gastric cancer. Approval has been granted in 
EU. 
 
NCCN guidelines in mCRC for the use of capecitabine in: 
 
• 
Monotherapy in patients intolerant of additional chemotherapy or when 
bevacizumab is contraindicated. 
• 
Combination with bevacizumab in patients intolerant of additional 
chemotherapy or as part of maintenance regimen. 
• 
Combination with oxaliplatin in patients in whom bevacizumab is 
contraindicated. 
• 
Combination with oxaliplatin and bevacizumab. 
 
1.211 
Safety Summary for Combination Therapies in mCRC 
 
Capecitabine in combination with oxaliplatin (XELOX): the most 
frequently occurring AEs in patients with mCRC who received first-
line or second-line treatment with XELOX were GI disorders, of 
which the most common were nausea and diarrhea. Nervous system 
disorders were also frequently reported, of which the most common 
were paresthesia and peripheral neuropathy. Diarrhea was the most 
common grade 3/4 AE (unrelated and related to treatment) as well as 
the most common treatment-related SAE. In colorectal cancer 
patients who received XELOX in an adjuvant setting, a similar safety 
profile was seen. 
 
Xeloda in combination with oxaliplatin and bevacizumab 
(XELOX+BV): the safety profile of patients with mCRC who 
received first-line treatment with XELOX+BV was similar to that of 
XELOX. The most common AEs were nausea, vomiting and 
paresthesia. There was a moderate increase in the incidence of 
vomiting and PPE. Diarrhea was the most common grade 3/4 AE 
(unrelated and related to treatment) as well as the most common 
treatment-related SAE. An increase in the incidence of vascular 
disorders was observed, mainly due to the incidence of deep vein 
thrombosis. 
 
See the capecitabine package insert for additional safety information. 
 
1.22 
Bevacizumab 
 
Bevacizumab (Avastin®) is a recombinant humanized monoclonal IgG1 
antibody that binds to and inhibits the biologic activity of human vascular 
endothelial growth factor (VEGF) in in vitro and in vivo assay systems41. 
Bevacizumab contains human framework regions and the complementarity-
determining regions of a murine antibody that binds to VEGF. Bevacizumab 
has an approximate molecular weight of 149 kD. Bevacizumab is produced in a 


 
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  Addendum 6 
mammalian cell (Chinese Hamster Ovary, CHO) expression system in a 
nutrient medium containing the antibiotic gentamicin. Gentamicin is not 
detectable in the final product. 
 
Bevacizumab binds VEGF and prevents the interaction of VEGF to its 
receptors (Flt-1 and KDR) on the surface of endothelial cells. The interaction 
of VEGF with its receptors leads to endothelial cell proliferation and new 
blood vessel formation in in vitro models of angiogenesis. Administration of 
bevacizumab to xenotransplant models of colon cancer in nude (athymic) mice 
caused reduction of microvascular growth and inhibition of metastatic disease 
progression. 
 
In the United States, bevacizumab is indicated for the following: 
 
Metastatic Colorectal Cancer (mCRC): 
Bevacizumab in combination with fluoropyrimidine-based chemotherapy is 
indicated for treatment of patients with metastatic carcinoma of the colon or 
rectum. 
 
Advanced, metastatic or recurrent Non-Small Cell Lung Cancer 
(NSCLC): 
Bevacizumab, in addition to platinum-based chemotherapy, is indicated for 
first-line treatment of patients with unresectable, advanced, metastatic or 
recurrent, non-squamous, non-small cell lung cancer. 
 
Advanced and/or metastatic Renal Cell Cancer (mRCC): 
Bevacizumab in combination with interferon alfa-2a is indicated for first-line 
treatment of patients with advanced and/or metastatic renal cell cancer. 
 
Malignant Glioma (WHO Grade IV) - Glioblastoma: 
Bevacizumab, as a single agent, is indicated for the treatment of patients with 
glioblastoma after relapse or disease progression. 
 
Epithelial Ovarian, Fallopian Tube and Primary Peritoneal Cancer: 
Bevacizumab, in combination with carboplatin and paclitaxel is indicated for 
the front-line treatment of epithelial ovarian, fallopian tube, or primary 
peritoneal cancer. 
 
Bevacizumab, in combination with carboplatin and gemcitabine is indicated for 
the treatment of patients with recurrent, platinum-sensitive, epithelial ovarian, 
fallopian tube, or primary peritoneal cancer. 
 
Bevacizumab in combination with paclitaxel, topotecan or pegylated liposomal 
doxorubicin is indicated for the treatment of patients with recurrent, platinum-
resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who 
received no more than two prior chemotherapy regimens. 
 
Cervical Cancer: 
Bevacizumab in combination with paclitaxel and cisplatin or paclitaxel and 
topotecan is indicated for the treatment of persistent, recurrent, or metastatic 
carcinoma of the cervix. 


 
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  Addendum 6 
 
1.221 
Safety  
 
A number of phase I, II, and III clinical trials have established the 
clinical safety and bevacizumab-associated adverse events.  
 
Most common adverse reactions (incidence >10% and at least twice 
the control arm rate) are epistaxis, headache, hypertension, rhinitis, 
proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation 
disorder, back pain and exfoliative dermatitis (Roche 2013). 
 
Hypertension: 
An increased incidence of hypertension (all grades) of up to 42.1% 
has been observed in patients treated with bevacizumab compared to 
up to 14% in the comparator arm. In clinical trials across all 
indications the overall incidence of NCI-CTC Grade 3 and 4 
hypertension in patients receiving bevacizumab ranged from 0.4% to 
17.9%. Grade 4 hypertension (hypertensive crisis) occurred in up to 
1.0% of bevacizumab-treated patients, compared to up to 0.2% of 
patients treated with the same chemotherapy alone. Very rare cases 
of hypertensive encephalopathy have been reported, some of which 
were fatal. The risk of bevacizumab-associated hypertension did not 
correlate with the patients’ baseline characteristics, underlying 
disease or concomitant therapy. 
 
Analyses of the clinical safety data suggest that the occurrence of 
hypertension with bevacizumab therapy is likely to be dose-
dependent. Monitor blood pressure every two to three weeks during 
treatment with bevacizumab. Treat with appropriate anti-
hypertensives such as angiotensin-converting enzyme inhibitors, 
diuretics and calcium-channel blockers and monitor blood pressure 
regularly.  Continue to monitor blood pressure at regular intervals in 
patients with bevacizumab -induced or –exacerbated hypertension 
after discontinuation of bevacizumab.  
 
Temporary interruption of bevacizumab therapy is recommended in 
patients with hypertension requiring medical therapy until adequate 
control is achieved. Bevacizumab should be permanently 
discontinued if medically significant hypertension cannot be 
adequately controlled with antihypertensive therapy. Bevacizumab 
should be permanently discontinued in patients who develop 
hypertensive crisis or hypertensive encephalopathy. 
 
Proteinuria: 
In clinical trials, proteinuria has been reported within the range of 
0.7% to 38% of patients receiving bevacizumab. Proteinuria ranged 
in severity from clinically asymptomatic, transient, trace proteinuria 
to nephrotic syndrome. Grade 3 proteinuria was reported in up to 
8.1% of treated patients. Grade 4 proteinuria (nephrotic syndrome) 
was seen in up to 1.4% of treated patients. In the event of Grade 4 
proteinuria bevacizumab treatment should be permanently 


 
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  Addendum 6 
discontinued. The proteinuria seen in bevacizumab clinical trials was 
not associated with renal impairment and rarely required permanent 
discontinuation of bevacizumab therapy. 
 
Analyses of the clinical safety data suggest that the occurrence of 
proteinuria with bevacizumab therapy is likely to be dose-dependent. 
Patients with a history of hypertension may be at increased risk for 
the development of proteinuria when treated with bevacizumab. 
There is evidence suggesting that Grade 1 proteinuria may be related 
to bevacizumab dose. Testing for proteinuria is recommended prior 
to start of bevacizumab therapy. In most clinical studies urine protein 
levels of ≥2g/24h led to the holding of bevacizumab until recovery to 
<2g/24h. 
 
Venous thromboembolism (including deep venous thrombosis, 
pulmonary embolism, and thrombophlebitis: 
Patients may be at risk of developing venous thromboembolic 
events, including pulmonary embolism under bevacizumab 
treatment. In clinical trials across all indications the overall incidence 
of VTE events was 2.8%−17.3% in the bevacizumab-containing 
arms compared with 3.2%−15.6% in the chemotherapy control arms.  
Venous thromboembolic events include deep venous thrombosis and 
pulmonary embolism. 
 
Grade 3-5 venous thromboembolic events have been reported in up 
to 7.8% of patients treated with chemotherapy plus bevacizumab 
compared with up to 4.9% in patients with chemotherapy alone. 
Patients who have experienced a venous thromboembolic event may 
be at higher risk for a recurrence if they receive bevacizumab in 
combination with chemotherapy versus chemotherapy alone. 
 
From a clinical trial in patients with persistent, recurrent, or 
metastatic cervical cancer (study GOG-0240), grade 3-5 venous 
thromboembolic events have been reported in up to 10.6% of 
patients treated with chemotherapy and bevacizumab compared with 
up to 5.4% in patients with chemotherapy alone. 
 
In clinical trial BO21990, Grade 3-5 venous thromboembolic events 
were observed in 7.6% of patients with newly diagnosed 
glioblastoma treated with bevacizumab in combination with 
chemotherapy and radiotherapy, compared to 8.0 % of patients 
treated with chemotherapy and radiotherapy alone. 
 
Bevacizumab should be discontinued in patients with life-threatening 
(Grade 4) venous thromboembolic events, including pulmonary 
embolism. Patients with thromboembolic events ≤ Grade 3 need to 
be closely monitored. 
 
Arterial Thromboembolism: 
An increased incidence of ATE events was observed in patients 
treated with bevacizumab across indications including 


 
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  Addendum 6 
cerebrovascular accidents, myocardial infarction, transient ischemic 
attacks, and other arterial thromboembolic events. Bevacizumab 
should be permanently discontinued in patients who develop arterial 
thromboembolic events. 
 
In clinical trials, the overall incidence ranged up to 5.9% in the 
bevacizumab- containing arms compared up to 1.7% in the 
chemotherapy control arms. Fatal outcome was reported in 0.8% of 
patients receiving bevacizumab in combination with chemotherapy 
compared to 0.5% of patients receiving chemotherapy alone. 
Cerebrovascular accidents (including transient ischemic attacks) 
were reported in up to 2.3% of bevacizumab treated patients versus 
0.5% of patients in the control group: myocardial infarction was 
reported in 1.4% of bevacizumab treated versus 0.7% of patients in 
the observed control group. 
 
In one clinical trial, AVF2192g, patients with metastatic colorectal 
cancer who were not candidates for treatment with irinotecan were 
included. In this trial arterial thromboembolic events were observed 
in 11% (11/100) of bevacizumab patients compared to 5.8% (6/104) 
in the chemotherapy control group. In an uncontrolled clinical trial, 
AVF3708g, in patients with relapsed glioblastoma, arterial 
thromboembolic events were observed in 6.3% (5/79) of patients 
who received bevacizumab in combination with irinotecan compared 
to 4.8% (4/84) of patients who received bevacizumab alone. 
 
Patients receiving bevacizumab plus chemotherapy with a history of 
arterial thromboembolism, diabetes or age greater than 65 years have 
an increased risk of developing arterial thromboembolic events 
during bevacizumab therapy. Caution should be taken when treating 
such patients with bevacizumab.  
 
Aspirin is a standard therapy for primary and secondary prophylaxis 
of arterial thromboembolic events in patients at high risk of such 
events, and the use of aspirin ≤ 325 mg daily was allowed in the five 
randomized studies discussed above. Use of aspirin was assessed 
routinely as a baseline or concomitant medication in these trials, 
though safety analyses specifically regarding aspirin use were not 
preplanned. Due to the relatively small numbers of aspirin users and 
arterial thromboembolic events, retrospective analyses of the ability 
of aspirin to affect the risk of such events were inconclusive. 
However, similarly retrospective analyses suggested that the use of 
up to 325 mg of aspirin daily does not increase the risk of grade 1-2 
or grade 3-4 bleeding events, and similar data with respect to 
metastatic colorectal cancer patients were presented at ASCO 2005 
(Hambleton, Skillings et al. 2005).  
 
Gastrointestinal perforation: 
Bevacizumab has been associated with serious cases of 
gastrointestinal perforation. Gastrointestinal perforations have been 
reported in clinical trials with an incidence of <1% in patients with 


 
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  Addendum 6 
metastatic breast cancer or non-squamous NSCLC, up to 2% in 
metastatic renal cell cancer, newly diagnosed glioblastoma, or in 
patients with ovarian cancer receiving front-line treatment, and up to 
2.7% (including gastrointestinal fistula and abscess) in patients with 
metastatic colorectal cancer. Cases of GI perforations have also been 
observed in patients with relapsed glioblastoma. Fatal outcome was 
reported in approximately a third of serious cases of gastrointestinal 
perforations, which represents between 0.2-1.0% of all bevacizumab 
treated patients. 
 
In bevacizumab clinical trials, gastrointestinal fistulae (all grade) 
have been reported with an incidence of up to 2% in patients with 
metastatic colorectal cancer and ovarian cancer, but were also 
reported less commonly in patients with other types of cancer. 
 
From a clinical trial in patients with persistent, recurrent, or 
metastatic cervical cancer (study GOG-0240), GI perforations, 
including gastrointestinal fistulae and abscess (all grade) were 
reported in 10.1% of bevacizumab treated patients, all of whom had 
a history of prior pelvic radiation. Fatal outcome was reported in 
0.9% of bevacizumab-treated patients. Most patients reported as 
having GI perforations in this study (15 out of 22) had GI-vaginal 
fistulae. 
 
The presentation of these events varied in type and severity, ranging 
from free air seen on the plain abdominal X-ray, which resolved 
without treatment, to intestinal perforation with abdominal abscess 
and fatal outcome. In some cases underlying intra-abdominal 
inflammation was present, either from gastric ulcer disease, tumor 
necrosis, diverticulitis or chemotherapy-associated colitis. A causal 
association of intra-abdominal inflammatory process and 
gastrointestinal perforation to bevacizumab has not been established. 
 
Patients may be at increased risk for the development of 
gastrointestinal perforation and gallbladder perforation when treated 
with bevacizumab. Bevacizumab should be permanently 
discontinued in patients who develop gastrointestinal perforation. 
 
Fistula: 
Bevacizumab use has been associated with serious cases of fistulae 
including events resulting in death. From a clinical trial in patients 
with persistent, recurrent, or metastatic cervical cancer (study GOG-
0240), 4.1% of bevacizumab-treated patients and 2.3% of control 
patients were reported to have had vaginal, vesical or female genital 
tract fistulae (all grade), some of which were GI vaginal fistulae. The 
overall rate of GI-vaginal fistulae (all grade), combining both those 
reported as GI perforations and those reported as fistulae and abscess 
(as stated above) was 8.2% in bevacizumab-treated patients and 
0.9% in control patients. Uncommon (≥0.1% to <1.0%) reports of 
other types of fistulae that involve areas of the body other than the 
gastrointestinal tract (e.g., bronchopleural, urogenital, biliary 


 
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  Addendum 6 
fistulae) were observed across various indications. Fistulae have also 
been reported in post-marketing experience. Events were reported at 
various time points during treatment ranging from one week to 
greater than 1 year from initiation of bevacizumab, with most events 
occurring within the first 6 months of therapy.  
 
Permanently discontinue bevacizumab in patients with 
tracheoesophageal fistulae or any Grade 4 fistula. Limited 
information is available on the continued use of bevacizumab in 
patients with other fistulae. In cases of internal fistula not arising in 
the GI tract, discontinuation of bevacizumab should be considered. 
 
Wound healing complications: 
Bevacizumab may adversely affect the wound healing process. 
Serious wound healing complications with a fatal outcome have been 
reported.  
 
Necrotizing fasciitis including fatal cases, has rarely been reported in 
patients treated with bevacizumab; usually secondary to wound 
healing complications, gastrointestinal perforation or fistula 
formation. Bevacizumab therapy should be discontinued in patients 
who develop necrotizing fasciitis, and appropriate treatment should 
be promptly initiated.  
 
As bevacizumab may adversely impact wound healing, patients who 
had major surgery within the last 28 days prior to starting 
bevacizumab treatment were excluded from participation in Phase III 
trials. 
 
Across mCRC clinical trials there was no increased risk of post-
operative bleeding or wound healing complications observed in 
patients who underwent major surgery between 28-60 days prior to 
starting bevacizumab therapy. An increased incidence of post-
operative bleeding or wound healing complications occurring within 
60 days of major surgery was observed if the patient was being 
treated with bevacizumab at the time of surgery.  The incidence 
varied between 10% (4/40) and 20% (3/15).  
 
In locally recurrent and metastatic breast and ovarian cancer trials, 
Grade 3-5 wound healing complications were observed in up to 1.1% 
of patients receiving bevacizumab compared with up to 0.9 % of 
patients in the control arms. 
 
In the study of patients with relapsed glioblastoma (study 
AVF3708g), the incidence of post-operative wound healing 
complications (craniotomy site wound dehiscence and cerebrospinal 
fluid leak) was 3.6% in patients treated with single- agent 
bevacizumab and 1.3% in patients treated with bevacizumab plus 
irinotecan. 
 
In patients with newly diagnosed glioblastoma (study BO21990) the 


 
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  Addendum 6 
incidence of Grade 3-5 post-operative wound healing complications 
(including complications following craniotomy) was 3.3% when 
treated with bevacizumab in combination with chemotherapy and 
radiotherapy, compared with 1.6 % when treated with chemotherapy 
and radiotherapy alone. 
 
Bevacizumab should not be initiated for at least 28 days following 
surgery and until the surgical wound is fully healed. In patients who 
experience wound healing complications during bevacizumab 
treatment, bevacizumab should be withheld until the wound is fully 
healed. Bevacizumab therapy should be withheld for elective 
surgery. The appropriate interval between the last dose of 
bevacizumab and elective surgery is unknown; however, the half-life 
of bevacizumab is estimated to be 20 days. Suspend bevacizumab for 
at least 28 days prior to elective surgery. Do no administer 
bevacizumab until the wound is fully healed. 
 
Hemorrhage: 
In clinical trials across all indications the overall incidence of NCI-
CTC Grade 3-5 bleeding events ranged from 0.4% to 6.9% in 
bevacizumab-treated patients, compared to 0 to 4.5% of patients in 
the chemotherapy control group. The hemorrhagic events that have 
been observed in bevacizumab clinical studies were predominantly 
tumor- associated hemorrhage (see below) and minor mucocutaneous 
hemorrhage (e.g., epistaxis). Bevacizumab should be permanently 
discontinued in patients who experience Grade 3 or 4 bleeding 
during bevacizumab therapy. 
 
Tumor-Associated Hemorrhage: 
Major or massive pulmonary hemorrhage or hemoptysis has been 
observed primarily in patients with NSCLC. Possible risk factors 
include squamous cell histology, treatment with anti-rheumatic/anti-
inflammatory drugs, treatment with anticoagulants, prior 
radiotherapy, bevacizumab therapy, previous medical history of 
atherosclerosis, central tumor location and cavitation of tumors prior 
to or during therapy. The only variables that showed statistically 
significant correlations with bleeding were bevacizumab therapy and 
squamous cell histology. Patients with NSCLC of known squamous 
cell histology or mixed cell type with predominant squamous cell 
histology were excluded from subsequent studies, while patients with 
unknown tumor histology were included. 
 
In patients with NSCLC excluding predominant squamous histology, 
all Grade events were seen with a frequency of up to 9.0% when 
treated with bevacizumab plus chemotherapy compared with 5.0% in 
the patients treated with chemotherapy alone. Grade 3-5 events have 
been observed in up to 2.3% of patients treated with bevacizumab 
plus chemotherapy as compared with <1.0% with chemotherapy 
alone. Major or massive pulmonary hemorrhage/hemoptysis can 
occur suddenly and up to two thirds of the serious pulmonary 
hemorrhages resulted in a fatal outcome.  


 
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  Addendum 6 
 
Patients with non–small cell lung cancer treated with bevacizumab 
may be at risk for serious, and in some cases fatal, pulmonary 
hemorrhage/hemoptysis. Patients with recent pulmonary 
hemorrhage/ hemoptysis (>1/2 teaspoon red blood) should not be 
treated with bevacizumab. 
 
Lung cancer trials: 
Of patients experiencing pulmonary hemorrhages requiring medical 
intervention, many had cavitation and/or necrosis of the tumor, either 
preexisting or developing during bevacizumab therapy. Patients 
developing lung cavitation on treatment should be assessed by the 
treating physician for risk-benefit. 
 
In Study E4599, in which squamous cell carcinoma was excluded, 
the rate of any type of Grade ≥3 hemorrhage was 1.0% in the control 
arm (carboplatin and paclitaxel) versus 4.1% in the carboplatin and 
paclitaxel + bevacizumab arm (Sandler, Gray et al. 2006). 
 
GI hemorrhages, including rectal bleeding and melena have been 
reported in patients with CRC, and have been assessed as 
tumor-associated hemorrhages. 
 
Tumor-associated hemorrhages were also seen rarely in other tumor 
types and locations and included cases of CNS bleeding in patients 
with CNS metastases and in patients with glioblastoma. 
 
The incidence of CNS bleeding in patients with untreated CNS 
metastases receiving bevacizumab has not been prospectively 
evaluated in randomized clinical studies. In an exploratory 
retrospective analysis of data from 13 completed randomized trials in 
patients with various tumor types, 3 patients out of 91 (3.3%) with 
brain metastases experienced CNS bleeding (all Grade 4) when 
treated with bevacizumab, compared to 1 case (Grade 5) out of 96 
patients (1.0%) that were not exposed to bevacizumab. In two 
subsequent studies in patients with treated brain metastases (which 
included around 800 patients), one case of Grade 2 CNS hemorrhage 
was reported.  
 
Intracranial hemorrhage can occur in patients with relapsed 
glioblastoma. In study AVF3708g, CNS hemorrhage was reported in 
2.4% (2/84) of patients in the bevacizumab alone arm (Grade 1); and 
in 3.8% (3/79) of patients treated with bevacizumab and irinotecan 
(Grades 1, 2 and 4). 
 
Patients with untreated CNS metastases were routinely excluded 
from clinical trials with bevacizumab, based on imaging procedures 
or signs and symptoms. Therefore, the risk of CNS hemorrhage in 
such patient has not been prospectively evaluated in randomized 
clinical studies. Patients should be monitored for signs and 
symptoms of CNS bleeding, and bevacizumab treatment 


 
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  Addendum 6 
discontinued in cases of intracranial bleeding. 
 
Mucocutaneous Hemorrhage: 
Across all bevacizumab clinical trials, mucocutaneous hemorrhage 
has been seen in 50% of patients treated with bevacizumab. These 
were most commonly NCI-CTC Grade 1 epistaxis that lasted less 
than 5 minutes, resolved without medical intervention and did not 
require any changes in bevacizumab treatment regimen. Clinical 
safety data suggest that the incidence of minor mucocutaneous 
hemorrhage (e.g. epistaxis) may be dose-dependent. 
 
There have also been less common events of minor mucocutaneous 
hemorrhage in other locations, such as gingival bleeding and vaginal 
bleeding. 
 
Posterior Reversible Encephalopathy Syndrome (PRES): 
PRES is a rare neurologic disorder that can present with the 
following signs and symptoms (among others):  seizures, headache, 
altered mental status, visual disturbance, or cortical blindness, with 
or without associated hypertension. Brain imaging is mandatory to 
confirm the diagnosis of PRES. Two confirmed cases (0.8%) of 
PRES have been reported in one clinical study. Symptoms usually 
resolve or improve within days, although some patients have 
experienced neurologic sequelae. 
 
In patients who develop PRES, treatment of specific symptoms, 
including control of hypertension, is recommended along with 
discontinuation of bevacizumab. The safety of reinitiating 
bevacizumab therapy in patients previously experiencing PRES is 
not known (Glusker, Recht et al. 2006; Ozcan, Wong et al. 2006) 
 
Congestive Heart Failure: 
In clinical trials CHF was observed in all cancer indications studied 
to date, but predominantly in patients with metastatic breast cancer. 
In five Phase III studies (AVF2119g, E2100, BO17708, AVF3694g 
and AVF3693g) in patients with metastatic breast cancer, Grade ≥ 3 
CHF was reported in up to 3.5% of patients treated with 
bevacizumab in combination with chemotherapy compared with up 
to 0.9% in the control arms. For patients in study AVF3694g who 
received anthracyclines concomitantly with bevacizumab, the 
incidences of Grade ≥ 3 CHF for the respective bevacizumab and 
control arms were similar to those in the other studies in mBC: 2.9% 
in the anthracycline + Bv arm and 0% in the anthracycline + placebo 
arm. In addition, in study AVF3694g the incidence of any grade 
CHF was similar between the anthracycline + Bv (6.2%) and the 
anthracycline + placebo arms (6.0%). Most patients who developed 
CHF during mBC trials showed improved symptoms and/or left 
ventricular function following appropriate medical therapy. 
 
In most clinical trials of bevacizumab, patients with pre-existing 
CHF of NYHA II – IV were excluded; therefore, no information is 


 
19  
 
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  Addendum 6 
available on the risk of CHF in this population.  
 
Prior anthracyclines exposure and/or prior radiotherapy to the chest 
wall may be possible risk factors for the development of CHF. 
Caution should be exercised before initiating bevacizumab therapy in 
patients with these risk factors. 
 
An increased incidence of CHF has been observed in a clinical trial 
of patients with diffuse large B-cell lymphoma (BO20603) when 
receiving bevacizumab with a cumulative doxorubicin dose greater 
than 300 mg/m2. This phase III clinical trial compared 
rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone (R-
CHOP) plus bevacizumab to R-CHOP without bevacizumab. While 
the incidence of CHF in both arms was above that previously 
observed for doxorubicin therapy the rate was higher in the R-CHOP 
plus bevacizumab arm. 
 
Events consistent with congestive heart failure (CHF) were reported 
in clinical trials. The findings ranged from asymptomatic declines in 
left ventricular ejection fraction to symptomatic CHF, requiring 
treatment or hospitalization.  
 
Caution should be exercised when treating patients with clinically 
significant cardiovascular disease such as pre-existing coronary 
artery disease, or congestive heart failure with bevacizumab. Patients 
receiving concomitant anthracyclines or with prior exposure to 
anthracyclines should have a baseline MUGA scans or 
echocardiograms (ECHOs) with a normal LVEF. 
 
Ovarian Failure/Fertility: 
The incidence of new cases of ovarian failure, defined as amenorrhea 
lasting 3 or more months, FSH level ≥ 30mIU/ml and a negative 
serum β-HCG pregnancy test, has been evaluated. New cases of 
ovarian failure were reported more frequently in patients receiving 
bevacizumab. After discontinuation of bevacizumab treatment, 
ovarian function recovered in the majority of women. Long term 
effects of treatment with bevacizumab on fertility are unknown.  
 
Neutropenia: 
Increased rates of severe neutropenia, febrile neutropenia, or 
infection with severe neutropenia (including some fatalities) have 
been observed in patients treated with some myelotoxic 
chemotherapy regimens plus bevacizumab in comparison to 
chemotherapy alone. 
 
Hypersensitivity reactions, infusion reactions: 
Patients may be at risk of developing infusion / hypersensitivity 
reactions. Close observation of the patient during and following the 
administration of bevacizumab is recommended as expected for any 
infusion of a therapeutic humanized monoclonal antibody. If a 
reaction occurs, the infusion should be discontinued and appropriate 


 
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  Addendum 6 
medical therapies should be administered. A systematic 
premedication is not warranted. 
 
In some clinical trials anaphylactic and anaphylactoid-type reactions 
were reported more frequently in patients receiving bevacizumab in 
combination with chemotherapies than with chemotherapy alone. 
The incidence of these reactions in some clinical trials of 
bevacizumab is common (up to 5% in bevacizumab-treated patients). 
 
Laboratory Abnormalities: 
Decreased neutrophil count, decreased white blood count, and 
presence of urine protein may be associated with bevacizumab 
treatment. Across clinical trials, the following Grade 3 and 4 
laboratory abnormalities were seen with an increased (≥2.0%) 
incidence in patients treated with bevacizumab compared to those in 
the control groups: hyperglycemia, decreased hemoglobin, 
hypokalemia, hyponatremia, decreased white blood cell count, 
increased PT (prothrombin time), normalized ratio.  
 
Additional Adverse Events: 
See the bevacizumab Investigator Brochure for additional details 
regarding the safety experience with bevacizumab. 
 
1.23 
Atezolizumab 
 
TECENTRIQ™ (atezolizumab) is a humanized immunoglobulin (IgG1) 
monoclonal antibody that is produced in Chinese hamster ovary (CHO) cells. 
Atezolizumab targets programmed death−ligand 1 (PD-L1) on tumor-
infiltrating immune cells (ICs) or tumor cells (TCs) and prevents interaction 
with the programmed death−1 (PD-1) receptor and B7.1 (CD80), both of which 
function as inhibitory receptors expressed on T cells and other immune 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. Atezolizumab was 
engineered to eliminate Fc-effector function via a single amino acid 
substitution at position 298 on the heavy chain, which results in a non-
glycosylated antibody that has minimal binding to Fc receptors and, 
consequently, eliminates detectable Fc-effector function. By eliminating Fc-
effector function and antibody-dependent cell-mediated cytotoxicity, antibody-
mediated clearance of activated effector T cells is also eliminated.  
 
Expression of PD-L1 is prevalent among many human tumors (Dong et al. 
2002), and its overexpression is associated with poor prognosis for patients 
with certain cancers (Thompson et al. 2006; Hamanashi et al. 2007; Okazaki 
and Honjo 2007; Hino et al. 2010). Therefore, interruption of the PD-L1/PD-1 
pathway represents an attractive strategy to reinvigorate tumor-specific T-cell 
immunity. 
 
Atezolizumab was approved by the U.S. FDA in May 2016 for the treatment of 
patients with locally advanced or mUC who 1) have disease progression during 
or following platinum-containing chemotherapy or 2) have disease progression 


 
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  Addendum 6 
within 12 months of neoadjudvant or adjuvant treatment with platinum-
containing chemotherapy. 
 
1.231 
Toxicology 
 
Toxicology studies consisted of a 2-week, non−Good Laboratory 
Practice (GLP), repeat-dose pilot study in mice with a 4-week 
recovery period; 8- and 26-week, GLP, repeat-dose studies in 
cynomolgus monkeys with 12- and 13-week recovery periods, 
respectively; a non-GLP in vitro cytokine release assay; a GLP in 
vitro hemolytic potential and blood compatibility assay; and a GLP 
tissue cross-reactivity study using human and cynomolgus monkey 
tissues.  
 
Atezolizumab was well tolerated in C57BL/6 and CD-1 mice at 
doses of up to 50 mg/kg weekly for 2 weeks (total of three doses). 
Minimal neuropathy, as evidenced by microscopic findings in the 
sciatic nerve, was noted in C57BL/6 mice at ≥ 10 mg/kg. This 
minimal neuropathy was attributed to blockade of PD-L1 by 
atezolizumab as it is consistent with the observation that female 
NOD-H2b/b Pdcd1−/− mice (PD-1−deficient) spontaneously 
develop autoimmune inflammation in multiple tissues, including 
peripheral nerves, between 20 and 25 weeks of age, while no such 
lesions were observed in age-matched PD-1−sufficient mice 
(Yoshida et al. 2008). No clinical observations were noted with this 
finding. No atezolizumab-related microscopic findings were 
observed in CD-1 mice. 
 
Atezolizumab was also well tolerated in cynomolgus monkeys 
following doses of up to 50 mg/kg for up to 26 weeks.  
Atezolizumab-related arteritis/periarteritis in several organs is 
consistent with the primary pharmacology of PD-L1 inhibition and 
the deregulation of peripheral tolerance. 
1.232 
Clinical Pharmacology 
 
Exposure to atezolizumab increased dose proportionally over the 
dose range of 1 mg/kg to 20 mg/kg, including the fixed dose of 1200 
mg administered every 3 weeks (q3w). On the basis of a population 
pharmacokinetic (popPK) analysis that included 472 patients in 
the dose range of 1 mg/kg to 20 mg/kg, the typical population 
clearance (CL) was 0.20 L/day, the volume of distribution at steady 
state (Vss) was 6.9 L, and the terminal half-life (t1/2) was 27 days. 
The popPK analysis suggested that steady state was obtained after 6 
to 9 weeks (2 to 3 cycles) of repeated dosing. The systemic 
accumulation in area under the concentration-time curve (AUC), 
maximum concentration (Cmax), and trough concentration (Cmin) 
was 1.91, 1.46, and 2.75-fold, respectively. 
 
Based on an analysis of exposure-safety, and exposure-efficacy data, 
the following factors had no clinically relevant effect: age (21−89 
years), body weight, gender, positive ATA status, albumin levels, 


 
22  
 
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  Addendum 6 
tumor burden, region or ethnicity, renal impairment, mild hepatic 
impairment, level of PD-L1 expression, or Eastern Cooperative 
Oncology Group (ECOG) status. 
 
The effect of moderate or severe hepatic impairment (bilirubin > 
upper limit of normal [ULN] and AST > ULN or bilirubin ≥ 1.0 to 
1.5 • ULN and any AST elevation) on the pharmacokinetics of 
atezolizumab is unknown. 
 
No formal PK drug-drug interaction studies have been conducted 
with atezolizumab. The drug interaction potential of atezolizumab is 
unknown. 
 
1.233 
Clinical Studies 
 
As of May 10, 2016, clinical data on atezolizumab as a single agent 
or in combination with chemotherapy or targeted agents are available 
from 17 studies as follows: 
 
• 
Monotherapy: Studies JO28944, PCD4989g, GO29293 
(hereinafter referred to as IMvigor 210), GO29625 
(hereinafter referred to as FIR), GO28753 (hereinafter 
referred to as POPLAR), GO28754 (hereinafter referred to 
as BIRCH), and WO29074 (hereinafter referred to as 
IMmotion 150, where Arm B evaluates atezolizumab as a 
single agent) 
 
• 
Combination: Studies GP28328, GP28384, GP28363, 
GO29383, IMmotion 150 (where Arm A evaluates 
atezolizumab in combination with bevacizumab), WP29158, 
GO29322, BP29428, GO29674, BP29435, and BP29392 
 
Refer to atezolizumab (MPDL3280A) Investigator’s Brochure 
Version 8 July 2016 for details of ongoing studies. 
   
1.234 
Safety 
 
As of 10 May 2016, an estimated total of 6053 patients with solid 
tumor and hematologic malignancies have received atezolizumab in 
clinical trial participation as a single agent or in combination with 
cytotoxic chemotherapy and/or targeted therapy.  
 
Safety findings of single-agent atezolizumab across multiple tumor 
types in the clinical development program are consistent with the 
known mechanism of action of atezolizumab and the underlying 
disease. Overall, treatment with atezolizumab is well tolerated, with 
a manageable adverse event profile. Currently, no maximum 
tolerated dose, no dose-limiting toxicities, and no clear dose-related 
trends in the incidence of adverse events have been determined. 
Across all studies and tumor types, the most commonly reported 
adverse events with single-agent atezolizumab include fatigue, 


 
23  
 
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  Addendum 6 
nausea, decreased appetite, diarrhea, constipation, and cough. 
 
The adverse events observed with atezolizumab in combination with 
chemotherapy and/or targeted therapies are consistent with the 
known risks of each study treatment. Systemic immune activation, 
characterized by an excessive immune response, is a potential risk 
associated with atezolizumab when used in combination with another 
immunomodulating compound. 
 
The percentage of patients who discontinued atezolizumab due to 
any adverse event is consistent when used as a single agent or in 
combination with chemotherapy (e.g., 5.4% in Study PCD4989g and 
5.8% in Study GP28328, respectively). The percentage of patients 
with any Grade 5 adverse event was similar when used as a single 
agent or in combination with chemotherapy (e.g., 1.6% in Study 
PCD4989g and 1.0% in Study GP28328). 
 
Please refer to atezolizumab (MPDL3280A) Investigator’s Brochure 
Version 8 July 2016 for a detailed discussion of available safety data 
from select studies in the atezolizumab clinical program. 
 
Immune-related adverse events are consistent with the role of the 
PD-L1/PD-1 pathway in regulating peripheral tolerance. Given the 
mechanism of action of atezolizumab, events associated with 
inflammation and/or immune-related adverse events are closely 
monitored during the atezolizumab clinical program. As of this IB 
update, immune-related adverse events associated with atezolizumab 
include hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, 
hypothyroidism, hyperthyroidism, adrenal insufficiency, Guillain-
Barré syndrome, myasthenic syndrome/myasthenia gravis, 
and meningoencephalitis.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
24  
 
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  Addendum 6 
Table 1.234 Serious Adverse Drug Reactions for Atezolizumab in 
All Indications for Regulatory Reporting Purposes Only 
 
 


 
25  
 
 ACCRU # RU021416I 
 
 
  Addendum 6 
 
 


 
26  
 
 ACCRU # RU021416I 
 
 
  Addendum 6 
 


 
27  
 
 ACCRU # RU021416I 
 
 
  Addendum 6 
 


 
28  
 
 ACCRU # RU021416I 
 
 
  Addendum 6 
 


 
29  
 
 ACCRU # RU021416I 
 
 
  Addendum 6 
 


 
30  
 
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  Addendum 6 
 
 
 
Important Identified Risks 
The classification of an adverse event as an identified risk/adverse drug 
reaction (ADR) or a potential risk is based on the data available at the 
time of assessment. Data obtained at later dates may refute the 
connection between an adverse event and atezolizumab and lead to an 
ADR being subsequently reclassified as an adverse event. 
 
As of May 10, 2016, the information below presents a summary of 
important identified risks for atezolizumab. The safety data presented 
below is primarily based on pooled single-agent data from 1547 
patients with mUC and NSCLC from IMvigor 210, POPLAR, 
BIRCH, FIR, and Study PCD4989g. 
 
To date, there are no additional identified risks/ADRs specific to the 
combination of atezolizumab when given with another therapeutic 
agent. The identified risks/ADRs of other therapeutic agents used in 
combination with atezolizumab can be found in their respective IBs or 
Prescribing Information. 
 
A summary of important identified risks is presented below. 
 
Immune-related hepatitis:  Cases of hepatitis, some leading to fatal 
outcomes, have been observed in clinical trials with atezolizumab. 
Most of the hepatic events identified were non-serious elevations of 
liver enzymes. Hepatitis occurred in 0.3% (4/1547) of patients who 
received atezolizumab. The median time to onset was 1.1 months 
(range: 9 days to 7.9 months). The median duration was 1.2 months 
(range: 21 days to 1.9 + months; + denotes a censored value). Hepatitis 
requiring the use of corticosteroids occurred in 0.1% (2/1547) of 
patients receiving atezolizumab. All of these events resolved with the 
exception of one case of Grade 1 hepatitis, which was resolving at the 
time of data cutoff. Additionally, 1 patient (< 0.1%) experienced 
hepatic failure (with fatal outcome, considered unrelated to study 
therapy). 
 
Immune-related pneumonitis: Pneumonitis occurred in 3.0% 
(47/1547) of patients who received atezolizumab. The majority of 


 
31  
 
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  Addendum 6 
patients experienced only mild to moderate events. Of the 47 patients, 
66% of the All NSCLC group and 67% of the All UC group 
experienced events with a maximum severity of Grade 1 or 2. One 
event was fatal in the All NSCLC group (considered unrelated to 
atezolizumab), and no events were fatal in the All UC group. The 
median time to onset was 2.9 months (range: 3 days to 18.7 months). 
The median duration was 1.4 months (range: 0 days to 12.6 + months; 
+ denotes a censored value). Pneumonitis led to discontinuation of 
atezolizumab in 6 (0.4%) patients. Pneumonitis requiring the use of 
corticosteroids occurred in 1.6% (24/1547) of patients receiving 
atezolizumab. As expected, pneumonitis events occurred more 
frequently in the NSCLC patient population, most likely due to higher 
baseline incidence, higher prevalence of other risk factors, and 
atezolizumab-induced immunologic response to the tumor. 
 
Immune-related colitis: Cases of diarrhea or colitis have been 
observed in clinical trials with atezolizumab. Colitis occurred in 1.0% 
(15/1547) of patients who received atezolizumab. The median time to 
onset was 2.7 months (range: 15 days to 7.3 months). The median 
duration was 2.5 months (range: 6 days to 8.3 + months; + denotes a 
censored value). Colitis led to the discontinuation of atezolizumab in 3 
(0.2%) patients. Colitis requiring the use of corticosteroids occurred in 
0.3% (4/1547) of patients receiving atezolizumab. 
 
Immune-related pancreatitis: Pancreatitis, including amylase 
increased and lipase increased, occurred in 0.5% (7/1547) of patients 
who received atezolizumab. Most events identified were non-serious 
elevations in lipase or amylase. A total of 2 (0.1%) patients 
experienced pancreatitis, including 1 patient with acute pancreatitis. 
The median time to onset was 2.6 months (range: 8 days to 10.9 
months). The median duration was 1.8 months (range: 3 days to 
5.9 + months; + denotes a censored value). 
 
Immune-related diabetes mellitus: Diabetes mellitus occurred in 
0.3% (5/1547) of patients who received atezolizumab. Of these, 2 cases 
were serious and 3 were considered non-serious. The time to onset 
ranged from 1.6 to 6.5 months. Diabetes mellitus led to the 
discontinuation of atezolizumab in 1 (< 0.1%) patient. 
 
Immune-related hypothyroidism: Hypothyroidism occurred in 3.6% 
(56/1547) of patients who received atezolizumab. The median time to 
onset was 4.8 months (range: 15 days to 11.3 months). Events have 
generally been mild, and patients who received treatment with thyroid 
replacement were able to continue on study treatment. 
 
Immune-related hyperthyroidism: Hyperthyroidism occurred in 
0.8% (13/1547) of patients who received atezolizumab. The median 
time to onset was 3.5 months (range: 21 days to 9.1 months). No 
severe events were identified. 
 
Immune-related adrenal insufficiency: Adrenal insufficiency 


 
32  
 
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  Addendum 6 
occurred in 0.1% (2/1547) of patients who received atezolizumab. The 
time to onset for the 2 patients (Grade 1−2) was 3 days and 5.2 months. 
Both patients required the use of corticosteroids. 
 
Immune-related Guillain-Barré syndrome: Guillain-Barré 
syndrome, which may be life threatening, was observed in a patient 
receiving atezolizumab. Patients should be monitored for symptoms of 
motor and sensory neuropathy. Guillain-Barré syndrome occurred in < 
0.1% (1/1547) of patients who received atezolizumab. The time to 
onset for this event was 8.1 months, and the duration was 1.2 months. 
This patient discontinued atezolizumab due to Guillain-Barré 
syndrome. 
 
Immune-related myasthenic syndrome/myasthenia gravis: 
Myasthenic syndrome/myasthenia gravis were observed in patients 
receiving atezolizumab. Patients should be monitored for symptoms of 
motor and sensory neuropathy. Two cases of myasthenia gravis or 
myasthenic syndrome have been reported from across the entire 
development program as of 25 Febrauary 2016. The first case 
concerned a 64-year-old male patient receiving atezolizumab 
monotherapy for RCC in the Study PCD5989g (GO27831). The patient 
was positive for acetylcholine receptor binding antibodies and 
acetylcholine receptor modulating antibodies. The event was 
considered serious and the patient was treated with corticosteroids and 
discontinued from the study. A second case of myasthenia gravis was 
received concerning a 64-year-old male patient receiving atezolizumab 
in combination with ipilimumab in Study GO29322. The event was 
considered serious, and the patient was treated with corticosteroids and 
mycophenolate and discontinued from the study. 
 
Immune-related meningoencephalitis: Encephalitis occurred in < 
0.1% (1/1547) of patients who received atezolizumab. This patient 
developed serious Grade 3 encephalitis on Study Day 16 while 
participating in the BIRCH study and fully recovered (duration 13 
days) following treatment with antibiotics and steroids in addition to 
anti-viral and anti-convulsant medications. 
 
Infusion-related reactions: Infusion-related reactions are known to 
occur with the administration of monoclonal antibodies. The signs and 
symptoms of infusion-related reactions share considerable overlap with 
several very common atezolizumab ADRs including influenza-like 
illness, pyrexia, and rash. The identified reactions occurred within 24 
hours of atezolizumab administration and were generally mild to 
moderate in severity, and only 8 patients (0.5%) developed serious 
adverse events. Nineteen (1.2%) of 1547 patients were reported to have 
experienced the event of infusion reaction (with one serious event). 
Across all 1547 patients, 12 patients (0.8%) were reported to have 
hypersensitivity (with one serious event), and none were reported to 
have experienced anaphylactic or anaphylactoid reactions. 
 
Important Potential Risks 


 
33  
 
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  Addendum 6 
The classification of an adverse event as a potential risk is based on the 
mechanism of action of atezolizumab, nonclinical findings, and other 
agents with similar mechanisms of action. Atezolizumab belongs to the 
class of immune-checkpoint inhibitors that enhance the magnitude and 
quality of tumor-specific T-cell responses by blocking molecules (such 
as PD-1, PD-L1, or cytotoxic T-lymphocyte antigen 4) that negatively 
regulate T-cell activation (Gangadhar and Vonderheide 2014). 
 
A summary of important potential risks is presented below. 
 
Anti-therapeutic antibodies: After a single IV administration to 
cynomolgus monkeys, anti-atezolizumab antibodies were detected in 
12 of 12 animals (100%) at Day 14; 11 of 12 animals remained ATA 
positive after Day 14 until the end of the study. Fifty of 56 animals 
(89%) given atezolizumab showed ATAs following nine weekly doses. 
While ATAs affected the pharmacokinetics of some animals, average 
exposure for ATA-positive and ATA-negative animals was similar. 
ATAs have been observed in the clinical trials to date for 
atezolizumab; however, at doses of 10 mg/kg and above, they do not 
appear to affect exposure. The incidence of SAEs was increased in 
ATA-positive patients (40.2%) compared with ATA-negative patients 
(33.5%), but no specific trend in either MedDRA SOC or individual 
adverse event preferred term was identified in ATA-positive patients. 
In all safety-evaluable patients with available post-treatment ATA 
status (n = 888), the incidence of hypersensitivity events and 
infusion-related reactions was low and consistent between 
ATApositive and ATA-negative patients. Hypersensitivity events were 
reported in 18 patients (1.4%): 8 ATA-negative (1.1%) and 10 
ATApositive (1.9%) patients. Infusion-related reactions occurred in 20 
patients (1.6%): 11 ATA-negative (1.5%) and 9 ATA-positive (1.7%) 
patients. 
 
The incidences of all grade adverse events, Grade 5 adverse events, 
adverse events leading to treatment withdrawal, adverse events 
leading to dose interruption, and AESIs were similar irrespective of 
post-baseline ATA status (negative or positive). Differences were 
observed in Grade 3−4 adverse events (38.4% in ATA-negative vs. 
44.3% in ATA-positive patients), driven mainly by more adverse 
events reported in the gastrointestinal disorders SOC (5.7% vs. 
8.5%), but no individual preferred term could be identified to explain 
this difference. 
 
Embryofetal toxicity: Several nonclinical studies have demonstrated 
that the PD-L1/PD-1 signaling pathway is critical in establishing and 
maintaining maternal/fetal tolerance, which is essential for embryo-
fetal survival during gestation (Guleria et al. 2005; Habicht et al. 2007; 
D’Addio et al. 2011). Inhibition of the PD-L1/PD-1 pathway has not 
been reported to result in teratogenic effects, and syngeneic 
homozygous knockout fetuses (PD-L1 or PD-1 knockouts) develop 
normally and have not shown skeletal or visceral defects. 
Administration of atezolizumab is expected to have an adverse effect 


 
34  
 
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  Addendum 6 
on pregnancy via modulation of maternal/fetal tolerance, and poses a 
risk to the human fetus, including embryo-lethality via an increased 
risk of immune-mediated rejection. 
 
No reproductive or teratogenicity studies in animals have been 
conducted with atezolizumab. There are no clinical studies of 
atezolizumab in pregnant women. Atezolizumab is not 
recommended during pregnancy unless the potential benefit for the 
mother outweighs the potential risk to the fetus. 
 
Other Potential Risks and Class Effects 
Other safety events of interest that are currently being monitored in the 
atezolizumab clinical program include the following: immune-related 
myositis, immune-related nephritis, immune-related uveitis, immune-
related myopathies, and rhabdomyolysis. 
 
Immune-Related Myositis:  Three cases in the atezolizumab global 
safety database were identified, including one case of myasthenia 
gravis (which is an identified risk for atezolizumab), one case of 
polymyalgia rheumatic, and one case of dermatomyositis from BIRCH. 
The dermatomyositis case had features consistent with cancer-
associated myositis, and there was insufficient evidence to support the 
attribution of a causal relationship between myositis and atezolizumab. 
Myositis is an ADR for other immune-checkpoint inhibitors. Myositis 
remains a potential risk for atezolizumab and will continue to be 
monitored by routine pharmacovigilance. 
 
Immune-Related Nephritis: Nephritis is a concern, given the 
mechanism of action of atezolizumab and findings from other immune-
modulating agents. A search of the atezolizumab global safety database 
retrieved a total of two cases, including one case of nephritis from 
Study GP28384 and one case of nephrotic syndrome from Study 
GO29432. Both had clear alternative explanations, and the available 
evidence did not demonstrate that atezolizumab was causally 
associated with nephritis. Nephritis remains a potential risk for 
atezolizumab and will continue to be monitored by routine 
pharmacovigilance. 
 
Immune-Related Uveitis: Three cases (representing approximately 
0.1% of atezolizumab patients) containing four events were identified, 
originating from Studies GP28384 and WP29158. All three cases were 
nonserious and contained compelling alternative explanations. Uveitis 
is not considered an important risk for atezolizumab, and it will 
continue to be monitored by routine pharmacovigilance. 
 
Immune-Related Myopathies, Including Rhabdomyolysis: Reports 
of myopathies, including rhabdomyolysis, have been observed across 
the clinical development program of atezolizumab. Patients who 
present with signs or symptoms of muscular pain should be assessed 
for inflammatory causes for muscle pains. Management of these 
patients should be along institutional guidelines. 


 
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  Addendum 6 
 
 
 
 
1.3 
Study Rationale 
 
Preclinical and clinical data suggest that anti-VEGF therapy may augment 
immunotherapy, including anti-PD-L1 treatment. Preliminary data from patients with 
refractory metastatic colorectal cancer suggest that bevacizumab may increase the 
immunogenicity of colorectal cancers, that the combination of atezolizumab plus 
bevacizumab may be associated with clinically meaningful response rates and disease 
control, and that there are candidate biomarkers that may help identify those patients 
most likely to benefit from this combination regimen. The proposed randomized phase II 
study is meant to follow up these promising but preliminary findings. 
 
1.4 
Correlative Research 
 
The importance of developing cancer biomarkers offers the potential to identify patients 
most likely to benefit and/or have toxicity from novel therapies and to define mechanisms 
of resistance that may potentially improve the clinical outcomes of cancer patients and 
the cost-effectiveness of cancer therapies. In the last decade, our understanding of tumor 
angiogenesis, pro-cancer inflammation and anti-tumor immunity have increased 
dramatically, as have the technologies available to assess these biologies. The VEGF and 
PD axes are among the most important targets in these areas. The key drivers of cancer 
biology are the targets of bevacizumab and atezolizumab, respectively. 


 
36  
 
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  Addendum 6 
 
Archived FFPE tumor samples, plasma, serum, and circulating immune cells will be 
collected and analyzed with the goal of better understanding the mechanisms of action, 
sensitivity, resistance, and toxicity for bevacizumab and atezolizumab, and the biology of 
colorectal cancer. Studies will be performed using optimized assays under the supervision 
of the Duke Phase I Biomarker Laboratory at Duke University Medical Center, which 
acts as a molecular profiling laboratory for tissue- and blood-based biomarkers of 
targeted therapies, and the Duke Immune Profiling Core (DIPC) Laboratory, which acts 
as a core facility to study the immune correlates of immune directed therapies. 
 
All analyses will be based upon the best science and technology at the time of analysis, 
sample quantities, and available funding. Patterns of expression will be described, 
expression among markers will be correlated, and expression will be correlated with 
clinical outcomes. Details of statistical analyses are described in the statistical section of 
the protocol. 
 
1.41 
Tissue Based Biomarkers: Archival formalin-fixed paraffin-embedded (FFPE) 
tumor tissue will be analyzed by immunohistochemistry and quantitative 
polymerase chain reaction (qPCR) assays, although other technologies may be 
utilized. Candidate markers may include, but are not limited to, VEGF, IL6, 
and PD axis ligands, receptors, and co-receptors and other markers related to 
tumor angiogenesis, inflammation, and immunity, and colon cancer biology. 
MSI status may also be analyzed by IHC or PCR; mutational load may be 
assessed by NGS. Immune cell populations may also be analyzed including, 
but not limited to, CD3, CD4, CD8, CD56, CD68, Foxo-P3, Th17 cells. 
 
1.42 
Plasma and Serum Biomarkers: Plasma and serum markers will be analyzed by 
multiplex ELISA approaches, although other technologies may be used. 
Candidate markers may include, but are not limited to, VEGF-A, -C, -D, 
VEGFR-1, -2, -3, IL6, IL6R, s-gp130, IL11, IL17A, IL17E, IL17R, IL22, 
IL22, IL23, and TGFβ. Other markers related to tumor angiogenesis, 
inflammation, and immunity, and colon cancer biology may also be evaluated. 
Analyses of cell free DNA in plasma may also be considered to assess genetic 
alterations, using technologies such as next generation genomic sequencing or 
digital PCR. Candidate alterations include, but are not limited to, mutations in 
Ras and Raf. 
 
1.43 
Circulating Immune Cell Biomarkers: Immune cell correlates using flow-based 
assays will be performed in collaboration with the Duke Immune Profiling 
Core (DIPC) laboratory. Cells to be used in flow-based assays will be obtained 
from individual patients’ acid citrate dextrose (ACD) anti-coagulated fresh 
whole blood that have been processed to isolate peripheral blood mononuclear 
cells (PBMC), cryopreserved, and stored in liquid nitrogen (LN2) freezers for 
batch processing. 
 
It is anticipated that two fifteen color polychromatic flow cytometry panels will 
be used to analyze changes in the immune cell subtypes that are expected to be 
altered by treatment. Other technologies approaches may also be considered. 
The 13-color base panels to identify immune cell types and related markers 
will be determined based upon the best science available at the time of 
analysis. The lymphoid panel focuses on T-cell activation, maturation, 


 
37  
 
 ACCRU # RU021416I 
 
 
  Addendum 6 
regulation, and exhaustion. The myeloid panel focuses on myeloid derived 
suppressor cells (MDSC), M1/M2 polarization, and dendritic cells (DC, pDC). 
The markers included in each respective panel have been reported to be of 
value in the context of prognostic or predictive immune markers in cancer 
studies (Blank, Gajewski et al. 2005; Blank and Mackensen 2007; Keir, Butte 
et al. 2008; Brahmer, Tykodi et al. 2012; Sznol, McDermott et al. 2015). While 
the majority of immune markers reported are associated with the tumor 
microenvironment, measurement of peripheral MDSCs has been associated 
with progression free survival in the context of neoadjuvant ipilimumab 
therapy for melanoma. The two additional markers for each panel are included 
to enable assaying for novel markers based on literature current at the time of 
funding as well as scientific data supporting the use for each additional marker. 
Data will be analyzed using novel computational methods developed at Duke 
that can be used to identify multi-dimensional populations and evaluate 
changes in these populations across treatment (Chan, Feng et al. 2008; 
Frelinger, Ottinger et al. 2010). 
 
1.44 
Pharmacogenomic Biomarkers: Germ-line DNA will be isolated from 
peripheral blood mononuclear cells and stored for potential pharmacogenomics 
analyses. Candidate gene of interest for analysis include those known to 
regulate angiogenesis, inflammation, immunity, auto-immunity, and antibody 
or drug action of clearance, such as VEGF, NOS, IL6, IL17, Fc Receptors, and 
MHCs. 
 
 
2.0 
Goals 
 
2.1 
Primary 
 
2.11 
To estimate the efficacy of capecitabine/bevacizumab + atezolizumab, as 
compared with capecitabine/bevacizumab + placebo in refractory metastatic 
colorectal cancer (mCRC) as measured by progression-free survival (defined as 
the time of randomization to the first occurrence of progression based on 
Response Evaluation Criteria in Solid Tumors version 1.1, clinical progression, 
or death from any cause on study as determined by the Investigator). 
 
2.2 
Secondary 
 
2.21 
To estimate the efficacy of capecitabine/bevacizumab + atezolizumab, as 
compared with capecitabine/bevacizumab + placebo in refractory mCRC as 
measured by objective response rate (defined as partial response plus complete 
response) as determined by the Investigator using Response Evaluation Criteria 
in Solid Tumors version 1.1 and immune-related response criteria (irRC). 
 
2.22 
To estimate the efficacy of capecitabine/bevacizumab + atezolizumab as 
compared with capecitabine/bevacizumab + placebo in refractory mCRC as 
measured by overall survival (defined as death from any cause from the time of 
randomization until study completion). 
 
2.23 
To evaluate the safety and tolerability of atezolizumab in combination with 
bevacizumab and capecitabine in refractory mCRC as measured by the serious 


 
38  
 
 ACCRU # RU021416I 
 
 
  Addendum 6 
adverse events and adverse events ≥ grade 3 according to National Cancer 
Institute Common Terminology Criteria for Adverse Events version 4.0. 
 
2.3 
Correlative Research 
 
2.31 
To explore any correlation between tissue and blood based biomarkers and 
clinical outcomes. 
 
 
3.0 
Patient Eligibility 
 
3.1 
Randomization – Inclusion Criteria  
 
3.11 
Age ≥18 years. 
 
3.12 
Histologically confirmed colorectal cancer that is either clinically or 
histologically proven to be metastatic and has progressed on regimens 
containing a fluoropyrimidine (e.g., 5-fluorouracil or capecitabine), oxaliplatin, 
irinotecan, bevacizumab and an anti-EGFR antibody (if tumor is RAS wild-
type), or where the treatment was not tolerated or contraindicated. 
 
3.13 
Measurable disease as defined in Section 11.0. Note: Previously irradiated sites 
can be included if there is documented disease progression in that site.  
 
3.14 
Capecitabine and bevacizumab considered appropriate treatment for the 
patient. 
 
3.15 
ECOG Performance Status (PS) 0-1. (Form is available on the ACCRU web 
site) 
 
3.16 
The following laboratory values obtained ≤7 days prior to randomization.  
 
• 
Absolute neutrophil count ≥ 1,500/μL 
• 
Platelets ≥ 100,000/μL 
• 
Total bilirubin ≤ 1.5 X upper limit of normal (ULN) Patients with known 
Gilbert’s Syndrome who have serum bilirubin ≤ 3 X ULN may enroll. 
• 
AST/ALT ≤ 1.5 X ULN; < 3X ULN if known hepatic metastases 
• 
Hemoglobin ≥ 9 g/dL Continuation of erythropoietin products is permitted. 
Hemoglobin must be stable ≥ 9 g/dL ≥14 days without blood transfusion to 
maintain hemoglobin level. 
• 
Calculated creatinine clearance must be ≥50 ml/min using the Cockcroft-
Gault formula below or a 24 hour urine: 
 


 
39  
 
 ACCRU # RU021416I 
 
 
  Addendum 6 
 
3.17 
The following laboratory values obtained ≤14 days prior to randomization. 
• 
PT/PTT/INR ≤1.5 X ULN if not anticoagulated.  
 
 
Within local institutional guidelines per local physician if anticoagulated. 
 
 3.18 
Negative pregnancy test done ≤7 days prior to randomization, for women of 
childbearing potential only. 
 
3.19a 
Provide informed written consent. 
 
3.19b 
Willingness to return to enrolling institution for follow-up (during the Active 
Monitoring Phase of the study). 
 
3.19c 
Willingness to provide tissue and blood samples for correlative research 
purposes (see Sections 6.0, 14.0 and 17.0).  
 
3.19d 
Life expectancy of  ≥3 months. 
 
3.2 
Randomization – Exclusion Criteria  
 
3.21 
Any of the following because this study involves an investigational agent 
whose genotoxic, mutagenic and teratogenic effects on the developing fetus 
and newborn are unknown: 
 
• 
Pregnant women 
• 
Nursing women 
• 
Women of child-bearing potential must agree to use two forms of adequate 
contraception from time of initial consent, for the duration of study 
participation, and for ≥6 months after the last dose of study drug. 
Medically acceptable contraceptives include: (1) surgical sterilization (such 
as a tubal ligation or hysterectomy), (2) approved hormonal contraceptives 
(such as birth control pills, patches, implants or injections), (3) barrier 
methods (such as a condom or diaphragm) used with a spermicide, or (4) 
an intrauterine device (IUD). Contraceptive measures such as Plan B™, 
sold for emergency use after unprotected sex, are not acceptable methods 
for routine use. Postmenopausal woman must have been amenorrheic for at 
least 2 years to be considered of non-childbearing potential. Sexually 
active men must use at least one form of adequate contraception from time 
of initial consent, for the duration of study participation, and for ≥ 6 
months after the last dose of study drug.   
 
3.22 
Chemotherapy, biologic anti-cancer therapy, or central field radiation therapy 
Cockcroft-Gault Equation: 
 
Creatinine clearance for males =   
(140 - age)(weight in kg)_______ 
 
 
 
 
 
 
(72)(serum creatinine in mg/dL) 
 
Creatinine clearance for females =   
(140 - age)(weight in kg)(0.85)__ 
 
 
 
 
 
 
(72)(serum creatinine in mg/dL) 


 
40  
 
 ACCRU # RU021416I 
 
 
  Addendum 6 
≤28 days prior to randomization. Note: Local or stereotactic radiation ≤14 days 
prior to randomization. 
 
3.23 
Any investigational agent ≤28 days or 5 half-lives prior to randomization 
(whichever is longer). 
 
3.24 
Prior treatment with atezolizumab or another PD-L1/PD-1 therapy. 
 
3.25 
History of allergic reactions attributed to therapeutic antibodies. Note: Patients 
with reactions to chimeric antibodies may be permitted on a case by case basis 
with approval by Study Chair by contacting the Data Manager. 
 
3.26 
Known untreated CNS metastases. Note: Patients with radiated or resected 
lesions are permitted, provided the lesions are fully treated and inactive, 
patients are asymptomatic, and no steroids have been administered for this 
purpose ≤30 days prior to randomization.  
 
3.27 
Inadequately controlled hypertension (defined as average systolic blood 
pressure >150 mmHg and/or diastolic blood pressure >100 mmHg).  
 
3.28 
History of hypertensive crisis or hypertensive encephalopathy. 
 
3.29a 
New York Heart Association (NYHA) Grade II or greater congestive heart 
failure (Form is available on the ACCRU web site 
https://www.accru.org/accru/forms/NonProtocolSpecificForms/index.html).  
 
3.29b 
History of myocardial infarction, unstable angina, cardiac or other vascular 
stenting, angioplasty, or surgery ≤12 months prior to randomization. 
 
3.29c 
Active coronary heart disease evidenced as angina or requiring medications to 
prevent angina. 
 
3.29d 
History of stroke or transient ischemic attack, or other arterial thrombosis ≤12 
months prior to randomization. 
 
3.29e 
Symptomatic peripheral vascular disease. 
 
3.29f 
Any other significant vascular disease (e.g., aortic aneurysm, aortic dissection, 
or carotid stenosis that requires medical or surgical intervention, including 
angioplasty or stenting).  
 
3.29g 
Any previous NCI CTCAE Grade 4 venous thromboembolism.  
 
3.29h 
Clinically-significant evidence of bleeding diathesis or coagulopathy as so 
judged by the treating physician. 
 
3.29i 
History of active gastrointestinal (GI) bleeding or other major bleeding ≤12 
months prior to randomization. Note: Patients who do not have resolution of 
the predisposing risk factor (e.g., resection of a bleeding tumor, treatment and 
endoscopic documentation of a resolved ulcer) will also be excluded.  
 


 
41  
 
 ACCRU # RU021416I 
 
 
  Addendum 6 
3.29j 
Major surgical procedure, open biopsy, or significant traumatic injury ≤56 days 
prior to randomization.  
 
3.29k 
Anticipation of need for major surgical procedure ≤6 months after 
randomization. 
 
3.29l 
Minor surgical procedure ≤7 days prior to randomization. Exception: Insertion 
of an indwelling catheter or percutaneous needle biopsy ≤48 hours prior to 
randomization. 
 
3.29m 
History of intra-abdominal abscess ≤6 months prior to randomization. Note: If 
the affected area was surgically resected, and there is no further risk to the area, 
patients may enroll. 
 
3.29n 
History of abdominal or other significant fistula, gastrointestinal or other organ 
perforation. Note: If the affected area was surgically resected, and there is no 
further risk to the area, patients may enroll. 
 
3.29o 
Serious, non-healing wound, ulcer, or bone fracture as so judged by the treating 
physician. 
 
3.29p 
Known proteinuria defined by ≥2+ protein by urinalysis (UA) or ≥1 gram 
protein by 24 hour urine collection. Note: Subjects that are ≥2+ or greater on 
dipstick but <1 g protein on 24 hour urine ARE eligible to participate. 
 
3.29q 
Intolerance to bevacizumab defined as any NCI CTCAE Grade 3 or Grade 4 
toxicity attributed to this agent that required discontinuation of bevacizumab 
(e.g., arterial thromboembolism [ATE], perforation, wound healing difficulty, 
proteinuria, reversible posterior leukoencephalopathy syndrome [RPLS]). 
Note: Patients with prior Grade 3 bevacizumab-related hypertension may be 
permitted if hypertension was manageable with standard oral antihypertensives 
as so judged by the treating physician. 
 
3.29r 
Known dihydropyrimidine dehydrogenase (DPD) deficiency. 
 
3.29s 
Impairment of GI function or GI disease that may significantly alter 
capecitabine drug absorption. 
 
3.29t 
Active inflammatory bowel disease. 
 
3.29u 
History of diverticulitis, chronic ulcerative lower GI disease such as Crohn’s 
disease or ulcerative colitis, or other symptomatic lower GI conditions that 
might predispose to perforations. 
 
3.29v 
History of autoimmune disease including, but not limited to, systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular 
thrombosis associated with antiphospholipid syndrome, Wegener’s 
granulomatosis, Sjögren’s syndrome, Bell’s palsy, Guillain-Barré syndrome, 
multiple sclerosis, autoimmune thyroid disease, vasculitis, or 
glomerulonephritis. Note: Patients with a history of autoimmune-related 
hypothyroidism on a stable dose of thyroid replacement hormone may be 


 
42  
 
 ACCRU # RU021416I 
 
 
  Addendum 6 
eligible for this study. 
 
3.29w 
Active current infection or history of recurrent bacterial, viral, fungal, 
mycobacterial or other infections, including but not limited to tuberculosis and 
atypical mycobacterial disease, hepatitis B and C, herpes zoster, and HIV, but 
excluding fungal infections of nail beds. 
 
3.29x       Vaccination with a live or attenuated vaccine ≤28 days prior to randomization. 
Note: Other types of vaccines, including inactivated/killed, toxoid (inactivated 
toxoid), and subunit/conjugate are all permitted at any time.   
 
3.29y 
Any reversible treatment-related toxicity that has not resolved to NCI CTCAE 
Grade ≤1 except neuropathy. 
 
3.29z 
Other concurrent severe and/or uncontrolled medical disease, psychiatric 
illness, or social situation, which could compromise safety of treatment as so 
judged by the treating physician. Note: This includes but is not limited to: 
severely impaired lung function, uncontrolled diabetes (history of consistent 
blood glucose readings above 300 mg/dL or less than 50 mg/dL), severe 
infection, severe malnutrition, ventricular arrhythmias, known active vasculitis 
of any cause, tumor invasion of any major blood vessel, chronic liver or renal 
disease, and active upper GI tract ulceration. 
 
3.29aa 
Unwilling to or unable to comply with the protocol. 
 
3.29bb 
Current or recent (≤10 days prior to randomization) use of aspirin (>325 
mg/day), or clopidogrel (>75 mg/day).  
 
3.29cc 
Current or recent (≤10 days prior to randomization) use of therapeutic oral or 
parenteral anticoagulants or thrombolytic agents for therapeutic purposes, 
unless the patient has been on a stable dose of anticoagulants for at least 2 
weeks at the time of randomization. Note: The use of full-dose oral or 
parenteral anticoagulants is permitted as long as the INR or aPTT is within 
therapeutic limits (according to the medical standard of the institution) and the 
patient has been on a stable dose of anticoagulants ≥14 days at the time of 
randomization. Prophylactic use of anticoagulants is allowed. 
 
3.29dd 
History or recent diagnosis of demyelinating disease. 
 
3.29ee 
History of other carcinoma ≤3 years. Exception: If risk of recurrence is known 
to be under 5% at time of randomization. 
 
3.29ff 
Current or recent (≤90 days prior to randomization) endoluminal stent in the 
stomach, bowel, colon or rectum. 
 
3.29gg 
Colonoscopy, sigmoidoscopy, or proctoscopy ≤7 days prior to randomization. 
 
3.29hh 
Current or recent (≤28 days prior to randomization) use of sorivudine, 
brivudine, and St. John’s Wort. 
 
3.29ii 
Primary or secondary immunodeficiency (history of or currently active) unless 


 
43  
 
 ACCRU # RU021416I 
 
 
  Addendum 6 
related to primary disease under investigation. 
 
3.29jj 
Prior allogeneic bone marrow transplantation or prior solid organ 
transplantation. 
 
3.29kk 
Treatment with systemic immunosuppressive medications (including but not 
limited to prednisone, cyclophosphamide, azathioprine, methotrexate, 
thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) ≤14 days prior 
to randomization.  Exception: Patients who have received acute, low-dose, 
systemic immunosuppressant medications (e.g. a one-time dose of 
dexamethasone for nausea) are eligible.  The use of inhaled corticosteroids and 
mineralcorticoids (e.g. fludrocortisone) for patients with orthostatic 
hypotension or adrenocortical insufficiency is allowed. 
 
 
4.0 
Test Schedule 
 
NOTE: Treatments and assessments on schedule are expected to improve patient outcomes. 
However, it is known that routine scheduling issues may occur. For this reason, +3 day window 
for day 1 of each cycle is allowed. Special scheduling issues may also arise on occasion for 
personal reasons. In such cases, cycles may be delayed by up to 2 weeks without the approval of 
the Study Chair. Scheduling issues occurring outside of this window must be pre-approved by the 
Study Chair by contacting the Data Manager. If such issues are not approved by the Study Chair, 
they will be recorded as protocol deviations. In case of toxicity, treatments should be delayed in 
accordance with dose modifications (Section 8.0). Additional monitoring or interventions beyond 
those listed below should also be done as deemed clinically appropriate. 
 
 


 
44  
 
 ACCRU # RU021416I 
 
 
  Addendum 6 
Tests and Procedures 
Active Monitoring Phase 
 
Baseline 
(prior to 
Cycle 1 Day 
1 treatment) 
Cycle 
(21 
days)20 
Restaging 
Off Treatment  
Follow-up 
+/- 7 days 
Observation 
+/- 14 days 
 
≤14 
Days 
≤7 
Day 1 
Every 3 Cycles 
30 days after Last 
Study Drug 
Every 12 Weeks 
Informed Consent1 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Physical Exam 
X 
 
X 
 
X 
 
Adverse Event Evaluation2 
X 
 
Continuous Assessment 
 
Concomitant Medications 
X 
 
Continuous Assessment 
 
Vital Signs3 
X 
 
X 
 
X 
 
Height 
X 
 
 
 
 
 
Weight 
X 
 
X 
 
X 
 
ECOG Performance Status 
X 
 
X 
 
X 
 
CBC with differential4 
 
X 
X 
 
X 
 
Chemistries with liver function 
tests5 
 
X 
X 
 
X 
 
TSH, free T3 and free T421 
X 
 
 
 
 
 
ECG6 
X 
 
 
 
 
 
β-HCG7 
 
X 
 
X 
X 
 
UA or 24 hour urine for protein8 
X 
 
X 
 
X 
 
Coagulation tests9 
X 
 
 
 
 
 
Randomization10 
 
X 
 
 
 
 
Capecitabine11 
 
 
Days 1-14 
 
 
 
Bevacizumab12 
 
 
X 
 
 
 
Atezolizumab or Placebo12 
 
 
X 
 
 
 
Blood Biomarkers15, R 
 
 
X22 
X 
X 
 
Whole Blood14, R 
 
 
X22 
 
 
 
Blood Immune Cells16, R 
 
 
X22 
X 
 
 
Archived Paraffin Tumor13, R 
 
 
X 
 
 
 
Radiographic Assessment17 
X 
 
 
X 
 
X19 
Tumor Blood Bio-Markers 
(CEA)18 
X 
 
 
X 
 
X19 
Anti-cancer Treatment 
 
 
 
 
 
X19 
1. Informed consent may occur ≤30 days prior to randomization. 
2. Using NCI CTCAE version 4.0. 
3. Vital signs include: temperature, heart rate, and blood pressure. 
4. CBC with differential includes: hemoglobin, hematocrit, platelets, WBC and ANC. At baseline must be ≤7 
days prior to randomization; and Cycle 2 and higher may be drawn up to 3 days prior to day 1 of each 
cycle. 
5. Chemistry with LFTs includes: albumin, BUN, creatinine, calculated creatinine clearance using Cockcroft-
Gault (at baseline and as clinically indicated), glucose, potassium, total bilirubin, ALT, AST, and alkaline 
phosphatase (ALP). At baseline must be ≤7 days prior to randomization on C1D1; and Cycle 2 and higher 
may be drawn up to 3 days prior to day 1 of each cycle. 
6. 12-lead ECG. At baseline ≤14 days prior to randomization; and as clinically indicated. 
7. Serum pregnancy test in women of childbearing potential only. At baseline must be serum ≤7 days prior to 
randomization; serum or urine at every restaging; serum or urine at off-treatment follow-up. Refer to 
Section 10.0 for pregnancy guidelines. 
8. Urine analysis (UA) or 24-hour urine for protein. At baseline must be ≤14 days prior to randomization; day 
1 on Cycle 2 and all subsequent cycles; (if result not available prior to treatment on day 1, may use result 
from previous cycle for current cycle); and off-treatment follow-up. Note: If UA is ≥2+, confirm with 24-
hour urine prior to the initiation of the next cycle. Refer to Section 8.63 for procedure to obtain a urine 


 
45  
 
 ACCRU # RU021416I 
 
 
  Addendum 6 
protein/creatinine (UPC) ration from random urine sample. Protein and creatinine concentrations should be 
available on standard reports of urinalyses, if protein and creatinine concentrations are not routinely 
reported at an institution, their measurements and reports may need to be requested. 
  9. PT/PTT/INR. At baseline must be ≤14 days prior to randomization; and if on anticoagulation should have 
clinically appropriate monitoring per institutional guidelines and as clinically indicated. 
10. Must be ≤7 days of Cycle 1 Day 1. 
11. Commercial supply. Days 1-14 of 21-day cycle. 
12. Study supply. Day 1 of 21-day cycle. 
13. Archived tumor collection may occur outside the screening period and at a timepoint determined by the 
Study Chair. See Section 17.0 for details. 
14. Whole blood collected at baseline only (may be drawn pre-dose on Cycle 1 Day 1). Refer to Section 14.0 
for details. 
15. Plasma and serum biomarkers will be collected at baseline (may be draw pre-dose on Cycle 1 Day 1); 
every restaging (prior to Cycle 4 treatment prior to Cycle 7 treatment, etc.); at progression or off-treatment 
visit (if discontinued from study drug for reason other than progression); and off-treatment follow-up. 
Refer to Section 14.0 for details. 
16. Circulating immune cells will be collected at baseline (may be drawn pre-dose on Cycle 1 Day 1) and at the 
first restaging (prior to Cycle 4 treatment) and at progression/off-treatment. Refer to Section 14.0 for 
details. 
17. Radiographic assessments (CT and/or MRI) of chest, abdomen, and pelvis using the same method of 
assessment throughout study. At baseline must be ≤28 days prior to randomization; every restaging (may 
occur ≤14 days prior to Day 1 of the new cycle); and as clinically indicated. If bone metastasis is present, 
obtain a baseline bone scan and repeat every 18 weeks and as clinically indicated. Additional modalities to 
track non-measurable disease, such as bone scan, PET scan, may also be used as clinically indicated. 
18. Blood tumor bio-markers (CEA) or other tumor markers. At baseline must be ≤28 days prior to 
randomization; every restaging (may occur ≤14 days prior to Day 1 of the new cycle); and as clinically 
indicated. If CEA is not expressed, CEA need not be performed. If another tumor marker is used (e.g., 
CA19-9), that tumor marker should be assessed. 
19. 
 
 
 
 
 
 
20. 
21. 
22. 
If a subject comes off treatment with no documented disease progression, follow-up is every 12 weeks or 
as clinically indicated with tumor assessments and blood tumor markers (i.e., CEA or other tumor markers) 
until disease progression or receipt of subsequent anti-cancer treatment is documented. Note: If subject is 
not able to return to the consenting institution after the Active Monitoring Phase, subject health records 
such as medical oncology physician notes, laboratory results, and/or radiology reports with tumor 
assessments from another institution is permissible for tumor assessment of disease progression or 
documentation of subsequent anti-cancer treatment. 
≤3 day window for day 1 of each cycle is allowed for cycles 2 and up.Baseline (≤14 prior to Cycle 1 Day 1 
treatment) and then as clinically indicated. 
To be collected prior to dosing on C1D1 
R Research funded (see Section 19.0) 


 
46  
 
 ACCRU # RU021416I 
 
 
  Addendum 6 
 
5.0 
Stratification Factors: 
 
5.1 
Stratification Factors 
 
5.11 
ECOG Performance Status: 0 vs. 1. 
 
5.12 
RAS Status: Wild-type vs. mutant. 
 
5.121 
If mutant and known, site will select the appropriate mutant status from the 
following: (Note: Mutant RAS status is not utilized in stratification.) 
 
5.1211 
KRAS: Exon 2 (codon 12, 13)  
 
5.1212 
KRAS: Exon 3 (codon 59, 61)  
 
5.1213 
KRAS: Exon 4 (codon 117, 146) 
 
5.1214 
NRAS: Exon 2 (codon 12, 13)  
 
5.1215 
NRAS: Exon 3 (codon 59, 61)  
 
5.1216 
NRAS: Exon 4 (codon 117, 146) 
 
5.1217 
Other (Please list) 
 
 
6.0 
Registration/Randomization Procedures 
 
6.1 
Randomization Procedures 
 
6.11 
To register a patient, access the ACCRU web page at www.accru.org, click on “Training 
Page” and enter the registration/randomization application. 
 
The registration/randomization application is available 24 hours a day, 7 days a week. 
Back up and/or system support contact information is available on the Web site. If 
unable to access the Web site, call the Academic and Community Cancer Research 
United (ACCRU) Registration Office at (507) 284-4130 between the hours of 8 a.m. and 
4:30 p.m. Central Time (Monday through Friday). 
 
The instructions for the registration/randomization application are available by using the 
Help button. Prior to initiation of protocol study intervention, this process must be 
completed in its entirety and an ACCRU subject ID number must be available as noted in 
the instructions. It is the responsibility of the individual and institution registering the 
patient to confirm the process has been successfully completed prior to release of the 
study agent. Patient randomization via the registration/randomization application can be 
confirmed in any of the following ways: 
 
• 
Contact the ACCRU Registration Office (507)-284-4130. If the patient was fully 
registered, the ACCRU Registration Office staff can access the information from the 
centralized database and confirm the randomization. 
• 
Refer to “Instructions for Remote Registration” in section “Finding/Displaying 
Information about A Registered Subject.” 
 
6.2 
Correlative Research 


 
47  
 
 ACCRU # RU021416I 
 
 
  Addendum 6 
 
 
A mandatory correlative research component is part of this study. The patient will be automatically 
registered onto this component (see Sections 3.0, 14.0 and 17.0). 
 
6.21 
Prior to accepting the registration/randomization, the registration/randomization 
application will verify the following: 
 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information 
 
6.22 
Documentation of IRB approval must be on file in the Registration Office before an 
investigator may register/randomize any patients. 
 
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office (fax: 
507-284-0885). If the necessary documentation is not submitted in advance of attempting 
patient registration/randomization, the registration/randomization will not be accepted 
and the patient may not be enrolled in the protocol until the situation is resolved. 
 
When the study has been permanently closed to patient enrollment, submission of annual 
IRB approvals to the Registration Office is no longer necessary. 
 
6.23 
At the time of randomization, the following will be recorded: 
 
• 
Patient has/has not given permission to store and use his/her sample(s) for future 
research to learn about, prevent, or treat cancer. 
• 
Patient has/has not given permission to store and use his/her sample(s) for future 
research to learn, prevent, or treat other health problems (for example: diabetes, 
Alzheimer’s disease, or heart disease). 
• 
Patient has/has not given permission for ACCRU to give his/her sample(s) to 
outside researchers. 
 
6.24 
Treatment on this protocol must commence at an ACCRU institution under the 
supervision of a medical oncologist. 
 
6.25 
Treatment cannot begin prior to randomization and must begin ≤7 days after 
randomization. 
 
6.26 
Pretreatment tests/procedures (see Section 4.0) must be completed within the guidelines 
specified on the test schedule. 
 
6.27 
All required baseline symptoms (see Section 10.5) must be documented and graded. 
 
6.28 
Study drug is available on site. 
 
6.29a 
Blood draw kit is available on site. Kits must be used for this study. 
 
6.29b 
Randomization Procedures 
 
6.29b1 
The factors defined in Section 5.0, together with the registering membership, 
will be used as stratification factors. 


 
48  
 
 ACCRU # RU021416I 
 
 
  Addendum 6 
 
 
6.29b2 
After the patient has been registered into the study, the values of the 
stratification factors will be recorded, and the patient will be assigned to one of 
the following treatment groups using the Pocock and Simon dynamic 
allocation procedure which balances the marginal distributions of the 
stratification factors between the treatment groups. (Pocock, Simon 1975)  
 
- 
Bevacizumab + Capecitabine + Atezolizumab  
- 
Bevacizumab + Capecitabine + Placebo 
 
6.3 
Procedures for Double-Blinding the Treatment Assignment 
 
6.31 
After the treatment assignment has been ascertained by the registration/randomization 
application, the registration specialist will notify the designated data 
manager/nurse/pharmacist at the patient’s institution. The name of this contact person is 
to be entered in the designated space on the eligibility checklist so the Registration 
Office personnel have it for each patient at the time of randomization. Make sure this 
contact person will be available at the time of randomization so he or she can take a call 
from the registration specialist if necessary. This contact person may not be involved in 
assessing adverse events or any other outcome measure and should not be the same 
person listed on page one of the Eligibility Checklist Form as the person completing the 
form. The last page of the Eligibility Checklist Form should provide the sources of 
communication, either fax or e-mail, and the appropriate contact information. The 
registration specialist will then communicate the treatment assignment to the designated 
contact at the patient’s institution. 
 
6.32 
The treatment assignment will be to bevacizumab + Capecitabine + Atezolizumab or 
bevacizumab + Capecitabine + Placebo. Genentech will provide supplies labeled for 
investigational use to Biologics. Each participating institution will order the drug from 
Biologics using the protocol-specific Drug Order Request Form. Each participating 
institution will be responsible for monitoring drug supplies and will use the Drug Order 
Request Form to order additional supplies as needed. Upon receipt of orders, Biologics 
will send bulk supply to participating institutions. The atezolizumab/placebo solution 
will be prepared and labeled by the unblinded pharmacist as “atezolizumab/placebo 
study drug 1 dose” so that the contents are not discernible to the person administering the 
treatment.  
  
6.33 
The unblinded pharmacist will maintain records that indicate the identity of the patient 
and their corresponding treatment assignment. 
 
 
7.0 
Protocol Treatment 
 
7.1 
Dose Levels 
 
Subjects will be randomized 2:1 to one of the blinded arms described in the table below. Cycles are 
21 days in length. 
 
Atezolizumab/placebo will be given before the bevacizumab infusion. Subjects randomized to the 
Bevacizumab + Capecitabine + Atezolizumab arm will receive atezolizumab at 1200 mg IV on day 
1 of each cycle. Subjects randomized to the Bevacizumab + Capecitabine + Placebo arm will 
receive an equivalent volume of placebo (for atezolizumab) on day 1 of each cycle. All subjects 
will receive capecitabine orally twice per day on days 1-14 of each cycle. 
 


 
49  
 
 ACCRU # RU021416I 
 
 
  Addendum 6 
 
Dose Levels 
               Agent 
Dose Level 
Route 
Day(s) 
ReRx 
 
Atezolizumab/Placebo1 
1200 mg 
IV 
1 
Every 21 days 
 
Bevacizumab2 
7.5 mg/kg 
IV 
1 
 
*Capecitabine3 
850 or 1000 
mg/m2 
PO 
1-14 BID 
1. 
Atezolizumab/placebo will be prepared by an unblinded pharmacist. The infusion drug will be 
prepared and labeled for blinding purposes. Atezolizumab/placebo infusion will be given before the 
bevacizumab infusion. Do not administer as bolus or push. The initial dose of atezolizumab/placebo 
will be delivered over 60 (±15) minutes. If the first infusion is tolerated without infusion-associated 
adverse events, the second infusion may be delivered over 30 (±10) minutes. If the 30-minute 
infusion is well tolerated, the third and all subsequent infusions may be delivered over 30 (±10) 
minutes until disease progression or unacceptable toxicity. If a patient has an infusion related reaction 
during the atezolizumab infusion, vitals should be recorded after the atezolizumab administration if 
clinically indicated (even up to 1 hour). Bevacizumab administration may be delayed until the patient 
is clinically stable and appropriate to treat. 
2. 
Bevacizumab will be calculated on the basis of milligrams of drug per kilogram of body weight at 
baseline and will be recalculated based upon weight per local institutional standards. The initial dose 
of bevacizumab will be delivered over 90 (±15) minutes. If the first infusion is tolerated without 
infusion associated adverse events (fever and/or chills), the second infusion may be delivered over 60 
(±10) minutes. If the 60 minute infusion is well tolerated, all subsequent infusions may be delivered 
over 30 (±10) minutes. The IV infusion lines should be properly flushed with 0.9% Sodium Chloride 
between administrations of other drugs. 
3. 
Capecitabine 850 mg/m2 or 1000 mg/m2 may be used based upon local physician and patient 
preferences. Capecitabine is taken orally twice per day on days 1-14 of 21-day cycle. The dose of 
capecitabine will be calculated on the basis of milligrams of drug per square meter of body surface 
area (BSA) at baseline and will be recalculated based upon weight per local institutional standards. 
The method of dose adjustments for capecitabine should be based upon prescribing information and 
local institutional standards. 
*Missed capecitabine doses are not to be re-taken. 
 
7.2 
Patients can be instructed in administration techniques and granted treatment independence with 
nursing staff approval. 
 
7.3 
For this protocol, the patient must return to the consenting ACCRU institution for evaluation at 
least every 21 days during treatment (Active Monitoring Phase) and if possible every 12 weeks 
during observation. 
 
7.4 
Treatment by a local medical doctor (LMD) is not allowed. 
 
7.5 
Breaking Codes in Double–Blinded Studies 
 
Situations requiring codes to be broken: 
 
Unblinding will not be routinely performed but may be considered on a case-by-case basis as 
described below. 
 
• 
In the event of an emergency for an individual patient. 
• 
In the event that it would be helpful for the future clinical care of an individual patient after 
she/he has completed participation in the trial. 
• 
If a subject is considering enrollment to another study while in the follow up period and prior 
drug administration information is required for enrollment in new study. 
 
In the event of an emergency, call the 
 to break the 
code on Monday through Friday, 8:00 a.m. to 4:30 p.m. Central Time. If the code must be broken 
after hours, assume the patient was assigned to active treatment and treat accordingly. Place a call 


 
50  
 
 ACCRU # RU021416I 
 
 
  Addendum 6 
 
to the ACCRU Registration Office and leave a message informing them of the need to un-blind a 
patient. Provide your contact information so that ACCRU Registration Office personnel can return 
the call the next business day. 
 
On a case by case basis, if in the judgment of the attending physician, it would be helpful for the 
future clinical care of the individual patient, the code may be broken after the patient has 
completed the study. That is, after the patient has been fully evaluated and all evaluation 
information has been recorded by the attending physician and the patient (if appropriate), the 
ACCRU Registration Office may be called to find out which study therapy the patient was 
receiving. 
 
All Investigators, study personnel and subjects will be blinded to the study treatment assignments. 
However, each site will have designated pharmacists that will not be blinded to the study treatment 
assignments. 
 
8.0 
Dosage Modification Based on Adverse Events 
 
8.1 
Please refer to prescribing information for capecitabine and bevacizumab as well as investigator 
brochures for capecitabine, bevacizumab, and atezolizumab for further information on toxicities 
and management information. The following are general guidelines for dose modifications and 
toxicity management for this study: 
 
• 
Toxicity will be graded according to the NCI Common Terminology Criteria for Adverse 
Events (NCI CTCAE) version 4.0. 
• 
All dose modifications and dose holds along with study drug attributions must be recorded. 
• 
Subjects must be followed at least weekly when any drug is held for any toxicity until the 
toxicity returns to Grade ≤1 or is determined to be chronic or irreversible. 
• 
If toxicity could be related to either the study drug (atezolizumab/placebo) or to the 
chemotherapy backbone capecitabine or bevacizumab, dose modifications will be performed 
on all drugs possibly causing that toxicity. 
• 
Subjects should be managed under the assumption they are on active treatment and unblinding 
should be reserved for toxicities that cannot be managed otherwise. 
• 
Subjects that are unblinded will be removed from study treatment but will be followed until 
resolution of toxicity, disease progression and survival as appropriate. 
• 
For toxicity management, the doses of bevacizumab and atezolizumab/placebo can only held. 
There are no dose reductions or other dose modifications of these agents for toxicity. 
• 
Held doses of drug will not be made up at a later date.  
• 
Aggressive and more conservative dose reductions or holds are permitted if felt to be clinically 
indicated. The treating physician may elect greater dose reduction based upon the duration of 
the adverse event or additional circumstance, etc. 
• 
Follow dose modifications or holds for any agent(s) thought to be related to toxicity. 
• 
If several toxicities occur at the same time, the dose modifications or holds should be according 
to the highest grade observed. 
• 
If a subject experiences a Grade 4 event more than once, retreatment (even with dose 
modifications) must be approved by the Lead Study Chair prior to re-dosing. 
• 
When treatment is temporarily interrupted because of toxicity, treatment cycles should be 
restarted such that the atezolizumab/placebo and bevacizumab infusions remain synchronized 
and aligned with the capecitabine schedule. However, if it is anticipated that capecitabine will 
be delayed by ≥2 weeks, then atezolizumab/placebo and bevacizumab should be given without 
capecitabine if there is no contraindication. 
• 
If a subject is deemed to have been benefiting from therapy and the treatment delay was not 
directly related to study treatment (e.g., scheduling conflicts or intercurrent illness) then subject 
may continue therapy on a case-by-case basis after consultation with the Study Chair. 


 
51  
 
 ACCRU # RU021416I 
 
 
  Addendum 6 
 
• 
Bevacizumab and atezolizumab/placebo do not need to be held together or given together. For 
example, if there is a bevacizumab-related adverse effect, the bevacizumab may need to be 
held, while atezolizumab/placebo may be able to be continued. However, in cases in which the 
adverse effect may be related to either bevacizumab or atezolizumab/placebo, both drugs may 
need to be held. 
• 
Dose adjustments for weight-based or BSA-based chemotherapy are per local institutional 
standards. For most sites, the preferred method is to adjust the dose only if the weight changes 
by more than 10%. Subsequent dose recalculations (for second or higher occurrences of ≥10% 
weight change) are based on the most recent baseline weight. Another acceptable method of 
dose adjustment is to dose on actual weight, even if the subject’s weight change is less than 
10%. 
 
8.2 
Treatment Parameters for Day 1 of Each Cycle 
 
Treatment on Day 1 of each cycle should be delayed until: 
 
• 
Absolute neutrophil count (ANC) is >1,000/mm3 and platelet count is >75,000/mm3 
• 
Recovery to Grade ≤ 1 from any clinically significant treatment-related non-hematologic 
toxicity. Subjects may continue drug with Grade 2 toxicity if not considered clinically 
significant by treating physician. 
• 
Laboratory only abnormalities are permitted but must meet the following criteria. However, 
caution is needed to ensure re-treatment is considered safe and in the interest of the subject. 
 
1. Abnormal lab is not considered clinically significant in the treating physician’s judgment 
(with the exception of ANC and platelet count). 
2. Subject has no clinical symptoms. 
3. Abnormal lab does not require treatment modifications or delays or result in a medical 
intervention. 
 
8.3 
Dose Modifications for Capecitabine 
 
Management of capecitabine toxicity should follow the prescribing information and local 
institutional standards. Dose modification levels for capecitabine are listed in Table 8.31. These 
dose modification levels are applied to toxicity-specific tables in Section 8.6 of the protocol. The 
“next lower” dose level is defined as the next dose below what the subject had most recently been 
taking. In the case where a dose reduction is required and there is no lower dose level, capecitabine 
should be discontinued. If capecitabine is held or discontinued for toxicity or intolerance, subjects 
may continue on study with the remaining agents as clinically indicated. 
 
Table 8.31 
Capecitabine Dose Levels 
Dose Modification 
Level 
Capecitabine (orally, days 1-14, mg/m2) 
Initial Dose*  
1000 
850 
-1 
850 
680 
-2 
680 
545 
-3 
545  
Discontinue 
-4 
Discontinue  
 
*Starting dose level of capecitabine. 


 
52  
 
 ACCRU # RU021416I 
 
 
  Addendum 6 
 
 
For common capecitabine-related toxicity including, but not limited to diarrhea and 
nausea/vomiting that are not included in a toxicity-specific table in Section 8.6 of the protocol, the 
guidelines in Table 7.2 for dose adjustments will be performed on the capecitabine dosing. 
 
Table 8.32 
Management of Capecitabine Common Toxicities 
Toxicity 
Grade* 
Occurrence 
Capecitabine 
Dose 
Modification 
1000 mg/m2 
Initial Dose 
Dose 
Modification 
850 mg/m2 
Initial Dose 
Grade 1 
Any 
Maintain current 
dose level 
1000 
850 
Grade 2 
1st 
Hold until recovery 
to grade ≤1 -OR- 
Discontinue after 
dose level reduction 
of 545 mg/m2 
1000 
850 
2nd 
850 
680 
3rd 
680 
545 
4th 
545 
 
Grade 3 
1st 
Hold until recovery 
to grade ≤1 -OR- 
Discontinue after 
dose level reduction 
of 545 mg/m2 
850 
680 
2nd 
680 
545 
3rd 
545 
 
Grade 4 
1st 
If treating physician 
and Study Chair 
deems it is in the 
patient’s best interest 
to continue, hold 
until recovery to 
grade ≤ 1-OR-
Discontinue after 
dose level reduction 
of 545 mg/m2 
680 
545 
2nd  
545 
 
*Use National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0. 
 
For subjects who experience dose reductions due to toxicity, dose re-escalations are permitted as 
long as the subject tolerates the reduced dose with Grade 1 or lower toxicity for a minimum of 2 
consecutive cycles. The treating physician, patient, and Lead Study Chair must agree that 
escalation is in the best interest of the patient.  
 
8.4 
Dose Modifications for bevacizumab 
 
No reductions in bevacizumab dose are allowed in this study. 
 
Infusion of bevacizumab should be interrupted in subjects who develop dyspnea or clinically 
significant hypotension. Refer to Section 8.661 for management of infusion-related reactions.   
 
If adverse events occur that necessitate holding bevacizumab, the dose will remain unchanged once 
treatment resumes. Temporary suspension of bevacizumab must occur if a subject experiences a 
serious adverse event or a Grade 3 or 4 non-serious adverse event assessed by the treating 
physician as related to bevacizumab. If the event resolves to Grade ≤1, bevacizumab may be 
restarted at the same dose level. If bevacizumab is delayed due to toxicity for >42 days beyond 


 
53  
 
 ACCRU # RU021416I 
 
 
  Addendum 6 
 
when the next dose should have been given, the subject must be permanently discontinued from 
bevacizumab. 
 
The appropriate interval between the last dose of bevacizumab and major surgery is unknown. 
Because bevacizumab has a half-life of approximately 21 days, elective surgery should be delayed 
whenever possible, but if necessary, bevacizumab should be held for ≥28 days prior to the 
procedure. Re-initiation of bevacizumab following surgery should not occur for ≥28 days and until 
wounds have fully healed. Re-initiation of bevacizumab after surgery requires documented 
approval from the Lead Study Chair. 
 
8.5 
Dose Modifications for Atezolizumab 
 
No reduction or modification of the atezolizumab dose will be allowed. Any toxicity associated or 
possibly associated with atezolizumab treatment should be managed according to standard medical 
practice. 
Withhold Atezolizumab for any of the following:  
• 
Grade 2 pulmonary events, including pneumonitis 
• 
Grade 2 aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total bilirubin  
• 
Grade 2 or 3 diarrhea or colitis 
• 
Symptomatic hypothyroidism 
• 
Symptomatic hyperthyroidism 
• 
Symptomatic, Grade 2-4 adrenal insufficiency 
• 
Grade 3 or 4 hyperglycemia 
• 
Grade 2 ocular events 
• 
Grade 2 infusion-related reaction (refer to Section 8.661 for management of infusion-related 
reactions) 
• 
Grade 3 or 4 amylase and/or lipase elevation 
• 
Grade 2 or 3 immune-related pancreatitis 
• 
Grade 3 dermatologic event 
• 
Grade 2 immune-related neuropathy 
Atezolizumab may be resumed in patients whose adverse reactions recover to Grade 0–1.  
Permanently discontinue Atezolizumab for any of the following:  
• 
Grade 2 that does not resolve to Grade 1 or better within 12 weeks, Grade 3 or 4 pulmonary 
events, including pneumonitis 
• 
Grade 2 that does not resolve to Grade 1 or better within 12 weeks, Grade 3 or 4 AST or ALT 
or total bilirubin greater than 3 times ULN 
• 
Grade 2 or 3 that does not resolve to Grade 1 or better within 12 weeks or Grade 4 diarrhea or 
colitis 
• 
Symptomatic, Grade 2-4 that does not resolve to Grade 1 or better within 12 weeks adrenal 
insufficiency 
• 
Grade 2 that does not resolve to Grade 1 or better within 12 weeks, Grade 3 or 4 ocular events 
• 
Grade 3 or 4 infusion-related reaction (refer to Section 8.661 for management of infusion-
related reactions) 
• 
Grade 3 or 4 that does not resolve to Grade 1 or better within 12 weeks amylase and/or lipase 
elevation 
• 
Grade 2 or 3 that does not resolve to Grade 1 or better within 12 weeks, or Grade 4 immune-
related pancreatitis  


 
54  
 
 ACCRU # RU021416I 
 
 
  Addendum 6 
 
• 
Grade 3 that does not resolve to Grade 1 or better within 12 weeks, or Grade 4 dermatologic 
event 
• 
Grade 2 that does not resolve to Grade 1 or better within 12 weeks, Grade 3 or 4 immune-
related neuropathy 
• 
Any grade Myasthenia Gravis or Guillain-Barre syndrome 
• 
Any grade immune-related meningoencephalitis 
Additional tests, such as autoimmune serology or biopsies, may be used to determine a possible 
immunogenic etiology. While most immune-related adverse events (IRAEs) observed with 
immunomodulatory agents have been mild and self-limiting, such events should be recognized 
early and treated promptly to avoid potential major complications. Discontinuation of atezolizumab 
may not have immediate therapeutic effect, and there is no available antidote for atezolizumab. In 
severe cases, immune-related toxicities may be acutely managed with topical corticosteroids, 
systemic corticosteroids, or TNF-α inhibitors. 
 
The primary approach to Grade 1-2 IRAEs is supportive and symptomatic care; for higher grade 
IRAEs, steroids by mouth or parenteral given, and either skipping a dose or holding therapy is 
appropriate. Recurrent Grade 2 IRAEs may also mandate skipping a dose of atezolizumab/placebo 
or the use of steroids. 
 
Patients should be assessed clinically for toxicity prior to, during, and after each infusion. If 
unmanageable toxicity thought to be due to atezolizumab/placebo occurs at any time during the 
study, treatment with atezolizumab/placebo should be discontinued. If atezolizumab/placebo is 
held because of adverse events >42 days beyond when next dose should have been given, the 
patient will be discontinued from study treatment. If patients must be tapered off steroids used to 
treat adverse events, study treatment may be held for >42 days. The acceptable length of 
interruption will depend on agreement between the treating physician and the Lead Study Chair. 
 
Dose interruptions for reason(s) other than toxicity may be allowed with the Lead Study Chair 
approval. The acceptable length of interruption will depend on agreement between the treating 
physician and the Lead Study Chair. 
 
Consideration for benefit/risk balance should be made by the treating physician, 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 study drug. 
 
8.6 
Toxicity Management 
 
8.61 
Hematologic Toxicities 
 
Treating physicians should be vigilant and alert to early and overt signs of 
myelosuppression, infection, febrile neutropenia and related events, so that these 
complications can be promptly and appropriately managed. Patients should be made 
aware of these signs and encouraged to seek medical attention at the earliest opportunity. 
 
Dose Modifications for Thrombocytopenia 
Thrombocytopenia 
Toxicity Grade* 
Occurrence 
Capecitabine 
Bevacizumab 
Atezolizumab/ 
Placebo 
Grade 2 
Any 
Maintain current 
dose 
Maintain current 
dose 
Maintain current 
dose 
Grade 3 
1st to 3rd  
Hold until recovery 
to grade ≤1,then 
resume at one dose 
level lower 
Hold until recovery 
to grade ≤1, then 
resume at current 
dose 
Hold until recovery 
to grade ≤1, then 
resume at current 
dose 


 
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  Addendum 6 
 
Thrombocytopenia 
Toxicity Grade* 
Occurrence 
Capecitabine 
Bevacizumab 
Atezolizumab/ 
Placebo 
4th 
Discontinue 
Hold until recovery 
to grade ≤1, then 
resume at current 
dose with approval of 
Study Chair 
Hold until recovery 
to grade ≤1, then 
resume at current 
dose with approval 
of Study Chair 
Grade 4  
 
1st 
Hold until recovery 
to grade ≤1, then 
resume at two dose 
levels lower 
Hold until recovery 
to grade ≤1, then 
resume at current 
dose 
Hold until recovery 
to grade ≤1, then 
resume at current 
dose 
2nd 
Discontinue 
Hold until recovery 
to grade ≤1, then 
resume at current 
dose with approval of 
Study Chair 
Hold until recovery 
to grade ≤1, then 
resume at current 
dose with approval 
of Study Chair 
* 
Platelet count decreased is the corresponding adverse event term from NCI CTCAE version 4.0 
for reporting purposes. 
 
Dose Modifications for Neutropenia  
Neutropenia 
Toxicity Grade* 
Occurrence 
Capecitabine 
Bevacizumab 
Atezolizumab/ 
Placebo 
Grade 2  
Any 
Maintain current 
dose 
Maintain current 
dose 
Maintain current 
dose 
Grade 3  
1st to 3rd 
Hold until recovery 
to grade ≤1, then 
resume at one dose 
level lower 
Maintain current 
dose 
Hold until recovery 
to grade ≤1, then 
resume at current 
dose 
4th 
Discontinue 
Hold until recovery 
to grade ≤1, then 
resume at current 
dose with approval of 
Study Chair 
Hold until recovery 
to grade ≤1, then 
resume at current 
dose with approval 
of Study Chair 
Grade 4  
1st 
Hold until recovery 
to grade ≤1, then 
resume at two dose 
levels lower 
Hold until recovery 
to grade ≤1, then 
resume at current 
dose 
Hold until recovery 
to grade ≤1, then 
resume at current 
dose 
2nd  
Discontinue 
Hold until recovery 
to grade ≤1, then 
resume at current 
dose with approval of 
Study Chair 
Hold until recovery 
to grade ≤1, then 
resume at current 
dose with approval 
of Study Chair 
* 
Decreased neutrophil count is the corresponding adverse event term from NCI CTCAE version 
4.0 for reporting purposes. 
 
 
Dose Modifications for Febrile Neutropenia 
Febrile Neutropenia 
Toxicity Grade* 
Occurrence 
Capecitabine 
Bevacizumab 
Atezolizumab/ 
Placebo 
Grade 3  
 
1st 
Hold until recovery 
of fever and 
neutropenia to grade 
≤1, then resume at 
two dose levels 
lower 
Hold until recovery 
of fever and 
neutropenia to grade 
≤1, then resume at 
current dose 
Hold until recovery 
of fever and 
neutropenia to grade 
≤1, then resume at 
current dose 
2nd 
Discontinue 
Hold until recovery 
of fever and 
neutropenia to grade 
≤1, then resume at 
current dose 
Hold until recovery 
of fever and 
neutropenia to grade 
≤1, then resume at 
current dose 


 
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  Addendum 6 
 
Febrile Neutropenia 
Toxicity Grade* 
Occurrence 
Capecitabine 
Bevacizumab 
Atezolizumab/ 
Placebo 
3rd 
Discontinue 
Hold until recovery 
of fever and 
neutropenia to grade 
≤1, then resume at 
current dose with 
approval of Study 
Chair 
Hold until recovery 
of fever and 
neutropenia to grade 
≤1, then resume at 
current dose with 
approval of Study 
Chair 
Grade 4  
 
1st 
Hold until recovery 
of fever and 
neutropenia to grade 
≤1, then resume at 
two dose levels 
lower
Hold until recovery 
of fever and 
neutropenia to grade 
≤1, then resume at 
current dose 
Hold until recovery 
of fever and 
neutropenia to grade 
≤1, then resume at 
current dose 
2nd 
Discontinue 
Hold until recovery 
of fever and 
neutropenia to grade 
≤1, then resume at 
current dose with 
approval of Study 
Chair 
Hold until recovery 
of fever and 
neutropenia to grade 
≤1, then resume at 
current dose with 
approval of Study 
Chair 
* 
Febrile neutropenia is the corresponding adverse event term from NCI CTCAE version 4.0 for 
reporting purposes. 
 
8.62 
Hypertension 
 
Early and aggressive medical management of hypertension is strongly recommended to 
minimize the need for dose holding. Addition or adjustment of blood pressure 
medications should be considered for blood pressure values persistently >150/100. In 
addition, blood pressure medications should be added or adjusted for blood pressure 
values requiring dose holding. 
 
Refer to Section 9.92 for hypertension supportive care guidelines. 
 
Dose Modifications for Hypertension 
Hypertension Toxicity 
Grade* 
Occurrence 
Capecitabine 
Bevacizumab  
Atezolizumab/ 
Placebo 
Grade 2 
Any 
Maintain current dose 
Maintain current 
dose 
Maintain current dose 
Grade 3  
Asymptomatic 
1st to 3rd  
Maintain current dose 
Hold until BP is 
≤150/100 for at least 
one week, then resume 
at current dose 
Maintain current dose 
4th 
Maintain current dose 
Discontinue 
Maintain current dose 
Grade 3  
Symptomatic 
1st to 3rd  
Maintain current dose 
Hold until symptoms 
have resolved and BP 
is ≤150/100 for at least 
two weeks, then 
resume at current dose 
Maintain current dose 
4th 
Maintain current dose 
Discontinue 
Maintain current dose 


 
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  Addendum 6 
 
Hypertension Toxicity 
Grade* 
Occurrence 
Capecitabine 
Bevacizumab  
Atezolizumab/ 
Placebo 
Grade 4  
(including RPLS 
confirmed by MRI or 
hypertensive 
encephalopathy) 
1st 
Hold until recovery to 
grade ≤1, then resume 
at current dose with 
approval of Study 
Chair 
Discontinue 
Hold until recovery to 
grade ≤1, then resume 
at current dose with 
approval of Study 
Chair 
* 
Hypertension is the corresponding adverse event term from NCI CTCAE version 4.0 for reporting 
purposes. Other applicable adverse event terms to consider may include reversible posterior 
leukoencephalopathy syndrome. 
 
8.63 
Proteinuria 
 
Proteinuria will be monitored by urinalysis (UA) dipstick or 24 hour urine every cycle 
(every 21 days). UA dipstick values ≥2+ protein should be confirmed by 24 hour 
collection and management based upon 24 hour protein values. 
 
After Cycle 1, urine protein should be completed on day 1 on each cycle. However, if 
result is not available prior to treatment on day 1, the urine protein result from the 
previous cycle may be used for to determine treatment for current cycle. 
 
UPC = protein concentration (mg /dL) / creatinine concentration (mg /dL). To obtain 
urine protein/creatinine (UPC) ratio from random urine sample (i.e., not 24-hour urine): 
 
a. Obtain at least 4 ml of a random urine sample. 
b. Determine protein concentration (mg/dL)  
c. Determine creatinine concentration (mg/dL)  
d. Divide b by c 
 
UPC directly correlates with the amount of protein excreted in the urine per 24 hours 
(i.e., UPC of 1 should be equivalent to 1g protein in a 24hr urine collection). 
 
Dose modifications are based on urine protein values and nephrotic syndrome versus 
CTCAE grading scale. 
 
 
Dose Modifications for Proteinuria 
Proteinuria* 
Occurrence 
Capecitabine 
Bevacizumab 
Atezolizumab/ 
Placebo 
>2.0g/24 hrs 
(Note: UA ≥2+ aor 
UPCR ≥1, 24hr urine 
protein collection 
must be performed.) 
1st to 3rd  
Maintain current 
dose 
Hold until recovery 
to 24hr urine protein 
<2g, then resume at 
current dose 
Maintain current 
dose 
4th  
Hold until recovery 
to 24hr urine protein 
<2g, then resume at 
current dose 
Discontinue 
Maintain current 
dose 
Nephrotic Syndrome 
1st 
Hold until recovery 
to 24hr urine protein 
<2g, then resume 
current dose with 
approval of Study 
Chair 
Discontinue 
Hold until recovery 
to 24hr urine protein 
<2g, then resume 
current dose with 
approval of Study 
Chair 
* 
Proteinuria is the corresponding adverse event term from NCI CTCAE version 4.0 for reporting 
purposes. 
 


 
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  Addendum 6 
 
 
Dose Modifications for Hemorrhage 
Hemorrhage 
Toxicity Grade* 
Occurrence 
Capecitabine 
Bevacizumab 
Atezolizumab/ 
Placebo 
Grade 2  
non-pulmonary or 
non-CNS 
Any 
Maintain current 
dose 
Maintain current dose 
Maintain current 
dose 
Grade 2  
pulmonary  
Any 
Hold until recovery 
to grade ≤1, then 
resume at current 
dose 
Discontinue 
Hold until recovery 
to grade ≤1, then 
resume at current 
dose 
Grade 3 or 4 
Any 
Hold until recovery 
to grade ≤1, then 
resume at current 
dose with approval 
of Study Chair 
Discontinue 
Hold until recovery 
to grade ≤1, then 
resume at current 
dose with approval 
of Study Chair 
Any grade CNS 
hemorrhage 
Any 
Hold until recovery 
to grade ≤1, then 
resume at current 
dose with approval 
of Study Chair 
Discontinue 
Hold until recovery 
to grade ≤1, then 
resume at current 
dose with approval 
of Study Chair 
* 
The following terms from NCI CTCAE version 4.0 may be considered for reporting purposes: 
Vitreous hemorrhage, Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, Duodenal 
hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, 
Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, 
Lower gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal 
hemorrhage, Retroperitoneal hemorrhage, Upper Gastrointestinal hemorrhage, Hepatic 
hemorrhage, Intraoperative hemorrhage, Postoperative hemorrhage, Tracheal hemorrhage, 
Intracranial hemorrhage, Renal hemorrhage, Ovarian hemorrhage, Prostatic hemorrhage, 
Spermatic cord hemorrhage, Testicular hemorrhage, Uterine hemorrhage, Vaginal hemorrhage, 
Bronchopulmonary hemorrhage, Laryngeal hemorrhage, Mediastinal hemorrhage, Pharyngeal 
hemorrhage, and Pleural hemorrhage. 
 
Dose Modifications for Venous Thromboembolic Events (VTE) 
VTE Toxicity 
Grade* 
Occurrence 
Capecitabine 
Bevacizumab 
Atezolizumab/ 
Placebo 
Grade 2 
Any 
Maintain current 
dose 
Maintain current 
dose 
Maintain current 
dose 
Grade 3** 
Any 
Hold until stable 
full-dose 
anticoagulation is 
achieved (at least 48 
hours), then resume 
at current dose if not 
thrombocytopenic 
(i.e., platelet count 
decreased is ≤ grade 
1) with approval of 
Study Chair 
Hold until stable full-
dose anticoagulation 
is achieved (at least 
48 hours), then 
resume at current 
dose if not 
thrombocytopenic 
(i.e., platelet count 
decreased  is ≤ grade 
1) with approval of 
Study Chair 
Hold until stable 
full-dose 
anticoagulation is 
achieved (at least 48 
hours), then resume 
at current dose if not 
thrombocytopenic 
(i.e., platelet count 
decreased is ≤ grade 
1) with approval of 
Study Chair 
Grade 4** 
1st  
Hold until stable 
full-dose 
anticoagulation is 
achieved (at least 48 
hours), then resume 
at current dose if not 
thrombocytopenic 
(i.e., platelet count 
decreased is ≤ grade 
1) with approval of 
Study Chair 
Discontinue  
Hold until stable 
full-dose 
anticoagulation is 
achieved (at least 48 
hours), then resume 
at current dose if not 
thrombocytopenic 
(i.e., platelet count 
decreased is ≤ grade 
1) with approval of 
Study Chair 
* 
The following terms from NCI CTCAE version 4.0 may be considered for reporting purposes: 
Superior vena cava syndrome, Portal vein thrombosis, and Vascular access complication. 


 
59  
 
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  Addendum 6 
 
** The following criteria must be met by patients who experience a Grade 3 or 4 VTE: (a) No 
evidence of tumor involving major blood vessels on current CT scan; (b) No use of warfarin; (c) 
No use of anti-platelet agents during full dose anticoagulation; (d) May use low molecular 
weight heparin or oral factor Xa inhibitors; (e) No Grade 3 or 4 hemorrhagic event while on 
anticoagulation; and (f) Clinically stable on a stable dose of low molecular weight heparin  or 
other anticoagulant for at least 48 hours prior to resuming study drug treatment. 
 
 
Dose Modifications for Arterial Thromboembolic Events (ATE) 
ATE Toxicity 
Grade* 
Occurrence 
Capecitabine 
Bevacizumab 
Atezolizumab/ 
Placebo 
Any Grade 
1st 
Discontinue 
Discontinue 
Discontinue 
* 
The following terms from NCI CTCAE version 4.0 may be considered for reporting purposes: 
Stroke, Acute coronary syndrome, Myocardial infarction, Visceral arterial ischemia, Ischemia 
cerebrovascular. 
 
 
Dose Modifications for Congestive Heart Failure (CHF) 
CHF Toxicity 
Grade* 
Occurrence 
Capecitabine 
Bevacizumab 
Atezolizumab/ 
Placebo 
Grade 2 
Any 
Maintain current 
dose 
Maintain current 
dose 
Maintain current 
dose 
Grade 3 
1st 
Hold until recovery 
to grade ≤1, then 
resume at current 
dose 
Discontinue 
Hold until recovery 
to grade ≤1, then 
resume at current 
dose 
2nd 
Hold until recovery 
to grade ≤1, then 
resume at current 
dose with approval 
of Study Chair 
Discontinue 
Hold until recovery 
to grade ≤1, then 
resume at current 
dose with approval 
of Study Chair 
3rd 
Discontinue 
Discontinue 
Hold until recovery 
to grade ≤1, then 
resume at current 
dose with approval 
of Study Chair 
Grade 4 
1st  
Discontinue 
Discontinue 
Discontinue 
* 
The following terms from NCI CTCAE version 4.0 may be considered for reporting purposes: 
Heart failure, Left Ventricular Systolic Dysfunction, Restrictive cardiomyopathy, and Right 
ventricular dysfunction.  
 
 
 


 
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  Addendum 6 
 
 
 
8.64 
Hepatotoxicities 
 
Subjects with Grade 3-4 hepatotoxicity should be evaluated for disease progression. If 
disease progression is found, discontinue study treatment. It is also recommended that 
subjects with Grade 3-4 hepatotoxicity be evaluated for biliary obstruction. If biliary 
obstruction is found to be the cause of the elevated bilirubin and is corrected, study 
treatment may resume at current dose level once bilirubin has resolved to Grade <2. If 
biliary obstruction is due to progressive disease and cannot be fixed, study treatment 
should be discontinued. 
 
 
Dose Modifications for Hepatotoxicities 
Hepatic Toxicity 
Grade*  
Occurrence 
Capecitabine 
Bevacizumab 
Atezolizumab/ 
Placebo 
Grade 2** 
 
 
1st  
Maintain current 
dose 
Maintain current 
dose 
Hold until recover 
to grade ≤1, then 
resume at current 
dose 
2nd  
Hold until recovery 
to grade ≤1, then 
resume one dose 
lower 
Maintain current 
dose 
Hold until recover 
to grade ≤1, then 
resume at current 
dose 
3rd  
Hold until recovery 
to grade ≤1, then 
resume one dose 
lower 
Maintain current 
dose 
Hold until recovery 
to grade ≤1, then 
resume at current 
dose 
4th  
Hold until recovery 
to grade ≤1, then 
resume one dose 
lower 
Maintain current 
dose 
Hold until recovery 
to grade ≤1, then 
resume at current 
dose 
5th 
Discontinue 
Maintain current 
dose 
Hold until recovery 
to grade ≤1, then 
resume at current 
dose 
6th  
Discontinue 
Maintain current 
dose 
Discontinue 
Grade 3*** 
1st 
Hold until recovery 
to grade ≤2, then 
restart at one dose 
level lower 
Maintain current 
dose 
Discontinue 
2nd  
Hold until recovery 
to grade ≤2, then 
restart at one dose 
level lower 
Maintain current 
dose 
Discontinue 
3rd  
Hold until recovery 
to grade ≤2, then 
restart at one dose 
level lower 
Maintain current 
dose 
Discontinue 
4th 
Discontinue 
Maintain current 
dose 
Discontinue 
5th  
Discontinue 
Hold until recovery 
to grade ≤2, then 
resume at current 
dose with approval of 
Study Chair 
Discontinue 


 
61  
 
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  Addendum 6 
 
Hepatic Toxicity 
Grade*  
Occurrence 
Capecitabine 
Bevacizumab 
Atezolizumab/ 
Placebo 
Grade 4*** 
1st 
Hold until recovery 
to grade ≤2, then 
restart at  two dose 
levels lower  
Hold until recovery 
to grade ≤2, then 
resume at current 
dose  
Discontinue  
2nd  
Discontinue 
Hold until recovery 
to grade ≤2, then 
resume at current 
dose with approval of 
Study Chair 
Discontinue 
* 
Alanine aminotransferase increased, Aspartate aminotransferase increased, and Blood bilirubin 
increased are the corresponding adverse event terms from NCI CTCAE version 4.0 for reporting 
purposes. 
**   If toxicity has not resolved to Grade ≤ 1 within 12 weeks, permanently discontinue 
atezolizumab/placebo. 
*** If toxicity has not resolved to Grade ≤ 2 within 8 weeks, discontinue study treatment. 
 
 
8.65 
Perforation, Fistula, Abscess, and Obstruction 
 
Timely diagnosis and appropriate treatment may reduce the potential for complications 
of diverticulitis and thus reduce the risk of GI perforations. Therefore, patients should be 
made aware of the symptomatology potentially indicative of diverticular disease, and 
they should be instructed to alert their healthcare provider as soon as possible if these 
symptoms arise. Patients with a history of diverticulitis, chronic ulcerative lower GI 
disease such as Crohn’s disease or ulcerative colitis, or other symptomatic lower GI 
conditions that might predispose to perforations are excluded from the current study.  
 
 
Dose Modifications for Perforation, Fistula or Abscess 
Perforation/ Fistula/ 
Abscess Toxicity 
Grade* 
Occurrence 
Capecitabine 
Bevacizumab 
Atezolizumab/ 
Placebo 
Grade 1 
Any 
Maintain current 
dose with caution 
Maintain current dose 
with caution 
Maintain current 
dose with caution 
Grade 2 and higher 
1st 
Discontinue 
Discontinue 
Discontinue 
* 
The following terms from NCI CTCAE version 4.0 may be considered for reporting purposes: 
Colonic perforation, Duodenal perforation, Esophageal perforation, Gastric perforation, Ileal 
perforation, Jejunal perforation, Rectal perforation, Small intestine perforation, Gall bladder 
perforation, Perforation bile duct, Laryngeal fistula, Pharyngeal fistula, Anal fistula, Colonic 
fistula, Duodenal fistula, Enterovesical fistula, Esophageal fistula, Gastric fistula, 
Gastrointestinal fistula, Ileal fistula, Jejunal fistula, Oral cavity fistula, Pancreatic fistula, Rectal 
fistula, Salivary gland fistula, Biliary fistula, Gallbladder fistula, Abdominal infection, 
Anorectal infection, Biliary tract infection, Cecal infection, Duodenal infection, Esophageal 
infection, Gallbladder infection, Hepatic infection, Pancreas infection, Pelvic infection, 
Peritoneal infection, Small intestine infection, Splenic infection, Stoma site infection, Wound 
infection, and Infections and infestations - Other. 
 
 
 


 
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  Addendum 6 
 
 
Dose Modifications for GI Obstruction 
GI Obstruction 
Toxicity Grade* 
Occurrence 
Capecitabine 
Bevacizumab 
Atezolizumab/ 
Placebo 
Grade 2 
Any 
Hold until recovery 
to grade ≤1, then 
resume at current 
dose. 
 
Hold for partial 
obstruction 
requiring medical 
intervention. 
 
Resume at current 
dose when 
obstruction is 
resolved. 
Hold until recovery 
to grade ≤1, then 
resume at current 
dose. 
 
Hold for partial 
obstruction requiring 
medical intervention. 
 
Resume at current 
dose when 
obstruction is 
resolved. 
Hold until recovery 
to grade ≤1, then 
resume at current 
dose. 
 
Hold for partial 
obstruction 
requiring medical 
intervention. 
 
Resume at current 
dose when 
obstruction is 
resolved. 
Grade 3 
Any 
Hold until recovery 
to grade ≤1, then 
resume at current 
dose with approval 
of Study Chair. 
 
Hold for complete 
obstruction. If 
surgery is 
necessary, resume 
all study drugs at 
current doses after 
full recovery from 
surgery with 
approval of Study 
Chair. 
Hold until recovery 
to grade ≤1, then 
resume at current 
dose with approval of 
Study Chair. 
 
Hold for complete 
obstruction. If 
surgery is necessary, 
resume all study 
drugs at current doses 
after full recovery 
from surgery with 
approval of Study 
Chair. 
Hold until recovery 
to grade ≤1, then 
resume at current 
dose with approval 
of Study Chair. 
 
Hold for complete 
obstruction. If 
surgery is 
necessary, resume 
all study drugs at 
current doses after 
full recovery from 
surgery with 
approval of Study 
Chair. 
Grade 4 
1st 
Discontinue 
Discontinue 
Discontinue 
* 
The following terms from NCI CTCAE version 4.0 may be considered for reporting purposes: 
Gallbladder obstruction, Intestinal stoma obstruction, Tracheal obstruction, Colonic obstruction, 
Duodenal obstruction, Esophageal obstruction, Ileal obstruction, Jejunal obstruction, 
Obstruction gastric, Rectal obstruction, and Small intestine obstruction. 
 
8.66 
Hypersensitivity or Anaphylaxis 
 
An infusion reaction is defined as an adverse event occurring during and within 24 hours 
after the infusion. The most serious of these infusion reactions are hypersensitivity or 
anaphylactic reactions. 
 
Signs of a possible hypersensitivity or anaphylactic reaction include but are not limited 
to: 
 
• 
fever, chills, pruritus, urticaria, angioedema, and skin rash. 
• 
cardiopulmonary reactions, including chest pain, dyspnea, hypotension or 
hypertension. 
 
Healthcare professionals administering atezolizumab/placebo infusions should be trained 
in the appropriate administrative procedures, be able to recognize the symptoms 
associated with potential anaphylactic or hypersensitivity reactions, and have the 
appropriate medication available for immediate use in case of anaphylaxis or 
hypersensitivity reaction during or after administration of atezolizumab/placebo. 
Healthcare professionals should also instruct patients to seek medical attention if they 


 
63  
 
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  Addendum 6 
 
experience symptoms of a hypersensitivity reaction outside of the clinic. In the event of a 
serious hypersensitivity or anaphylactic reaction, atezolizumab/placebo should be 
permanently discontinued. 
 
Acute infusion reactions are to be managed by institutional standards. Use of H1 and H2 
blockers are encouraged. The use of IV or PO steroids is permitted. However, since this 
study is placebo controlled and patients may be receiving atezolizumab therapy, the dose 
of steroids should be as low as needed to treat the reaction. Prophylactic steroids to 
prevent infusion reactions are not permitted. For infusions reactions that cannot be 
managed with prophylactic H1 and H2 blockers, atezolizumab placebo should be 
discontinued. 
 
8.661 
Infusion Reactions 
 
8.6611 
Infusion of bevacizumab should be interrupted for subjects who 
develop dyspnea or clinically significant hypotension during the 
bevacizumab infusion.  
 
If a subject experiences an infusion-associated adverse event, he or 
she may be premedicated for the next study drug infusion; 
however, the infusion time may not be decreased for the 
subsequent infusion. If the next infusion is well tolerated with 
premedication, the subsequent infusion time may then be 
decreased by 30 (±10) minutes as long as the subject continues to 
be premedicated. If a subject experiences an infusion associated 
adverse event with the 60 minute infusion, all subsequent doses 
should be given over 90 (±15) minutes. Similarly, if a subject 
experiences an infusion associated adverse event with the 30 
minute infusion, all subsequent doses should be given over 60 
(±10) minutes. 
 
Subjects who experience Grade 3 or 4 allergic reaction, adult 
respiratory distress syndrome, or bronchospasm (regardless of 
grade) will be discontinued from bevacizumab treatment. 
 
8.6612 
No pre-medication will be permitted for the first dose of 
atezolizumab/placebo. Subjects who experience infusion-related 
symptoms may be pre-medicated for subsequent infusions with 
standard of care agents. 
 
The infusion should be slowed to 50% or less or interrupted for 
subjects who experience Grade 1infusion-associated symptoms. 
For subjects who experience Grade 2 infusion-related reactions, 
interrupt the infusion. When the subject’s symptoms have 
completely resolved, the infusion may be continued at no more 
than 50% of the rate prior to the reaction and increased in 50% 
increments every 30 minutes if well tolerated. Infusions may be 
restarted at the full rate during the next cycle.  
 
Subjects who experience Grade 3 or 4 allergic reaction, adult 
respiratory distress syndrome, or bronchospasm (regardless of 
grade) will be discontinued from atezolizumab/placebo treatment. 
 
 


 
64  
 
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  Addendum 6 
 
 
8.67 
Opportunistic Infections and Serious Infections 
 
Atezolizumab/placebo should not be administered to patients with active infections 
including active inflammatory bowel disease, history of diverticulitis, autoimmune 
diseases, active current infection or history of recurrent bacterial, viral, fungal, 
mycobacterial, or other infections, including but not limited to tuberculosis and atypical 
mycobacterial disease, hepatitis B and C, herpes zoster, HIV, EBV, CMV, or those with 
a recent history of oral or IV antibiotics or prophylactic antibiotics (e.g., for prevention 
of a urinary tract infection or chronic obstructive pulmonary disease). The effects of 
atezolizumab/placebo on CRP, neutrophils, and the signs and symptoms of infection 
should be considered when evaluating a patient for a potential infection. 
 
Vigilance for timely detection of serious infection is recommended as signs and 
symptoms of acute inflammation may be lessened due to suppression of the acute phase 
reaction. Patients must be instructed to contact their physician immediately when any 
symptoms suggesting infection appear, in order to assure rapid evaluation and 
appropriate treatment. 
 
If a patient develops a serious infection, administration of atezolizumab/placebo is to be 
interrupted until the infection is controlled. The treating physician should consider the 
benefit-risk before resuming treatment with atezolizumab/placebo. 
 
8.68 
Wound Requiring Intervention 
 
Dose Modifications for Wound Requiring Medical or Surgical Intervention  
Wound Toxicity 
Grade* 
Occurrence 
Capecitabine 
Bevacizumab 
Atezolizumab/ 
Placebo 
Grade 1 
Any 
Continue 
Discontinue 
Continue 
Grade 2 
Any 
Hold until recovery 
to grade <1, then 
resume at current 
dose  
Discontinue 
Hold until recovery 
to grade <1, then 
resume at current 
dose  
Grade 3 
1st 
Hold until recovery 
to grade ≤1, then 
resume at current 
dose with approval 
of Study Chair 
Discontinue 
Hold until recovery 
to grade ≤1, then 
resume at current 
dose with approval 
of Study Chair 
Grade 4 
1st  
Discontinue 
Discontinue 
Discontinue 
* 
The following terms from NCI CTCAE version 4.0 may be considered for reporting purposes: 
Wound infection, Wound complication, Wound dehiscence, Abdominal soft tissue necrosis, and 
Pelvic soft tissue necrosis. 
 
 
 


 
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  Addendum 6 
 
 
 
8.69 
Other Related Toxicities 
 
Dose Modifications for Posterior Reversible Encephalopathy Syndrome (PRES) 
Toxicity Grade* 
Occurrence 
Capecitabine 
Bevacizumab 
Atezolizumab/ 
Placebo 
Any Grade 
(confirmed by MRI) 
Any 
Hold until recovery 
to grade ≤1, then 
resume at current 
dose with approval 
of Study Chair 
Discontinue 
Hold until recovery 
to grade ≤1, then 
resume at current 
dose with approval 
of Study Chair 
* 
Use National Cancer Institute Common Terminology Criteria for Adverse Events (NCI 
CTCAE) version 4.0. 
 
 
Dose Modifications for Other Unspecified Study Treatment Related Toxicity 
Toxicity Grade* 
Occurrence 
Capecitabine 
Bevacizumab 
Atezolizumab/ 
Placebo 
Grade 2 
Any 
Maintain current 
dose unless treating 
physician deems it 
clinically necessary 
to hold until 
recovery to grade ≤1 
Maintain current dose 
unless treating 
physician deems it 
clinically necessary 
to hold until recovery 
to grade ≤1 
Maintain current 
dose unless treating 
physician deems it 
clinically necessary 
to hold until 
recovery to grade ≤1 
Grade 3 
Any  
Hold until recovery 
to grade ≤1, then 
resume at current or 
reduced dose with 
approval of Study 
Chair 
Hold until recovery 
to grade ≤1, then 
resume at current 
dose with approval of 
Study Chair 
Hold until recovery 
to grade ≤1, then 
resume at current 
dose with approval 
of Study Chair 
Grade 4 
Any 
Hold until recovery 
to grade ≤1, then 
resume at current or 
reduced dose with 
approval of Study 
Chair 
Hold until recovery 
to grade ≤1, then 
resume at current or 
reduced dose with 
approval of Study 
Chair 
Hold until recovery 
to grade ≤1, then 
resume at current or 
reduced dose with 
approval of Study 
Chair 
* 
Use National Cancer Institute Common Terminology Criteria for Adverse Events (NCI 
CTCAE) version 4.0. 
 
 
8.7 
Surgery 
 
Consultation should occur between the treating physician and surgeon(s) as to timing of surgery 
and planned treatment interruptions. If subject on treatment require elective major surgery, it is 
recommended that bevacizumab and atezolizumab/placebo be held for 4-8 weeks prior to the 
surgical procedure. Holding capecitabine for at least 4 weeks is generally recommended to ensure 
the subject’s performance status is optimal for surgery. Subject undergoing a major surgical 
procedure should not begin/restart bevacizumab or atezolizumab/placebo until at least 4 weeks 
after that procedure and provided that adequate wound healing and general recuperation is 
documented. In the case of high risk procedures such as liver resection, thoracotomy, or 
neurosurgery, it is recommended that treatment be restarted no earlier than 8 weeks after surgery. 
Subjects should have re-staging procedures performed before restarting study treatment. 
 
• 
Minor surgery, such as cataract surgery and placement of central venous catheters, should 
preferably be scheduled at least 2 weeks after the last dose of bevacizumab and 


 
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  Addendum 6 
 
atezolizumab/placebo. Post-procedure, study drugs should be postponed one week and/or until 
complete wound healing has taken place. 
• 
Minor procedures, such as tooth extractions, can proceed without any adjustment in 
bevacizumab and atezolizumab/placebo.   
• 
Very minor procedures, such as dental fillings and cleanings, can proceed without interruption 
of study drugs.  
• 
In medical circumstances often requiring surgery (e.g., bowel obstruction), due to the possible 
need for surgery in the setting of bowel obstruction; subjects with bowel obstruction requiring 
bowel rest should have the study treatment held until the bowel obstruction has resolved. 
 
9.0 
Ancillary Treatment/Supportive Care 
 
9.1 
Patients may be premedicated with standard-of-care methods to control nausea and vomiting. Since 
systemic corticosteroids may attenuate potential beneficial immunologic effects of protocol 
treatments, alternatives to these agents should be considered. 
 
9.2 
Blood products and growth factors should be utilized as clinically warranted and following 
institutional policies and recommendations. The use of growth factors should follow published 
guidelines of the American Society of Clinical Oncology (ASCO) Update of Recommendation for 
the Use of White Blood Cell Growth Factors: An Evidence-Based Clinical Practice Guideline 
(Smith, Khatcheressian et al. 2006).  
 
9.3 
Patients should receive full supportive care while on this study. This includes blood product 
support, antibiotic treatment, and treatment of other newly diagnosed or concurrent medical 
conditions. All blood products and concomitant medications such as antidiarrheals, analgesics, 
and/or antiemetics received from the first day of study treatment administration until 30 days after 
the final dose will be recorded in the medical records. 
 
9.4 
General Exclusions 
 
The following therapies are excluded at all times while on study: 
 
• 
Any non-protocol investigational agent. 
• 
Any non-protocol chemotherapy or targeted anti-cancer therapy. 
• 
Any non-protocol cancer immunotherapy or other biologic therapy. 
• 
Radiotherapy (except for palliative therapy for treatment of known bony metastasis). 
• 
Warfarin. 
• 
Sorivudine and Brivudine (5-bromovinyluracil is a metabolite of these antiviral agents, and is a 
potent inhibitor of dihydropyrimidine dehydrogenase, the enzyme that catabolizes 5-FU. 
Subjects should not receive concurrent therapy with either of these antiviral agents while 
receiving capecitabine. If a subject has received prior sorivudine or brivudine, then at least four 
weeks must elapse before the subject receives capecitabine therapy.). 
• 
St John’s Wort (Due to risk of overlapping toxicities with capecitabine, subjects should not 
receive concurrent therapy with this agent while receiving capecitabine.). 
 
9.5 
Therapies to be used with Caution 
 
The following therapies may only be considered if there is clear medical indication with no 
alternatives. Permission for use must be obtained from the Lead Study Chair. 
 
• 
Vitamin B6 (pyridoxine) 
• 
Allopurinol (Oxypurinol, a metabolite of allopurinol, can potentially interfere with 5-FU 
anabolism via orotate phosphoribosyltransferase. Although this was originally used as a 


 
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strategy to protect normal tissues from 5-FU-associated toxicity, further laboratory studies 
suggested possible antagonism of the anticancer activity of 5-FU in some tumor models. If a 
subject is receiving allopurinol, allopurinol should be discontinued prior to starting on this 
regimen, and another agent substituted for it.) 
• 
Phenytoin (Increased phenytoin plasma concentrations have been reported during concomitant 
use of capecitabine with phenytoin, suggesting a potential interaction. Subjects taking 
phenytoin concomitantly with capecitabine should be regularly monitored for increased 
phenytoin plasma concentrations and associated clinical symptoms.) 
 
9.6 
Hematopoietic Growth Factors 
 
Growth factors (e.g., G-CSF, GM-CSF, erythropoietin, platelet growth factors, etc.) may be 
prescribed by the treating physician for rescue from severe hematologic events if clinically 
appropriate. Therapeutic growth factor usage is permitted per American Society of Clinical 
Oncology (ASCO) and treating physician guidelines. 
 
Prophylactic use is not permitted (except for erythropoietin stimulating agents) given the potential 
interaction with continuously dosed chemotherapies in this regimen.  Similarly, use of growth 
factor to meet re-dosing criteria or to avoid dose delays is not permitted.   
 
Dose reduction and/or holding drugs as noted in Section 8.71 are the preferred approach for 
minimizing hematologic toxicity.   
 
9.7 
Anticoagulation 
 
Full dose anti-coagulation is permitted with low molecular weight heparins and factor Xa 
inhibitors. Due to interactions with diet and with capecitabine, warfarin is prohibited.  
 
Prophylactic use of anticoagulation at baseline and during study treatment for the maintenance of 
patency of permanent indwelling central venous access devices is permitted. Treating physicians 
are urged to use caution with patients in the setting of thrombocytopenia while on full-dose 
anticoagulation.  
 
9.8 
Vaccinations 
 
Live/attenuated vaccines should not be given within 4 weeks prior to baseline and during the study 
as clinical safety has not been established. 
 
9.9 
Supportive Care Recommendations 
 
9.91 
Stomatitis/Oral Mucositis/Mouth Ulcers  
 
Stomatitis/oral mucositis/mouth ulcers due to capecitabine should be treated using local 
supportive care. If examination reveals mouth ulcers rather than a more general 
inflammation of the mouth, please classify the adverse event as such.  
 
The paradigm below is recommended for treatment of stomatitis/oral mucositis/mouth 
ulcers: 
 
Toxicity 
Grade* 
Recommended Treatment 
Grade 1 
Non-alcoholic mouth wash or salt water (0.9%) mouth wash 
several times a day until resolution. 


 
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Toxicity 
Grade* 
Recommended Treatment 
Grade 2 or 3 
Topical analgesic mouth treatments (i.e. local anesthetics 
such as benzocaine, butyl aminobenzoate, tetracaine 
hydrochloride, menthol, or phenol) with or without topical 
corticosteroids, such as triamcinolone oral paste 0.1% 
(Kenalog in Orabase®). 
* 
Use National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE) version 4.0. 
 
 
If possible, patients avoid agents containing hydrogen peroxide, iodine, and thyme 
derivatives as they may tend to worsen mouth ulcers. Patients should be reminded to 
check for these agents in toothpastes and mouthwashes. 
 
9.92 
Hypertension 
 
Early and aggressive medical management of hypertension is strongly recommended to 
minimize the need for dose holding and/or dose reductions. Addition or adjustment of 
blood pressure medications should be considered for blood pressure values persistently 
>150/100. In addition, blood pressure medications should be added or adjusted for blood 
pressure values requiring dose holding or interruptions. 
 
The anti-hypertensive regimen is left to discretion of the treating physician. 
 
Blood pressure should be treated to maintain blood pressure measurements ≤150/100. 
 
Other general recommendations include the following: 
 
• 
Diuretics should be avoided or used with caution in subjects with volume depletion, 
anorexia, or diarrhea. 
• 
Beta blockers should be avoided or used with caution in subjects with fatigue. 
 
9.93 
Diarrhea, Nausea, or Vomiting 
 
Symptoms of diarrhea and/or abdominal cramping may occur at any time and should be 
managed according to the prescribing information for capecitabine, atezolizumab, and 
standard institutional practice. Aggressive support of toxicity and disease symptoms is 
encouraged.  
 
Anti-emetics and supportive medications are permitted. Aggressive support of toxicity 
and disease symptoms is encouraged. Loperamide should be used with caution. 
 
Intravenous (IV) hydration and use of loperamide is recommended for diarrhea, as well 
as close observation.  If control takes longer than 2 days, medical evaluation including 
relevant diagnostic procedures, alternative treatment and possible investigation of 
dihydropyrimidine dehydrogenase (DPD) deficiency should be considered. 
 
For diarrhea, which could be attributed to either capecitabine or to atezolizumab, 
treatment should also follow the guidelines for the treatment of autoimmune colitis 
related to atezolizumab. Treatment of study-related diarrhea will, however, be at the 
discretion of the treating physician. The following are offered as suggestions for 
management of study-related diarrhea. 
 


 
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  Addendum 6 
 
For patients with grade 1 diarrhea, the treating physician may consider conservative 
treatment with anti-diarrheal medications and intravenous fluids. 
 
For patients with grade 2 diarrhea, the treating physician may consider treatment 
interruption and conservative treatment with anti-diarrheal medications and intravenous 
fluids for signs and symptoms of dehydration. If the symptoms do not improve and/or 
worsen after 72 hours, more aggressive management could be considered including 
evaluation by a gastroenterologist for consideration of endoscopic examination with 
biopsy and treatment with oral corticosteroids (prednisone 1-2 mg/kg per day or the 
equivalent). When the signs and symptoms have improved to grade ≤1, a steroid taper is 
suggested. 
 
For patients with grade 3 or 4 diarrhea, the treating physician should strongly consider 
empiric treatment of a presumed autoimmune colitis related to atezolizumab therapy. 
Suggestions include treatment interruption, evaluation by a gastroenterologist for 
consideration of endoscopic examination with biopsy, and corticosteroids 
(methylprednisolone 135 mg IV every 6 hours followed by high-dose oral steroids such 
as prednisone 1-2 mg/kg by mouth per day or dexamethasone 4 mg by mouth every 4 
hours). If intravenous steroids followed by high-dose oral steroids do not reduce the 
initial symptoms in patients with grade 3 or 4 diarrhea within 48-72 hours, anti-TNF-
alpha antibody therapy (e.g., infliximab) should strongly be considered. Once symptoms 
improve to grade ≤1, a steroid taper is suggested over 6-8 weeks in patients with diffuse 
and severe ulceration and/or bleeding. If symptoms worsen during the steroid taper, 
initiating a re-tapering of steroids starting at a higher dose followed by a more prolonged 
taper and re-administration of anti-TNF-alpha therapy should be considered. Unblinding 
will not be routinely performed but may be considered on a case-by-case basis as noted 
above in section 7.5. 
 
Subjects should also be instructed to notify the treating physician or nurse for the 
occurrence of bloody or black stools, symptoms of dehydration, fever, inability to take 
liquids by mouth, inability to control diarrhea (return to baseline) within 24 hours. 
Subjects with diarrhea should be evaluated frequently by a nurse or physician until 
resolution of diarrhea. 
 
For severe diarrhea (i.e., Grade 3 and 4), hospital admission, I.V. fluids, corticosteroids, 
and electrolytes should be administered as appropriate. Clostridium Difficile (C. diff) 
testing is strongly recommended.  
 
9.94 
Hand-Foot Syndrome  
 
Hand-Foot Syndrome should be treated according to the prescribing information for 
capecitabine and standard institutional practice. This may include the use of emollients 
such as Aveeno®, Lubriderm®, Udder Cream®, and Bag Balm®.   
 
10.0 
Adverse Event (AE) Reporting and Monitoring 
 
The site principal investigator is responsible for reporting any/all serious adverse events to the sponsor as 
described within the protocol, regardless of attribution to study agent or treatment procedure. The 
sponsor/sponsor-investigator is responsible for notifying FDA and all participating investigators in a 
written safety report of any of the following:  
 
• 
Any suspected adverse reaction that is both serious and unexpected. 
• 
Any findings from laboratory animal or in vitro testing that suggest a significant risk for human 
subjects, including reports of mutagenicity, teratogenicity, or carcinogenicity. 


 
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• 
Any findings from epidemiological studies, pooled analysis of multiple studies, or clinical studies, 
whether or not conducted under an IND and whether or not conducted by the sponsor, that suggest a 
significant risk in humans exposed to the drug. 
• 
Any clinically important increase in the rate of a serious suspected adverse reaction over the rate stated 
in the protocol or Investigator’s Brochure (IB). 
 
Definitions 
 
Adverse Event 
Any untoward medical occurrence associated with the use of a drug in humans, whether or not considered 
drug related. 
 
This includes the following:  
• 
AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with metastatic colorectal cancer 
that were not present prior to the AE reporting period. 
• 
Complications that occur as a result of the protocol-mandated interventions (e.g., invasive 
procedures such as cardiac catheterizations) 
• 
If applicable, AEs that occur prior to assignment of study treatment associated with 
medication washout, no treatment run-in, or other protocol-mandated intervention. 
• 
Preexisting medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during the 
protocol-specified AE reporting period. 
o A preexisting medical condition is one that is present at the start of the study. Such 
conditions should be reported as medical and surgical history. A preexisting 
medical condition should be re-assessed throughout the trial and reported as an AE 
or SAE only if the frequency, severity, or character of the condition worsens 
during the study. When reporting such events, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., “more frequent headaches”). 
 
Suspected Adverse Reaction 
Any adverse event for which there is a reasonable possibility that the drug caused the adverse event. 
 
Expedited Reporting 
Events reported to sponsor within 24 hours, 5 days or 10 days of study team becoming aware of the event. 
 
Routine Reporting 
Events reported to sponsor via case report forms 
 
Events of Interest 
Events that would not typically be considered to meet the criteria for expedited reporting, but that for a 
specific protocol are being reported via expedited means in order to facilitate the review of safety data (may 
be requested by the FDA or the sponsor). 
 
10.1 
Adverse Event Characteristics 
 
CTCAE term (AE description) and grade: The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for AE reporting. All appropriate treatment areas should have access to a copy of the 
CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP web 
site:
 
 
a. Adverse event monitoring and reporting is a routine part of every clinical trial. 


 
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  Addendum 6 
 
b. Identify the grade and severity of the event using the CTCAE version 4.0. 
c. Determine whether the event is expected or unexpected (see Section 10.2). 
d. Determine if the adverse event is related to the study intervention (agent, treatment or 
procedure) (see Section 10.3). 
e. Determine whether the event must be reported as an expedited report. If yes, determine the 
timeframe/mechanism (see Section 10.4). 
f. 
Determine if other reporting is required (see Section 10.5). 
 
Note: All AEs reported via expedited mechanisms must also be reported via the routine data 
reporting mechanisms defined by the protocol (see Sections 10.6 and 18.0). 
 
10.11 
Each CTCAE term in the current version is a unique representation of a specific event 
used for medical documentation and scientific analysis and is a single MedDRA Lowest 
Level Term (LLT). 
 
NOTE: A severe AE, as defined by the above grading scale, is NOT the same as serious 
AE which is defined in the table in Section 10.4. 
 
10.2 
Expected vs. Unexpected Events  
 
Expected events - are those described within the Section 15.0 of the protocol, the study specific 
consent form, package insert (if applicable), and/or the investigator brochure, (if an investigator 
brochure is not required, otherwise described in the general investigational plan).  
 
Unexpected adverse events or suspected adverse reactions are those not listed in Section 15.0 of the 
protocol, the study specific consent form, package insert (if applicable), or in the investigator 
brochure (or are not listed at the specificity or severity that has been observed); if an investigator 
brochure is not required or available, is not consistent with the risk information described in the 
general investigational plan. 
 
Unexpected also refers to adverse events or suspected adverse reactions that are mentioned in the 
investigator brochure as occurring with a class of drugs but have not been observed with the drug 
under investigation. 
 
Unanticipated Adverse Device Event (UADE) 
Any serious adverse effect on health or safety or any life-threatening problem or death caused by, 
or associated with, a device, if that effect, problem, or death was not previously identified in nature, 
severity, or degree of incidence in the investigational plan or application (including a 
supplementary plan or application), or any other unanticipated serious problem associated with a 
device that relates to the rights, safety, or welfare of subjects  
 
10.3 
Assessment of Attribution 
 
All AEs and SAEs, whether volunteered by the subject, discovered by the study personnel 
during questioning, or detected through physical examination, laboratory test, or other means, 
will be reported appropriately. Each reported AE or SAE will be described by its evaluation 
date, grade, attribution to any treatment, and actions taken (if applicable). 
 
 
When assessing whether an adverse event is related to a medical treatment or procedure, the 
following attribution categories are utilized: 
 
Definite - The adverse event is clearly related to the agent(s). 
Probable - The adverse event is likely related to the agent(s). 


 
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Possible - The adverse event may be related to the agent(s). 
Unlikely - The adverse event is doubtfully related to the agent(s). 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
 
Events determined to be possibly, probably or definitely attributed to a medical 
treatment suggest there is evidence to indicate a causal relationship between the 
drug/device and the adverse event.  
 
10.31 
AEs Experienced Utilizing Investigational Agents and Commercial Agent(s) on the 
SAME (Combination) Arm 
 
When a commercial agent(s) is (are) used on the same treatment arm as the 
investigational agent/intervention (also, investigational drug, biologic, cellular 
product, or other investigational therapy under an IND), the entire combination 
(arm) is then considered an investigational intervention for reporting. 
These AEs should be assessed as specified in the appropriate IND/IDE 
reporting guidelines in Section 10.4 
 
10.4 
Expedited Adverse Event Reporting Requirements for IND/IDE Agents 
 
10.41 
Phase 1 and Early Phase 2 Studies: Expedited Reporting via the ACCRU Adverse 
Event Expedited Report Form for Adverse Events That Occur Within 30 Days1 of the 
Last Dose of the Investigational Agent 
 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
 
NOTE: Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they 
are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
 
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 
21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the sponsor within 
the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
7 Calendar Days 
24-Hour  
3 Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 


 
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Expedited AE reporting timelines are defined as: 
 
o 
“24-Hour; 3 Calendar Days” - The AE must initially be reported within 24 hours of learning of the AE, 
followed by a complete expedited report within 3 calendar days of the initial 24-hour report. 
o 
“7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar 
days of learning of the AE. 
 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
 
Expedited 24-hour notification followed by complete report within 3 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
 
Expedited 7 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
 
Effective Date: May 5, 2011 
 
Special Instructions: 
 
 
• 
Follow site-specific reporting guidelines. 
• 
Submit the 
 
via fax 
  The ACCRU SAE Coordinator will forward a copy of the expedited 
reports within 1 business day of receipt using the Genentech Fax Coversheet to: 
 
Genentech Drug Safety at Fax: 
 
• 
The ACCRU SAE Coordinator will forward to 
 The 
ACCRU IND Coordinator will assist the sponsor-investigator in notifying the FDA if required.  
 
• 
Genentech AEs of Special Interest (AESI): AEs of Special Interest are defined by Genentech 
as a potential safety problem identified as a result of ongoing safety monitoring of their 
products. As such, surveillance for the AESIs in Appendix II MUST be undertaken at each 
treatment evaluation. Development of one of these AESIs (≥ grade 1 unless otherwise noted) 
MUST be reported in terms of CTCAE v4.0 grade and attribution (please refer to the table 
below): 
 
Adverse Event 
Form(s) 
Needed 
Site 
timeline 
to report 
to 
ACCRU 
ACCRU timeline to 
report to sponsor 
Non-Serious 
Adverse Event 
(Sections 10.52-
10.53) 
Adverse Events 
form (see CRF 
packet) 
At each 
evaluation 
Quarterly 
Adverse Events 
of Special 
Interest (Section 
10.41 special 
instructions and 
Appendix II)* 
Adverse Events 
of Special 
Interest Form** 
At each 
occurrence  
Within 1 business day of 
receipt 
Adverse Events 
form (if criteria 
in 10.5 is met) 
Quarterly 


 
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Adverse Event 
Form(s) 
Needed 
Site 
timeline 
to report 
to 
ACCRU 
ACCRU timeline to 
report to sponsor 
Pregnancy 
(Sections 10.41 
and 10.54) 
ACCRU 
Adverse Event 
Expedited 
Report Form** 
 
At each 
occurrence 
Within 1 business day of 
receipt 
Adverse Events 
form (if criteria 
in 10.5 is met) 
 
Quarterly 
Serious Adverse 
Events (Section 
10.41)* 
ACCRU 
Adverse Event 
Expedited 
Report Form** 
At each 
occurrence 
Within 1 business day of 
receipt 
Adverse Events 
form (see CRF 
packet) 
Quarterly 
*If an adverse event meets the criteria for both an AE of Special Interest and a Serious 
Adverse Event, please report only as a Serious Adverse Event. 
** The Adverse Events of Special Interest Form and ACCRU Adverse Event 
Expedited Report Form are available on the ACCRU web site 
  
 
10.42 Reporting of re-occurring SAEs 
ALL SERIOUS adverse events that meet the criteria outlined in table 10.41 MUST be 
immediately reported to the sponsor within the timeframes detailed in the corresponding 
table. This reporting includes, but is not limited to SAEs that re-occur again after 
resolution. 
 
10.5 
Other Required Reporting 
 
10.51 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOs) in general, 
include any incident, experience, or outcome that meets all of the following criteria: 
 
1. Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB-
approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
2. Related or possibly related to participation in the research (in this guidance 
document, possibly related means there is a reasonable possibility that the incident, 
experience, or outcome may have been caused by the procedures involved in the 
research); and 
3. Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. 
 
Some unanticipated problems involve social or economic harm instead of the physical 
or psychological harm associated with adverse events.  In other cases, unanticipated 
problems place subjects or others at increased risk of harm, but no harm occurs. 
 


 
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Note: If there is no language in the protocol indicating that pregnancy is not considered 
an adverse experience for this trial, and if the consent form does not indicate that 
subjects should not get pregnant/impregnate others, then any pregnancy in a 
subject/patient or a male patient’s partner (spontaneously reported) which occurs during 
the study or within 120 days of completing the study should be reported as a UPIRTSO. 
 
If the event meets the criteria for an UPIRTSO, submit to your IRB as required by your 
institutional policies.   
 
10.52 
Baseline and Adverse Events Evaluations 
 
Pre-treatment symptoms/conditions to be graded at baseline and adverse events to be 
graded starting with day 1 treatment and at each evaluation per the CTCAE v4.0 
grading unless otherwise stated in the table below: Please note: if an SAE were to occur 
prior to day 1 treatment, please collect that SAE from the day of consent. 
 
System Organ 
Class (SOC) 
Adverse event/Symptoms 
Baseline 
Each 
evaluation 
Gastrointestinal 
Disorders 
Diarrhea 
# of stools 
X 
Nausea 
X 
X 
Vomiting 
X 
X 
General 
Disorders and 
Administration 
Fatigue 
 
 
X 
 
 
X 
 
 
 
10.53 
Case Report Forms - Academic and Community Cancer Research United (ACCRU) 
 
Submit the following AEs not specified in Section 10.5 (paper or electronic, as 
applicable): 
 
10.531 
Grade 2, 3, 4 and 5 AEs regardless of attribution to the study treatment or 
procedure. 
 
10.532 
Grade 5 AEs (Deaths) 
 
10.5321 
Any death within 30 days of the patient’s last study treatment or 
procedure regardless of attribution to the study treatment or 
procedure. 
 
10.5322 
Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly treatment 
related must also be submitted as a Grade 5 AE, with a CTCAE 
type and attribution assigned. 
 
 


 
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10.54 
Pregnancy  
 
• 
During the course of the trial, all female subjects of childbearing potential should be 
instructed to contact the treating physician immediately if they suspect they might 
have conceived a child. In addition, a missed or late menstrual period should be 
reported to the treating physician. If a female subject, or an investigator, suspects a 
pregnancy prior to administration of study drugs, the study drugs must be withheld 
until the results of a pregnancy test are available. If pregnancy is confirmed the 
subject must not receive study medications and must be withdrawn from the study. 
All supporters of the study will be informed if a pregnancy occurs. 
• 
Throughout the entire pregnancy, additional contact should be made with the subject 
and in some cases with the healthcare provider, to identify spontaneous abortions and 
elective terminations, as well as any medical reasons for elective termination. In 
addition, the investigator should include perinatal and neonatal outcome. Infants 
should be followed for a minimum of 8 weeks.  
• 
If a male subject is suspected of having fathered a child while on study drugs, the 
pregnant female partner must be notified and counseled regarding the possible risk to 
the fetus. In addition, the treating physician must follow the course of the pregnancy, 
including prenatal and neonatal outcome. Infants should be followed for a minimum 
of 8 weeks.  
• 
The subject must be instructed to stop taking capecitabine if she becomes pregnant 
during the study and immediately inform the investigator. The investigator should 
counsel the subject, and discuss the risk of continuing with the pregnancy and the 
possible effect on the fetus. Monitoring of the subject should continue until 
conclusion of the pregnancy. Pregnancy occurring in the partner of a subject 
participating in the study must also be treated as describe above. 
• 
If a female subject becomes pregnant while receiving investigational therapy or ≤120 
days after the last dose of study drug, a report should be completed and expeditiously 
submitted to the Genentech, Inc. Follow-up to obtain the outcome of the pregnancy 
should also occur. Abortion, whether accidental, therapeutic, or spontaneous, should 
always be classified as serious, and expeditiously reported as an SAE. Similarly, any 
cancer or congenital anomaly/birth defect in a child born to a female subject exposed 
to the study drugs should be reported as an SAE. 
 
10.55 
Post-Study Adverse Events 
 
The investigator should expeditiously report any SAE occurring after a subject has 
completed or discontinued study participation if attributed to prior exposure to 
atezolizumab or bevacizumab. 
 
10.56 
Reconciliation: ACCRU agrees to conduct reconciliation for the product. Genentech and 
ACCRU will agree to the reconciliation periodicity and format, but agree at maximum to 
exchange quarterly line listings of cases received by the other party. If discrepancies are 
identified, the Sponsor and Genentech will cooperate in resolving the discrepancies. The 
responsible individuals for each party shall handle the matter on a case-by-case basis 
until satisfactory resolution. 
 
 


 
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10.57 
IND Annual Reports: All IND annual reports submitted to the FDA by the Sponsor-
Investigator should be copied to Genentech. Copies of such reports should be faxed to 
Genentech Drug Safety: 
 
 
 
 
 
 
 
 
10.58 
All non-serious adverse events originating from the study will be forwarded by ACCRU 
in a quarterly report to Genentech. 
 
10.59 
Study Close-Out: Any study report submitted to the FDA by the Sponsor-Investigator 
should be copied to Genentech. This includes all Clinical Study Reports (final study 
report). Additionally, any literature articles that are a result of the study should be sent to 
Genentech. Copies of such reports should be mailed to the assigned Clinical Operations 
contact for the study. 
 
11.0 
Treatment Evaluation Using RECIST Guideline 
 
NOTE: This study uses protocol RECIST v1.1 template dated 2/16/2011. See the footnote for the table 
regarding measureable disease in Section 11.44, as it pertains to data collection and analysis. 
 
Response and progression will be evaluated in this study using the new international criteria proposed by 
the revised Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1) (Eisenhauer, 
Therasse et al. 2009). Changes in the largest diameter (unidimensional measurement) of the tumor lesions 
and the short axis measurements in the case of lymph nodes are used in the RECIST guideline (Pocock and 
Simon 1975).  However, if the patient is considered to have pseudo-progression by Immune-Related 
Response Criteria (Wolchok, Hoos et al. 2009), please contact the Study Chair. Pseudo-progression is 
usually accompanied by improvements in CEA and tumor symptoms. Such patients may be allowed to 
continue treatment on a case by case basis with permission of the Study Chair by contacting the Data 
Manager. 
 
11.1 
Schedule of Evaluations: For the purposes of this study, patients should be reevaluated at least 
every 21 days during treatment and if possible every 12 weeks if discontinued from treatment for 
reasons other than disease progression. 
 
11.2 
Definitions of Measurable and Non-Measurable Disease 
 
11.21 
Measurable Disease 
 
11.211 
A non-nodal lesion is considered measurable if its longest diameter can be 
accurately measured as ≥2.0 cm with chest x-ray, or as ≥1.0 cm with CT scan, 
CT component of a PET/CT, or MRI. 
 
11.212 
A superficial non-nodal lesion is measurable if its longest diameter is ≥1.0 cm 
in diameter as assessed using calipers (e.g. skin nodules) or imaging. In the 
case of skin lesions, documentation by color photography, including a ruler to 
estimate the size of the lesion, is recommended. 
 
11.213 
A malignant lymph node is considered measurable if its short axis is >1.5 cm 
when assessed by CT scan (CT scan slice thickness recommended to be no 


 
78  
 
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  Addendum 6 
 
greater than 5 mm). 
 
NOTE: Tumor lesions in a previously irradiated area are not considered 
measurable disease. 
 
11.22 
Non-Measurable Disease 
 
All other lesions (or sites of disease) are considered non-measurable disease, including 
pathological nodes (those with a short axis ≥1.0 to <1.5 cm). Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonis, inflammatory breast disease, and abdominal masses (not followed by CT 
or MRI), are considered as non-measurable as well. 
 
Note: “Cystic lesions” thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred for 
selection as target lesions. In addition, lymph nodes that have a short axis <1.0 cm are 
considered non- pathological (i.e., normal) and should not be recorded or followed. 
 
11.3 
Guidelines for Evaluation of Measurable Disease 
 
11.31 
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 must be used to characterize 
each identified and reported lesion at baseline and during follow-up. For patients 
having only lesions measuring at least 1 cm to less than 2 cm must use CT imaging 
for both pre- and post-treatment tumor assessments. 
• 
Imaging-based evaluation is preferred to evaluation by clinical examination when 
both methods have been used at the same evaluation to assess the antitumor effect of a 
treatment. 
 
11.32 
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 prior scans. Body scans should be performed with breath-hold 
scanning techniques, if possible. 
• 
PET-CT: If the site can document that the CT performed as part of a PET-CT is of 
identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT 
portion of the PET-CT can be used for RECIST measurements and can be used 
interchangeably with conventional CT in accurately measuring cancer lesions over 
time. 
• 
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. 


 
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• 
Physical Examination: For superficial non-nodal lesions, physical examination is 
acceptable, but imaging is preferable, if both can be done. In the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the 
lesion, is recommended. 
 
11.33 
Measurement at Follow-up Evaluation: 
 
• 
In the case of stable disease (SD), follow-up measurements must have met the SD 
criteria at least once after study entry at a minimum interval of 8 weeks (see Section 
11.44). 
 
11.4 
Measurement of Effect 
 
11.41 
Target Lesions & Target Lymph Nodes 
 
• 
Measurable lesions (as defined in Section 11.21) up to a maximum of 5 lesions, 
representative of all involved organs, should be identified as “Target Lesions” and 
recorded and measured at baseline. These lesions can be non-nodal or nodal (as 
defined in 11.21), where no more than 2 lesions are from the same organ and no more 
than 2 malignant nodal lesions are selected. 
 
Note: If fewer than 5, target lesions and target lymph nodes are identified (as there 
often will be) there is no reason to perform additional studies beyond those specified 
in the protocol to discover new lesions. 
 
• 
Target lesions and target lymph nodes should be selected on the basis of their size, be 
representative of all involved sites of disease, but in addition should be those that lend 
themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion (or malignant lymph node) does not lend itself to 
reproducible measurements in which circumstance the next largest lesion (or 
malignant lymph node) which can be measured reproducibly should be selected. 
• 
Baseline Sum of Dimensions (BSD): A sum of the longest diameter for all target 
lesions plus the sum of the short axis of all the target lymph nodes will be calculated 
and reported as the baseline sum of dimensions (BSD). The BSD will be used as 
reference to further characterize any objective tumor response in the measurable 
dimension of the disease. 
• 
Post-Baseline Sum of the Dimensions (PBSD): A sum of the longest diameter for all 
target lesions plus the sum of the short axis of all the target lymph nodes will be 
calculated and reported as the post-baseline sum of dimensions (PBSD). If the 
radiologist is able to provide an actual measure for the target lesion (or target lymph 
node), that should be recorded, even if it is below 0.5 cm. If the target lesion (or target 
lymph node) is believed to be present and is faintly seen but too small to measure, a 
default value of 0.5 cm should be assigned. If it is the opinion of the radiologist that 
the target lesion or target lymph node has likely disappeared, the measurement should 
be recorded as 0 cm. 
• 
The minimum sum of the dimensions (MSD) is the minimum of the BSD and the 
PBSD. 
 
11.42 
Non-Target Lesions & Non-Target Lymph Nodes 
 
Non-measurable sites of disease (Section 11.22) are classified as non- target lesions or 
non-target lymph nodes and should also be recorded at baseline. These lesions and lymph 
nodes should be followed in accord with 11.433. 
 
 


 
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11.43 
Response Criteria 
 
11.431 
All target lesions and target lymph nodes followed by CT/MRI/PET-CT/Chest 
X-ray/physical examination must be measured on re-evaluation at evaluation 
times specified in Section 11.1. Specifically, a change in objective status to 
either a PR or CR cannot be done without re-measuring target lesions and 
target lymph nodes. 
 
Note: Non-target lesions and non-target lymph nodes should be evaluated at 
each assessment, especially in the case of first response or confirmation of 
response. In selected circumstances, certain non-target organs may be 
evaluated less frequently. For example, bone scans may need to be repeated 
only when complete response is identified in target disease or when 
progression in bone is suspected. 
 
11.432 
Evaluation of Target Lesions 
 
• 
Complete Response (CR): All of the following must be true: 
 
a. Disappearance of all target lesions. 
b. Each target lymph node must have reduction in short axis to <1.0 cm. 
c. Normalization of tumor biomarkers. 
 
• 
Partial Response (PR): At least a 30% decrease in PBSD (sum of the 
longest diameter for all target lesions plus the sum of the short axis of all 
the target lymph nodes at current evaluation) taking as reference the BSD 
(see Section 11.41). 
 
• 
Progression (PD): At least one of the following must be true: 
 
a. At least one new malignant lesion, which also includes any lymph node 
that was normal at baseline (< 1.0 cm short axis) and increased to ≥ 1.0 
cm short axis during follow-up.  
b. At least a 20% increase in PBSD (sum of the longest diameter for all 
target lesions plus the sum of the short axis of all the target lymph 
nodes at current evaluation) taking as reference the MSD (Section 
11.41). In addition, the PBSD must also demonstrate an absolute 
increase of at least 0.5 cm from the MSD.  
c. See Section 11.32 for details in regards to the requirements for PD via 
FDG-PET imaging. 
 
• 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR, nor 
sufficient increase to qualify for PD taking as reference the MSD. 
 
11.433 
Evaluation of Non-Target Lesions & Non-target Lymph Nodes 
 
• 
Complete Response (CR): All of the following must be true: 
 
a. Disappearance of all non-target lesions. 
b. Each non-target lymph node must have a reduction in short axis to <1.0 
cm. 
c. Normalization of tumor biomarkers 
 


 
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• 
Non-CR/Non-PD: Persistence of one or more non-target lesions or non-
target lymph nodes and/or maintenance of tumor marker level above the 
normal limits. 
• 
Progression (PD): At least one of the following must be true: 
 
a. At least one new malignant lesion, which also includes any lymph node 
that was normal at baseline (<1.0 cm short axis) and increased to ≥1.0 
cm short axis during follow-up. 
b. Unequivocal progression of existing non-target lesions and non-target 
lymph nodes. (NOTE: Unequivocal progression should not normally 
trump target lesion and target lymph node status. It must be 
representative of overall disease status change.) 
c. See Section 11.32 for details in regards to the requirements for PD via 
FDG-PET imaging. 
 
11.44 
Overall Objective Status 
 
The overall objective status for an evaluation is determined by combining the patient’s 
status on target lesions, target lymph nodes, non-target lesions, non-target lymph nodes, 
and new disease as defined in the following tables:  
 
For Patients with Measurable Disease 
 
Target Lesions & 
Target Lymph 
Nodes 
Non-Target Lesions 
& Non-Target 
Lymph Nodes 
New Sites of 
Disease 
Overall 
Objective 
Status 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
CR 
Non-CR/Non-PD 
No 
PR 
CR/PR 
Not All Evaluated* 
No 
PR** 
SD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
SD 
Not all Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
Not Evaluated 
(NE) 
PD 
Unequivocal PD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes or No 
PD 
CR/PR/SD/PD/Not 
all Evaluated 
Unequivocal PD 
Yes or No 
PD 
CR/PR/SD/PD/Not 
all Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes 
PD 
* 
See Section 11.431 
** NOTE: This study uses the protocol RECIST v1.1 template dated 
2/16/2011. For data collection and analysis purposes the objective status 
changed from SD to PR in the ACCRU protocol RECIST v1.1 template as 
of 2/16/2011 and to match RECIST v1.1 requirements. 
 
 


 
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For Patients with Non-Measurable Disease Only: 
 
Non-Target Lesions & 
Non-Target Lymph Nodes 
New Sites of 
Disease 
Overall Objective 
Status 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Non-PD  
Not All Evaluated* 
No 
Not Evaluated (NE) 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* 
See Section 11.431 
 
12.0 
Descriptive Factors 
 
12.1 
RAF Status: Wild-type vs. mutant. 
 
12.11 
If mutant, select appropriate alteration from the following: 
 
12.111 
V600E vs. other (please list) 
 
12.2 
MSI Status: Microsatellite Stable (MSS) or Mismatch Repair (MMR) Proficient vs. Microsatellite 
Unstable or Microsatellite Instability present or Mismatch Repair Deficient. 
 
12.21 
List test used: 
 
12.221 
Immunohistochemistry (IHC) 
 
12.222 
Polymerase Chain Reaction (PCR) 
 
12.223 
Both IHC and PCR 
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient 
 
13.1 
All patients will remain on treatment until progression of disease, unacceptable toxicity, refusal to 
continue, or other reason for treatment discontinuation. 
 
13.2 
Patients who develop PD while receiving therapy will go to the event-monitoring phase. 
 
13.3 
Patients who go off protocol treatment for reasons other than PD and receive no subsequent anti-
cancer therapy will go to Observation and then event monitoring per Section 18.0. 
 
13.4 
A patient is deemed ineligible if after randomization, it is determined that at the time of 
randomization, the patient did not satisfy each and every eligibility criteria for study entry. The 
patient may continue treatment off-protocol at the discretion of the physician as long as there are 
no safety concerns, and the patient was properly registered. The patient will go directly to the 
event-monitoring phase of the study (or off study, if applicable). 
 
• 
If the patient received treatment, all data up until the point of confirmation of ineligibility must 
be submitted. Event monitoring will be required per Section 18.0 of the protocol. 
• 
If the patient never received treatment, on-study material must be submitted. Event monitoring 
will be required per Section 18.0 of the protocol. 
• 
Up to 14 patients withdrawn prior to treatment or determined to be ineligible will be replaced. 
 
 


 
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13.5 
A patient is deemed a major violation, if protocol requirements regarding treatment in cycle 1 of 
the initial therapy are severely violated that evaluability for primary end point is questionable. All 
data up until the point of confirmation of a major violation must be submitted. The patient will go 
directly to the event-monitoring phase of the study. The patient may continue treatment off-
protocol at the discretion of the physician as long as there are no safety concerns, and the patient 
was properly registered. Event monitoring will be required per Section 18.0 of the protocol. 
 
13.6 
A patient is deemed a cancel if he/she is removed from the study for any reason before any study 
treatment is given. On-study material and the End of Active Treatment/Cancel Notification Form 
must be submitted. The patient will go directly to the event-monitoring phase of the study, and 
event monitoring will be required per Section 18.0 of the protocol. Up to 14 patients withdrawn 
prior to treatment or determined to be ineligible will be replaced. 
 
14.0 
Body Fluid Biospecimens   
 
14.1 
Summary Table of Research Blood/Blood Products to Be Collected for This Protocol 
 
Indicate if 
specimen is 
mandatory or 
optional 
Collection tube 
description and/or 
additive (color of 
tube top) 
Volume to collect 
per tube (number 
of tubes to be 
collected) 
Blood product 
being processed 
and submitted by 
participating site 
When to 
submit? 
Reason for 
Submission 
Mandatory 
EDTA K2 
(Pink) 
6 mL (1) 
Whole Blood 
Baseline 
Genotyping 
Mandatory 
EDTA K2 
(Purple) 
6 mL (2) 
Plasma 
Multiple 
timepoints 
Blood 
Biomarkers 
Mandatory 
SST 
(Gold) 
5 mL (1) 
Serum 
Multiple 
timepoints 
Blood 
Biomarkers 
Mandatory 
ACD 
(Yellow) 
8.5 mL (3) 
Whole Blood 
Multiple 
timepoints 
Blood 
Biomarkers 
 
14.11 
Kits are required for this study. 
 
14.111 
The kit contains supplies and instructions for collecting, processing, and 
shipping specimens. 
 
14.112 
Participating institutions may obtain kits by completing and faxing the Supply 
Order Form (found in the Forms Packet) to the number listed on the form. Fill 
out the site address to where the kits will be shipped on the Fax Supply form. 
Because we are now being charged for all outgoing kits, a small, but sufficient, 
supply of the specimen collection kits should be ordered prior to patient entry. 
Do not send the unused kits back to BAP. 
 
14.113 
Kits will be sent via FedEx® Ground at no additional cost to the participating 
institutions. Allow up to two weeks to receive the kits. Kits will arrive inside 
the shipping boxes. 
 
14.114 
Kits will not be sent via rush delivery service unless the participating 
institution provides their own FedEx® account number or alternate billing 
number for express service. ACCRU will not cover the cost for rush delivery 
of kits. 
 
 


 
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  Addendum 6 
 
 
14.115 
Summary Table of Research Blood to Be Collected for This Protocol 
 
Collection 
container 
description 
Volume to collect 
(number of 
containers to be 
collected) 
Baseline1  
Restaging2 
Off 
Treatment3 
Off 
Treatment 
Follow up4 
Site to 
process 
Storage/ 
shipping 
conditions5 
EDTA K2 
(Pink) 
6mL (1) 
X 
 
 
 
No 
Freeze 
(Brown shipper) 
EDTA K2 
(Purple) 
6 mL (2) 
X 
X 
X 
X 
Yes 
Freeze 
(Brown shipper) 
SST (Gold) 
5 mL (1) 
X 
X 
X 
X 
Yes 
Freeze (Brown 
shipper) 
ACD 
(Yellow)6 
8.5 mL (3) 
X 
X7 
X 
 
No 
Ambient (White 
shipper) 
1. May occur prior to treatment on Cycle 1 Day 1. 
2. At time of radiographic assessments (i.e., prior to Cycle 4, prior to Cycle 7, etc.) which may occur ≤14 days prior to day 1 
of new cycle. 
3. Discontinuation of study treatment. 
4. 30 days from last dose of study drug. 
5. After all samples have been processed according to kit instructions, ship all specimens according to shipping instructions 
(see Section 14.12 for detailed shipping instructions). 
6. Samples only viable for 1 overnight shipment. Email 
 prior to shipping. 
7. At first restaging only (i.e., prior to Cycle 4 only). 
 
 
14.12 
Shipping 
 
14.121 
Verify ALL sections of the Blood Specimen Submission Form (see CRF 
Packet), BAP Requisition Form (provided in kit), and specimen collection 
labels are completed and filled in correctly.   
 
14.122 
Specimens must be shipped the same day they are drawn. 
 
14.123 
Ship ACD whole blood specimens in the White shipping box Priority 
Overnight service Monday – Thursday ONLY Ambient Temp to Duke 
University according to kit instructions. ATTN:
 
 
 
 
14.124 
Ship EDTA whole blood, plasma and serum specimens in the Brown shipping 
box via Priority Overnight service, Monday – Thursday on Dry Ice, to BAP 
Freezer according to kit instructions. Do not send samples on Fridays, 
weekends, or just prior to federal holidays. Brown shippers will arrive at BAP 
Freezer and specimens will be immediately forwarded to the
 
 
 
14.125 
The BAP kits will include a smart shipper label (3x5 white barcoded label) 
affixed to the boxes. The smart shipper label is a pre-addressed which replaces 
the need for airbills. Shipping costs will be covered by ACCRU only if the 
provided shippers are used. ATTENTION: Brown shippers will be sent to 
BAP Freezer and White shippers will be sent to Duke University. Use extra 
caution to ensure the correct samples go in the different shippers. 


 
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14.2 
Study Methodology and Storage Information 
 
14.21 
Blood/blood product samples will be collected for the following research  
 
14.211 
DNA will be extracted from whole blood and stored for future 
pharmacogenetic assays (e.g., genetic polymorphisms such as those known to 
regulate angiogenesis, inflammation, immunity, auto-immunity, and antibody 
or drug action of clearance) that may correlate with efficacy and tolerability. 
The Duke Phase I Biomarker Laboratory located at Duke University may 
analyze the DNA for the presence of markers of interest including, but not 
limited to VEGF, NOS, IL6, IL17, Fc Receptors, and MHCs, using standard 
laboratory protocols. 
 
14.212 
Plasma and serum will be analyzed for the presence of markers related to 
tumor angiogenesis, inflammation, immunity, colon cancer biology, and other 
factors that may correlate with efficacy and tolerability. The Duke Phase I 
Biomarker Laboratory located at Duke University Medical Center may analyze 
the plasma and serum for the presence of markers of interest including, but not 
limited to VEGF-A, -C, -D, VEGFR-1, -2, -3, IL6, IL6R, s-gp130, IL11, 
IL17A, IL17E, IL17R, IL22, IL23, and TGFβ, using standard laboratory 
protocols. 
 
14.213 
Circulating immune cells will be analyzed for lymphoid focus on T-cell 
activation, maturation, regulation, and exhaustion and myeloid focus on 
myeloid derived suppressor cells (MDSC), M1/M2 polarization, and dendritic 
cells (DC, pDC). The Duke Immune Profiling Core Laboratory located at 
Duke University Medical Center may analyze the circulating immune cells for 
the presence of markers of interest including, but not limited to Amine, CD3, 
CD4, CD45RO, CD38, CD278-ICOS, FoxP3, CD25, Tim3, CD152-CTLA4, 
IDO, CD223-LAG3, CD279-PD1, CD11b, CD33, HLA-DR, CD123, CD11c, 
CD304-BDCA4, CD86, CD163, CD206, CD16, CD68, using standard 
laboratory protocols. 
 
14.214 
As part of ongoing research of Dr. Herbert Hurwitz and other ACCRU 
investigators, any DNA, immune cell, plasma and/or serum samples left over 
from the analysis of this study will be stored for future research studies on 
molecular determinants of efficacy and tolerability, according to patient 
consent information. Leftover samples will be stored frozen at -70ºC by Duke 
University until specific analyses are identified. As protocols are developed, 
they will be presented for IRB review and approval. 
 
14.3 
Return of Genetic Testing Research Results 
 
Because the results generated by the genetic testing included in this section are not currently 
anticipated to have clinical relevance to the patient or their family members, the genetic results will 
not be disclosed to the patients or their physicians. 
 
If at any time, genetic results are obtained that may have clinical relevance, IRB review and 
approval will be sought regarding the most appropriate manner of disclosure and whether or not 
validation in a CLIA-certified setting will be required.  Sharing of research data with individual 
patients should only occur when data have been validated by multiple studies and testing has been 
done in CLIA-approved laboratories. 
 


 
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15.0 
Drug Information 
 
 
IND #130760 
 
15.1 
Bevacizumab (Avastin) 
 
• 
Investigator brochure: Available on the ACCRU website. 
 
15.11 
Background: Bevacizumab is classified as an Anti-VEGF Monoclonal Antibody and a 
Vascular Endothelial Growth Factor (VEGF) Inhibitor. Bevacizumab is a recombinant, 
humanized monoclonal immunoglobulin G1 (IgG1) antibody which binds to, and 
neutralizes, vascular endothelial growth factor (VEGF), preventing its association with 
endothelial receptors, Flt-1 and KDR. VEGF binding initiates angiogenesis (endothelial 
proliferation and the formation of new blood vessels). The inhibition of microvascular 
growth is believed to retard the growth of all tissues (including metastatic tissue).  
 
15.12 
Formulation: Bevacizumab is manufactured by recombinant DNA technology, using a 
genetically engineered Chinese hamster ovary (CHO) cell line. The protein is purified 
from the cell culture medium by routine methods of column chromatography and 
filtration. The final product is tested for quality, identity, safety, purity, potency, 
strength, and excipient/chemical composition according to International Conference on 
Harmonisation (ICH) guidelines. The purity of bevacizumab is >95%. 
 
Bevacizumab is supplied in 100 mg (4 mL) and 400 mg (16 mL) glass vials, each with a 
concentration of 25 mg/mL. Vials contain bevacizumab with phosphate, trehalose, 
polysorbate 20, and sterile water for injection (SWFI), USP. Vials contain no 
preservative and are suitable for single use only. 
 
15.13 
Preparation and storage: Bevacizumab vials should be stored in a refrigerator at 2°C-
8°C. Keep vial in the outer carton due to light sensitivity. DO NOT FREEZE. DO NOT 
SHAKE. 
 
Chemical and physical in-use stability has been demonstrated for 48 hours at 2°C-30°C 
in 0.9% sodium chloride solution. Do not administer or mix with dextrose solution. 
From a microbiological point of view, the product should be used immediately. If not 
used immediately, in-use storage times and conditions are the responsibility of the user 
and would normally not be longer than 24 hours at 2°C to 8°C, unless dilution has taken 
place in controlled and validated aseptic conditions. 
 
Withdraw the necessary amount of bevacizumab and dilute to the required administration 
volume with 0.9% sodium chloride solution. The concentration of the final bevacizumab 
solution should be kept within the range of 1.4 - 16.5 mg/mL. Discard any unused 
portion left in a vial, as the product contains no preservatives. Parenteral drug products 
should be inspected visually for particulate matter and discoloration prior to 
administration. 
 
15.14 
Administration: Do not administer as an intravenous push or bolus. Administer only as 
an intravenous (IV) infusion. Do not initiate bevacizumab for 28 days following major 
surgery and until surgical wound is fully healed. 
 
Refer to Section 7 for protocol-specific administration instructions. Guidelines 
recommended by the manufacturer are included for reference. 
 


 
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First infusion: Administer infusion over 90 minutes.  
Subsequent infusions: Administer second infusion over 60 minutes if first infusion is 
tolerated; administer all subsequent infusions over 30 minutes if infusion over 60 
minutes is tolerated.  
 
15.15 
Pharmacokinetic information: 
Distribution: Vd: 3.28L 
Half-life elimination: 3-4 weeks 
Clearance: 0.22L/day. A low serum albumin and high tumor burden increase clearance 
by 30% and 7% respectively. Clearance increases with increasing body weight, and is 
15% slower in women than men. 
Time to steady state: 100 days 
 
15.16 
Potential Drug Interactions: 
 
No clinically relevant pharmacokinetic interaction of co-administered chemotherapy on 
bevacizumab pharmacokinetics has been observed based on the results of a population 
PK analysis. There was neither statistical significance nor clinically relevant difference 
in clearance of bevacizumab in patients receiving bevacizumab monotherapy compared 
with patients receiving bevacizumab in combination with Interferon alpha 2a or other 
chemotherapies (IFL, 5-FU/LV, carboplatin/paclitaxel, capecitabine, doxorubicin or 
cisplatin/gemcitabine). 
 
No clinically relevant interaction of bevacizumab was observed on the pharmacokinetics 
of co-administered interferon alpha 2a, erlotinib (and its active metabolite OSI-420), or 
the chemotherapies irinotecan (and its active metabolite SN38), capecitabine, oxaliplatin 
(as determined by measurement of free and total platinum), and cisplatin. Conclusions on 
the impact of bevacizumab on gemcitabine pharmacokinetics cannot be drawn.  
 
Combination of bevacizumab and sunitinib malate: In two clinical trials studies of 
metastatic renal cell carcinoma, microangiopathic hemolytic anemia (MAHA) was 
reported in 7 of 19 patients’ treated with bevacizumab (10 mg/kg every two 
weeks) and sunitinib malate (50 mg daily) combination. MAHA is a hemolytic 
disorder which can present with red cell fragmentation, anemia, and 
thrombocytopenia. In addition, hypertension (including hypertensive crisis), 
elevated creatinine, and neurological symptoms were observed in some of these 
patients. All of these findings were reversible upon discontinuation of 
bevacizumab and sunitinib malate. 
15.17 
Known potential adverse events: Consult the investigator’s brochure and package 
insert for the most current and complete information. U.S. Boxed Warnings report that 
severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, CNS 
hemorrhage, epistaxis, and vaginal bleeding, occurs up to 5-fold more frequently in 
patients receiving bevacizumab products. Do not administer bevacizumab products to 
patients with a recent history of hemoptysis. Discontinue in patients who develop grade 3 
to 4 hemorrhage.Percentages reported as Monotherapy and as part of combination 
chemotherapy regimens. 
 
Very Common (≥ 1/10) Infections and infestations: paronychia 
Blood and lymphatic system disorders: febrile neutropenia, leucopenia, 
neutropenia, thrombocytopenia 
Metabolism and nutrition disorders: anorexia, hypomagnesemia, hyponatremia 
Nervous system disorders: peripheral sensory neuropathy, dysgeusia, headache, 
dysarthria 
Eye disorders: eye disorder, increased lacrimation 


 
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Vascular disorders: hypertension 
Respiratory, thoracic and mediastinal disorders: dyspnea, epistaxis, rhinitis, cough 
Gastrointestinal disorders: diarrhea, nausea, vomiting, abdominal pain, constipation, 
stomatitis, rectal hemorrhage 
Endocrine disorders: ovarian failure 
Skin and subcutaneous tissue disorders: exfoliative dermatitis, dry skin, skin 
discoloration 
Musculoskeletal, connective tissue, and bone disorders: arthralgia 
Renal and urinary disorders: proteinuria 
General disorders and administration site conditions: asthenia, fatigue, pyrexia, pain, 
mucosal inflammation 
Investigations: weight decreased 
 
Common (≥ 1/100 to < 1/10) Infections and infestations: sepsis, abscess, cellulitis, 
infection 
Blood and lymphatic system disorders: anemia, lymphopenia 
Metabolism and nutrition disorders: dehydration 
Cardiac disorders: cardiac failure congestive, supraventricular tachycardia  
Vascular disorders: arterial thromboembolism, deep vein thrombosis, hemorrhage 
Respiratory, thoracic and mediastinal disorders: pulmonary embolism, hypoxia 
Gastrointestinal disorders: intestinal perforation, ileus, intestinal obstruction, recto-
vaginal fistula, gastrointestinal disorder, proctalgia 
Skin and subcutaneous tissue disorders: palmar-plantar erythrodysesthesia syndrome 
Musculoskeletal, connective tissue, and bone disorders: muscular weakness, 
myalgia, arthralgia, back pain 
Renal and urinary disorders: urinary tract infection 
General disorders and administration site conditions: lethargy 
Reproductive system and breast: pelvic painRare (≥ 1/10,000 to < 1/1,000) 
Infections and infestations: necrotizing fasciitis 
 
 
Nervous system disorders: posterior reversible encephalopathy syndrome 
 
15.18Drug procurement: Genentech, Inc. will supply the drug to Clinical Research Services, a 
division of Rx Crossroads by McKesson. Each participating ACCRU treating location will 
order the drug from Clinical Research Services, a division of Rx Crossroads by McKesson. 
Fax the Drug Order Request Form (found in the forms packet) to: 
 
 
 
 
Each participating ACCRU treating location will be responsible for monitoring the 
supply of bevacizumab and will use the Drug Order Request Form to order 
additional supplies as needed. 
 
Outdated or remaining drug is to be destroyed on-site as per procedures in place at each 
institution. 
 
Temperature excursions that occur at the site should be reported by the site using the 
IMP Deviation Form found on the ACCRU web site for this study and emailed to: 
  Any shipment deviations (those not occurring at the 
site) should be reported to Clinical Research Services, a division of Rx Crossroads by 
McKesson via email to: 
Clinical Research 
Services, a division of Rx Crossroads by McKesson will complete the IMP Deviation 


 
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  Addendum 6 
 
Form and report shipment deviations to Genentech via email to: 
  (those not occurring at the site). 
 
15.19 
Nursing guidelines: 
 
15.191 
Monitor patients closely for infusion type reactions, including fever, chills, 
myalgias, rigors, or other allergic reactions. While this is less likely given that 
bevacizumab is a humanized antibody, there still exists the potential for severe 
allergic reactions. If these signs or symptoms occur stop the infusion 
immediately and contact MD. Have emergency equipment nearby and be 
prepared to administer emergency treatment as ordered by MD. 
 
15.192 
Monitor urine dipstick or UPC as required by the test schedule. 
 
15.193 
Evaluate IV site regularly for signs of infiltration. 
 
15.194 
Bleeding in the absence of thrombocytopenia is a dose limiting toxicity. 
Monitor patient closely for hemorrhagic events, including CNS hemorrhage, 
epistaxis, hematemesis and hemoptysis. Most cases of bleeding have occurred 
at the tumor site. Advise patient about the potential for bleeding or thrombosis. 
 
15.195 
In patients receiving treatment for lung cancer, hemoptysis and pulmonary 
hemorrhage occurred in up to 10% of patients in one study. Monitor these 
patients especially closely.  
 
15.196 
Patient may experience Grade 1-2 nausea, however vomiting is uncommon. 
Medicate as ordered and monitor for effectiveness.  
 
15.197 
Monitor for skin rash, instruct patient to report to MD. 
 
15.198 
Monitor blood pressure. Administer antihypertensives as ordered by MD. 
  
15.199a Monitor for signs and symptoms of deep vein thrombosis (DVT) or pulmonary 
embolism (PE), or myocardial infarction (MI) including new or worsening 
angina. These have been reported with therapy. Instruct patient to report any 
calf pain, chest pain or shortness of breath to MD immediately. 
 
15.199b Asthenia and headache were reported commonly during therapy (in up to 70% 
and 50% of patients respectively). Administer acetaminophen as needed. 
Monitor for its effectiveness. Avoid the use of aspirin, or ibuprofen as this may 
interfere with the coagulation cascade and further add to the risk of bleeding. 
 
15.199c Monitor CBC, including platelets. Instruct patient to report signs and 
symptoms of infection, unusual bruising or bleeding to the MD. 
  
15.199d Patients receiving warfarin therapy for thrombosis should have their PT or INR 
monitored weekly until two stable therapeutic levels are attained. For patients 
on warfarin for venous access prophylaxis, routine monitoring is satisfactory. 
 
15.199e A rare but serious complication of bevacizumab is wound dehiscence. Patients 
who have had recent surgery or have other open wounds should be monitored 
carefully. 
 
15.199f Gastrointestinal perforation with or without abdominal abscess is rare but 


 
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  Addendum 6 
 
possible. This may present itself as vague abdominal pain associated with 
constipation and vomiting. Instruct patient to report abdominal pain to the MD. 
 
15.199g Reversible Posterior Leukoencephalopathy Syndrome (RPLS) is a rare (<1%) 
but serious condition. Presenting symptoms may include changes in mental 
status, visual disturbance, seizure, or other CNS changes. Patients with this 
syndrome generally had HTN as well, therefore BP monitoring is important. 
Instruct patient to report any mental status changes, visual changes, seizures, 
or other CNS changes to the MD immediately. These may be a sign of RPLS 
or more serious condition, such as hemorrhagic event in the CNS.  
 
15.199h Warn female patients of the possibility of ovarian failure and subsequent 
infertility. Vaginal hemorrhage is also possible. Instruct patients to report any 
heavy or unusual vaginal bleeding to health care team. 
 
15.199i 
Warn female patients of the risk of recto-vaginal fistula. 
 
15.199j 
Agent may cause increased cardiotoxic effects of anthracyclines as well as 
toxic effects of irinotecan, sorafenib, and sunitinib. Patients who on are on dual 
therapy with these agents should be monitored closely. 
 
15.2 
Capecitabine (Xeloda) 
 
15.21 
Background: Capecitabine is classified as an antineoplastic agent, Antimetabolite 
(Pyrimidine Analog). Capecitabine is a prodrug of fluorouracil. It undergoes hydrolysis 
in the liver and tissues to form fluorouracil which is the active moiety. Fluorouracil is a 
fluorinated Pyrimidine Antimetabolite that inhibits thymidylate synthetase, blocking the 
methylation of deoxyuridylic acid to thymidylic acid, interfering with DNA, and to a 
lesser degree, RNA synthesis. Fluorouracil appears to be phase specific for the G1 and S 
phases of the cell cycle. 
 
15.22 
Formulation: Commercially available in 150 mg and 500 mg tablets for oral 
administration. 
 
15.23 
Preparation, storage, and stability: Store at room temperature of 25ºC, with excursions 
between 15ºC and 30ºC permitted. 
 
15.24 
Administration: Usually administered in 2 divided doses taken 12 hours apart. Doses 
should be taken with water within 30 minutes after a meal (Because current safety and 
efficacy data are based upon administration with food, it is recommended that 
capecitabine be administered with food. In all clinical trials, patients are instructed to 
take with water within 30 minutes after a meal). 
 
Since capecitabine tablets cannot be split, subjects may take different numbers of pills in 
the morning and evening in order to achieve the appropriate dose. Use of only 500mg 
tablets is encouraged to minimize the risk of dosing or compliance errors. If the local 
institutional standard is to use 150 mg size tablet, this is permissible. 
 
15.25 
Pharmacokinetic information: 
Absorption: Rapid and extensive 
Protein Binding: <60%; ~35% to albumin 
 
Metabolism:  
Hepatic: Inactive metabolites  


 
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Tissue, Active metabolite, Fluorouracil 
Distribution: Vd: 46 mL/kg 
Half-life elimination: 0.5-1 hour 
Time to peak: 1.5 hours; Fluorouracil, 2 hours 
Excretion: Urine (96%), Feces (<3%) 
 
15.26 
Potential Drug Interactions: 
Increased Effect/Toxicity: Phenytoin and warfarin levels or effects may be increased. 
[U.S. Boxed Warning] Capecitabine may increase the anticoagulant effects of warfarin; 
monitor closely. 
 
Nutrition Interactions: Food reduced the rate and extent of absorption of capecitabine. 
 
15.27 
Known potential adverse events: Consult the package insert for the most current and 
complete information. Frequency listed derived from Monotherapy trials. 
 
Common known potential toxicities, >10%: 
Cardiovascular: Edema 
Central nervous system: Fatigue, fever, pain 
Dermatologic: Palmar-plantar erythrodysesthesia (hand-and-foot syndrome), 
dermatitis. 
Gastrointestinal: Diarrhea may be dose limiting, nausea, vomiting, abdominal 
pain, stomatitis, appetite decreased, anorexia, constipation. 
Hematologic: Lymphopenia, anemia, neutropenia, thrombocytopenia. 
Hepatic: Bilirubin increased. 
Neuromuscular & skeletal: Paresthesia. 
Ocular: Eye irritation. 
Respiratory: Dyspnea. 
 
Less common known potential toxicities, 5% - 10%: 
Cardiovascular: Venous thrombosis, chest pain. 
Central Nervous System: Headache, lethargy, dizziness, insomnia, mood 
alteration, depression. 
Dermatologic: Nail disorder, rash, skin discoloration, alopecia, Erythema. 
Endocrine& metabolic: Dehydration. 
Gastrointestinal: Motility disorder, oral discomfort, dyspepsia, upper GI 
inflammatory disorders, hemorrhage, ileus, taste perversion. 
Neuromuscular & skeletal: Back pain, weakness, neuropathy, myalgia, arthralgia, 
limb pain 
Ocular: Abnormal vision, conjunctivitis. 
Respiratory: Cough. 
Miscellaneous: Viral infection. 
 
Rare known potential toxicities, <5% (Limited to important or life-
threatening):  
Angina, ascites, asthma, atrial fibrillation, Bradycardia, bronchitis, 
bronchopneumonia, bronchospasm, cachexia, cardiac arrest, cardiac failure, 
cardiomyopathy, cerebral vascular accident, cholestasis, coagulation disorder, 
colitis, deep vein thrombosis, diaphoresis, duodenitis, dysphagia, dysrhythmia, 
ECG changes, encephalopathy, epistaxis, fungal infection, gastric ulcer, 
gastroenteritis, hematemesis, hemoptysis, hepatic failure, hepatic fibrosis, 
hepatitis, hypokalemia, hypomagnesemia, hyper-/hypotension, hypersensitivity, 
hypertriglyceridemia, idiopathic thrombocytopenia purpura, ileus, infection, 
intestinal obstruction, keratoconjunctivitis, lacrimal duct stenosis, leukopenia, loss 


 
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of consciousness, lymphedema, MI, multifocal leukoencephalopathy, myocardial 
ischemia, myocarditis, necrotizing enterocolitis (typhlitis), oral candidiasis, 
pericardial effusion, thrombocytopenic purpura, pancytopenia, photosensitivity 
reaction, pneumonia, pruritus, pulmonary embolism, radiation recall syndrome, 
renal impairment, respiratory distress, sedation, sepsis, skin ulceration, 
tachycardia, thrombophlebitis, toxic megacolon, tremor, ventricular extrasystoles. 
 
15.28 
Drug procurement: Commercial supplies. Pharmacies or clinics shall obtain supplies 
from normal commercial supply chain or wholesaler. 
 
15.29 
Nursing guidelines: 
 
15.291 
Instruct patients to take the tablets within 30 minutes of a meal (breakfast and 
dinner). Tablets should be swallowed with 6 8 oz. of water. 
 
15.292 
Instruct patient to avoid taking a missed dose, to never double up on a dose, 
and to notify the health care team if a dose has been missed. 
 
15.293 
Diarrhea can be severe and dose-limiting. Instruct patient to contact the health 
care team immediately if they experience >4 BMs/day and/or nocturnal 
diarrhea above baseline. Monitor carefully for dehydration and need for fluid 
and electrolyte replacement. Standard antidiarrheal treatment, e.g., loperamide 
is recommended. 
 
15.294 
Nausea and vomiting can be severe and dose-limiting. Instruct patient to report 
nausea and vomiting to the health care team if they experience >2 episodes of 
emesis in a 24-hour period. Initiate symptomatic treatment. 
 
15.295 
Hand and Foot Syndrome is common and dose-limiting (redness, swelling, 
pain, numbness, tingling, blistering, and moist desquamation).Instruct patient 
to notify health care team immediately if symptoms appear. Chemotherapy 
may have to be discontinued until symptoms subside with future dose 
reduction initiated. The syndrome may recur with a rechallenge.  
 
• 
Advise patient to apply cool compress for comfort. 
• 
Advise patient to avoid harsh soaps and to use alcohol-free emollients. 
• 
Administer analgesics as prescribed. 
• 
Administer systemic steroids and pyridoxine as prescribed. 
 
15.296 
Treat stomatitis symptomatically -- may try dabbing vitamin E oil on lesions. 
Do not swallow oil. Advise frequent and careful oral hygiene. 
 
15.297 
Assess for warfarin use. Patients taking Coumadin-derivative anticoagulants 
concomitantly with capecitabine should be monitored regularly for alterations 
in their coagulation parameters (PT or INR). 
 
15.298 
Carefully assess patient’s understanding and need of instruction in adequate 
birth control measures. Discuss importance of avoiding pregnancy. 
Periodically re-assess. 
 
15.299a Renal impairment: Check creatinine values weekly and calculate creatinine 
clearance weekly for signs of renal impairment. Follow dose modifications. 
 
15.299b The use of Sorivudine or its analogue, Brivudine, is contraindicated for this 


 
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study due to a possible, even fatal, drug reaction. Assess patient’s drug use. 
Impress on patients the importance of avoiding these drugs while on study. 
 
15.299c Cardiotoxicity (including MI, angina, dysrhythmias, and cardiac arrest) has 
been seen with capecitabine. Observe patients closely for signs of cardiac 
dysfunction. Instruct patient to report any chest pain or palpitations to the 
health care team immediately or seek emergency medical attention. 
 
15.299d  Monitor patient closely who are taking concomitant phenytoin therapy. There 
have been reports of increased levels of phenytoin in patients who are also 
taking capecitabine. These patients may require more frequent monitoring of 
their phenytoin levels and dose adjustments as necessary. 
 
15.299e Cimetidine may alter the clearance of capecitabine and cause toxic levels. 
Cimetidine should be avoided while taking capecitabine. 
 
15.3 
Atezolizumab (RO5541267) for IV administration 
 
• 
Investigator brochure: Available on the ACCRU website. 
 
15.31 
Background: Atezolizumab is a human immunoglobulin (IgG1) monoclonal antibody 
that is produced in Chinese hamster ovary (CHO) cells. Atezolizumab targets 
programmed death-ligand 1 (PD-L1) on immune cells or tumor cells and prevents 
interaction with either programmed death−1 (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. Atezolizumab shows anti-tumor activity in various nonclinical models 
and is being investigated as a potential therapy for cancer patients with locally advanced 
or metastatic malignancies. 
 
15.32 
Formulation: Atezolizumab is supplied in a single use vial as a colorless-to-slightly-
yellow, sterile, preservative-free clear liquid solution intended for IV administration. 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. The 
atezolizumab drug product is formulated as 60 mg/mL atezolizumab in 20 mM histidine 
acetate, 120 mM sucrose, 0.04% polysorbate 20, pH 5.8. 
 
15.33 
Preparation and storage: Atezolizumab must be refrigerated at 2°C−8°C (36°F−46°F) 
upon receipt until use. No preservative is used in atezolizumab drug product; therefore, 
the vial is intended for single use only. Discard any unused portion of drug left in a vial. 
Vial contents should not be frozen or shaken and should be protected from direct 
sunlight. Atezolizumab is administered only using 0.9% sodium chloride 250mL 
Atezolizumab IV bags and infusion lines equipped with 0.2 micron in-line filters (filter 
membrane of polyethersulfone [PES]). Bags may be constructed of polyvinyl chloride 
(PVC), polyethylene, or polyolefin (PO).  The final diluted concentration must be 
between 2.4 mg/mL and 9.6 mg/mL.  For flat or fixed dosing (e.g. 800 mg, 840 mg, or 
1200 mg) in 250 mL IV infusion bags, the prepared solution of atezolizumab may be 
stored at 2°C−8°C (36°F−46°F) for 24 hours or at ambient temperature ≤ 25°C (77°F) 
for 8 hours.  For weight-based dosing using a 250-mL IV bag or smaller, the dose 
solution may be stored for 24 hours at 2°C−8°C (36°F−46°F) including no more than 4 
hours at room temperature prior to administration. If the dose 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. Do not shake or freeze infusion bags 


 
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containing the dose solution. 
 
15.34 
Administration: The initial dose of atezolizumab will be delivered over 60 (± 15) 
minutes. Do not administer as bolus or push. If the first infusion is tolerated without 
infusion-associated adverse effects, the second infusion may be delivered over 30 (± 10) 
minutes. If the 30-minute infusion is well tolerated, the third and all subsequent infusions 
may be delivered over 30 (± 10) minutes. Atezolizumab will be administered with tubing 
and an in-line filter. The bag would read “Atezolizumab/placebo. 
 
15.35 Pharmacokinetic information:  
 
Distibution:  Vdss:  6.9 L 
 
Half-life elimination:  27 days 
 
Hepatic Impairment:  No clinically relevant effect with mild hepatic impairment.  
The effect of moderate or severe hepatic impairment on the pharmacokinetics of 
atezolizumab is unknown. 
Renal Impairment:  No clinically relevant effect with renal impairment. 
  
15.36 Potential Drug Interactions: No formal PK drug-drug interaction studies have been 
conducted with atezolizumab.  The drug interaction potential of atezolizumab is unknown.   
 
15.37 Known potential toxicities: The most commonly (>10%) reported AEs include fatigue, 
decreased appetite, cough, nausea, dyspnea, constipation, diarrhea pyrexia, vomiting, 
arthralgia, back pain, asthenia, anemia, pruritus, rash, headache, and peripheral edema. 
Consult the package insert and investigator’s brochure for the most current and complete 
information.  
 
 
15.38 
Drug procurement: Genentech Inc. will supply the atezolizumab to Biologics, Inc. Each 
participating ACCRU treating location will order the drug from Biologics, Inc. Fax the 
Drug Order Request Form (found in the forms packet) to: 
 
 
 
 
Each participating ACCRU treating location will be responsible for monitoring the 
supply of atezolizumab and will use the Drug Order Request Form to order additional 
supplies as needed. 
 
Outdated or remaining drug is to be destroyed on-site as per procedures in place at each 
institution. 
 
Temperature excursions that occur at the site should be reported by the site using the 
IMP Deviation Form found on the ACCRU web site for this study and emailed to: 
. Please include the Genentech protocol number: 
ML29034 on your form.  Any shipment deviations (those not occurring at the site) 
should be reported to Biologics, Inc. via email to: 
 Biologics, Inc. will complete the IMP 
Deviation Form and report shipment deviations (those not occurring at the site). 
 
15.39 
Nursing Guidelines 
 
15.391 
Anti PD-L1 side effects vary greatly from those of traditional chemotherapy 


 
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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. 
 
15.392 
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. 
 
15.393 
Rash/pruritus/dermatitis is seen. Patients should report any rash to the study 
team. Treat per section 8.0 and monitor for effectiveness. 
 
15.394 
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. 
 
15.395 
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. 
 
15.396 
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. 
 
15.397 
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. 
 
15.398 
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. 
 
15.4 
Placebo for Atezolizumab 
 
The placebo will be normal saline (NS, 0.9% sodium chloride).  
 
15.41 Administration: To protect the blinding, the initial dose of placebo will be delivered over 
60 (±15) minutes. Do not administer as bolus or push. If the first infusion is tolerated 
without infusion-associated adverse effects, the second infusion may be delivered over 30 
(±10) minutes. If the 30-minute infusion is well tolerated, the third and all subsequent 
infusions may be delivered over 30 (±10) minutes. Placebo will be administered with 
tubing and an in-line filter. The bag would read “Atezolizumab/placebo . 
 
16.0 
Statistical Considerations and Methodology 
 
16.1 
Study Design 
 


 
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16.11 
This is a randomized, double-blind, placebo-controlled, phase II study for patients with 
refractory mCRC. One hundred and thirty five (135) subjects will be randomized 2:1 to 
bevacizumab and capecitabine plus atezolizumab or bevacizumab and capecitabine plus 
placebo. 
 
16.12 
Study Populations 
 
Primary and secondary efficacy analyses will include all eligible, randomized patients, 
with patients allocated to the treatment arm to which they were randomized regardless of 
the treatment received (modified ITT). 
 
Safety analyses will include all randomized patients who received at least one dose of 
study treatment, with patients allocated to the treatment arm associated with the regimen 
actually received. 
 
16.2 
Statistical Design and Analysis for Primary Endpoint 
 
16.21 
Progression free survival (PFS) is the primary endpoint in this study. PFS is defined as 
the time from randomization to the first documentation of disease progression by 
RECIST (v1.1) or death from any cause. Patients without documentation of disease 
progression or death on study will be censored at the time of last tumor assessment.  
Patients who are alive and have no tumor measurement post-baseline will be censored 
for PFS at Day 1 post-randomization.   
 
16.22 
Statistical Design 
 
To ensure one hundred twenty (120) eligible (meeting the inclusion and exclusion 
criteria), 135 total subjects will be randomized in a 2:1 ratio to receive 
capecitabine/bevacizumab/atezolizumab  or capecitabine/bevacizumab/placebo.  The 
median PFS in the capecitabine/bevacizumab/placebo arm is assumed to be 
approximately 2 months (8.7 weeks) based on results of published studies of patients 
with refractory colorectal cancer. 
 
The primary comparisons will be superiority of the active treatment for the PFS 
endpoint, atezolizumab versus placebo testing at 1-sided α=0.1. A PFS hazard ratio of 
0.65 (active treatment versus placebo) is detectable with 80% power (1-sided α=0.1). 
Assumptions include exponential survival, a 52-week accrual period with uniform 
patient entry, and a 52-week follow-up period. 
 
No interim analyses for futility or efficacy will be conducted. At the time of final 
analysis, a total of 110 events are required. Assuming 12% of subjects will be ineligible 
or withdraw from the trial, the target of 120 eligible subjects will require approximately 
135 randomized subjects. 
 
16.23 
Study Operating Characteristics 
 
The table below shows the operating characteristics assuming the PFS follows exponential survival 
functions. The percent of times that 1) the study would stop early due to futility and 2) the study 
would conclude that bevacizumab + capecitabine + ateloziumab is superior to bevacizumab + 
capecitabine + placebo at the final analysis are tabulated by true medians of PFS and the true 
hazard ratio. Proportions are based on 10,000 replicates in the simulation study. 
 
 


 
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True Median PFS (Weeks) 
True 
hazard 
ratio 
% of times that 
bevacizumab + 
capecitabine + 
atezolizumab is 
superior at the final 
analysis 
Bevacizumab 
+ 
Capecitabine 
+ Placebo 
Bevacizumab 
+ 
Capecitabine 
+ 
Atezolizumab 
8.7 
13.4 
0.65 
81.4 
8.7 
12.3 
0.71 
67.1 
8.7 
11.1 
0.78 
47.3 
8.7 
9.9 
0.88 
27.1 
8.7 
8.7 
1 
11 
 
16.24 
Analysis Plan 
 
 
Final Analysis Decision Rules 
 
The primary efficacy analysis will be performed at the time when 110 PFS events have 
occurred. The specific hazard ratio and critical p-values for declaring superiority or 
futility are specified in the table below. Specifically, at the final analysis, if p-value is 
less than or equal to 0.10, the bevacizumab + capecitabine + atezolizumab regimen will 
be deemed effective; otherwise, bevacizumab + capecitabine + atezolizumab regimen 
will be considered to have not met the criteria for efficacy. Brookmeyer, R. and J. 
Crowley, A Confidence Interval for the Median Survival Time. Biometrics, 1982. 38(1): 
p. 29-41. 
 
 
 
Analysis time 
point (% 
events) 
Number 
of PFS 
events 
Critical p-
value for 
efficacy 
HR for 
efficacy 
Critical p-
value for 
futility 
HR for 
futility 
100% (Final) 
110 
0.10 
0.772 
0.10 
0.772 
 
 
Analysis Plan Final Analyses: PFS will be compared between treatment arms using the 
un-stratified log-rank test at one-sided level of 0.10 and the p-value will be used for 
decision making. The HR for PFS will be estimated using a Cox proportional hazards 
model and the 95% CI for the HR will be provided. Results from a stratified analysis will 
also be provided. Kaplan-Meier methodology will be used to estimate the median PFS 
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 PFS for each 
treatment arm [28].  
 
 
16.3 
Sample Size, Accrual Time and Study Duration 
 
Accounting for approximately 12% ineligibility and dropout, the total sample size is 135 patients to 
be enrolled over 52 weeks (2-3 patients per week) with 52 weeks of follow-up. Patients will be 
randomized 2:1 to active or placebo. 
 


 
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For purpose of ClinicalTrials.gov reporting, the primary endpoint completion date (PECD) for this 
study is the time the 110th PFS event occurs. Per design, the maximum study duration is estimated 
to be 104 months (52-month accrual time + 52-month follow-up) from the first patient randomized. 
 
16.4 
Supplementary Analysis Plans 
 
16.41 
Secondary Endpoints 
 
 
• 
Overall Survival (OS): OS time is defined as the time from randomization to death due to any 
cause. Patients who are alive will be censored at last follow-up for OS. The distribution of 
survival time will be estimated using the method of Kaplan-Meier. OS will be compared 
between treatment arms using the log-rank test. OS medians, survival rates and HR will be 
estimated along with 95% confidence intervals. 
• 
Objective Response: Objective response by RECIST v1.1 criteria will be estimated using 
objective response rate (ORR) where ORR is defined as the number of evaluable patients 
achieving a response (PR or CR per RECIST v1.1) during treatment with study therapy divided 
by the total number of evaluable patients. Rates of response will be compared across arms using 
a Chi-Square Test for Proportion. Point estimates will be generated for objective response rates 
within each arm along with 95% binomial confidence intervals XX. ”CJ Clopper and ES 
Pearson, “The use of confidence or fiducial limits illustrated in the case of the binomial.” 
Biometrika 26:404-413, 1934.” 
• 
 
• 
Toxicity Profile: As per NCI CTCAE v4.0, the term toxicity is defined as adverse events that are 
classified as possibly, probably, or definitely related to study treatment. Toxicities will be 
evaluated via the ordinal CTCAE standard toxicity grading. The analyses will be conducted 
according the safety population as defined in Section 16.12.  
 
 
 
16.42 
Subset Analysis 
 
Approximately 5% of patients’ tumors (4 on atezolizumab and 2 on  placebo) are 
expected to exhibit MSI high and approximately 95% (76 on atezolizumab and 38 on  
placebo) are expected to be MSI stable. Potential differences in PFS and OS will also be 
investigated in the subset of patients with known MSI stable tumors (n=114). These 
analyses will be considered exploratory. 
 
16.5 
Monitoring the Study 
 
16.51 
Adverse Event Stopping Rule 
 
This trial will be monitored for safety by the Mayo Clinic Cancer Center (MCCC) Data 
and Safety Monitoring Board (DSMB). According to the MCCC Directive: DSMB, the 
DSMB will review safety data on this trial every six months. Data on all Grade 3 or 
greater adverse events regardless of attribution will be provided by treatment arm. Study 
investigators will comply with DSMB requests and follow their recommendations.  
 
The proportions of patients experiencing treatment-related Grade 4 and 5 adverse events 
will be monitored on each treatment arm. The rate of these events is expected to be low 
among patients treated with placebo. 


 
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If at any time after at least 20 patients have been randomized to the experimental arm 
(total of 30 patients randomized), the proportion of patients in that arm experiencing 
treatment-related Grade 5 events exceeds 10%, or the proportion of patients in the 
experimental arm experiencing Grade 4 or 5 non-hematological events exceeds 20%, 
accrual to the study will be suspended and a detailed review of all Grade 4 and Grade 5 
events and SAEs will be promptly conducted to better assess causality with respect to 
treatment, disease, and inter-current illness. The study may then be closed or amended as 
appropriate. 
 
16.52 
Accrual Monitoring Stopping Rule 
 
There is no formal plan to monitor for slow accrual. 
 
16.6 
Study Reporting 
 
This study will be monitored by the Mayo Clinic Data Safety Monitoring Board (DSMB). Reports 
containing patient characteristics, toxicity, and administrative information will be provided to the 
DSMB every 3 or six months, with the first report due at the first reporting period after study 
initiation. Reporting time points are: January 31, April 30, July 31, and October 31. 
 
 


 
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17.0 
Pathology Considerations/Tissue Biospecimens 
 
17.1 
Tissue Biospecimen Submission  
 
17.11 
Summary Table of Tissue Biospecimens for This Protocol 
 
Mandatory 
or 
optional** 
When to 
submit 
Reason for 
submission 
(background/ 
methodology 
section) 
Where to find 
specific details 
for biospecimen 
submission 
Ten (10) 4-micron, 
unstained slides and 
two (2) corresponding 
H&E slides from 
primary tumors (if 
available) 
Mandatory 
≤30 days from 
randomization 
Correlative 
studies (Section 
17.4) 
Section 17.2 
Ten (10) 4-micron, 
unstained slides and 
two (2) corresponding 
H&E slides from 
metastatic tumors (if 
available) 
Mandatory 
≤30 days from 
randomization 
Correlative 
studies (Section 
17.4) 
Section 17.2 
Up to fifteen (15) 4-
micron, unstained 
slides and two (2) 
corresponding H&E 
slides from primary 
tumors (if available) 
Mandatory 
Within 12 
months of the 
analysis of the 
primary 
endpoint 
when 
requested by 
study chair 
Correlative 
studies (Section 
17.4) 
Section 17.2 
Up to fifteen (15) 4-
micron, unstained 
slides and two (2) 
corresponding H&E 
slides from metastatic 
tumors (if available) 
Mandatory 
Within 12 
months of the 
analysis of the 
primary 
endpoint 
when 
requested by 
study chair 
Correlative 
studies (Section 
17.4) 
Section 17.2 
* 
If an institution is not able to provide the tissue, it does not cause the patient to be ineligible; 
however the collection of these tissues is strongly recommended. 
**Note that sites can collect EITHER primary or metastatic tumor. It is not required to collect 
both. 
 
 
17.2 
Tissue Slides Collection and Preparation 
 
17.21 
Tissue submitted ≤30 days from randomization 
 
17.211 
Submit from both primary and metastatic tumors, 10 unstained, uncharged 
slides cut at 4 microns and 2 corresponding H&E slides cut at 4 microns on 
charged slides.  Label the slides with patient Id, study number, accession 
number, order of sections (i.e., 1-12) and date of preparation.  If institutional 


 
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labeling method for clinical slides does not include all required information, 
DO NOT use sticky labels to cover the original label.  Please add label to the 
back top of slide. 
 
17.212 
The following materials are mandatory for shipment with the slides: 
 
• 
Surgical Pathology Report 
• 
Specimen Submission: Tissue 
• 
Please fill out the Specimen Submission Tissue form found on the 
ACCRU website;
 
 
 
17.213 
Follow the cutting instructions provided below: 
 
• 
Ensure good preparation practices to avoid contamination. 
 
o A clean microtome blade should be used for each paraffin block to 
avoid genetic contamination. 
o Blade and tweezers should be wiped with an RNaseZap wipe. 
 
• 
Request pathologist review of tissue by H&E to confirm the presence of 
tumor tissue within the sample. 
• 
Obtain slides and ship to ACCRU within 30 days after randomization. 
 
For each available primary and metastatic paraffin tumor block: 
 
1. Face the block (i.e. cut 1-2 microns of the top section) and discard the cut 
tissue. 
2. Cut 4 microns of the top section. 
3. Place top cut section on a slide and H&E stain. 
4. Cut up to (10) 4 micron sections and place on unstained slides. 
5. Cut 4 microns of the bottom section (i.e. after the 10th or last unstained 
slide). 
6. Place bottom cut section on a slide and H&E stain. 
7. Affix label on each side. 
8. Store slides at ambient temperature. 
9. Insert slides into container for shipment to ACCRU. 
 
NOTE: ACCRU will batch ship slides to Duke Lab on a quarterly basis. 
 
17.22 
Tissue submitted within 12 months of the analysis of the primary endpoint (upon 
request) 
 
17.221 
Submit if available from both primary and metastatic tumors, 15 unstained, 
charged slides cut at 4 microns and 2 corresponding H&E slides cut at 4 
microns on charged slides. Label the slides with patient Id, study number, 
accession number, order of sections (i.e., 1-17) and date of preparation.  Please 
do NOT use sticky labels on slides. 
 
17.222 
The following materials are mandatory for shipment with the slides: 
 
• 
Surgical Pathology Report 
• 
Specimen Submission: Tissue 
• 
Please fill out the Specimen Submission Tissue form found on the 


 
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ACCRU website; 
  under the Case Report Form tab and 
send in with the Pathology Report and Tissue. 
 
17.223 
Follow the cutting instructions provided below: 
 
• 
Ensure good preparation practices to avoid contamination. 
 
o A clean microtome blade should be used for each paraffin block to 
avoid genetic contamination. 
o Blade and tweezers should be wiped with an RNaseZap wipe. 
 
• 
Request pathologist review of tissue by H&E to confirm the presence of 
tumor tissue within the sample. 
• 
Obtain slides and ship to ACCRU within 30 days of receipt of study memo 
requesting 2nd collection of archived tumor tissue. 
 
For each available primary and/or metastatic paraffin tumor block: 
 
1. Face the block (i.e. cut 1-2 microns of the top section) and discard the cut 
tissue. 
2. Cut 4 microns of the top section. 
3. Place top cut section on a slide and H&E stain. 
4. Cut up to (15) 4 micron sections and place on unstained slides. 
5. Cut 4 microns of the bottom section (i.e. after the 15th or last unstained 
slide). 
6. Place bottom cut section on a slide and H&E stain. 
7. Affix label on each side. 
8. Store slides at ambient temperature. 
9. Insert slides into container for shipment to ACCRU. 
 
NOTE: ACCRU will batch ship slides to Duke Lab on a quarterly basis. 
 
17.3 
Ship all slides and accompanying materials to the ACCRU Research Coordinating Center at the 
following address: 
 
 
 
 
 
17.4 
Study Methodology and Storage Information 
 
17.41 
The correlative research goal of this study is to explore any correlation between tissue 
and blood based biomarkers and clinical outcomes. In the current study, we will collect 
pre-treatment tumor samples to evaluate specific protein biomarkers associated with 
sensitivity or resistance to the agents under study by immunohistochemistry (IHC). Once 
these samples have been selected for analysis and the slides cut, the tissue will be 
macrodissected, RNA/DNA isolated, and assessment of gene expression, mutational 
analyses, and/or sequencing approaches that include both standard and Next Gen 
sequencing platforms may be performed. 
 
Submitted tissue samples will be analyzed as follows: 
 


 
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17.411 
Available pre-treatment FFPE tumor tissue slides will be collected and 
processed for each subject. H&E slides will be reviewed by a cytotechnologist 
to assess tumor content of the specimen. Appropriately identified tumor 
sections will then be used to isolate RNA and DNA. RNA and DNA isolation 
will be performed by the Duke Phase I Biomarker Laboratory. 
 
FFPE tumor tissue slides will also be collected to assess correlation of specific 
protein biomarkers and responses to treatment in each of the treatment arms by 
immunohistochemistry (IHC). The specific protein biomarkers will be 
determined at a later date. IHC stains will be performed in the Duke University 
Medical Center Department of Pathology. Analyses of the stained slides will 
be performed in a blinded fashion without knowledge of the patient outcome 
or treatment of study by a board certified pathologist at Duke University 
Medical Center. 
 
17.42 
At the completion of the study, any unused/remaining material will be stored in the 
ACCRU Central Operations Office or Duke Phase I Biomarker Lab (Attn: Pathology 
Coordinator) for future research according to the patient consent permission (see Section 
6.0). Potential future research may include immunohistochemistry (IHC) analyses and 
DNA extraction. When a protocol is developed, it will be presented for IRB review and 
approval. 
 
 
17.5 
Return of Genetic Testing Research Results  
 
Because the results generated by the genetic testing included in this section are not currently 
anticipated to have clinical relevance to the patient or their family members, the genetic results will 
not be disclosed to the patients or their physicians. 
 
If, at any time, genetic results are obtained that may have clinical relevance, IRB review and 
approval will be sought regarding the most appropriate manner of disclosure and whether or not 
validation in a CLIA certified setting will be required. Sharing of research data with individual 
patients should only occur when data have been validated by multiple studies and testing has been 
done in CLIA-approved laboratories. 
 
 
 


 
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18.0 
Records and Data Collection Procedures 
 
Access the RAVE system through the iMedidata portal at https://login.imedidata.com. All data must be 
entered by Remote Date Entry (RDE) and completed by qualified and authorized personnel. All data on the 
CRF must reflect the corresponding source document. Please refer to the ACCRU website for instructions  
https://www.accru.org/main/member/standard.xhtml?path=%2FMember%2FTraining 
 
18.1 
Submission Timetable 
 
Initial Material(s)   
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
Institutional Contacts 
≤2 weeks after randomization 
On-Study  
On-Study: Prior Surgery2 
On-Study: Prior Systemic Therapy2 
On-Study: Prior Radiation2 
Adverse Events: Baseline 
RECIST Measurements: Baseline 
Op and Pathology Reports (See Section 
17.0)1 
Supporting Documentation: Baseline 
Specimen Submission: Blood - Baseline (see 
Section 14.0) 
Specimen Submission: Tissue - Baseline (see 
Section 17.0) 
Patient Status: Baseline 
Concomitant Medications 
Off Treatment 
Submit ≤2 weeks after randomization if 
withdrawal/refusal occurs prior to beginning protocol 
therapy 
1. Upload Op and Path Reports via the Supporting Documentation: Baseline form. This is in addition to 
the pathology material requirements for tissue submission (Section 17.0). 
2. Submit only if applicable. 
 
 
Test Schedule Material(s)  
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
At each evaluation 
during treatment 
At end of 
treatment 
Observation 
Treatment (Intervention)  
X 
 
 
Treatment (Intervention): Dose 
Modifications, Omissions and  
X2 
 
 
Adverse Events: Solicited 
X 
X 
 


 
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CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
At each evaluation 
during treatment 
At end of 
treatment 
Observation 
Adverse Events: Other 
X 
X 
 
RECIST Measurements 
X1 
X1 
X1 
Supporting Documentation 
X1 
X1 
X1 
Laboratory Tests and Results 
X 
X 
 
Specimen Submission: Blood 
X (see Section 14.0) 
 
 
Specimen Submission: Tissue3 
X (see Section 17.0) 
 
 
Patient Status: Treatment (Intervention) 
X 
X 
 
Concomitant Medications 
X 
X 
 
Off Treatment 
 
X 
 
Patient Status: Clinical Follow-
Up/Observation 
 
 
X 
Notice of New Primary2 
X 
X 
X 
Consent Withdrawal (choose appropriate 
form)2 
• 
Consent Withdrawal: Specimen Only 
• 
Consent Withdrawal: Clinical Follow-Up 
Only 
• 
Consent Withdrawal: All Follow-Up 
X 
X 
X 
Lost to Follow-Up2 
X 
X 
X 
Deviation Form2 
X 
X 
X 
Non Protocol Treatment2 
 
 
X 
1. Upload a copy of documentation of progression in RAVE on the Supporting Documentation Form. 
2. Submit only if applicable. 
3. 2nd submission will be upon request from the study chair. 
 
 
Follow-up Material(s)   
CRF 
Event Monitoring Phase1 
q. 3 
months 
until 
PD 
At PD 
After PD q. 
6 mos. 
Death 
At Each 
Event 
Occurrence 
Patient Status: Survival and Disease Status 
Follow-Up/Event Monitoring 
X2 
X2 
X 
X 
 
Non Protocol Treatment 3 
 
 
 
 
At each 
occurrence 
Adverse Events: Late3 
 
 
 
 
At each 
occurrence 
Lost to Follow-Up3 
 
 
 
 
At each 
occurrence 
Notice of New Primary3 
 
 
 
 
At each 
occurrence 
Consent Withdrawal (choose appropriate 
form)3 
• 
Consent Withdrawal: Specimen Only 
• 
Consent Withdrawal: Clinical Follow-Up 
 
 
 
 
At each 
occurrence 


 
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CRF 
Event Monitoring Phase1 
q. 3 
months 
until 
PD 
At PD 
After PD q. 
6 mos. 
Death 
At Each 
Event 
Occurrence 
Only 
• 
Consent Withdrawal: All Follow-Up 
Specimen Submission: Tissue 
 
 
 
 
X4 
1. If a patient is still alive 5 years after randomization, no further follow-up is required. 
2. Upload a copy of documentation of progression in RAVE on the Supporting Documentation Form. 
3. Submit only if applicable. 
4. 2nd submission will be upon request from the study chair. 
 
 
19.0 
Budget 
 
19.1 
Each site should review the test schedule (Section 4.0), taking into account local and regional 
coverage policies, to determine which items are standard of care and which are research at their 
site. Refer to the payment synopsis for funding provided per accrual for covering study costs, as 
well as any additional invoiceables that may be allowed. 
 
19.2 
Tests to be research funded: Mandatory blood and tissue sample collection for correlative research. 
 
19.3 
Other budget concerns: Bevacizumab and Atezolizumab will be provided by Genentech. 
Capecitabine and placebo agents will not be supplied, but are commercially available. 
 
 
 
 


 
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20.0 
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Motzer, R. J., B. I. Rini, et al. (2015). "Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized 
Phase II Trial." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 33(13): 
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(Pts) with advanced gastric cancer." Annals of Oncology 25(5): 1-41. 
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